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Head and Neck Pathology

Presented by: The Oakstone Institute

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Date of Original Release: April 1, 2014

Date Credits Expire: April 1, 2017

This educational activity is a DVD format. The

activity was designed to provide hospital and
l b
laboratory based diagnostic pathologists, as
b dd h l
well as academic pathologists and their
trainees. ENT and oral/dental surgeons and
oncologists and their trainees.
Medical oncologists and their trainees.
It is estimated that it should take the average
It is estimated that it should take the average
learner 13 hours to complete the activity.
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 DESIGNATION

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of dentistry or AGD endorsement. (6/1/2005) to (5/31/2017)
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The following content contributors report no relevant
financial relationships with commercial interests:

Ivan Damjanov, MD, PhD Anamarija Morovic Perry, MD

University of Kansas School of
University of Kansas School of University of Manitoba
University of Manitoba
Medicine Reports no commercial interest
Reports no commercial interest

Fang Fan, MD, PhD Kyle Perry MD

University of Kansas School of University of Manitoba
Medicine Reports no commercial interest
Reports no commercial interest

Nina Gale, MD, PhD Roderick HW Simpson, MD

University of Ljubljana Professor of Pathology, University
Faculty of Medicine of Calgary
Reports no commercial interest Reports no commercial interest

The following content contributors report no relevant

financial relationships with commercial interests:
Alena Skalova, MD, PhD
Department of Pathology
Department of Pathology
Charles University
Faculty of Medicine in Plzen
Reports no commercial interest

J. Craig Whitt, DDS, MS, MBA

Oral Pathology, School of Dentistry
Reports no commercial interest
 LEARNING OBJECTIVES
After viewing this program, participants will be better able to:
• Discuss the most recent histopathological classifications of oral,
laryngeal and pharyngeal tumors and with special emphasis on the
laryngeal and pharyngeal tumors and with special emphasis on the
latest recommendations of the experts of WHO, we will present four
lectures. A correlation will be made between the histopathology and
the response of these tumors to therapy. These review lectures will
also deal with recent advances in the understanding of rental
tumors and related conditions (such as e.g., cysts).

• Discuss the main features of salivary gland tumors and related

condition we will present four lectures. The lecturers will present
condition we will present four lectures. The lecturers will present
recent classifications of salivary gland tumors and explicate the
newly recognized subtypes. The lectures will emphasize why it is
important to understand the biology and molecular genetic basis of
salivary glands for the modern classification and treatment of
these tumors.

LEARNING OBJECTIVES
After viewing this program, participants will be better able to:
• Discuss and illustrate the value of diagnostic fine needle aspiration
biopsy of Head and Neck lesions, two review lectures will be
presented. The purpose of these lectures is to discuss the basic
principles and add data and review new developments relying on
recent publications.

• Discuss and review the most salient pathologic features of the

thyroid, parathyroid and paraganglia of the neck and
to illustrate the diagnostic difficulties one might encounter in this
respect we will present four lectures The lecturers will devote four
respect we will present four lectures. The lecturers will devote four
lectures to pathology of neoplastic and non‐neoplastic diseases
affecting these organs.
 LEARNING OBJECTIVES
After viewing this program, participants will be better able to:
• Discuss the most important aspects and the most common forms of
Head and Neck Lymphoma we will present one lecture. The main
emphasis will be on the difficulties one might face in correctly
diagnosing these neoplasms.

Head and Neck

Pathology
Provided by:
 Oakstone Institute
Head and Neck Pathology
April 1, 2014

ion
#

rat

#
ge

isc
Du
Pa

DD
tal
ok

DV
Bo

To
Topic/Speaker
Squamous Cell Carcinoma of the Head and Neck , Precursors and its Variants
Nina Gale, MD, PhD 1 0:57:17 1

The Surgical Pathology of Odontogenic Cysts

34 0:32:11 1
J. Craig Whitt, DDS, MS, MBA
The Surgical Pathology of Odontogenic Tumors
77 0:47:43 1
J. Craig Whitt, DDS, MS, MBA
Benign Sinonasal Tumors and Non-Neoplastic Pseudotumorous Lesions
125 0:38:46 1
Alena Skalova, MD, PhD
Malignant Sinonasal Tumors
174 0:52:35 2
Roderick HW Simpson, MD
Benign Tumors and Pseudotumorous Non-Neoplastic Lesions of Salivary
Glands 246 0:52:20 2
Roderick HW Simpson, MD
Classical Conventional Classification of Salivary Gland Tumors
326 0:56:58 2
Roderick HW Simpson, MD
Molecular Classification of Salivary Gland Carcinomas
411 00:50:38
50 38 3
Alena Skalova, MD, PhD
Review-Consensus Talk on Salivary Gland Tumors Malignant
453 0:58:30 3
Alena Skalova, MD, PhD
Fine Needle Aspiration Biopsy of Salivary Gland Lesions
512 0:38:28 3
Fang Fan,MD,PhD
Thyroiditis and Related Conditions
545 0:56:10 4
Ivan Damjanov, MD, PhD
Thyroid Tumors-Common Benign and Malignant Tumors
584 0:54:50 4
Kyle Perry, MD
Thyroid Tumors-Less Common Entities
621 0:38:39 4
Kyle Perry, MD
Parathyroid Glands, Paragangliomas and Soft Tissue Tumors of the Neck
660 0:43:36 5
Kyle Perry, MD
Fine Needle Aspiration Biopsy of Thyroid Tumors and Related Lesions
710 0:51:12 5
Fang Fan,MD,PhD
Nasopharyngeal Lymphomas
749 0:54:22 5
Anamarija Morovic Perry,MD
Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Squamous intraepithelial
g
lesions and malignant
tumors of the larynx
Nina Gale
Nina Zidar
University of Ljubljana
Ljubljana,
Ljubljana, Slovenia

• Dysplasia (intraepithelial neoplasia, atypical epithelial

hyperplasia, potentially malignant lesion, precursor lesions)
architectural epithelial changes accompanied by cytological
atypia)

• Laryngeal dysplasia
– Incidence 2 -10 /100,000

• Squamous intraepithelial lesions (SILs)

- architectural and cytological changes of the squamous
epithelium that follow a still not entirely recognized group of
genetic changes in the process of laryngeal carcinogenesis -
the whole spectrum of epithelial changes ranging from
reactive lesion to carcinoma in situ

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Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Modified genetic progression model for

head and neck cancer (HNSCC)
J Clin Pathol 2006

Cancer genes at
frequently altered
chromosome locations
in HNSCC (>50%) in
multiple studies; not
involved in HNSCC –
chromosomes 12 and
16

Leemans CR et al. Nature

Reviews Cancer 2011

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Etiology of SILs and invasive squamous cell

carcinoma (SCC)

• Smoking and alcohol abuse

• Gastroesophageal reflux disease

Coca-Pelaz A et al. Eur Arch Otorhinolaryngol 2013
• Occupational dust exposure
Langevin SM et al. Cancer Med 2013
• Helicobacter pylori
Guilemany JM et al. Eur Arch Otorhinolaryngol 2013

• Human papilomavirus (HPV) ??

• HPV detection rates in

large series of laryngeal
SCC 7.4 – 58.8%
(24%) (Torrente MC et al.
Head&Neck 2011)

• The figure of 24% of

laryngeal SCC positive
for HPV is too high; a
figure of 10% or less is
more realistic (zur Hausen H
2011)

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Biological evidence for a causal role

(transcriptionally active) of HPV 16 in a
small fraction of laryngeal SCC
– 102 cases of SCC tested for 51 mucosal HPV
types, viral load, HPVmRNA, expression of
p16, pRb, cyclin D1, and p53)
– HPV 16 – a causative role in a small
subgroup of laryngeal SCC - <5%
Halec G et al. Br J Cancer 2013

• The prevalence of HPV infection in laryngeal

SILs – 0% - 56%, an overall prevalence of
HPV infection 12.4%, HPV16 the most frequent
HPV genotype (Poljak M et al
al. Acta Otolaryngol
1997, Brito H et al. Acta Otolaryngol 2000)
• High-risk HPV DNA in normal laryngeal
mucosa and benign lesions (Garcia-Milian R et
al. 1998, Duray A et al. 2011)
• Occasional finding of HPV DNA in laryngeal SCC
and SILs is probably the result not of viral
infection, but rather of an incidental HPV
colonization of the laryngeal mucosa

4
Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Histological classification of laryngeal SILs (WHO

2005) - central disputed aspect of these lesions

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Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Amended Ljubljana classification

• Low grade SIL (SH and BPH according to the LC)
• High grade SIL (AH according to the LC)
• CIS (the same entity as described in the LC)

Gale N et al. Head Neck Pathol 2014; accepted for publication

Gale N et al. Submitted to Histopathology 2014

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

SH/BPH 1,1%
(12/1089)

1.5-21
1.5 21 yrs,
yrs mean 7.9

AH 9,5%
(17/179)
2 24 yrs, mean 6
2-24 6.2
2

% of progression SH/BPH and AH of 1268 patients to SCC, from

1979 to 2004, in Ljubljana, Slovenia

Gale N et al. Histopathology 2009

International group of the head and neck pathologists – an

attempt to devise unified classification of laryngeal SILs

Cardesa A, El-Mofty S, Gale N , Helliwell T, Prasad M, Sandison A, Volavšek

M, Wenig B, Zidar N (Lisbon 2013)

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Copyright © The Oakstone Institute, 2014. All Rights Reserved.

high-grade SIL

low-grade SIL

CIS

Low grade SIL - with low malignant potential, a

spectrum of morphological changes from a simple
hyperplasia up to an augmentation of basal and
parabasal cells occupying up to the lower half of the
epithelium, the upper part remains unchanged,
containing re gular prickle cells
low grade SIL
low-grade

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Copyright © The Oakstone Institute, 2014. All Rights Reserved.

low-grade
SIL

High grade SIL - a potentially pre-malignant lesion

with a spectrum of changes including augmentation of
immature epithelial cells, which occupy the lower half
or more of the epithelial thickness

high-grade SIL

9
 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

high-grade SIL

high-grade SIL

high-grade SIL

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high-grade SIL

CIS– morphological features of conventional

carcinoma, e.g., structural and cellular abnormalities
but without invasion (intraepithelial carcinoma).

high-grade SIL CIS

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Copyright © The Oakstone Institute, 2014. All Rights Reserved.

CIS

CIS

Accurate diagnosis of SILs

• Multiple biopsies within the diseased
area of sufficient size
• Additional
Additi l serial
i l sections
ti  HE staining
t i i
– a golden standard
• Various ancillary methods 
immunohistochemical markers 
keratins of different MW, proliferative
markers presence of myofibroblasts,
markers, myofibroblasts
proteins of different pathways (PTEN,
eIF-4E..), reactivation of telomerase, ...

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Copyright © The Oakstone Institute, 2014. All Rights Reserved.

3 2.51
2.5
1.82
2

1.5

1 0.74

0.5 0.09 0.18

0.02
0

N
SMA SMA
Reactivation of hTER in
laryngeal carcinogenesis
Kojc N et al. Human Pathol 2005
Luzar B et al. Mod Pathol
PI3K/AKT/PTEN 2003
/mTOR/eIF4E
signaling
cascade
d in
i SCC
developement
 central role in
metabolism, cell
growth,
apoptosis,
differentiation
and survival
eIF4E PTEN

Conclusions
• HE staining – gold standard for diagnosis of SILs
• HPV infection - not important etiological factor of
laryngeal and SILs and SCC
• Three classifications of SILs - WHO “Tumours
Tumours of
the Head and Neck” 2005 - not optimal
• Attempt to unify different classifications with a
new proposal (the amended Ljubljana
classification):
– low grade SIL
– high grade SIL
– carcinoma in situ
• It is based on the retrospective study – the
results justify to divide the SILs into low-grade
SILs and high-grade SILs; additional category - CIS
is mandatory especially for laryngeal SILs from
the therapeutical point of view

13
Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Laryngeal squamous cell

carcinoma (SCC)
• The second most common head and neck
SCC
• The age standardized incidence (0-74
years) 5.5/100.000 males and
0.6/100,000 females
• 12,740 new patients in the USA in 2011
(10,160 males and 2,580 females)
Barnes L et al. WHO 2005
Cardesa A et al. WHO 2005
Wong TS et al. J Oncol 2012

Laryngeal SCC
・supraglottic
・glottic
・subglottic
・transglottic

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More than 90% of laryngeal SCC

– conventional SCC

Subtypes of laryngeal SCC

and prognosis
• Verrucous 
• Spindle cell
• Papillary 
• Basaloid (HPV -) 
• Acantholytic
• Adenosquamous 
• Lymphoepithelial 

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Verrucous SCC (VSCC)

• Well differentiated low grade variant, exophytic warty tumor,
blunt intrastromal invagination folds with pushing borders, bland
cytologically, few mitoses, no metastases
• 4% of all laryngeal SCC
• Strongly associated with tobacco and alcohol abuse, not
associated with HPV infection
• Glottis most frequently affected, biopsy large enough to include
deep margins
• Conservative treatment
• Hybrid VSCC – coexistence with conventional SCC –
biological behavior and treatment identical to conventional SCC
• Diff. diagnosis – verrucous hyperplasia, exophytic/papillary SCC,
squamous papilloma
Cardesa A, Zidar N. WHO 2005
Odar K et al. J Cell Mol Med 2013
Patel KR et al. Hum Pathol 2013

Verrucous
carcinoma

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Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Hybrid verrucous carcinoma

desmoplakin

Cardesa A et al. Virchows Arch 2011

Odar K et al. Ann Diagn Pathol 2012

Spindle cell SCC (SCSCC)

• SCC with biphasic appearance
• 0-2% of all laryngeal SCC
• Strongly associated with tobacco and alcohol abuse,
not associated with HPV infection
• Glottis most frequently affected, polypoid mass
• Micro - imperceptible blending between squamous
and spindle cells, storiform, solid and fascicular
architecture, mild to moderate pleomorphism, mitotic
rate , desmoplastic stromal fibrosis
• Immuno –CK present in up to 70% (CK AE1/AE3)
• 5-year
5 year disease free overall survival 63 - 94%
• Diff. diagnosis – sarcomas, mucosal melanoma,
nodular fasciitis, inflammatory myofibroblastic tumor
Thompson LD et al. Am J Surg Pathol 2002
Cardesa A, Zidar N. WHO 2005
Zidar N et al. Virchows Arch 2008

17
Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Spindle cell
carcinoma

vimentin

AE1/AE3

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Spindle cell SCC Neoplastic

Epithelial – Mesenchymal
Transition
Altered
Cadherin Expression
E→N Switch*

mRNA
up Regulation Snail
Slug, Twist and SIP1+

miRNA
down Regulation
miR200 and miR205
Zidar N et al. Virchows Arch 2008*
Kojc N et al. Virchows Arch 2009 +
Zidar N et al. Hum Pathol 2011

Basaloid SCC
• Predominantly basaloid cells associated with
squamous differentiation
• Strongly associated with tobacco and alcohol abuse,
HPV -
• Piriform sinus, supraglottis, transglottis
• At presentation higher stage than other SCC
• Majority of patients die within 3 years
• Micro – lobular pattern, basaloid cells, focally
squamous differentiation, comedo necroses, high
mitotic index
• Immuno – CK AE1/AE3+, neuroendocrine markers
–
• Dif. diagnosis – neuroendocrine carcinoma, adenoid
cystic carcinoma
Cardeasa A et al. WHO 2005
Fritsch VA, Lentsch EJ. Head Neck 2014

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Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Basaloid carcinoma

Acantholytic SCC
• Uncommon variant, characterized by acantholysis of
tumor cells creating pseudolumina and false
appearance of glandular differentiation
• Supraglottis,
Supraglottis hypopharynx
• No special clinical and gross features
• Micro - conventional SCC associated with foci of
acantholysis – appearance of glandular formation
with acantholytic and dyskeratotic cells, acantholysis
may form anatomizing spaces and channels
mimicking angiosarcoma
• Prognosis similar to conventional SCC
• Dif. diagnosis – adenosquamous SCC, adenoid cystic
carcinoma, mucoepidermoid carcinoma,
angiosarcoma
Wenig B. ModPathol 2002
Cardeasa A et al. WHO 2005
Zidar N et al. J Clin Pathol 2006

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Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Acantholytic
carcinoma

Papillary SCC
• A distinct variant of SCC with exophytic, papillary
growth and favorable prognosis, may evolve from
preexisting squamous papilloma?
• Associated with tobacco and alcohol abuse, HPV
infection?
• Low tumor stage T1 or T2 – supraglottis
• Micro - multiple thin filiform projections covered by
neoplastic immature basaloid cells, in situ or foci of
invasion
• Dif. diagnosis – squamous papilloma, verrucous SCC,
papillary hyperplasia

Cardeasa A et al. WHO 2005

Mehrad M et al. Am J Surg Pathol 2013

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Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Papillary
carcinoma

Adenosquamous SCC
• Biphasic tumor, admixture of true adenocarcinoma and
SCC, 1% of SCC in the head and neck
• Strongly associated with tobacco and alcohol abuse
• Any region of larynx
• Significantly
S f l worse prognosis than
h conventionall SCC
• Majority of patients with lymph node metastases at
presentation, lung metastases in 25%
• Micro – separation of both components, SCC
component in situ or invasive, adenocarcinoma away
from surface – tubular, alveolar or glandular pattern,
mucin – intraluminal or intacellular, not required for
diagnosis metastases with adeno,
diagnosis, adeno SCC or both
components
• Diff. diagnosis – mucoepidermoid carcinoma,
acantholytic SCC, basaloid SCC, necrotizing
sialometaplasia
Alos L et al. Histopathology 2004
Cardeasa A et al. WHO 2005
Masand RP et al. Head Neck Pathol 2011

22
Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Adenosquamous
carcinoma

WHO
2005
Head and
Neckk
Tumours

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Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Lymphoepithelial SCC
• Undifferentiated SCC with prominent
lymphoplasmocytic infiltrate, morphologically
indistinguishable from nasopharyngeal carcinoma
• Smoking and alcohol abuse, EBV rarely demonstrated
• Aggressive SCC, propensity for regional lymph node
and distant metastases
• Larynx and hypopharynx
• Micro – islands of undifferentiated carcinoma, large
cells with clear vesicular nuclei and prominent
nucleoli,
l li llymphocytic
h ti iinfiltration
filt ti
Tsang WY , Chan JKC WHO 2005
Coskun BU et al. Auris nasus Larynx 2005

Lymphoepithelial
carcinoma

EBER

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Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Surgical pathology report of laryngeal SCC

– type of surgical procedure – chordectomy, hemi-,
supraglottic-, or total laryngectomy
– site of origin
– histologic type and grade
– presence of lymphovascular, perineural,
cartilaginous
til i and/or
d/ extralaryngeal
t l l invasion
i i
– status of resection margins
– neck dissection
– pTNM

Neck dissection
• Number of examined lymph nodes
(LN), specified for each level
• Number and size of positive LN,
specified
p for each level
• Extracapsular tumor spread for each
level
• Synchronous second primary or
second metastatic tumor (thyroid ca)

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Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Metastatic disease with

intracapsular lymph
vessel invasion

Metastatic disease
with extracapsular
invasion - worse
prognosis

26
 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Metastasis of
laryngeal SCC and
occult thyroid ca

Differential diagnosis of laryngeal SCC

・Well differentiated SCC - usually clear-cut
Changes after radiation – epithelial,
・Changes epithelial endothelial
and stromal atypias
・Necrotizing sialometaplasia
・Pseudoepithelial hyperplasia – granular cell tumor
・Squamous cell papilloma
・Poorly
Poorly differentiated SCC
• Malignant melanoma
• Malignant lymphoma
• Neuroendocrine carcinoma

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Pseudoepithelial hyperplasia –
Changes after radiation granular cell tumor

Squamous cell
Necrotizing sialometaplasia papilloma with atypias

Synaptophysin

Neuroendocrine carcinoma Malignant melanoma

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Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Treatment
• Treatment goals – cure, voice sparing,
optimal swallowing
• Larynx function – preserving treatment
with negative resection margins (3-5mm)
• Surgical procedures - chordectomy, partial
laryngectomy, total laryngectomy/neck
dissection - along with radiotherapy,
neoadjuvant chemotherapy

Prognosis
• pTNM – site, size and stage – close
correlation with disease free and overall
survival
i l
• T1: 90% 5-year survival rate
• T4:<50% 5-year survival rate
• Glottic: 80-85% 5-year survival rate
• Supraglottic: 65% 5-year
5 year survival rate
• Subglottic: 40% 5-year survival rate

29
 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Worse prognosis

• Lymph node metastases and/or distant

metastases
• Perineural invasion
• Extracapsular spread in LN metastases –
single most adverse prognostic factor
• High proliferation index correlates with poorly
diff
differentiated
ti t d SCC and
d LN metastases
t t
• Distant metastases – rare, in late disease (lung,
liver, bone)

Molecular markers of SCC behavior

– CDKN2A (p16/ink4a)
– p53
– EGFR
– VEGFR
– PTGS2 (COX2)
– matrix metalloproteinases
– PTEN
Mäkitie AA, Monni O. Expert Rev Anticancer Ther 2009
Squarize CH et al. Neoplasia 2013

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Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Rare laryngeal
malignant tumors:
-neuroendocrine ca
-chondrosarcoma
-plasmocytoma
malignant
-malignant
melanoma

Chondrosarcoma Plasmocytoma

Thank you!

31
 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

References
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2. Leemans CR et al. The molecular biology of head and neck cancer. Nat Rev Cancer 2011;11:9-22
3. Coca-Pelaz A et al. Reflux and aerodigestive tract diseases. Eur Arch Otorhinolaryngol 2013;270:417-23
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6. Torrente MC et al. Human papillomavirus infections in laryngeal cancer. Head Neck 2011;33:581-6
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8. Poljak M et al. Human papillomaviruses: a study of their prevalence in the epithelial hyperplastic lesions of the larynx. Acta
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15. Sarioglu S et al. Inter-observer agreement in laryngeal pre-neoplastic lesions. Head Neck Pathol 2010;4:276-80
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case series and meta-analysis. Clin Otolaryngol 2010; 35(5):364-72
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classification 2014; Submitted to Histopathology
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Neck. Head Neck Pathol. 2014 Acceted for publication.
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22. Luzar B et al. Telomerase reactivation is an early event in laryngeal carcinogenesis. Mod Pathol 2003;16:841-8
23. Barnes L et al. Tumours of the hypopharynx, larynx, and Trachea: Introduction. In: Barnes L, Eveson JW, Reichart P,
Sidransky D, editors. World Health Organization classification of tumours - Pathology and genetics of head and neck
tumours. Lyon: IARC Press; 2005. p. 111-117.
24. Cardesa A et al. Squamous cell carcinoma. In: Barnes L, Eveson JW, Reichart P, Sidransky D, editors. World Health
Organization classification of tumours - Pathology and genetics of head and neck tumours.
tumours Lyon: IARC Press; 2005.
2005
p. 118-121.
25. Wong TS et al. Epigenetic dysregulation in laryngeal squamous cell carcinoma. J Oncol 2012;2012:739461
26. Cardesa A, Zidar N. Verrucous carcinoma. In: Barnes L, Eveson JW, Reichart P, Sidransky D, editors. World Health
Organization classification of tumours - Pathology and genetics of head and neck tumours. Lyon: IARC Press; 2005.
p 122-123.
27. Odar K et al. Verrucous carcinoma of the head and neck - not a human papillomavirus-related tumour? J Cell Mol
Med. 2013 [Epub ahead of print]

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

28. Patel KR et al. Verrucous carcinomas of the head and neck, including those with associated squamous cell
carcinoma, lack transcriptionally active high-risk human papillomavirus. Hum Pathol 2013;44:2385-92
29. Cardesa A et al. The Kaiser's cancer revisited: was Virchow totally wrong? Virchows Arch 2011;458:649-57
30. Odar K et al. Desmosomal proteins and microRNAs-markers for hybrid tumors (verrucous carcinoma with
foci of squamous cell carcinoma). Ann Diagn Pathol. 2012;16:157-8.
31. Thompson LD et al. Spindle cell (sarcomatoid) carcinomas of the larynx: a clinicopathologic study of 187
cases. Am J Surg Pathol 2002;26:153-70
32. Cardesa A, Zidar N. Spindle cell carcinom. In: Barnes L, Eveson JW, Reichart P, Sidransky D, editors. World
Health Organization classification of tumours - Pathology and genetics of head and neck tumours
tumours. Lyon:
Lyon IARC
Press; 2005. p. 127-128
33. Zidar N et al. Cadherin-catenin complex and transcription factor Snail-1 in spindle cell carcinoma of the head
and neck. Virchows Arch. 2008;453:267-74
34. Cardesa A et al Basaloid squamousc cell carcinoma. In: Barnes L, Eveson JW, Reichart P, Sidransky D,
editors. World Health Organization classification of tumours - Pathology and genetics of head and neck
tumours. Lyon: IARC Press; 2005. p 124-125.
35. Fritsch VA, Lentsch EJ. Basaloid squamous cell carcinoma of the larynx: Analysis of 145 cases with
comparison to conventional squamous cell carcinoma. Head Neck 2014;36:164-70
36. Wenig BM. Squamous cell carcinoma of the upper aerodigestive tract: precursors and problematic variants.
Mod Pathol 2002;15y:229-54
2002;15y:229 54
37. Cardesa A et al. Acantholytic squamous cell carcinoma. In: Barnes L, Eveson JW, Reichart P, Sidransky D,
editors. World Health Organization classification of tumours - Pathology and genetics of head and neck
tumours. Lyon: IARC Press; 2005. p 129
38. Zidar N et al. Pseudovascular adenoid squamous-cell carcinoma of the oral cavity--a report of two cases. J
Clin Pathol 2006;59:1206-8
39. Cardesa A et al. Papillary squamous cell carcinoma. In: Barnes L, Eveson JW, Reichart P, Sidransky D,
editors. World Health Organization classification of tumours - Pathology and genetics of head and neck
tumours. Lyon: IARC Press; 2005. p 126

40. Mehrad M et al . Papillary squamous cell carcinoma of the head and neck: clinicopathologic
and molecular features with special reference to human papillomavirus. Am J Surg Pathol
2013;37:1349-56
41. Cardesa A, Zidar N.Spindle cell carcinoma. In: Barnes L, Eveson JW, Reichart P, Sidransky D,
editors. World Health Organization classification of tumours - Pathology and genetics of
head and neck tumours. Lyon: IARC Press; 2005. p 127-8
42. Alos L et al. Adenosquamous carcinoma of the head and neck: criteria for diagnosis in a
study
t d off 12 cases. Hi
Histopathology
t th l 2004 2004;44:570-9
44 570 9
43. Cardesa A et al. Adenosquamous carcinoma. In: Barnes L, Eveson JW, Reichart P, Sidransky
D, editors. World Health Organization classification of tumours - Pathology and genetics of
head and neck tumours. Lyon: IARC Press; 2005. p 130-31
44. Masand RP et al. Adenosquamous carcinoma of the head and neck: relationship to human
papillomavirus and review of the literature. Head Neck Pathol 2011;5:108-16
45. Tsang WYW, Chan JKC. Lymphoepithelial carcinoma. In: Barnes L, Eveson JW, Reichart P,
Sidransky D, editors. World Health Organization classification of tumours - Pathology and
genetics of head and neck tumours. Lyon: IARC Press; 2005. p 132.
46. Coskun BU et al. Lymphoepithelial carcinoma of the larynx. Auris Nasus Larynx 2005;32:189-
93
47. Mäkitie AA, Monni. Molecular profiling of laryngeal cancer. Expert Rev Anticancer Ther 2009;
9:1251-60
48. Squarize CH et al. PTEN deficiency contributes to the development and progression of head
and neck cancer. Neoplasia 2013;15:461-71

33
 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

The Surgical Pathology of

Odontogenic Cysts

J. Craig Whitt, DDS, MS, MBA

Rinehart Professor
Oral and Maxillofacial Pathology
School of Dentistry
University of Missouri Kansas City

Disclosure Statement
Dr. Whitt reports no relevant financial
relationships with commercial interests
interests.

34
 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Definition of an Odontogenic Cyst

• Pathologic cavity

• Bone or soft tissue

• Odontogenic epithelium

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Anatomy of a Cyst

• Lumen

• Lining

• Wall

Classification of
Odontogenic Cysts

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Lumpers vs Splitters

Classification of Odontogenic
Cysts

• Inflammator or De
Inflammatory Developmental
elopmental

• Clinical/Radiographic features

• Hi t
Histopathologic
th l i features
f t

• Behavioral characteristics

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Classification of Odontogenic
Cysts by Clinical/Radiographic
Features

Classification of Odontogenic
Cysts by Histopathologic
Features

• Non-specific histology
• Odontogenic keratocyst
• Orthokeratinizing odontogenic cyst
• Calcifying odontogenic cyst
• Lateral periodontal cyst / Gingival cyst
• Glandular odontogenic cyst

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Classification of Odontogenic
Cysts by Behavioral
Characteristics

• Odontogenic Keratocyst
• Glandular Odontogenic Cyst
• Everything else

Odontogenesis

17

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Odontogenesis
Rests of Serres

Enamel Organ

18

Odontogenesis

19

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Reduced Enamel Epithelium

20

Odontogenesis

Follicular
Space

21

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Dental Follicle

22

Dental Follicle

23

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Hertwig’s Epithelial Root Sheath

Rests of
Malassez
M l

24

Rests of Malassez in
Periodontal Ligament

Periodontal
Ligament

Tooth
Rests of
Root
Malassez

26

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Sources of Odontogenic
Epithelium

• Rests of Serres - dental lamina

• Enamel organ
• Reduced enamel epithelium
• Rests of Malassez - root sheath
• B
Basal
l llayer off orall epithelium
ith li

Inflammatory Odontogenic Cysts

• Periapical Cyst

• Residual Cyst

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Periapical Cyst

• Most common
odontogenic cyst
• Periapex of non-vital
tooth
• Arises from rests of
Malassez
• Apical periodontal
cyst or Radicular
cyst

Periapical Cyst

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Periapical Cyst

Periapical Cyst

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Periapical Cyst

Residual Cyst

• A cyst that is “left

behind
behind”

• Edentulous areas

• History of tooth
removal

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Developmental Odontogenic
Cysts
• Dentigerous Cyst
• Eruption Cyst
• Dental Lamina Cysts
• Odontogenic Keratocyst
• Orthokeratinizing Odontogenic cyst
• C l if i Od
Calcifying Odontogenic
t i Cyst
C t
• Glandular Odontogenic Cyst
Any developmental odontogenic cyst
may become secondarily inflamed

Follicular Cysts

• Dentigerous
Dentigero s ccyst
st
• Eruption cyst

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Dentigerous Cyst
• Most common type
of developmental
odontogenic cyst

• Arises from dental

follicle

• Enlarged follicular
space > 4 mm

Dentigerous Cyst

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Dentigerous Cyst

50

Dentigerous Cyst

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Dentigerous Cyst

Dentigerous Cyst

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Dentigerous Cyst

Dentigerous Cyst
Rushton
Bodies

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Dentigerous Cyst

Mucous
Prosoplasia

Eruption Cyst
• A follicular cyst
round the crown of
an erupting tooth

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Eruption Cyst

Hyperplastic Dental Follicle

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Neoplastic Potential of
Dentigerous Cysts

• A l bl
Ameloblastoma

• Squamous cell
carcinoma

• Central
Mucoepidermoid
carcinoma

Odontogenic Keratocyst
• Posterior jaws of
teenagers, young
adults
• Aggressive growth
• 30% recurrence
• 2005 WHO
classification:
Keratinizing Cystic
Odontogenic
Tumor

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Odontogenic Keratocyst

Odontogenic Keratocyst
• Compact
epithelium, no
rete ridges
ridges, 8 to
10 cell layers
thick
• Corrugated
surface
parakeratin
• Palisaded,
hyperchromatic
basal layer

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Odontogenic Keratocyst

Odontogenic Keratocyst
Daughter Cysts

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Odontogenic Keratocyst
Extra-Osseous OKC

Clinical Settings of the OKC

• Non-syndrome-associated OKC - idiopathic

• Syndrome-associated OKC – multiple

OKCs common in the nevoid basal cell
carcinoma syndrome

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Basal Cell Nevus Syndrome

• Nevoid Basal Cell Carcinoma Syndrome

• G li syndrome
Gorlin d

• Gorlin-Goltz Syndrome

• Autosomal dominant - highly

g yp penetrant and
variably expressive

• Mutation in PTCH (PATCHED) tumor

supressor gene at 9q22.3

Basal Cell Nevus Syndrome

• Jaw cysts - Multiple OKCs

• Sk l l anomalies
Skeletal li - Bifid ribs
ib

• Skin tumors - Multiple, early onset basal cell

carcinomas

• Neoplasms - CNS – Medulloblastoma

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Basal Cell Nevus Syndrome

“Primordial Cyst”
• Radiographic
term
• A cyst that
develops in
place of a tooth
• Not a histologic
diagnosis
• Significance:
likely to be an
odontogenic
keratocyst

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Orthokeratinizing
Odontogenic Cyst
• Orthokeratin lining,
NOT parakeratin

• Originally described as
the “orthokeratinized
variant of the
odontogenic
keratocyst”

• Does not behave as an

odontogenic keratocyst

Orthokeratinizing
Odontogenic Cyst

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Calcifying
Odontogenic Cyst
Gorlin Cyst

WHO, 2005, reclassified as

Calcifying Cystic Odontogenic
Tumor

Calcifying Odontogenic Cyst

• Gorlin cyst, calcifying
and keratinizing
odontogenic cyst
• Anterior jaws of adults
• Radiolucent to mixed
• Ghost cells
• Sometimes associated
with odontomas
• WHO (2005):
Calcifying Cystic
Odontogenic Tumor

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Calcifying Odontogenic Cyst

Calcifying Odontogenic Cyst

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Calcifying Odontogenic Cyst

Calcifying Odontogenic Cyst

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Calcifying Odontogenic Cyst

Cysts of Dental Lamina Origin

• Lateral
periodontal cyst
p y

• Gingival cyst of
the adult

• Dental lamina
cyst of the
newborn

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Lateral Periodontal Cyst

• Dental lamina rests
(rests of Serres)

• Vital teeth of adult

males (3:1)

• Mandibular
premolar area

• Maxillary incisor-
canine area

Lateral Periodontal Cyst

• Thin, flattened
epithelial lining

• Plaques containing
clear cells,
sometimes swirled

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Gingival Cysts

• Gingival cyst of the adult

• Gingival cyst of the newborn

Gingival Cyst of the Adult

• Soft tissue
counterpart of the
lateral periodontal
cyst (LPC)

• Rests of Serres

• Same histology,
location and
demographics of
LPC

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Gingival Cyst of the Newborn

• Common on
alveolar ridge of
newborns

• Keratin-filled cysts
arising from
remnants of dental
lamina

• Spontaneously
marsupialize

Gingival Cyst of the Newborn

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Glandular Odontogenic Cyst

• Sialodontogenic cyst –
an odontogenic cyst
with glandular
(salivary) features
• Anterior jaws of
middle-aged adults,
mandible > maxilla
• Commonly multilocular,
crosses midline
• Aggressive behavior -
30% recurrence

Glandular Odontogenic Cyst-1

1. Surface eosinophillic cuboidal cells
(hobnail cells)
2. Apocrine snouting of hobnail cells
3. Intraepithelial microcysts or duct-like
spaces
4. Clear or vacuolated cells
5. Variable thickness of cyst epithelial lining

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Glandular Odontogenic Cyst-2

6. Epithelial spheres or plaque-like
thickenings
7. Papillary projections or tufting into the
cyst lumen
8. Mucous goblet cells
9. True cilia on the surface of the
eosinophillic cuboidal cells
10. Multiple cystic spaces

Glandular Odontogenic Cyst

Eosinophillic
surface cuboidal
cells (“hobnail”
cells) and clear
cells

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Glandular Odontogenic Cyst

Intraepithelial duct-like spaces lined by
eosinophillic cuboidal epithelial cells and
microcystic spaces.

Glandular Odontogenic Cyst

Surface cuboidal epithelial cells with
apocrine snouting and tufting

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Glandular Odontogenic Cyst

Vacuolated cells in basal and parabasal
layers, eosinophillic surface cuboidal cells
with mild apocrine snouting and variable
thickness of cyst lining

Glandular Odontogenic Cyst

Variable thickness of cyst lining with
plaque-like thickenings

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Glandular Odontogenic Cyst

Tufting, papillary projections into the cyst
lumen and clear cells

Glandular Odontogenic Cyst

Mucous goblet cells and clear cells

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Glandular Odontogenic Cyst

Plaque-like thickenings with epithelial
spherules, clear cells and surface
eosinophillic cells

Glandular Odontogenic Cyst

Cilia, clear cells, variable thickness cyst
lining and eosinophillic cuboidal surface
cells

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Glandular Odontogenic Cyst

Multiple compartments

Glandular Odontogenic Cyst

Daughter cyst with surface cuboidal
eosinophillic cells, apocrine snouting and
mild tufting; lumen to left lined by
cuboidal eosinophillic cells

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

REFERENCES
• Gnepp, DR, ed. Diagnostic Surgical
Pathology of the Head and Neck, 2e,
Saunders, 2009.
• Neville BW, Damm DD, Allen CM, Bouquot
J. Oral and Maxillofacial Pathology, 3e.
Saunders, 2008.

• Chi AC and Neville BW. Odontogenic Cysts

and Tumors. Surgical Pathology (2011)
4:1027-1091.

REFERENCES
• Jordan RCK and Speight PM. Current
concepts of odontogenic tumors. Diagnostic
Histopathology (2009) 15(6): 303-210.

• Fowler CB, Brannon RB, Kessler HP, Castle

JT and Kahn MA. Glandular Odontogenic
C t A
Cyst: Analysis
l i off 46 C
Cases with
ith S
Special
i l
Emphasis on Microscopic Criteria for
Diagnosis. Head and Neck Pathol (2011)
5:364-375.

76
 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

The Surgical Pathology of

Odontogenic Tumors

J. Craig Whitt, DDS, MS, MBA

Rinehart Professor
Oral and Maxillofacial Pathology
School of Dentistry
University of Missouri Kansas City

Disclosure Statement
Dr. Whitt reports no relevant financial
relationships with commercial interests
interests.

77
 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Odontogenic Tumors

• Paul Broca (1866)

“Od t
“Odontome””

• Kurt Thoma and Henry

G ld
Goldman (1946)

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Classification of Odontogenic
Tumors

• Ectodermal

• Ectomesenchymal

• Mixed

Epithelial Odontogenic Tumors

• Ameloblastoma
• Adenomatoid odontogenic tumor
• Calcifying epithelial odontogenic
tumor
• Keratocystic
K t ti odontogenic
d t i ttumor
• Squamous odontogenic tumor

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Mesenchymal Odontogenic Tumors

• Odontogenic myxoma
• Odontogenic fibroma
• Cementoblastoma

Mixed Odontogenic Tumors

• Ameloblastic fibroma
• Ameloblastic fibro-odontoma
fibro odontoma
• Calcifying cystic odontogenic tumor
• Dentinogenic ghost cell tumor
• Odontoameloblastoma

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The Spectrum of Odontogenic

Tumors

Ameloblastoma Odontoma

• Least differentiated • Most differentiated

• Most
M t aggressivei • Least
L t aggressive
i

Ameloblastoma
• The histopathology of ameloblastoma
recapitulates the enamel organ

• Ameloblastoma does not form hard tissue

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Histologic Patterns of
Ameloblastoma
• Follicular
• Plexiform
• Acanthomatous
• Desmoplastic
• Granular cell
• Basal cell

Follicular Ameloblastoma

16

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Follicular Ameloblastoma

• Hyperchromatism
• Palisading
• Reverse polarity
• Subnuclear
vacuolation 17

Plexiform Ameloblastoma

18

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Plexiform Ameloblastoma

19

Acanthomatous Ameloblastoma

20

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Granular Cell Ameloblastoma

21

Basal Cell Ameloblastoma

22

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Desmoplastic Ameloblastoma

23

Clinicopathologic Forms of
Ameloblastoma

• Solid/m ltic stic

Solid/multicystic

• Unicystic

• Desmoplastic

• Peripheral

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Solid/Multicystic Ameloblastoma
• Conventional
ameloblastoma
• Expansile, slow-
growing, locally
invasive lesion
• Typically posterior
mandible of adults
(mean = 35 y)
• Recurrence common
• Does not
metastasize

Solid/Multicystic Ameloblastoma

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Unicystic Ameloblastoma
• Unilocular radiolucency
• Posterior mandible – mimics a
dentigerous cyst
radiographically
• 2nd to 3rd decades ((Mean age
g
= 18 y)
• Lower recurrence rate

Unicystic Ameloblastoma

29

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Unicystic Ameloblastoma

30

Unicystic Ameloblastoma

31

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Unicystic Ameloblastoma

32

Histologic Signs of Early

Ameloblastoma
(Vickers-Gorlin Change)
• Nuclear
hyperchromatism
• Nuclear palasading
• Reverse polarity of
basal cell nuclei
• S b
Subnuclear
l
vacuolation

33

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Pathology of
Unicystic Ameloblastoma
• Luminal variant
- no tumor
infiltration into
the cyst wall
• Mural variant -
cystt wallll
infiltrated by
tumor

Desmoplastic Ameloblastoma
• Anterior jaws,
equally distributed
between mandible
and maxilla
• Mottled mixed
density with diffuse
margins
• Solid tumor with
dense, collagenous
stroma

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Peripheral Ameloblastoma

Ages of Ameloblastoma
• Unicystic 18 y

• Conventional 35 y

• Peripheral 53 y
40

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Keratocystic Odontogenic
Tumor
(WHO 2005)

Odontogenic
Odo oge c Keratocyst
e a ocys

Adenomatoid
Odontogenic Tumor

• Teenagers - 75%
• Mixed density
• Female - 2:1
• Maxilla - 2:1
• Anterior - 75%

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Adenomatoid
Odontogenic Tumor

44

Adenomatoid
Odontogenic Tumor

45

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Adenomatoid Odontogenic
Tumor

46

Adenomatoid Odontogenic
Tumor

47

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Adenomatoid
Odontogenic Tumor

48

Squamous
Odontogenic Tumor
• Presents as alveolar bone
loss in adults (Mean = 39 y)
• A well-circumscribed
lucency, often between roots
of teeth, often multifocal
• May arise from rests of
Malassez
• May be multifocal
• Treatment by curettage.
Some recurrences

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Squamous
Odontogenic Tumor
• Islands of well-
diff
differentiated
ti t d
squamous
epithelium
• Peripheral layer of
low cuboidal to
flattened cells
• Microsystic
degeneration and
calcification

Calcifying Epithelial
Odontogenic Tumor

Pindborg Tumor

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Calcifying Epithelial
Odontogenic Tumor
• Adults ((Mean = 40y)
y)

• Posterior mandible,
molar-ramus region

• Recurrence, but less

Recurrence
aggressive than
ameloblastoma

Calcifying Epithelial
Odontogenic Tumor
• A solid epithelial
p
tumor (not cystic)

• Contains amyloid

• Concentric
Liesegang ring
calcifications

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Calcifying Epithelial Odontogenic

Tumor - Amyloid

56

Calcifying Epithelial Odontogenic

Tumor – Liesegang Ring
Calcification

57

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Calcifying Epithelial Odontogenic

Tumor – Clear Cells

58

Calcifying Epithelial Odontogenic

Tumor – Cytologic Atypia

59

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Mesenchymal
Odontogenic Tumors

• Odontogenic m
myxoma
oma

• Odontogenic fibroma

• Cementoblastoma

Odontogenic Myxoma

• Ectomesenchymal odontogenic neoplasm

• Adults, anterior jaws, radiolucency, often
multilocular

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Odontogenic Myxoma

Odontogenic Myxoma

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Developing Tooth
Dental
Follicle

Developing
Tooth
Crown

Dental
Papilla

Enamel Matrix

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Dentin

Developing Tooth

Hard
Tissue Dental
Shell Papilla

Hard Tissue
Dental
Hard Follicle
Dental Tissue
Papilla with
Dental Premolar
Papilla

Apical View Proximal View

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Developing Tooth Bud

Dental Papilla

70

Dental Papilla or
Odontogenic Myxoma?

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Dental Papilla or
Odontogenic Myxoma?

Odontogenic Fibroma
Classification

Central Odontogenic Fibroma

• Simple type

• World Health Organization (WHO) type

Peripheral Odontogenic Fibroma

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Odontogenic Fibroma
Classification

Odontogenic Fibroma
Histology

Mature, fibrous stroma with varying

Mature
amounts of inactive odontogenic
epithelium

Epithelium-poor
Epithelium poor type - simple type

Epithelium-rich type - complex type

(WHO-type)

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Odontogenic Fibroma
Histology

Odontogenic Fibroma

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Hyperplastic dental follicles

were once reported as
odontogenic fibromas

Cementoblastoma

Young adults < 25 years

Mandibular first molar

Pain, expansion, root destruction

Does not recur after complete removal

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Cementoblastoma

Cementoblastoma

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Cementoblastoma

Cementoblastoma

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Mixed Odontogenic Tumors

• Odontoma

• Ameloblastic Fibroma

• Ameloblastic Fibro-Odontoma

• Calcifying Cystic Odontogenic Tumor

• Dentinogenic Ghost Cell Tumor

Mixed Odontogenic Tumors

Ameloblastic
Odontoma
Fibroma
Mimics early Mimics
Mi i end d
stage of stage of
odontogenesis odontogenesis

88

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Mixed Odontogenic Tumors

Ameloblastic
Ameloblastic Odontoma
Fibro-
Fibroma
Odontoma

Mimics
Mimics early Mimics end
intermediate
stage of stage of
stage of
odontogenesis odontogenesis
odontogenesis

89

Ameloblastic Fibroma
• “Kiddie” tumor (Mean = 14.8 y)

• A painless swelling of posterior mandible

• Well-circumscribed lucency, frequently

associated with the crowns of impacted
teeth

• Treatment by enucleation and curettage.

• May recur

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Ameloblastic Fibroma

Ameloblastic Fibroma

• Ectomesenchyme
Ectomesench me resembling dental
papilla

• Epithelial strands and cords resembling

dental lamina and enamel organ

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Ameloblastic Fibroma

Ameloblastic Fibroma

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Ameloblastic Fibro-Odontoma
• A “kiddie” tumor (mean age = 8 to 12y)
• Most frequent in posterior mandible
• A unilocular or multilocular mixed
density lesion, often associated with
the crown of an unerupted tooth
• Less common than ameloblastic
fibroma
• Treatment by enucleation. Recurrence
is rare

Ameloblastic Fibro-Odontoma

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Ameloblastic Fibro-Odontoma
• Histologic features of ameloblastic fibroma,
with the presence of dentin and enamel

The Spectrum of Odontogenic

Tumors

Ameloblastoma Odontoma

• Least differentiated • Most differentiated

• Most
M t aggressivei • Least
L t aggressive
i

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Odontoma
• Teenagers

• Mixed lucent-opaque
lucent opaque radiographically

• Hamartoma

• Well-circumscribed

• Treated by enucleation

• No recurrence

Odontoma

• Compound –
multiple small
multiple,
“toothlets”

• Complex –
disorganized
odontogenic
tissues

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Odontomas present in
Young People

Compound Odontoma

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Compound Odontoma

Complex Odontoma

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Calcifying Cystic
Odontogenic Tumor

g
Dentinogenic
Ghost Cell Tumor

CCOT vs DGGT

• CCOT - occurs primarily as a cystic

process

• DGCT – occurs as a more aggressive

solid tumor

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CCOT

DGGT

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CCOT vs DGGT
Calcifying Cystic Dentinogenic
Odontogenic Tumor Ghost Cell Tumor

Cystic Process Solid Tumor

REFERENCES
• Gnepp, DR, ed. Diagnostic Surgical
Pathology of the Head and Neck, 2e,
Saunders, 2009.
• Neville BW, Damm DD, Allen CM, Bouquot
J. Oral and Maxillofacial Pathology, 3e.
Saunders, 2008.

• Chi AC and Neville BW. Odontogenic Cysts

and Tumors. Surgical Pathology (2011)
4:1027-1091.

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REFERENCES
• Jordan RCK and Speight PM. Current
concepts of odontogenic tumors. Diagnostic
Histopathology (2009) 15(6): 303-210.

124
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Benign sinonasal tumors

andd non-neoplastic
l ti
pseudotumorous lesions
Prof. Alena Skalova, MD, PhD
Charles University, Faculty of Medicine
in Plzen, Czech Republic

Disclosure
Dr. Prof. Alena Skalova, MD, PhD
has nothing to disclose

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Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Anatomy of nasal cavity and sinonasal region

Benign lesions of sinonasal region

• Sinonasal polyps
– Inflammatory nasal
– antrochoanal
• Sinonasal hamartomatous lesions
• Benign epithelial neoplasms
– Papillomas
– Salivary
S li gland-type
l d adenomas
d
• Benign sinonasal soft tissue neoplasms

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SINONASAL
INFLAMMATORY POLYP

Sinonasal inflammatory polyps

• Most sinonasal polyps are of allergic origin
• consist largely
g y of myxoid
y edematous tissue
with pseudocysts containing eosinophilic
proteinaceous material and inflammatory
cells
• heavy infiltration by eosinophils
a ed tthickening
• marked c e go of base
basement
e t
membranes
• goblet cell metaplasia

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Symptoms include
nasal obstruction,
rhinorrhea, and
headache

ANTROCHOANAL POLYP

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Antrochoanal polyp

Antrochoanal angiomatoid polyp

• 3-6% of all patients with nasal polyps
• Usually solitary,
solitary at any age,
age most in young
adults
• Clinical symptoms
– nasal obstruction, epistaxis, rhinorrhea, and
headache
• susceptible
p to vascular injury
j y
– Origin within sinus, passage through
constrictive ostia- characteristic vascular
changes

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Angiomatoid nasal polyps

• Clinically distinctive benign lesions with
frequent recurrences
• may become
b partially
ll or extensively
l infarcted
f d
• which results in hemorrhage, necrosis and
erosion of the surrounding tissues including the
skeletal bones
• histological resemblance to various benign and
malignant
l tumors

Heffner DK. Sinonasal angiosarcoma? Not likely (a brief description

of infarcted nasal polyps). Ann Diagnostic Pathology 2010: 14: 233-234.

Histology of angiomatoid polyps

• Early vascular changes
– Hyperemia,
Hyperemia congestion,
congestion early hemorhagic
necrosis, interstitial edema
• Late vascular changes
– Congestion with organizing vascular
thrombi, neovascularization (granulation
tissue) fibrosis,
tissue), fibrosis ulcerations
ulcerations, necrosis
• prominent fibrous stroma surrounding
thick-walled blood vessels

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Angiomatoid nasal polyp composed of thick walled blood vessels

Angiomatoid nasal polyp with variably sized blood vessels

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Thick walled and dilated vessels in loose myxoid stroma

Organized thrombus

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Stromal hemorhage and edema, extravasation of RBCs

Reactive atypias of stromal fibroblasts

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Angiosarcoma-like vascular proliferation

Ulceration and reactive squamous metaplasia

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Ulceration, granulation tissue, bood vessel proliferation

Dilated blood vessels, granulation tissue

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Increased cellularity around blood vessels

Angiomatoid nasal polyps (ANP)

• 45 cases of ANP were retrieved from
consultation
co su tat o registry
eg st y in Pilsen
se
– 32 men and 13 women
• Sites included
– nasal septum (14/41)
– antrum Highmori (12/41), ethmoid sinuses (5/41)
lateral wall of nasal cavity
y (5/41), sphenoid
p sinus
(1/41), and non-specific nasal cavity (4/41)

Hadravsky, Skalova, Michal M. Angiomatoid nasal polyp: often misdiagnosed

and little known lesion. Report of 45 cases. Modern Pathology 2011: 24: 278A
Poster session, USCAP 2011, San Antonio

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Angiomatoid nasal polyps (ANP)

• X-ray or computed tomography scans were performed in
19 cases and bone erosions/deviations occurred in 4
cases of them
• Initial diagnoses submitted by referring pathologists
– angiofibroma 32%, hemangioma 24%, hemangiopericytoma
16%, angiosarcoma 12%, pyogenic granuloma and hemangio-
endotelioma, both at 8%
• None of the patients died of the disease and there has
been no progression in any patient
• Recurrence
R was recorded
d d in
i 30% (9/30)

Hadravsky , Skalova , Kacerovska, et al. Angiomatoid change in

polyps of nasal and paranasal regions: an underrecognized and
commonly misdiagnosed lesion-report of 45 cases.Virchows Arch
2012;460:203-209.

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SINONASAL
HAMARTOMATOUS
LESIONS

Hamartomas of respiratory tract

• Rare polypoid tumor-like lesions of
sinonasal mucosa and nasopharynx
– Occur predominantly in nasal cavity
• Respiratory epithelial adenomatoid
hamartoma (REAH)
• Seromucinous hamartoma
• nasal chondromesenchymal
hamartoma
• Mixed chondro-osseous REAH

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Wenig BM, Heffner DK.

Respiratory epithelial adenomatoid hamartomas
of the sinonasal tract and nasopharynx: a clinicopathologic
study of 31 cases.
Ann Otol Rhinol Laryngol 1995:104:639-645.

RESPIRATORY EPITHELIAL
ADENOMATOID
HAMARTOMA (REAH)
( )

Respiratory epithelial adenomatoid

hamartoma (REAH)
• 80% of p
patients with REAH are men
• Age range is from 2nd to 9th decade
• Symptoms include
– nasal obstruction
– Stuffiness
– Epistaxis
– Postnasal drainage
– Chronic rhinosinusitis

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Respiratory epithelial adenomatoid

hamartoma (REAH)
• 70% of REAHs occur in the nasal cavity
y
– Nasal septum, lateral nasal wall
• Maxillary sinus
• Frontal sinus
• Nasopharynx
p y

Etiology of REAH
• stimulation by inflammatory process
• Exuberant hyperplasia of the
epithelium
• Recent evidence suggests that REAH
is a neoplastic lesion

Ozolek& Hunt. Tumor supressor gene alterations in respiratory

adenomatoid hamartoma (REAH): comparison to sinonasal
adenocarcinoma and inflamed sinonasal mucosa. Am J Surg Pathol
2006;30:1576-80.

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REAH: Gross Findings

• Circumscribed and polypoid lesion
• Size up tp 5 cm, stalk may be present
• On cut surface, they are firm, tan-
white solid
• Occassionally cystic foci

REAH: Microscopic Findings

• Well-formed branching slit-like spaces
lined by respiratory epithelium
• Seromucinous gland hyperplasia with
periglandular hyalinization
• Mucinous and squamous metaplasia
mayy be present
• Stromal hyalinization, edema, increased
vascularity, chronic inflammation

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71-y old woman presented with nasal obstruction

Respiratory epithelial adenomatoid hamartoma (REAH)

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p63

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REAH: Differential Diagnosis

• Inflammatory polyp
– REAH is a single lesion
– Localized at posterior nasal septum
– Greater proliferation of glands
• Schneiderian papilloma
– Proliferating thickened epithelium with
intra-epithelial
intra epithelial mucous cysts and
inflammation
• Seromucinous hamartoma
• Low-grade sinonasal adenocarcinoma

Weinreb I, et al.
Seromucinous hamartomas: a clinicopathological study of a
sinonasal glandular lesion lacking myoepithelial cells.
Histopathology 2009:54:205-213

SEROMUCINOUS
HAMARTOMA

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Seromucinous (glandular)
hamartomas
• Uncommon, under-reported
Uncommon under reported entity
• polypoid lesions characterized by
epithelial proliferations of small
glands, acini, and tubules growing
haphazaradly in clusters and
lobules
• devoid of myoepithelial cells

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CK 14

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S-100

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CK 14

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Seromucinous hamartoma of
sinonasal tract
• Residual
d l lobular
l b l architecture,
h bl d
bland
morphology
• Absence of epithelial tufting, papillae,
back-to back glands
• Absence of invasion
• Spectrum ranging from pure glandular
hamartoma and REAH
• Avoid confusion with LG sinonasal
adenoca

Differential diagnosis of
sinonasal hamartomas
• Low-grade sinonasal
adenocarcinoma
–LG tubulo-papillary
adenocarcinoma
• Schneiderian benign papilloma
–Oncocytic variant
• Salivary gland type adenoma

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SINONASAL
ADENOCARCINOMAS
(SNAC)

Sinonasal adenocarcinomas (SNAC)

• uncommon malignancies that show a
variety of growth patterns
• classified as intestinal and non-
non
intestinal types, the latter
subclassified as low grade and high
grade

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Low-grade sinonasal
tubulopapillary adenocarcinoma
• Composed of closely packed tubular
structures
• Lined by single layer of bland
cuboidal to columnar cells with
lightly eosinophilic cytoplasm
• Glands are frequently back-to-back
• Mitoses are rare
• Invasive pattern

Low grade tubulopapillary adenocarcinoma of the nasal cavity in 72-y

old man, slowly growing tumour- of nasal mucosa, filling the middle
meatus, Presented with nasal obstruction and recurrent attacks of
chronic hyperplastic rhinitis for at least 5 years

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Low grade tubulopapillary adenocarcinoma

Intracytoplasmic vacuoles in LG tubulopapillary adenocarcinoma

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Sinonasal adenocarcinomas
(SNAC)
• Recently, some cases of low-grade
sinonasal
i l adenocarcinomas
d i
associated with REAH were reported
• possibly implicating REAH as a
precursor lesion for at least a subset
of SNAC

Jo, et al. Low-grade sinonasal adenocarcinomas. The association with

and distinction from respiratory epithelial adenomatoid hamartomas
and other glandular lesions. Am J Surg Pathol 2009:33:401-408.

Benign epithelial
neoplasms
p

Papillomas
Salivary gland-type lesions

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Sinonasal papillomas
• Squamous cell papilloma
• Nasal
N l vestibule
ib l
• Schneiderian papilloma
• Nasal cavities and paranasal sinuses
– Exophytic
– Inverted
– oncocytic

SQUAMOUS CELL
PAPILLOMA

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Squamous papilloma
• Seen in many anatomic locations
– namely nasal vestibule,
vestibule palate,
palate and
larynx
• Composed of variably sized
fibrovascular cores
• Lined by mature stratified squamous
epithelium
ith li (k ti i i )
(keratinizing)
• Cells are bland
• Generally not related to HPV

Differential diagnosis
• Schneiderian papilloma
– Lackk off mucous cells
ll
– transitional epithelium
– respiratory lining

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SCHNEIDERIAN
PAPILLOMA

Schneiderian papilloma of
nasal cavity
• Three types of benign tumors arise
f
from schneiderian
h id i membrane b
– Inverted papilloma
– Exophytic (fungiform) papilloma
– Oncocytic (cylindrical cell) papilloma
• HPV type 6,
6 11,
11 16,
16 and 18 has been
detected in both inverted and
exophytic

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Inverted schneiderian
papilloma
• Benign predominantly inverted
neoplastic lesion arising from
sinonasal mucosa
• Most arise from lateral nasal wall
• Composed of dilated duct-like
structures lined by multiple layers of
squamous, ciliated
ili d columnar,
l and
d
transitional epithelium
• Papilloma with dysplasia

Exophytic schneiderian
papilloma
• Benign exophytic neoplastic
proliferation
lif i arising
i i from
f
schneiderian membrane
• Branching fibrovascular fronds
• Cytologically identical to inverted
type
• Presence of mucous cells

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Oncocytic schneiderian
papilloma
• Benign mixed exophytic and
endophytic
d h ti tumor
t pattern
tt
• Epithelial cords lined by several
layers of columnar oncocytic
epithelaum
• Intraepithelial
p microcysts
y contain
neutrophils and mucin
• Dif.dg. low-grade tubulopapillary
adenocarcinoma

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Schneiderian benign papillomas

Oncocytic papilloma

Inverted papilloma

Exophytic papilloma

SALIVARY GLAND-TYPE
ADENOMA

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Salivary gland-type adenomas

• Pleomorphic adenoma is most
common benign glandular tumor of
sinonasal
i l area
• Most arise in nasal septa

SCLEROSING
POLYCYSTIC ADENOSIS

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Sclerosing polycystic
adenosis
• Rare sclerosing process of major
salivary glands
• Lobular proliferation of ducts and
acini with variably cystic change,
intraductal hyperplasia and
dysplastic changes
• Unique
U i case off SPA described
d ib d in
i
sinonasal tract in a 79-y old woman

Su et al. Hum Pathol 2013;44:1937-1940

Sclerosing polycystic adenosis

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Sclerosing polycystic adenosis

Sclerosing polycystic adenosis

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Sclerosing polycystic
adenosis

actin

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Benign sinonasal soft

tissue neoplasms

Hemangioma
Glomangiopericytoma-sinonasal type
hemangiopericytoma
Solitary fibrous tumor

SINONASAL
HEMANGIOMA

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Sinonasal hemangioma
• Should be distinguished
g from
granulation tissue
• Angiomatoid inflammatory polyps

SINONASAL
GLOMANGIOPERICYTOMA

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Sinonasal type
hemangiopericytoma
Glomangiopericytoma
• Better prognosis
prognosis, recurrences (<30%)
(<30%), no
meta
• Myoid differentiation (actin+) relationship
with glomus tumor, CD34 usually negative
• More likely arises from pericytes
• Dif dg
– angiomatoid polyp
– vascularized schneiderian papilloma
– solitary fibrous tumor

Sinonasal glomangiopericytoma

Prominent perivascular
hylinization

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SOLITARY FIBROUS
TUMOR

Solitary fibrous tumor

• benign spindle cell fibroblastic
proliferation with variable cellularity
and vascularity
• Occurs predominantly in adults
• Blood vessels prominent, thickened
vascular walls
• Focally hyalinized stroma
• CD34+
• S-100 protein/actin/desmin negative

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Solitary fibrous tumor

Differential diagnosis of STF

• Sinonasal glomangiopericytoma
– CD34 versus actin
• Nasopharyngeal angiofibroma
– not in nasal cavity

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Thank you for your attention

173
 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Malignant Sinonasal Tumours.

Roderick H.W. Simpson, BSc, MB ChB, MMed

(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Disclosure statement.
Dr. Roderick Simpson has no financial interest to
disclose, other than employment by:
University of Calgary, and Alberta Health Services.

174
 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Malignant Sinonasal Tumours.

Introduction.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB,
ChB MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Anatomy of Sinonasal Tract-1.

Mills SE et al. AFIP Fascicle 17.

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Anatomy of Sinonasal Tract-2: Sinuses.

Mills SE et al. AFIP Fascicle 17.

Sinonasal tumours: 2005 WHO Classification.

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Sinonasal malignancies.
________________________________________________________________________________________________________________________________________________________________________________

• Squamous cell ca (usual; non-keratinizing; variants).

• Adenoid Cystic-like Carcinoma.
• Adenocarcinoma (intestinal, non-intestinal).
• Sinonasal Undifferentiated Carcinoma (SNUC)
(SNUC).
• NUT Rearrangement Carcinoma.
• Neuroendocrine Carcinoma.
• Primary Sinonasal Malignant Melanoma.
• Olfactory Neuroblastoma.
________________________________________________________________________________________________________________________________________________________________________________

• Teratocarcinosarcoma, (+ other rare germ cell tumours).

• PNET/Ewing’s Sarcoma.
• Sarcomas of bone, cartilage and soft tissues.
• Malignant Lymphoma.
• Metastases.

Sinonasal Malignancies.
________________________________________________________________________________________________________________________________________________________________________________

Excluded from this presentation:

((will be covered in other lectures).
)
Malignant lymphomas.
Sarcomas.
Salivary type malignancies arising in sero-
mucinous glands.
g

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Sinonasal Malignancies.
________________________________________________________________________________________________________________________________________________________________________________

• Account for 0.2-0.8% of all human cancers;

3% of head and neck malignancies.
• Site
Sit incidence:
i id
Maxillary sinus 60%. Nasal cavity 20-30%.
Ethmoid sinus 10-15%. Sphenoid, frontal sinuses 1%.
• Geographical variation:
e g Higher rates in Japan,
e.g. Japan and parts of China and India.
India
• Most common type is squamous cell carcinoma.

Malignant tumours of the Nose.

Cardesa A, Alós L, Franchi A. In: Cardesa A, Slootweg PJ, eds. Pathology of the
Head and Neck Pathology. Springer, Berlin 2006.

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Sinonasal tumours:
Clinical stage.

Diagrammatic representation of tumor stage, based on a

maxillary sinus primary tumor (AJCC 2010).
T1: confined to the sinus with no bone destruction;
T2: tumor causing bone erosion into hard palate;
T3: tumor invades subcutaneous tissues (+ middle nasal meatus);
T4: tumor invades into anterior orbital content.
Thompson LDR et al. Head and Neck Pathol 2013; published online 15th September.

Malignant Sinonasal Tumours.

Squamous Cell Carcinoma.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB,
ChB MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

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Sinonasal Squamous Cell Carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

Histopathology:
1. Keratinising (usual type) - as elsewhere.
2. Non-keratinising (cylindric cell carcinoma).
________________________________________________________________________________________________________________________________________________________________________________

Variants: spindle cell, basaloid, verrucous,

acantholytic, etc.

Sinonasal Squamous Cell Carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

Incidence: rare (1-2% of all head/ neck malignancies).

Sex: M:F = 1.5:1.
Age: most are 55-65
55 65 years
years.
Site: maxilla (60-70%) > Nasal cavity (12-25%) >
ethmoid (10-25%) > sphenoid, frontal (1%)
Aetiology: risk factors include:
Tobacco smoking
smoking.
HPV (non-keratinising type).
Inverted sinonasal papilloma.
Radiation, Nickel.

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Sinonasal Squamous Cell Carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

Prognosis and Predictive factors.

Patients with nasal cavity SqCCas present earlier
than sinus neoplasms and generally fare better.
5 year survival nasal cavity SqCCas : 60%.
maxillary sinus: 42%.
Stage
g important.
p
________________________________________________________________________________________________________________________________________________________________________________

Non-keratinising squamous carcinoma do better.

Squamous cell ca of usual type: not a diagnostic problem,

but staging and assessment of margins are major issues.

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Malignant Sinonasal Tumours.

Non-keratinising Squamous Cell Carcinoma –

(Cylindric Cell Carcinoma).

Roderick H.W. Simpson, BSc, MB ChB, MMed

(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Sinonasal Cylindric cell carcinoma (non-

keratinising squamous cell carcinoma).
________________________________________________________________________________________________________________________________________________________________________________

• Often exophytic mass.

• Arise
A i from
f maxillary
ill antrum,
t ethmoid,
th id llateral
t l
nasal wall.
• Papillary fronds and invaginations.
• Expansile invasion; “pushing” edges.
• Thick ribbons of multilayered epithelium
epithelium.
• Cells often cylindrical in shape; basal palisading.
• Sometimes mixed with keratinising squamous ca.
• Many are p16+. El-Mofty SK, Lu DW. AJSP 2005; 29: 1367-72.

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Nose non-keratinizing squamous ca: architecture.

Non-keratinizing sq ca: rounded edges to tumour islands.

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Nose non-keratinizing squamous ca: atypia; mitoses.

Nose non-keratinizing sq ca: perpendicular nuclei; p16.

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Differential Diagnosis:
Inverted sinonasal (Schneiderian) papilloma.
________________________________________________________________________________________________________________________________________________________________________________

Main microscopic findings.

• Endophytic growth.
• Hyperplastic ribbons of basement membrane
enclosed multi-layered epithelium, 5-30 cells thick.
• No significant atypia – although some nuclear
variability can occur.
occur
• A few basal mitoses.
• p16 negative.
• HPV (any type) present in 20% (high risk in 3%).

Inverted papilloma: inverted and branching growth.

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Invert pap: no atypia; basal mitoses-cf. non-keratin sq ca)

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HPV-related sinonasal carcinomas. A and B, Most of the HPV-related sinonasal squamous cell
carcinomas were morphologically identical to HPV-related oropharyngeal carcinomas, exhibiting
little or no keratinization, tumor infiltration by lymphocytes, and limited desmoplastic stromal
reaction. C, All but 1 of the HPV+ diffusely positive for p16 in a nuclear and cytoplasmic
distribution. D, HPV positivity was defined by the presence of dot-like in situ hybridization
signals in tumor nuclei (high-risk HPV in situ hybridization).

HPV-related sinonasal carcinomas. A and B, Most of the HPV-related sinonasal squamous cell
carcinomas were morphologically identical to HPV-related oropharyngeal carcinomas, exhibiting
little or no keratinization, tumor infiltration by lymphocytes, and limited desmoplastic stromal
reaction. C, All but 1 of the HPV+ diffusely positive for p16 in a nuclear and cytoplasmic
distribution. D, HPV positivity was defined by the presence of dot-like in situ hybridization
signals in tumor nuclei (high-risk HPV in situ hybridization).

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Alos et al. Cancer 2009;115:2701-2709.

RESULTS: HPV DNA was detected in tumour tissue of

12/60 (20%). HPV16 - 11; HPV35 - 1.
IHC p16 stained all HPV+ and no HPV- tumours.
No differences were observed in terms of site or stage at
presentation between HPV-positive and -negative tumours.
CONCLUSIONS: A subgroup of sinonasal SCCs is
associated with HPV infection. These tumours have a
significantly better prognosis.

Malignant Sinonasal Tumours.

Adenoid Cystic-like Carcinomas.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB,
ChB MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

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Sinonasal Tract Adenoid Cystic Carcinoma: probably true

AdCCa arising in a minor sero-mucinous gland.

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HPV-related sinonasal carcinomas.

A, 4 HPV-associated carcinomas exhibited features of salivary gland
carcinomas particularly AdCCa
carcinomas, AdCCa. Although these tumors were
predominantly solid (right), they also showed cribriform areas with
duct formation (left).
B, The tumors were strongly immunoreactive to p16, and punctate
hybridization signals were seen in tumor nuclei on HPV in situ
hybridization (inset, high-risk HPV in situ hybridization).

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FISH for MYB – no gene rearrangement in 6/6.

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Malignant Sinonasal Tumours.

Adenoid Cystic-like Carcinomas.

Two recent cases:

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB,
ChB MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Case 1: female 78 years; primary maxilla tumour:

basaloid areas; PNI+.

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Case 1: maxilla tumour: focal lumen formation.

Case 1: maxilla tumour: p63; p16.

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Case 1: maxilla tumour: RT-PCR for HPV.

Courtesy of Dr. Doug Demetrick, Calgary.

Case 1: maxilla tumour: presumed in situ component looks

squamous.

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Case 2: male 49 years; primary maxilla tumour: AdCCa-

like, but probably basaloid SCC.

Case 2: AdCCa-like; scanty possible lumina – HE, p63.

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Case 2: AdCCa-like; PASD+ BM material; p16-.

Sinonasal Adenoid Cystic-like Carcinomas.

SUMMARY (January 2014)
Probably a heterogenous group of carcinomas with
some morphological similarities.
My personal view: 3 distinct entities.
1. True salivary-type AdCCa.
2. Adenoid cystic like carcinomas - p16+, i.e.
HPV-driven; possibly squamous.
3. Odd non-HPV-related basaloid squamous
carcinomas.
Await further developments.

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Malignant Sinonasal Tumours.

Adenocarcinoma.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB,
ChB MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Sinonasal Adenocarcinoma.
________________________________________________________________________________________________________________________________________________________________________________

10-20% of all primary sinonasal malignancies.

• Salivary or non
non-salivary:
salivary: (salivary carcinomas
classified as at any other site, e.g. parotid.)
• The non-salivary are intestinal or non-intestinal.
• All can be low or high grade.

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Intestinal type adenocarcinomas (ITAC).

________________________________________________________________________________________________________________________________________________________________________________

Sex: M>F.
Age:
g mean 58 ((rangeg 12-86).
)
Site: Ethmoid 40%, nasal cavity 27%, maxilla 20%.
Clinical: unilateral nasal obstruction, epistaxis,
rhinorrhoea.
10% LN mets at presentation.
Aetiology: exposure to wood, leather dust.

Intestinal type adenocarcinomas.

________________________________________________________________________________________________________________________________________________________________________________

Microscopic appearance.
Resemble adenocarcinomas of the large intestine.
Variable amount of mucin production.
production
Can be sub-classified:
Barnes Kleinsasser & Schroeder
Papillary PTCC-I*
Colonic PTCC-II*
PTCC-II
Solid PTCC-III*
Mucinous Alveolar-goblet
Signet-ring cell *PTCC=papillary
Mixed Transitional tubular cylinder cell.

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Sinonasal adenoca: intestinal type – colonic, papillary areas.

Sinonas adenoca: intestinal type - columnar cells; mitoses.

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Sinonasal adenoca: mucinous (signet ring cell type).

Sinonasal adenocarcinoma: intestinal type.

________________________________________________________________________________________________________________________________________________________________________________

Special stains and immunohistochemistry.

Positive: panCK, EMA, Ber EP4.
Mostly+: CK20 (73%), CK7 (43-93%),
CDX-2 (usually, but can be focal).
CEA (variable).
Often scattered cells or groups:
Synaptophysin, Chromogranin A.
Negative: TTF-1, PSA.

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Sinonasal adenoca, intestinal type: CK7, CK20.

Sinonasal adenoca, intestinal type: PASD, CDX-2.

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Intestinal type adenocarcinoma: Clinical Outcome.

________________________________________________________________________________________________________________________________________________________________________________

Locally aggressive, but LN and distant metastases

in 10-20%. Clinical staging not so helpful.
Prognosis
g depends
p to some degree
g on morphology.
p gy
Barnes Kleinsasser /Schroeder 3 year survival
Papillary PTCC-I 82%
Colonic PTCC-II 54%
Solid PTCC-III
PTCC III 36%
Mucinous Alveolar-goblet 48%
Signet-ring cell 0
Mixed Transitional 71%

Sinonasal Adenocarcinoma,
non-intestinal, low grade.
________________________________________________________________________________________________________________________________________________________________________________

Sex: Slight male predominance.

Age: 9-89
9-89.
Aetiology: No known occupational, environmental
factors.
Site: Ethmoid sinus especially, but also nasal
cavityy or sinuses.
Outcome: Excellent prognosis.

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Sinonasal Adenocarcinoma, non-intestinal, low

grade: Histopathology.
________________________________________________________________________________________________________________________________________________________________________________

• Papillae and/or small glands back-to-back.

• Single layer of cells; no basal-myoepithelial layer.
layer
• Non-ciliated cuboidal or low columnar cells.
• Uniform round nuclei.
• Scanty mitoses.
• CK7 CK19,
CK7, CK19 S S-100
100 positive
positive.
• CK20, CDX-2 negative.

Sinonasal Adenoca, non-intestinal, low grade:

papillary, tubular patterns.

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Sinonasal Adenoca, non-intestinal, low grade:

regular nuclei.

Sinonasal Adenoca, non-intestinal, low grade:

CK19, S-100.

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High grade non-intestinal adenocarcinomas.

________________________________________________________________________________________________________________________________________________________________________________

Rare and poorly characterised.

Sex: M 22, F 5.
Age: mean 55 (range 23-83)
23 83)
Site: 13 nose +sinuses; 10 nasal cavity only; 4 sinus only.
Aetiology: no known occupational factors.
Micro: marked nuclear/cytoplasmic pleomorphism;
mitoses++; necrosis+; occ clear cells
cells.
Blastomatous; apocrine; oncocytic/mucinous;
undifferentiated.
IHC: CK7 most +; CK20, CDX-2 neg.
Stelow EB et al. AJSP 2011; 35: 971-980.

Malignant Sinonasal Tumours.

Primary Clear Cell Carcinoma.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB,
ChB MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

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Primary sinonasal clear cell carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

• Few primary neoplasms of the sinonasal tract

characterised by clear cells.
• Most - salivary type arising from minor glands
glands.
• One other is “sinonasal renal
cell-like carcinoma”.
• Only 4 cases described.
• All low grade malignancies.
• Renal primary excluded by
imaging of kidneys.
• No recurrences/metastases
(follow up 2-10 years).

Primary sinonasal clear cell carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

Microscopic Findings
•Solid to nested, glandular growth pattern.
•Monomorphic population of cells with optically
clear cytoplasm.
•Generally regular nuclei; little atypia.
• No necrosis; mitotic figures sparse.
IHC: CK7 4/4.
CD10 1/2.
Vimentin 0/4.

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Primary sinonasal clear cell carcinoma.

1º sinonasal clear cell ca: IHC some different from RCC.

CAM5.2 CD10

CK7 CEA

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Malignant Sinonasal Tumours.

Sinonasal Undifferentiated Carcinoma (SNUC).

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB,
ChB MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Sinonasal Undifferentiated Carcinoma (SNUC).

________________________________________________________________________________________________________________________________________________________________________________

Definition: “a highly aggressive and clinicopathologically

distinctive carcinoma of uncertain histogenesis that
typically presents with locally extensive disease. It is
composed of pleomorphic tumour cells with frequent
necrosis” (WHO 2005)
necrosis”.
Age: median 53-58 (broad range).
Sex: M>F=2.5:1.
Site: Commonly originates as a large fungating mass of
the ethmoid region.
Frequently invades orbit, skull base, brain.
Highly aggressive and extensively destructive.

Aetiological factors: Cigarettes, Nickel exposure.

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Sinonasal Undifferentiated Carcinoma (SNUC).

________________________________________________________________________________________________________________________________________________________________________________

Definition: “a highly aggressive and clinicopathologically

distinctive carcinoma of uncertain histogenesis that
typically presents with locally extensive disease. It is
composed of pleomorphic tumour cells with frequent
necrosis” (WHO 2005)
necrosis”.
Age: median 53-58 (broad range).
Sex: M>F=2.5:1.
Site: Commonly originates as a large fungating mass of
the ethmoid region.
Frequently invades orbit, skull base, brain.
Highly aggressive and extensively destructive.

Aetiological factors: Cigarettes, Nickel exposure.

Sinonasal Undifferentiated Carcinoma (SNUC).

________________________________________________________________________________________________________________________________________________________________________________

Definition: “a highly aggressive and clinicopathologically

distinctive carcinoma of uncertain histogenesis that
typically presents with locally extensive disease. It is
composed of pleomorphic tumour cells with frequent
necrosis” (WHO 2005)
necrosis”.
Age: median 53-58 (broad range).
Sex: M>F=2.5:1.
Site: Commonly originates as a large fungating mass of
the ethmoid region.
Frequently invades orbit, skull base, brain.
Highly aggressive and extensively destructive.

Aetiological factors: Cigarettes, Nickel exposure.

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Sinonasal Undifferentiated Carcinoma (SNUC).

________________________________________________________________________________________________________________________________________________________________________________

Microscopic:
• Invasive undifferentiated carcinoma.
• Lobular architecture.
• Areas of necrosis.
• Large nuclei, prominent nucleoli, cytological atypia.
• Plentiful mitotic figures.
• No obvious squamous or glandular differentiation.
IHC: EMA+, CAM+, CK5/6-, CK14-, S-100-, EBER-.
EM: Poorly formed desmosomes.

SNUC: undifferentiated - no glandular, squamous areas.

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SNUC: atypia; variable cell size and appearance.

SNUC: MNF116, EMA.

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SNUC: S-100, EBER neg (unlike melanoma, nasophx ca).

Cytokeratin patterns in SNUC and other carcinomas.

Other markers: EMA+. S-100, CD45, HMB45, HER2,

synaptophysin all negative.

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Sinonasal Undifferentiated Carcinoma (SNUC).

________________________________________________________________________________________________________________________________________________________________________________

Differential diagnoses.
• NUT Midline Carcinoma.
• Neuroendocrine carcinoma
carcinoma.
• Nasopharyngeal carcinoma.
• Melanoma.
• Olfactory neuroblastoma.
Di
Diagnosis
i requires
i IHC for...
f
exclusion of other poorly differentiated sinonasal
malignancies.

Sinonasal Undifferentiated Carcinoma (SNUC).

________________________________________________________________________________________________________________________________________________________________________________

Prognosis:
80% of patients die within 5 years.
Median survival: 18 months
months.

Treatment:
Combination of radical surgery with radio- and
chemotherapy (Cisplatin) may help.

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Malignant Sinonasal Tumours.

NUT rearrangement (midline) carcinoma.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB,
ChB MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

NUT rearrangement carcinoma.

• Underdiagnosed.
• Wide age range (3-78).
• 35% occur in head and neck.
Most in midline of upper aerodigestive tract.
Occasional cases in salivary glands.

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Frontal sinus: NUT midline carcinoma.

Courtesy Dr. Harold Lau, Calgary.

NUT rearrangement carcinoma.

Microscopy:
• Sheets of undifferentiated malignant cells
resembling SNUC, but with occasional well
differentiated squamous islands.
• Areas of necrosis; high mitotic rate.
• p63+ beyond islands,  squamous lineage.
• Rearrangements of NUT (nuclear protein in
testis) gene localised to 15q14.
• NUT fused to BRD-4 on chromosome 19 - ⅔ cases.
• NUT specific antibody.

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NUT rearrangement ca: islands of tumour; necrosis.

NUT rearrangement ca: palisading; cytology.

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NUT carcinoma: occasional foci of abrupt keratinization.

NUT rearrangement ca: immunohistochemistry.

________________________________________________________________________________________________________________________________________________________________________________

NUT specific antibody. (Cell Signaling Technologies).

Cytokeratin5/6 +++.
p63 +++.
Synaptophysin sometimes patchy +.
TTF-1 recent Calgary case focally+.
EBER, S-100 Negative.

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NUT rearrangement carcinoma: CK5/6; p63.

NUT rearrangement ca: EBER, S-100 both –ve.

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NUT rearrangement carcinoma:

B C

B. Immunohistochemistry using a NUT specific antibody

(Cell Signaling Technologies) reveals speckled nuclear
staining.
staining
C. Fluorescent in situ hybridization (FISH) using a dual-
color breakapart probe flanking the NUT gene. The split-
apart red and green signals indicate rearrangement of the
NUT locus.
Christopher A. French. Head and Neck Pathol 2013; 7: 11–16.

NUT rearrangement carcinoma.

Outcome and therapy.
• Published cases few, but behaviour aggressive; 6.7
month median survival.
• Patients do much worse with metastases.
• Possible targeted therapy with Bromodomain
Inhibitors.

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Malignant Sinonasal Tumours.

Neuroendocrine carcinoma.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB,
ChB MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Neuroendocrine carcinoma.
________________________________________________________________________________________________________________________________________________________________________________

Most are small cell type (SCCNET).

• Very rare in sinonasal tract (unlike larynx, lung).
• Morphology
p gy approx.
pp same as Small cell Ca lung.
g
• Sheets of small to medium cells.
• Azzopardi DNA smear effect.
• Necrosis.
• High mitotic rate.
• Cytokeratin (broad spectrum)+, Synaptophysin+,
Chromogranin A+.
• CK20 – negative (unlike Merkel cell ca of skin,
salivary Small Cell Ca).

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Sinonasal Neuroendocrine ca: small, intermediate cells.

Sinonasal Neuroendocrine Ca: CAM5.2; synaptophysin.

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Malignant Sinonasal Tumours.

Sinonasal Malignant Melanoma.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB,
ChB MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Sinonasal malignant melanoma.

________________________________________________________________________________________________________________________________________________________________________________

Definition:
“a malignant neoplasm derived from the
melanocytes
l iin the
h mucosa”
” (WHO 2005).
2005)

• 3-23% of all sinonasal malignancies.

• Sinonasal melanomas account for 0.5 and 1.5%
of all melanomas.

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Sinonasal malignant melanoma.

________________________________________________________________________________________________________________________________________________________________________________

Sex: M:F = 56:59.

Age: mean 64 (range 13-93).
Race: White 90%, Black 10%.
Location: Left 57, Rt 46, bilat 3, midline 9.
Site: 34 Nasal cavity alone.
9 Nasopharynx alone.
3 Maxillary sinus alone.
39 Nasal cavity and sinuses
sinuses, NOS.
NOS
Size: mean 24 mm (range 5-65).
Thickness: mean 7.2 (range 2-19).

Thompson LDR et al. AJSP 2003; 27: 594-611.

Nose melanoma: CT (advanced); often polypoid (early).

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Sinonasal melanoma (Microscopic characteristics).

_________________________________________________________________________________________________________________________________________________________________________________________________________

Surface derivation: 23 (total number 115).

Pagetoid spread: 18
Growth pattern: Spindle 45, peritheliomatous 39,
solid sheet 60,, meningothelial
g 14.
Cell type: Spindle 29, epithelioid 46, plasmacytoid 25,
rhabdoid 3, undifferentiated 67.
Pigmented: 77
Giant cell formation: 49.
Mitotic count/10 HPF: 17.8 (mean).
Atypical mitoses: 92
Necrosis: 67
Perineural invasion: 4
Thompson LDR et al. AJSP 2003; 27: 594-611.

Nose melanoma: solid, myxoid areas; spindle cells.

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Sinonasal melanoma. Spindle and epithelioid cells.

Sinonasal melanoma: nuclear pleomorphism.

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Sinonasal melanoma: Relationship to surface

obvious in only a minority of cases.

Sinonasal melanoma: in situ Pagetoid spread.

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Sinonasal malignant melanoma.

________________________________________________________________________________________________________________________________________________________________________________

Immunohistochemistry % of cases positive:

S-100 91 95 HMB45 82 98
Tyrosinase
y 84 98 Melan A 70 100
MITF 62 95 Vimentin 97
NSE 46 CD117 37
CD99 23 Synaptoph 13
CD56 8 CD57 5
Negative: EMA, cytokeratins, chromogranin A, GFAP,
CD45, SMA, Desmin.
Thompson LDR et al. AJSP 2003; 27: 594-611.
Prasad ML et al. AJSP 2001; 25: 782-787.
New Marker: Sox-10 - 100% (Wang B, HNPathol 2013).

Nasal melanoma. S-100 protein, pan melanoma cocktail.

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Sinonasal melanoma: AE1/AE3, CD45.

Sinonasal Melanoma.
________________________________________________________________________________________________________________________________________________________________________________

• Clinical outcome:
Local recurrence: 67-92%
5 year survival: 17 47% (Barcelona 35%).
17-47% 35%)
• Poor prognostic indicators:
Clinical:
• Older age.
• Location in sinuses or nasopharynx.
• Tumour size >30 mm.

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Sinonasal Melanoma.
________________________________________________________________________________________________________________________________________________________________________________

Poor prognostic indicators:

Histology:
• undifferentiated
u d e e ed co
component
po e >25%
5% of
o tumour.
u ou .
• pseudosarcoma areas.
• necrosis.
• vascular invasion.
• plentiful mitotic figures.
• marked nuclear pleomorphism.
Depth of invasion:
• does not apply to mucosal melanomas, except....
tumours <0.5 mm better survival.

Malignant Sinonasal Tumours.

Olfactory Neuroblastoma.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB,
ChB MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

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Anatomy of Sinonasal Tract: Nasal Cavity.

Mills SE et al. AFIP Fascicle 17.

Olfactory Neuroblastoma.
________________________________________________________________________________________________________________________________________________________________________________

Definition: “a malignant neuroectodermal

tumour thought to originate from the olfactory
membrane of the sinonasal tract”. (WHO 2005).
S
Synonyms: aesthesioneuroblastoma,
th i bl t
olfactory placode tumour.
Incidence: 2-3% of sinonasal tumours.
Age: range 2-90 yrs; peaks in 2ndand 6th decades.
Sex : equal.
equal
Site: usually begins in upper nasal cavity (region of
cribriform plate).
Cell of origin: basal reserve cell of olfactory
neuroepithelium.

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Olfactory Neuroblastoma.
________________________________________________________________________________________________________________________________________________________________________________

Definition: “a malignant neuroectodermal

tumour thought to originate from the olfactory
membrane of the sinonasal tract”. (WHO 2005).
S
Synonyms: aesthesioneuroblastoma,
th i bl t
olfactory placode tumour.
Incidence: 2-3% of sinonasal tumours.
Age: range 2-90 yrs; peaks in 2ndand 6th decades.
Sex : equal.
equal
Site: usually begins in upper nasal cavity (region of
cribriform plate).
Cell of origin: basal reserve cell of olfactory
neuroepithelium.

Olfactory neuroblastoma.

Typical dumbbell shape of tumour in the nasal and

cranial cavities. Wenig et al. WHO 2005.

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Olfactory Neuroblastoma.
________________________________________________________________________________________________________________________________________________________________________________

Typical Microscopic findings:

•Islands of tumour cells set in a vascular stroma.
•Tumour cells - round to oval,
oval regular nuclei;
scanty pale cytoplasm.
•Mitotic figures generally infrequent.
•Rosettes or pseudo-rosettes only rarely found.
S ll amounts
•Small t off neurofibrillary
fib ill matrix.
t i
•No necrosis in low grade tumours.

Olfactory neuroblastoma: lobular architecture.

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ONB: Vascular; fibrillary stroma.

Low grade ONB: Generally regular cytology.

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Olfactory neuroblastoma: Pseudo-rosettes.

Olfactory Neuroblastoma: immunohistochemistry.

________________________________________________________________________________________________________________________________________________________________________________

Positive for:
• Synaptophysin.
• Chromogranin A A.
• NSE.
• S-100 - in sustentacular cells.
• Low MW cytokeratin - focally + in a few cases.
Negative for:
Desmin, myogenin, CD45, CD99.
Molecular:
• EWS/FLI-1 gene fusion absent.

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Olfact neuroblastoma: Synaptophysin, Chromogranin A.

ONB: S-100, CAM5.2 (some tumour cells true +).

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Olfactory Neuroblastoma: grading.

________________________________________________________________________________________________________________________________________________________________________________

Wenig et al. WHO 2005.

Many pathologists prefer a two grade system –

• low (Hyams 1 and 2)
• high (Hyams 3 and 4).

Olfactory Neuroblastoma: high grade - atypia.

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High grade ONB: Synaptophysin; S-100 (few sustentacular cells).

Olfactory neuroblastoma.
________________________________________________________________________________________________________________________________________________________________________________

Outcome and prognostic indicators:

•Prognosis largely depends on clinical stage, in
particular local extent of tumour
tumour.
• Histological grade, proliferation index also
helpful.

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Olfactory Neuroblastoma: clinical

staging (WHO 2005).

Wenig et al. WHO 2005.

Malignant Sinonasal Tumours.

Malignant lymphoma.
Bone and soft tissue sarcomas.
These will be included in other lectures.

Roderick H.W. Simpson, BSc, MB ChB, MMed

(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

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Malignant Sinonasal Tumours.

Rare primary malignancies.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB,
ChB MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Sinonasal Germ Cell Tumours.

________________________________________________________________________________________________________________________________________________________________________________

• Immature teratoma.
• Teratoma with malignant transformation.
• Yolk sac tumour (endodermal sinus tumour)
tumour).
• Sinonasal teratocarcinosarcoma.
• Mature teratoma.
• Dermoid cyst.
All exceptionally
ti ll rare, and
d mostt occur iin children,
hild
except sinonasal teratocarcinosarcoma.

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Sinonasal Teratocarcinosarcoma.
________________________________________________________________________________________________________________________________________________________________________________

Histopathology:
• Multiple tissues derived from 2 or 3 germ layers.
• Variable degrees of maturity (includes resp. epithelium).
• Intermingled carcinoma, sarcoma, neuroblastoma-like
components.

Cardesa A, Luna MA. In WHO 2005: 77.

Sinonasal teratocarcinosarcoma: neuroblastoma-like areas

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Sinonasal teratocarcinosarcoma: differentiated and

undifferentiated areas.

Sinonasal teratocarcinosarcoma: sarcomatous area

– HE; Desmin

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Sinonasal Teratocarcinosarcoma.
________________________________________________________________________________________________________________________________________________________________________________

Outcome:
• Locally aggressive - invades bone, orbit, brain.
• Local,
Local distant metastases.
metastases
• 60% dead by 3 years.

Malignant Sinonasal Tumours.

Metastases.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB,
ChB MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

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Metastatic tumours in the sinonasal tract.

________________________________________________________________________________________________________________________________________________________________________________

• Metastatic involvement of sinonasal tract is

exceptionally unusual.
• Even then metastatic involvement of the
sinonasal tract only rarely initial presentation,....
•...most patients already have advanced disease.
• Outcome poor - ±65% die within a year; 90% by
5 years
years.

Barnes et al. WHO Fascicle 2005.

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Nose: metastatic renal cell carcinoma.

Malignant Sinonasal Tumours.

Summary.
• Commonest malignancy is squamous carcinoma.
• Non-keratinizing squamous ca (and probably others)
driven by high risk HPV.
• Non-salivary adenocarcinoma divided into intestinal and
non-intestinal types.
• Primary sinonasal melanoma is not uncommon.
• Olfactory neuroblastoma arises in upper nasal cavity.
• NUT midline carcinoma probably under-recognized.

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The importance of the sinonasal region.

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Benign tumours and

pseudotumorous non-neoplastic
lesions of the salivary glands.

Roderick H.W. Simpson, BSc, MB ChB, MMed

(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Disclosure statement.
Dr. Roderick Simpson has no financial interest to
disclose, other than employment by:
University of Calgary, and Alberta Health Services.

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Benign tumours and

pseudotumorous non-neoplastic
lesions of the salivary glands.

Benign tumours: introduction.

Roderick H.W. Simpson, BSc, MB ChB, MMed

(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Revised WHO classification 2005.

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Benign salivary epithelial tumours.

________________________________________________________________________________________________________________________________________________________________________________

Adenoma: Pleomorphic adenoma.

Myoepithelioma (myoepithelial adenoma).
Basal cell adenoma.
Warthin’s tumour.
Oncocytoma (oncocytic adenoma).
Canalicular adenoma.
Cystadenoma (papillary, mucinous).
Sebaceous neoplasms: Adenoma; Lymphadenoma.
Lymphadenoma
Ductal papilloma: Inverted ductal papilloma.
Intraductal papilloma.
Sialadenoma papilliferum.
Probable neoplasm: Sclerosing polycystic adenosis.

Benign tumours and

pseudotumorous non-neoplastic
lesions of the salivary glands.

Pleomorphic Adenoma (Benign Mixed Tumour)

and Related Benign Adenomas.

Roderick H.W. Simpson, BSc, MB ChB, MMed

(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

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Benign salivary adenomas can be considered as a single

biological entity, with a spectrum of different appearances
depending on which cell types are most numerous.

Zarbo et al. Arch Pathol 2000; 124: 401. Slide courtesy of Anil Prasad.

PLEOMORPHIC ADENOMA.
________________________________________________________________________________________________________________________________________________________________________________

• Defined as “a tumour of variable capsulation

characterized microscopically by architectural
rather than cellular pleomorphism. Epithelial
and modified myoepithelial elements intermingle
most commonly with tissue of mucoid, myxoid or
chondroid appearance.” (WHO 2005).

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PLEOMORPHIC ADENOMA.
________________________________________________________________________________________________________________________________________________________________________________

• The most common salivary tumour - ±60%.

• Slight female predominance.
• Wide age range; mean 46 years oldold.
• Site: Parotid 80%,
Submandibular 10%,
Minor (oral, sinonasal, etc) 10%.

Pleomorphic adenoma: usually well circumscribed.

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PA: epithelium, myoepithelium and stroma.

Pleo Adenoma: varied appearance of myoepithelial cells.

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PLEOMORPHIC ADENOMA.
________________________________________________________________________________________________________________________________________________________________________________

Immunohistochemistry and Molecular Findings.

Epithelium: low MW cytokeratin, e.g. CAM5.2.
Myoepithel: S-100+; specific markers variable.
variable

Gene fusion unique in salivary glands:

Breakpoints affecting chromosomes 8q12 (>50% of cases)
12q14-15 (10-15%)
IInvolved
l d genes:
PLAG1 and HMGA2.

PLEOMORPHIC ADENOMA.
________________________________________________________________________________________________________________________________________________________________________________

Areas of diagnostic difficulty.

• Adenoid cystic-like areas.
• “Metaplasias”
Metaplasias .
• Myoepithelial atypia.
• Irregular edge.
• Tumour in vessels.
• Recurrence.
ecu e ce.
• Malignant change.

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Pleomorphic adenoma: basaloid area (ΔΔ Adenoid

cystic ca) in an otherwise typical PA. but, cytology
bland and very low MIB1 index.

Pleomorphic Adenoma: fat cells, squamous area + keratin.

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Pleomorphic Adenoma: areas of mucus production

can resemble mucoepidermoid carcinoma.

Benign PA - atypical “ancient change” nuclei: HE, MIB1

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PA: usually well-circumscribed with a thin capsule, but

sometimes pseudopodia extend beyond.

Pleomorphic Adenoma: stroma-rich tumours often less

well-circumscribed.

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•Biological significance of intravascular tumour in

PA nott clear;
l
•Probably innocuous - related to artefactual
spillage: FNA or intra-operative trauma.

Benign PA (post FNA) – tumour in vascular spaces:

HE, F8RA

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PLEOMORPHIC ADENOMA: recurrence.

________________________________________________________________________________________________________________________________________________________________________________

*Surprisingly little published*.

One study found recurrence more likely if:
• Capsular macro
macro-rupture
rupture with cell spillage in the
operation field.
• Micro-ruptures: no significant role.
• Other factors (multifocality, satellite nodule) not
significant.
• Cytogenetic
y g data on recurrences indicate that clonal
abnormalities might favour grafting of tumour cells
after a spillage has occurred, thus promoting
recurrence.
Chrestian MA. ESP Congress Paris 2005.

Recurrent Pleomorph Adenoma: multiple nodules.

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PLEOMORPHIC ADENOMA: malignant change.

_________________________________________________________________________________________________________________________________________________________________________________________________________

• in 3-4% of all pleomorphic adenomas.

More likely:
• IIncidence
id off malignancy
li - correlation
l ti between
b t length
l th off
history of PA and development of a carcinoma. So –
risk is ±1.5% up to 5 years, but 9.5% after 15+ yrs.
Most frequent types:
• Salivary
y duct carcinoma.
• Myoepithelial carcinoma.

BENIGN MYOEPITHELIOMA.
_____________________________________________________________________________________________________________________________________________

• First described in 1943.

• Included in the 1991
WHO Classification.
• Definition: A neoplasm
composed totally, or almost
totally of myoepithelial cells.
• Probably
P b bl not a separate
biological entity, i.e. part of
the same spectrum as
Pleomorphic Adenoma.

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BENIGN MYOEPITHELIOMA.
_____________________________________________________________________________________________________________________________________________

• Not a biological entity

entity, but
but...

• Keep as a separate diagnostic category,

as it displays particular microscopic
features that pose specific practical
problems in identification and
differential diagnosis.

BENIGN MYOEPITHELIOMA.
_____________________________________________________________________________________________________________________________________________

Microscopic Features:
Growth Patterns: solid.
myxoid.
reticular.
mixed.
Cell Types: epithelioid.
spindle.
hyaline (plasmacytoid).
clear.
oncocytic.
mucinous (probable).

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BENIGN MYOEPITHELIOMA: growth patterns.

Solid. Reticular.

BENIGN MYOEPITHELIOMA: growth patterns.

Myxoid; mixed myxoid with solid.

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Benign Myoepithelioma: cell types: Epithelioid.

BENIGN MYOEPITHELIOMA: cell types:

Spindle; Epithelioid/spindle cells.

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Myoepithelioma: cell types - Hyaline (plasmacytoid).

BENIGN MYOEPITHELIOMA: cell types:

Clear –rare (1/40 in one series); oncocytic.

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Benign Myoepithelioma: cell types: mucinous.

Benign Myoepithelioma: cell types: mucinous.

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Myoepithelioma: IHC - CAM 5.2; S-100 in most cases.

Myoepith’oma: Expression of “specific myoepithelial markers” may

be inconsistent, e.g. SMMHC. Also, occasional CK5/6+ basal cells.

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BENIGN MYOEPITHELIOMA:
occasional findings: fat cells.

BENIGN MYOEPITHELIOMA:
scanty (<5-10% of the tumour) ducts acceptable.

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BENIGN MYOEPITHELIOMA.
_____________________________________________________________________________________________________________________________________________

Differential from Myoepithelial Carcinoma:

No absolute criteria (other than metastasis),
but some pointers to malignancy are:
• Multinodularity.
• Invasiveness.
• Nuclear atypia.
• Significantly increased mitotic activity.
• Necrosis
Necrosis.
• MIB1 index >10% (Nagao et al 1998).

BENIGN MYOEPITHELIOMA.
_____________________________________________________________________________________________________________________________________________

Treatment (Exeter series n=11).

Incidental Finding at Autopsy: 1.
Parotid (n
(n=4):
4): Superficial parotidectomy 4.
Minor (n=6): Complete excision - 4; partial - 2.
Outcome:
Alive, no tumour: 8.
Alive, with disease: 2 (multiple recurrences, incomplete excision).
Summary:
Overall, clinical outcome of benign myoepitheliomas is the
same as for pleomorphic adenomas of similar size and
location, and that the treatment should be the same.

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BASAL CELL ADENOMA.

________________________________________________________________________________________________________________________________________________________________________________

• The revised WHO classification recognizes 4

histopathological subtypes - solid, tubular,
trabecular and membranous.
• M=F; mainly major glands.
Probably represent part of the spectrum of
myoepithelioma and pleomorphic adenoma.
• O
Occasional membranous – mayy be separate
p
biological entity - dermal analogue tumour:...
...associated with multiple skin appendage
tumours (cylindroma, eccrine spiradenoma).

BASAL CELL ADENOMA.

________________________________________________________________________________________________________________________________________________________________________________

• Islands, trabeculae of basaloid cells

• Component cells – 2 forms:
1. small with scanty cytoplasm and a round, dark nucleus,
2 larger with amphophilic or eosinophilic cytoplasm and an
2.
ovoid paler nucleus.
• The 2 types are intermixed, but smaller cells often at
periphery of islands  palisading.
• Ductal differentiation +/-; EMA highlights it.
• Little p
pleomorphism;
p mitotic figures
g rare.
• Variable surrounding PAS+ basement membrane.
• Stroma varies in amount and cellularity; S-100+ spindle
cells may be numerous.

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Basal Cell Adenoma: tubular pattern.

BCA: tubulo-trabecular, membranous (cylindroma-like).

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BCAdenoma: tubulo-trabecular, stromal cells.

Basal Cell Adenoma: tubulo-trabecular,

immunohistochemistry.

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Basal Cell Adenoma: overlap with PA.

BASAL CELL ADENOMA: differential diagnosis.

________________________________________________________________________________________________________________________________________________________________________________

• Most important is AdCCa. Pointers to adenoma:

no invasion, no nuclear atypia, few mitoses,
whorled eddies of epithelial cells. S
S-100+
100+ spindle
stromal cells.
• Membranous BCA often closely resembles basal
cell adenocarcinoma (often lacks cytological
atypia, mitotic figures).
Adenomas may be poorly circumscribed, but
no true invasiveness.

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BCA: can resemble adenoid cyst ca, but low Ki-67.

Canalicular Adenoma: clinical aspects.

________________________________________________________________________________________________________________________________________________________________________________

• ±2% of all salivary tumours.

• Location almost exclusively intraoral:
Upper lip 89/113
89/113. (AFIP 1991).
1991)
• Most tumours present when small - <20 mm.
• Completely benign.
• Occasionally recurs due to multifocality.

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Canalicular Adenoma: histopathology.

________________________________________________________________________________________________________________________________________________________________________________

• Overall basaloid appearance

• Branching and interconnecting bi-layered strands of
darkly staining epithelial cells.
• Loose vascular stroma.
• No pleomorphism; rare mitoses.
• Sometimes multifocal, and thus mimic true invasiveness
of cribriform AdCCa.
L k off d
Lack destructiveness
t ti and d bl
blood
d vessels
l iin th
the
cribriform spaces indicate canalicular adenoma.
S100+++. (AdCCa mostly negative).
Myoepithelial cells not identified.

Canalic Adenoma: well-circumscribed; can be mutifocal.

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Canalicular Adenoma: architecture and cytology.

Canalicular Adenoma: immuno – EMA, S-100.

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Can Ad: multifocal, pseudo-invasion, but low Ki-67 index.

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Normal salivary gland microanatomy.

Striated duct adenoma. Closely packed tubules.

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Striated duct adenoma. p63, CK14 (very few basal-

myoepithelial cells).

Benign tumours and

pseudotumorous non-neoplastic
lesions of the salivary glands.

Warthin’s Tumour.

Roderick H.W. Simpson, BSc, MB ChB, MMed

(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

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Warthin’s Tumour (adenolymphoma).

2nd commonest salivary tumour.
Age: mean 62 years (range 29-88).
Sex: previously male++, now almost equal.
Aetiology: 8 × more frequent in heavy smokers.
Site: parotid (esp. tail), rarely in periparotid LNs.
Multicentric in 12%,, bilateral in 6%.
Origin, either: 1. salivary inclusions in parotid LNs.
or 2. epithelial tumour + lymphoid reaction
Prognosis: recurrence ±2%, malignancy <1%.

Warthin: well-circumscribed, often cystic, 2 components.

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Warthin Tumour: oncocytic epithelial component.

Warthin’s tumour:
metaplastic (infarcted) variant.
________________________________________________________________________________________________________________________________________________________________________________

Incidence: c.7% of all Warthin’s tumours.

Age:
g mean 65 yyrs (range
( g 43-83).
)
Sex: previously mostly males.
Size: 10-30 mm (60%), 40-60 mm (40%).
Clinical: mass lesion; pain in 25%.
prior radiation in 40% (Seifert).
previous FNA (di Palma series).
Diff diagn: mucoepidermoid carcinoma,
1º or 2º squamous carcinoma.
Seifert et al 1980, Eveson & Cawson 1989, di Palma et al 1999.

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Metaplastic Warthin’s tumour: infarction on right.

Metaplastic Warthin’s tumour: histopathology.

Di Palma S, Simpson RHW, Skálová A, Michal M. Histopathology 1999; 35: 432-438.

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Metaplastic Warthin: cystic area with papillary ingrowths.

Metaplastic Warthin: ghost architecture in a necrotic area.

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Met Warthin: reticulin and CK highlight ghost Warthin.

Metaplastic Warthin’s tumour: squamous metaplasia

with pseudo-invasion.

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Metaplastic Warthin: squamous + goblet cell metaplasia.

Benign tumours and

pseudotumorous non-neoplastic
lesions of the salivary glands.

Miscellaneous Benign Salivary Tumours.

Roderick H.W. Simpson, BSc, MB ChB, MMed

(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

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HI05-18726 Sebaceous lymphadenoma.

Sebaceous lymphadenoma: sebaceous foci.

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Seb lymphadenoma: keratin; reaction to escape of sebum.

Benign Oncocytoma: well-circumscribed.

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Benign Oncocytoma: bland cytology.

Benign Oncocytoma: anti-mitochondrial antibody; PASD.

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Benign Oncocytoma: ΔΔ 2º renal carcinoma.

Inverted ductal papilloma: occur mainly in lower lip.

Schneiderian-like growth and ciliated epithelium.

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Benign tumours and

pseudotumorous non-neoplastic
lesions of the salivary glands.

Sclerosing Polycystic Adenosis.

Roderick H.W. Simpson, BSc, MB ChB, MMed

(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Parotid: Sclerosing Polycystic Adenosis.

_____________________________________________________________________________________________________________________________________________

• First described by Smith et al, 1996.

• ?analogous to fibrocystic disease of the breast?
• More in females; mean age ±40 yrs (range 9-75).
• Most in parotid, (also submandibular, minor glands).
• Prognosis favourable; recurrences in up to 33%.
ΔΔ: sclerosing muco-epidermoid ca.

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Sclerosing Polycystic Adenosis.

________________________________________________________________________________________________________________________________________________________________________________

Main Microscopic Findings.

•Well-circumscribed.
•composed of dense fibrous tissue; salivary acini, ducts
(
(some cystically
ti ll dilated).
dil t d)
________________________________________________________________________________________________________________________________________________________________________________

•Acini - cells with cytoplasmic granules, often large, deeply

eosinophilic.
•Ducts lined by various cell types, - apocrine, vacuolated,
relatively normal duct lining cells.
•No goblet cells; no squamous differentiation.
•Focally florid intraduct proliferation.
•Some nuclear atypia, ?dysplasia, ?like LG DCIS breast.
•Stroma densely fibrous; also a patchy lymphocytic
infiltrate with germinal centre formation.

SPA: Well-circumscribed; sclerosis, cysts and acini.

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Sclerosing Polycystic Adenosis.

________________________________________________________________________________________________________________________________________________________________________________

Main Microscopic Findings.

•Well-circumscribed.
•composed of dense fibrous tissue; salivary acini, ducts
(
(some cystically
ti ll dilated).
dil t d)
________________________________________________________________________________________________________________________________________________________________________________

•Acini - cells with cytoplasmic granules, often large, deeply

eosinophilic.
•Ducts lined by various cell types, - apocrine, vacuolated,
relatively normal duct lining cells.
•No goblet cells; no squamous differentiation.
•Focally florid intraduct proliferation.
•Some nuclear atypia, ?dysplasia, ?like LG DCIS breast.
•Stroma densely fibrous; also a patchy lymphocytic
infiltrate with germinal centre formation.

Sclerosing Polycystic Adenosis: acinar granules.

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Sclerosing Polycystic Adenosis.

________________________________________________________________________________________________________________________________________________________________________________

Main Microscopic Findings.

•Well-circumscribed.
•composed of dense fibrous tissue; salivary acini, ducts
(
(some cystically
ti ll dilated).
dil t d)
________________________________________________________________________________________________________________________________________________________________________________

•Acini - cells with cytoplasmic granules, often large, deeply

eosinophilic.
•Ducts lined by various cell types, - apocrine, vacuolated,
relatively normal duct lining cells.
•No goblet cells; no squamous differentiation.
•Focally florid intraduct proliferation.
•Some nuclear atypia, ?dysplasia, ?like LG DCIS breast.
•Stroma densely fibrous; also a patchy lymphocytic
infiltrate with germinal centre formation.

Sclerosing Polycystic Adenosis.

________________________________________________________________________________________________________________________________________________________________________________

Main Microscopic Findings.

•Well-circumscribed.
•composed of dense fibrous tissue; salivary acini, ducts
(
(some cystically
ti ll dilated).
dil t d)
________________________________________________________________________________________________________________________________________________________________________________

•Acini - cells with cytoplasmic granules, often large, deeply

eosinophilic.
•Ducts lined by various cell types, - apocrine, vacuolated,
relatively normal duct lining cells.
•No goblet cells; no squamous differentiation.
•Focally florid intraduct proliferation.
•Some nuclear atypia, ?dysplasia, ?like LG DCIS breast.
•Stroma densely fibrous; also a patchy lymphocytic
infiltrate with germinal centre formation.

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SPA: Apocrine and foamy cells.

SPA: Epithelial proliferation.

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Scl polycyst adenosis: proliferation + atypia.

Gnepp DR et al. AJSP 2006; 30:154-164 .

SMMHC+ myoepithelial CK14 stains some

layer. proliferating epithelial cells.

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Sclerosing Polycystic Adenosis.

________________________________________________________________________________________________________________________________________________________________________________

Main Microscopic Findings.

•Well-circumscribed.
•composed of dense fibrous tissue; salivary acini, ducts
(
(some cystically
ti ll dilated).
dil t d)
________________________________________________________________________________________________________________________________________________________________________________

•Acini - cells with cytoplasmic granules, often large, deeply

eosinophilic.
•Ducts lined by various cell types, - apocrine, vacuolated,
relatively normal duct lining cells.
•No goblet cells; no squamous differentiation.
•Focally florid intraduct proliferation.
•Some nuclear atypia, ?dysplasia, ?like LG DCIS breast.
•Stroma densely fibrous; also a patchy lymphocytic
infiltrate with germinal centre formation.

SPA: sclerosis; patchy inflammation.

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SPA: Whorled sclerosed lesions – can mimic carcinoma.

SPA: Whorled sclerosed lesions;CK7, SMMHC.

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Sclerosing Polycystic Adenosis: is it neoplastic?

Sclerosing Polycystic Adenosis: clonality.

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Sclerosing Polycystic Adenosis.

________________________________________________________________________________________________________________________________________________________________________________

Important Points.
• No deaths or metastases reported,
• ...but recurrence in up to ⅓ of cases.
• Molecular evidence of clonality.
• Probably a benign neoplasm.
• One case of invasive carcinoma reported in SPA.
Unanswered Questions.
• Is there ever true dysplasia, carcinoma in situ?

Fat-containing tumours and tumour-like masses.

________________________________________________________________________________________________________________________________________________________________________________

1. Fat-containing epithelial-myoepithelial tumours.

Pleomorphic adenoma with lipo-metaplasia.
Myoepithelioma with lipo-metaplasia.
2. Mixed lipo-epithelial tumours.
Sialolipoma.
Oncocytic lipoadenoma.
3. True adipose tissue neoplasms.
Ordinar lipoma.
Ordinary lipoma
Lipoma variants, e.g. spindle cell.
Liposarcoma.
4. Fat-containing salivary gland lesions.
Diffuse lipomatosis.

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Lipomas occasionally arise in the parotid. Some

contain acinar inclusions (sialolipoma).

Oncocytic lipoadenoma.
________________________________________________________________________________________________________________________________________________________________________________

Rare; few cases reported.

Sex: M=F.
Age: adult.
Site: major glands (both parotid, submandib).
Outcome: completely benign (but only a few cases
reported).

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Oncocytic lipoadenoma: well-circumscribed.

Oncocytic lipoadenoma: no atypia; p63+ basal cells.

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Benign cystadenoma.
________________________________________________________________________________________________________________________________________________________________________________

Sex: Female > Males.

Age: 57yrs (mean).
Site: 45% parotid; rest minor glands (lips
(lips, buccal
mucosa).
Micro:well-circumscribed (usually).
variable number of cysts (20% unicystic).
lining: columnar cuboidal (mostly).
columnar, (mostly)
mucous, oncocytic, epidermoid,
apocrine (focal OR predominant).
No atypia; no solid foci; no lymphoid tissue.

Benign cystadenoma.

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Cystadenoma: lining - apocrine, oncocytic cells.

Non-salivary tumours that may present as

salivary masses.
________________________________________________________________________________________________________________________________________________________________________________

Soft tissue tumours:

Nodular fasciitis.
Inflammatory myofibroblastic tumour (pseudotumour).
Nerve sheath tumours.
Granular cell tumour.
Various sarcomas.
Skin tumours:
Various, especially adnexal.
Lymphomas: } covered elsewhere.
Metastases: }

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Benign tumours and

pseudotumorous non-neoplastic
lesions of the salivary glands.

Non-neoplastic Diseases.

Roderick H.W. Simpson, BSc, MB ChB, MMed

(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Diseases of the Salivary glands.

_____________________________________________________________________________________________________________________________________________

• Developmental Disorders.
• Obstructive disorders.
• Infections.
• Non-infective inflammatory processes.
• Sialadenosis.
• Oncocytosis.
• Other metaplasias.
• Non-neoplastic cysts.
• Neoplasms.

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Benign tumours and

pseudotumorous non-neoplastic
lesions of the salivary glands.

Infections.

Roderick H.W. Simpson, BSc, MB ChB, MMed

(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Salivary Glands: infections.

_____________________________________________________________________________________________________________________________________________

Bacteria: Acute suppurative sialadenitis + abscess.

Tuberculosis.
Syphilis.
Viruses: Mumps.
Cytomegalovirus (CMV).
Epstein-Barr Virus (EBV).
Coxsackievirus.
Influenza virus.
Human Immunodeficiency Virus (HIV).

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Salivary Glands: infections.

_____________________________________________________________________________________________________________________________________________

Bacteria: Acute suppurative sialadenitis + abscess.

Tuberculosis.
Syphilis.
Viruses: Mumps.
Cytomegalovirus (CMV).
Epstein-Barr Virus (EBV).
Coxsackievirus.
Influenza virus.
Human Immunodeficiency Virus (HIV).

SALIVARY GLANDS – HIV INFECTION.

_____________________________________________________________________________________________________________________________________________

Lesions seen in AIDS:

Neoplasms: Malignant lymphoma.

Kaposi’s sarcoma.

Non-neoplastic:
N p Cystic lymphoid
Cy y p hyperplasia.
yp p
LESA (Lympho-epithelial sialadenitis).
Opportunistic infections, e.g. CMV.

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Cystic lymphoid hyperplasia of AIDS.

Parotid, AIDS cystic lymphoid hyperplasia.

H&E CAM 5.2

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Parotid, AIDS cystic lymphoid hyperplasia, L-E lesion.

H&E CAM 5.2

Benign tumours and

pseudotumorous non-neoplastic
lesions of the salivary glands.

Other inflammatory disorders.

Roderick H.W. Simpson, BSc, MB ChB, MMed

(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

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Salivary Gland: miscellaneous

inflammatory disorders.
_____________________________________________________________________________________________________________________________________________

• Sarcoidosis.
• Xanthogranulomatous sialadenitis.
• Rosai-Dorfman Disease.
• Necrotising Sialometaplasia.
• Kimura’ss Disease
Kimura Disease.
• Chronic Sclerosing Sialadenitis.
• Amyloidosis.

Salivary Gland: miscellaneous

inflammatory disorders.
_____________________________________________________________________________________________________________________________________________

• Sarcoidosis.
• Xanthogranulomatous sialadenitis.
• Rosai-Dorfman Disease.
• Necrotising Sialometaplasia.
• Kimura’ss Disease
Kimura Disease.
• Chronic Sclerosing Sialadenitis.
• Amyloidosis.

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NECROTISING SIALOMETAPLASIA (Salivary

gland infarction).
_____________________________________________________________________________________________________________________________________________

• Coagulative necrosis of acini

(esp in the early stages).
• Preservation of lobular
architecture.
• Squamous metaplasia
of duct epithelium.
• Mucinous goblet cells present
present.
• Pseudoepitheliomatous hyperpl.
of surface.
• Superficial resemblance to
mucoep, squamous ca.

Necrotising Sialometaplasia: infarcted mucous glands.

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Necrotising Sialometaplasia: squamous metaplasia.

Necrotising Sialometaplasia.
Lobular architecture preserved; residual mucous glands.

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Necrotising Sialometaplasia.
Lobular architecture preserved; pseudoepith hyperplasia

Left Nec Sialometaplasia: lobular architecture preserved.

Rt. Mucoepidermoid ca: invading normal salivary gland.

Necrotizing Mucoepidermoid
Sialometaplasia carcinoma

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Chronic Sclerosing Sialadenitis (Küttner Tumour).

________________________________________________________________________________________________________________________________________________________________________________

(WHO 1991):
A tumour-like condition of the submandibular
gland characterized ..... histologically by:
• progressive periductal sclerosis,
• dense lymphocytic infiltration with germinal
centre formation,
• reduction of the secretory parenchyma,
parenchyma
• fibrosis.

Submandibular gland - chronic sclerosing sialadenitis.

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Chronic sclerosing sialadenitis: spares ducts.

Chronic Sclerosing Sialadenitis (Küttner Tumour).

________________________________________________________________________________________________________________________________________________________________________________

Aetiology – several theories:

• Sialoliths are found in 29-83% of cases. But, are
they cause or consequence?
• Secretory dysfunction.
________________________________________________________________________________________________________________________________________________________________________________

• Prominent IgG4 plasma cells in a minority:

a. disease localized to submandibular glands.
b. associated with systemic disease (IgG4-RSD), e.g.
sclerosing pancreatitis, retro-peritoneal fibrosis.

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Chronic atrophic sialadenitis – duct obstruction by:

Calculus. Foreign material.

How common in IgG4 related sialadenitis?

• 3/129 contained >50 IgG4 plasma cells/HPF.

• Even then, they were part of a non-specific inflammatory
infiltrate.

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IgG4-related chronic sclerosing sialadenitis

(Küttner tumour).

Abundant IgG4-positive plasma cell infiltration in IgG4

chronic sclerosing sialadenitis - HE, IgG4.

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IgG4-related Sclerosing Diseases.

________________________________________________________________________________________________________________________________________________________________________________

• Chronic Sclerosing Sialadenitis (Küttner).

• Autoimmune Pancreatitis.
Pancreatitis
• Retroperitoneal Fibrosis.
• Orbital Pseudotumour.
• Eosinophilic Angiocentric Fibrosis (EAF).
• Ri d l’ Th
Riedel’s Thyroiditis.
iditi
• Probably many others, e.g....
....Occasional cases of Chronic Interstitial Nephritis.
Good review - Deshpande et al, Modern Pathol 2012; 25: 1181-1192.

Benign tumours and

pseudotumorous non-neoplastic
lesions of the salivary glands.

Oncocytic lesions and other metaplasias.

Roderick H.W. Simpson, BSc, MB ChB, MMed

(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

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Oncocytic lesions of the Salivary Glands.

_____________________________________________________________________________________________________________________________________________

• Focal oncocytosis.
• Diffuse oncocytosis.
• Ductal oncocytosis.
• Multifocal nodular oncocytic hyperplasia.
_____________________________________________________________________________________________________________________________________________

• Warthin’s tumour.
• Oncocytic metaplasia and differentiation in
adenomas and carcinomas.
• Benign oncocytoma.
• Oncocytic carcinoma.

Oncocytic lesions of the Salivary Glands.

_____________________________________________________________________________________________________________________________________________

• Focal oncocytosis.
• Diffuse oncocytosis.
• Ductal oncocytosis.
• Multifocal nodular oncocytic hyperplasia.
_____________________________________________________________________________________________________________________________________________

• Warthin’s tumour.
• Oncocytic metaplasia and differentiation in
adenomas and carcinomas.
• Benign oncocytoma.
• Oncocytic carcinoma.

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Multifocal nodular oncocytic hyperplasia (MNOH).

________________________________________________________________________________________________________________________________________________________________________________

• Consists of nodules of varying size, composed of

oncocytic cells, often clear cytoplasm.
• False
F l iimpressioni off iinvasion,
i but
b t no stromal
t l
acinar response.
• Can be mistaken for a clear cell neoplasm with
satellite deposits – especially if one nodule larger
than others.
• Sometimes bilateral.

Parotid: multifocal nodular oncocytic hyperplasia.

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MNOH: nodules of different sizes, no reaction in gland.

Parotid – MNOH: granular cytoplasm; mild nuclear

variation.

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Parotid – MNOH: MAB1273; EM.

Parotid – MNOH: granules MAB1273+, PASD neg.

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Benign tumours and

pseudotumorous non-neoplastic
lesions of the salivary glands.

Cysts.

Roderick H.W. Simpson, BSc, MB ChB, MMed

(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Cysts of the Salivary Glands: types.

_____________________________________________________________________________________________________________________________________________

1. Dysgenetic.
Polycystic dysgenetic disease.
2 Acquired cysts lined by epithelium.
2. epithelium
Lymphoepithelial cystic lesions (7%).
Duct cysts (11%).
3. Pseudocysts without an epithelial lining.
Extravasation mucocoele (75%), ranula (5%).
4. Cystic change in neoplasms.
e.g. Warthin, mucoepidermoid carcinoma
Rarely - Pleomorphic adenomas.
Figures from Hamburg Registry, probably pre-HIV epidemic.

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SALIVARY DUCT CYSTS.

_____________________________________________________________________________________________________________________________________________

• Acquired, due to dilatation of a salivary duct.

• Can follow obstruction.
• 85% iin parotid,
tid - unilateral.
il t l
• Circumscribed, unilocular, 10-30 mm (max 100).
• Wall: dense fibrous tissue, 1-3 mm thick,
• Mild-moderate chronic inflammation, not dense
as in
i lymphoepithelial
l h ith li l cyst. t
• Epithelium: squamous, cuboidal/columnar cells,
with occasional goblet cells and oncocytes.

Salivary duct cyst.

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Salivary Gland
Lympho-Epithelial Cystic Lesions.
_____________________________________________________________________________________________________________________________________________

• Warthin’s tumour.
• Benign lympho-epithelial cyst.
• LESA with dilated ducts.
• Cystic lymphoid hyperplasia of AIDS.
• MALT lymphoma
y p with dilated ducts.
• Cystic mucoepidermoid carcinoma with
lymphoid response.
• Cystic metastasis in an intra-parotid LN.

Simple Salivary Lympho-epithelial Cyst.

_____________________________________________________________________________________________________________________________________________

Sex: M:F=1.6:1 Age: mean 46 yrs (range 18-79).

Site: Parotid, solitary or occasionally bilateral.
Size: mean 25mm, maximum 70 mm.
Origin: Expanded salivary inclusions in LNs,
or Branchial cleft remnants.
Nature: Sjögren - no association;
many reports pre-date HIV epidemic.
Histolog : Lining: sq
Histology: squamous,
amo s respirator
respiratory, occ
occ. m
mucous.
co s
Stroma: lymphoid with germinal centres.
no lympho-epithelial lesions.
Outcome: do not recur.

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Salivary simple lympho-epithelial cyst.

Benign tumours and

pseudotumorous non-neoplastic
lesions of the salivary glands.

Intercalated duct lesions.

Roderick H.W. Simpson, BSc, MB ChB, MMed

(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

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Intercalated duct lesions.

________________________________________________________________________________________________________________________________________________________________________________

Site: parotid 82%.

Size: small and nodular (average size 3.1 mm).
• 3 architectural patterns: hyperplasia (20),
adenoma (9), hybrid forms (5).
• 19/32 (59%) of IDLs seen in conjunction with
another salivary gland tumour.
basal cell adenoma (8 cases),
Epithelial-myoepithelial ca (3 cases).
Others 8 (e.g. Pleo adenoma) ?chance finding.
Possible precursor lesion.
But how many exist, but are not biopsied?

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Intercalated duct hyperplasia: relation to N parotid.

ICH: architecture; inconspicuous myoepithelial cells,

residual acini

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Mozambique Spitting Cobra (M’fesi).

Venom produced by
modified salivary gland.

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Salivary Carcinomas: those diagnosed

mainly by their morphological appearance.

Roderick H.W. Simpson, BSc, MB ChB, MMed

(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Disclosure statement.
Dr. Roderick Simpson has no financial interest to
disclose, other than employment by:
University of Calgary, and Alberta Health Services.

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Salivary Carcinomas: those diagnosed

mainly by their morphological appearance.

Introduction.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB
ChB, MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Revised WHO classification 2005.

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Malignant Epithelial Salivary Tumours (WHO 2005 + since).

________________________________________________________________________________________________________________________________________________________________________________

*Not included in 2005 Classification.

Acinic cell carcinoma. Mucinous adenocarcinoma.
Mam An Secretory ca (MASC).* Oncocytic carcinoma.
Mucoepidermoid ca. Salivary duct carcinoma.
Adenoid cystic ca.
ca Adenocarcinoma NOS.
Adenocarcinoma, NOS
Polymorphous low grade Myoepithelial carcinoma.
adenoca (PLGA). Carcinoma ex pleo adenoma.
Cribriform adenoca (CATS).* Carcinosarcoma.
Epithelial-myoepithelial ca. Metastasising pleo adenoma.
Clear cell carcinoma, NOS. Squamous carcinoma.
Basal cell adenocarcinoma. Small cell carcinoma.
Sebaceous carcinoma. Large cell carcinoma.
Sebaceous lymphadenoca. Lymphoepithelial carcinoma.
Cystadenocarcinoma. NUT rearrangement ca.*
Low grade crib cystadenoca. Des small round cell tumour.*
Sialoblastoma. Metastatic carcinoma.

Malignant Epithelial Salivary Tumours (WHO 2005 + since).

________________________________________________________________________________________________________________________________________________________________________________

To be covered in this talk.

Acinic cell carcinoma. Mucinous adenocarcinoma.
Mam An Secretory ca (MASC). Oncocytic carcinoma.
Mucoepidermoid ca. Salivary duct carcinoma.
Adenoid cystic ca.
ca Adenocarcinoma NOS.
Adenocarcinoma, NOS
Polymorphous low grade Myoepithelial carcinoma.
adenoca (PLGA). Carcinoma ex pleo adenoma.
Cribriform adenoca (CATS). Carcinosarcoma.
Epithelial-myoepithelial ca. Metastasising pleo adenoma.
Clear cell carcinoma, NOS. Squamous carcinoma.
Basal cell adenocarcinoma. Small cell carcinoma.
Sebaceous carcinoma. Large cell carcinoma.
Sebaceous lymphadenoca. Lymphoepithelial carcinoma.
Cystadenocarcinoma. NUT rearrangement carcinoma.
Low grade crib cystadenoca. Des small round cell tumour.
Sialoblastoma. Metastatic carcinoma.

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Salivary Carcinomas: those diagnosed

mainly by their morphological appearance.

Acinic cell carcinoma.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB
ChB, MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Acinic cell carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

Definition (WHO 2005):

Acinic cell carcinoma is a malignant
epithelial neoplasm of salivary glands in
which at least some of the neoplastic cells
demonstrate serous acinar cell
differentiation which is characterized by
differentiation,
cytoplasmic zymogen secretory granules.
Salivary ductal cells are also a component
of this neoplasm.

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Acinic cell carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

Definition (WHO 2005):

Acinic cell carcinoma is a malignant
epithelial neoplasm of salivary glands in
which at least some of the neoplastic cells
demonstrate serous acinar cell
differentiation which is characterized by
differentiation,
cytoplasmic zymogen secretory granules.
Salivary ductal cells are also a component
of this neoplasm.

Acinic cell carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

Sex: women slightly more than men are affected.

Age: even distribution from 2nd to 7th decades.
4% under 20 years.
Site: parotid 92%
submand 2%
sublingual <1%
intraoral 1%
others/unknown 5%.

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ACINIC CELL CARCINOMA:

Spectrum of histological appearance.
________________________________________________________________________________________________________________________________________________________________________________

Growth Patterns. Cell types.

yp
solid acinar (serous; blue dot)
microcystic intercalated ductal
follicular microvesicular
papillary-cystic
papillary cystic hobnail
lymphoid rich, clear
(microfollicular)

Ac cell ca: growth patterns. Solid, microfollicular.

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Acinic cell ca: growth patterns. Follicular, papillary-cystic.

AcCCa: serous cells with granular cytoplasm (“blue

dot”); also box-like intercalated duct cells.

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PASD+ zymogen granules in normal acini & acinic cell ca.

Acinic cell carcinoma: cell types. Microvesicular, hobnail.

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Acinic cell carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

Clear cell change:

• Surprisingly uncommon
- 6% in one series
series.
• Even then, never pure.
• Scattered cells with PASD+
granules.
• The behaviour of the clear
cell-rich variant is the same
as other types of acinic cell
carcinoma.

Acinic cell ca: usually regular nuclei; few mitoses.

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Acinic cell carcinoma – immunohistochemistry for

diagnosis.
______________________________________________________________________________________________________________

Cytokeratin 7 +++
CAM5.2 +
AE1/AE3 ++
EMA (membr) +++
CEA (membr) +
Amylase Often +
DOG1 ++
Mammaglobin v. occ +
S-100 protein Sometimes +.
Vimentin, SMA, } All 0.
SMMHC, Calponin }

Acinic cell carcinoma – immunohistochemistry for

diagnosis.
______________________________________________________________________________________________________________

Cytokeratin 7 +++
CAM5.2 +
AE1/AE3 ++
EMA (membr) +++
CEA (membr) +
Amylase Often +
DOG1 ++
Mammaglobin v. occ +
S-100 protein Sometimes +.
Vimentin, SMA, } All 0.
SMMHC, Calponin }

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Acinic cell carcinoma: DOG-1.

Acinic cell carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

Outcome:
Recurrences: 35%
Metastases/death: 16%.
16%
Poor clinical prognostic factors:
• Multiple recurrences and neck LN metastasis.
• Distant metastasis.
• L
Large size
i ± involvement
i l t off deep
d lobe
l b off parotid.
tid
• Incomplete resection very important.

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Acinic cell carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

Histological prognostic indicators:

Attempts at histological grading have been
unreliable.
unreliable
Features often associated with more aggressive
tumours:
more mitoses, focal necrosis, neural invasion,
pleomorphism, infiltration, stromal hyalinization.
Transformation to a high grade malignancy:
Rare; characterized by cytological pleomorphism,
mitoses+++, very high Ki-67.

Alena paper title page.

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Acinic cell carcinoma: MIB1 index – 2%, 10%.

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Acinic cell carcinoma: high grade tranformation.

Acinic cell carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

Differential diagnosis:
Well differentiated serous Normal gland.
Oncocytoma.
Oncocytoma
MASC.
Clear cell Other clear cell tumours.
Papillary-cystic LG Salivary duct ca.
“Cystadenocarcinoma”.
Metastatic thyroid ca.
Any papillary cystic lesion of the parotid gland is
an acinic cell carcinoma, until proven otherwise.

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Acinic cell carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

Differential diagnosis:
Well differentiated serous Normal gland.
Oncocytoma.
Oncocytoma
MASC.
Clear cell Other clear cell tumours.
Papillary-cystic LG Salivary duct ca.
“Cystadenocarcinoma”.
Metastatic thyroid ca.
Any papillary cystic lesion of the parotid gland is
an acinic cell carcinoma, until proven otherwise.

Diff diag: Acinic cell ca: granule-rich; granule-poor.

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Acinic cell carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

Differential diagnosis from MASC, if no access to

FISH.
• Sex and Age of patient.
• Site.

• Morphology.
• Immunohistochemistry.

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Acinic cell carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

Differential diagnosis from MASC, if no access to

FISH.
• Sex and Age of patient – not helpful.
• Site - 11/14 extra-parotid “AcCCs” had ETV6
translocation, MASC.
• Morphology.
• Immunohistochemistry.
I hi t h i t

Bishop JA et al. Am J Surg Pathol 2013; 37: 1053-57.

Acinic cell carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

Differential diagnosis from MASC, if no access to

FISH.
• Sex and Age of patient.
• Site.

• Morphology – not helpful if granule-poor.

• Immunohistochemistry.

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Mammaglobin immunoreactivity in primary salivary gland

neoplasms.
________________________________________________________________________________________________________________________________________________________________________________

Diagnosis Mammaglobin+ cases/total (%) Comment

MASC 15/15 (100) All strong and diffuse
LGCCC/SDC 1/1 (100) Diffuse and strong
Sal duct ca 2/3 (67) Both strong and diffuse
PLGA 2/3 (67) Both strong, 1 diffuse;
1 focal
Mucoep ca 2/18 (11) Both strong and focal
Pleomorph ad 2/33 (6) 1 diffuse and strong,
1 focal and weak
Acinic cell ca 0/10 (0)
AdCCa 0/44 (0)
Adenoca, NOS 0/4 (0)
Total 24/131 (18)
Bishop JA et al. Human Pathol 2013; 44: 1982-88.

Mammaglobin immunoreactivity in primary salivary gland

neoplasms.
________________________________________________________________________________________________________________________________________________________________________________

Diagnosis Mammaglobin+ cases/total (%) Comment

MASC 15/15 (100) All strong and diffuse
LGCCC/SDC 1/1 (100) Diffuse and strong
Sal duct ca 2/3 (67) Both strong and diffuse
PLGA 2/3 (67) Both strong, 1 diffuse;
1 focal
Mucoep ca 2/18 (11) Both strong and focal
Pleomorph ad 2/33 (6) 1 diffuse and strong,
1 focal and weak
Acinic cell ca 0/10 (0)
AdCCa 0/44 (0)
Adenoca, NOS 0/4 (0)
Total 24/131 (18)
Bishop JA et al. Human Pathol 2013; 44: 1982-88.

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My view: Granule-poor Acinic Cell Carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

If you have access to FISH:

t(12;15) (p13;q25) ETV6-NTRK3 translocation: MASC.
No transloc’n;; FISHbreak in ETV6 g
gene: p
prob MASC.
If you don’t have access to FISH:
Cytoplasmic zymogen granules (blue dot): AcCCa.
BUT ?granule-poor AcCCa:
IHC: S-100, vimentin, mammaglobin: prob MASC.
DOG-1 +, mammaglobin neg: prob AcCCa.
More than half of “granule-poor AcCCas” turn out
to be MASCs.
Especially submandibular, minor glands.

Salivary Carcinomas: those diagnosed

mainly by their morphological appearance.

Polymorphous Low Grade Adenocarcinoma

(PLGA).

Roderick H.W. Simpson, BSc, MB ChB, MMed

(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

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Polymorphous low grade adenocarcinoma (PLGA).

________________________________________________________________________________________________________________________________________________________________________________

Definition: “a malignant epithelial tumour

characterized by cytological uniformity,
morphologic diversity,
diversity an infiltrative growth
pattern and low metastatic potential”.

Polymorphous low grade adenocarcinoma (PLGA).

________________________________________________________________________________________________________________________________________________________________________________

Definition: “a malignant epithelial tumour

characterized by cytological uniformity,
morphologic diversity,
diversity an infiltrative growth
pattern and low metastatic potential”.

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POLYMORPHOUS LOW GRADE

ADENOCARCINOMA.
AFIP Series - clinical findings:
__________________________________________________
Sex - M:F = 55:109.
Age - 57.6 years (range 23-94).
Site -palate: 119.
lip 22.
buccal mucosa 23.
Outcome -recur 15 (9.1%).
DoD 2 (1.2%).
Castle et al. Cancer 1999; 86: 207-219.

PLGA: Tumour is invasive.

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PLGA: Growth patterns: solid; cribriform.

PLGA: Growth patterns: tubulo-papillary; streaming.

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PLGAdenoca: different growth patterns in the same case.

PLGA: Regular nuclei.

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Polymorphous low grade adenocarcinoma:

perineural infiltration – HE, S-100.

POLYMORPHOUS LOW GRADE

ADENOCARCINOMA.
AFIP Series – immunohistochemistry (n=39):
__________________________________________________
Cytokeratin (AE1/AE3) 39.
CEA 21.
SMA 5.
S-100 Protein 38.
GFAP 6.
Bcl-2 protein 39.
p53 37.
Castle et al. Cancer 1999; 86: 207-219.

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Polymorphous low grade adenocarcinoma: IHC.

PLGA:
MIB1 index.
Mean 2.4%
Range 0.2
0 2 to 66.4%.
4%

Adenoid cystic
carcinoma.
Mean: 24.6%.
Range: 11.3 to 57%.

Skálová A, Simpson RHW,

Lehtonen H, Leivo I. 1997.

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Salivary PLGA.
Follow up, 10+ years. - 40 patients.

Local recurrence 13 (32.5%).

(32 5%)
Uncontrolled local disease 6 (15%).
Cervical LN metastases 6 (15%).
Distant metastases 3 (7.5%).
Died of/with tumour 5 (12 5%)
(12.5%).

Evans HL, Luna MA. Am J Surg Pathol 2000; 24: 1319-1328.

PLGA.
Modern Pathol 2002;
15 (Suppl 1): 223A.

Recurrences 
Incomplete excision
- 8/10.
Complete excision:
- 1/9.

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Salivary PLGA - High grade transformation.

________________________________________________________________________________________________________________________________________________________________________________

Diagnosis of high grade change.

Conventional morphological criteria - e.g.
severe nuclear atypia
yp + p prominent nucleoli,,
increased mitotic activity, areas of necrosis.

Polymorphous low grade adenocarcinoma (PLGA).

________________________________________________________________________________________________________________________________________________________________________________

Differential Diagnosis:
Pleomorphic Adenoma – esp superficial biopsy.
Adenoid Cystic Carcinoma – (nuclear)
morphology, IHC (S-100 weak, MIB1 >10%).
CATS – PTC-like nuclei, glomeruloid structures.
Neck LN metastases.

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Adenoid cystic ca: darker, angulated nuclei; more mitoses.

CATS: glomeruloid structures, PTC-like nuclei.

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Salivary Carcinomas: those diagnosed

mainly by their morphological appearance.

Epithelial-Myoepithelial Carcinoma.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB
ChB, MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Epithelial-Myoepithelial Carcinoma
________________________________________________________________________________________________________________________________________________________________________________

Incidence:0.5 – 1% of all salivary tumours.

Sex: 60% of patients are female.
Age: Mean 60 years (range 8-103)
Site: Parotid 83%, Submand 11%, minor 6%.
Arise de novo or occasionally in pleomorphic adenoma.
Analogous tumours described in the larynx,
bronchus, breast, lacrimal glands, biliary tract.

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Epithelial-Myoepithelial Carcinoma
________________________________________________________________________________________________________________________________________________________________________________

Microscopic:
Circumscribed or invasive.
Biphasic pattern throughout tumour (and in culture)
Small ductal lumina surrounded by:
1. inner layer of epithelial cells.
2. mantle of myoepithelial cells.
3
3. rim
i off b
basementt membrane
b material.
t i l
Usually little nuclear pleomorphism.
Previously considered mainly as a clear celled
tumour.

Epithelial-Myoepithelial Carcinoma:
composed of two cell types.

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Epithelial-Myoepithelial Carcinoma
________________________________________________________________________________________________________________________________________________________________________________

Immunohistochemistry:
All components:
broad spectrum cytokeratins (e.g. AE1/AE3).
Inner cells:
low-MW cytokeratins – CAM, CK7, CK19.
EMA
Outer cells:
Myoep markers: αSMA, SMMHC, p63, calponin.
Not specific: S-100 protein, CK14.
Basement membrane: collagen IV.

EMCa: IHC shows 2 separate layers.

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EMCa: often composed of clear cells.

Epithelial-Myoepithelial Carcinoma
________________________________________________________________________________________________________________________________________________________________________________

Microscopic variation:
Biphasic pattern throughout tumour, but:
Different components may predominate,
thus different histological patterns.

no clear cells

Am J Surg Pathol 2007; 31: 44-57.

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Epithelial-myoepithelial carcinoma:
papillary architecture.

Epithelial-myoepithelial carcinoma:
no clear cells (HE, SMMHC).

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EMCa: non-clear cells, including plasmacytoid, spindle-

shaped myoepithelial cells.

Epithelial-myoepithelial carcinoma:
apocrine epithelial cells (HE, SMMHC).

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Parotid EMCa, oncocytic inner cells.

Epithelial-myoepithelial ca: sebaceous differentiation.

SMMHC

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E-M Carcinoma – prominent stroma pattern.

Am J Surg Pathol
2007; 31: 44-57.
_______________________________________________________________________________________________________________________________________________________________________________

Clinical Outcome.
Recurrences: 36.3%.
(median disease-free survival 11.34 years).
Died of disease: 6.7%.
Most important predictors of recurrence.
• Margin status.
• Angiolymphatic invasion.
• Tumour necrosis.
• Myoepithelial anaplasia.

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• From: "Avrille Simpson"

<alethea@simpson1.eclipse.co.uk>
• To: "Rod Simpson"
<roderick.simpson@doctors.org.uk>; "Avrille
Simpson" <alethea@simpson1.eclipse.co.uk>
• Subject: download
• Date: 07 October
b 2010 21:03

E-MCa: HG transformation - epithelial. HE, Calponin.

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E-MCa: high grade transformation - SMMHC; MIB1.

Epithelial-Myoepithelial Carcinoma
________________________________________________________________________________________________________________________________________________________________________________

Differential Diagnosis:
Pleomorphic
p adenoma:
Can have EMCa-like areas, but only focally; also,
no true invasion.

Other tumours composed of clear cells:

Many, including metastatic renal cell carcinoma;
IHC is useful.

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CLASSIFICATION of CLEAR CELL TUMOURS

of the SALIVARY GLANDS.
Benign.
Pleo adenoma/myoepithelioma, seb adenoma, oncocytoma/MNOH.
Malignant, primary.
a). Carcinomas not usually characterized by clear cells, but with rare
clear cell variants.
e.g. mucoepidermoid and acinic cell carcinomas.
Clear cell myoepithelial carcinoma (malignant myoepithelioma).
b). Carcinomas usually characterized by clear cells.
i Dimorphic
i. Di hi epithelial-myoepithelial
ith li l ith li l carcinoma.
i
ii. Monomorphic Hyalinizing clear cell carcinoma (NOS).
iii. Other Sebaceous carcinoma.
Malignant, metastatic.
Carcinomas, especially kidney. Also melanoma.

EMCa - 2 cell types. HCCCa – monomorphic:

EMCa HCCCa.

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Salivary lesions composed of clear Cells:

Metastatic renal cell carcinoma.

Epi-myoepit Ca and intercalated duct hyperplasia.

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Salivary Carcinomas: those diagnosed

mainly by their morphological appearance.

Salivary Duct Carcinoma.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB
ChB, MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

SALIVARY DUCT CARCINOMA

_____________________________________________________________________________________________________________________________________________

First described in 1968 (Kleinsasser).

Definition (WHO 2005):

An aggressive adenocarcinoma which
resembles high-grade breast ductal
carcinoma.
carcinoma

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SALIVARY DUCT CARCINOMA

_____________________________________________________________________________________________________________________________________________

Clinical Findings:
Incidence: Not rare; 4-6% salivaryy carcinomas
(study in Finland 2013).
Sex: M:F = 4:1
Age: 65 yrs (mean) - range 27-old.
Sit
Site: 90% parotid,
tid 10% submandibular,
b dib l rarely
l minor.
i

Origin: de novo or pleomorph adenoma (or PLGA,

LGSDC).

Outcome: most (75%) die of disease.

SDCa can arise in a Pleomorphic Adenoma.

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What proportion of SDCs arise in a PA?

What proportion of SDCs arise in a PA?

No of cases of SDC: 44
Obvious PA: 8
Hyalinized nodule: 10
Molecular evidence of PA in “de novo” SDC: 5*
 evidence of PA in SDC: 23/44 (52%) ?55-60%.
________________________________________________________________________________________________________________________________________________________________________________

Molecular evidence of PA.

PLAG1 or HMGA2 rearrangement in
i 50-70%
50 70% off PAs.*
PA *
________________________________________________________________________________________________________________________________________________________________________________

Low grade CCC/SDC in high grade SDCs: 6/44

________________________________________________________________________________________________________________________________________________________________________________

CONCLUSION: Most SDCs arise in a PA.

Bahrami et al. Histopathology 2013; 63: 250-262.

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SALIVARY DUCT CARCINOMA

Microscopic Findings:
Resembles ductal carcinoma
i off the breast.
________________________________________________________________________________________________________________________________________________________________________________

DCIS - comedo, cribriform, papillary.

Microcalcification.
Invasive including perineural.
perineural
Nuclear pleomorphism.
Mitotic figures ++.

Salivary duct carcinoma: in situ lesion.

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SDC: as in breast, cancerization of acini; DCIS.

SDC invasive trabeculae and tubules.

Trabec1 , tubules2

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Invasive SDC: cribriform; poorly differentiated.

SDCa: perineural and lymphatic invasion.

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SDCa: intermediate, high grade nuclei.

SALIVARY DUCT CARCINOMA

Proposed Morphological Variants.
________________________________________________________________________________________________________________________________________________________________________________

Papillary (mentioned by Brandwein 1990).

Sarcomatoid (Henley et al 2000).
Mucinous (Simpson et al, 2003).
Micropapillary (Michal 2000, Nagao 2004).
Oncocytic (Simpson 2005).
Pure in situ (Anderson 1992).
Low grade – [Low grade cribriform
cystadenocarcinoma] (WHO 2005).

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Sarcomatoid Salivary Duct Carcinoma.

Salivary duct carcinoma, micropapillary growth pattern:

HE cell balls in spaces. EMA (“inside-out pattern”).

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Mucinous SDC: usual type SDC + colloid ca.

Oncocytic Salivary Duct Carcinoma.

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Salivary Duct Carcinoma; pure in situ lesion.

Salivary Duct carcinoma; pure in situ lesion.

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Salivary Duct carcinoma in situ: high grade nuclei.

SDCIS: myoepithelial cell rim.

CK14 p63

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SALIVARY DUCT CARCINOMA.

________________________________________________________________________________________________________________________________________________________________________________

DIFFERENTIAL DIAGNOSIS:

• Oncocytic carcinoma.
• Mucoepidermoid carcinoma, high grade.
• Myoepithelial carcinoma (Malignant
myoepithelioma).
y p )
• Metastatic carcinoma.

Myoepithelial ca: necrotic centres resemble DCIS lesions

of SDC.

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Myoepithelial ca: different from SDC.

Salivary Carcinomas: those diagnosed

mainly by their morphological appearance.

Salivary Duct Carcinoma:

immunohistochemical and molecular aspects.

R d i kH
Roderick H.W.
W SiSimpson, BS
BSc, MB ChB
ChB, MM
MMedd
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

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Salivary Duct Carcinoma: immunohistochemistry.

________________________________________________________________________________________________________________________________________________________________________________

USUALLY POSITIVE:
Cytokeratins:
Broad spectrum, low MW, CK7+,
CK7 , CK20-.
CK20 .
Other epithelial markers:
EMA, CEA, GCDFP15.
Hormone and other markers:
Androgen Receptors, occasionally PSA, MIB1 high.
____________________________________________________________________________________________________________________________________________________________

USUALLY NEGATIVE:
Myoepithelial markers (e.g. ASMA, SMMHC, p63,
CK14)*, S-100, Oestrogen and Progesterone Receptors.
*Except non-neoplastic cells in DCIS lesions.

Salivary Duct Carcinoma: immunohistochemistry.

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Hellquist HB, Karlsson MG, Nilsson C. J Pathol

1994; 172: 35-44.

SDCa: Androgen Receptors in 83% of cases.

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Androgen Receptor staining is largely restricted to

salivary duct carcinoma.

Moriki T. et al. Cancer Cytopathol 2001; 93: 344-350.

Immunohistochemistry for HER-2/neu protein:

Hercep Test (Dako): +++ 6/10, ++ 4/10.
Neomarker: +++ 6/11, ++ 2/11, + 3/11.
Novocastra: +++ 8/11, ++ 2/11, + 1/11.
FISH:
Amplified: 4/10; non-amplified: 6/10.

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Perou et al. Nature 2000; 406: 747-752.

Hu et al. BMC Genomics 2006;7:96

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SDC: proposed molecular classification.

Salivary duct carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

• AR (+? ERβ) in SDC perhaps analogous to ERα

in breast. THUS:
P ibl three
Possibly th phenotypes,
h t as iin b
breastt carcinoma:
i
• Luminal cell (67%):
Express CK 19, AR, ?ERβ.
• HER2 positive (16%):
E
Express CK19
CK19, HER2 protein i + gene amplification
lifi i .
• Basal cell-like (5%):
Express CK5/6, EGFR.
Di Palma S, Simpson RHW, Reis-Filho J et al. Histopathology 2012; 61: 629-643.

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Salivary Duct carcinoma: HER2+ type.

IHC 3+. SISH gene amplified.

SDC luminal: AR strong + (5+3), weaker+ (3+2).

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SDCa; basal phenotype: invasive, high grade.

Salivary Duct carcinoma; possible basal phenotype:

CK7 CK5/6

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Salivary duct carcinoma: outcome.

____________________________________________________________________________________________________________________________________________________________

• One of the most aggressive salivary cancers.

• 65+% die of disease, usually within 4 years.
• Widespread distant metastases to many organs
organs,
including lungs, bone, liver, brain, skin.

Salivary duct carcinoma: prognostic factors.

________________________________________________________________________________________________________________________________________________________________________________

Several factors suggested, but none reliable.

• Tumour size - ?lesions with diameter <30 mm.
better outcome, but fatal lesions <20 mm.
reported.
• Distant metastasis.
No correlation with p53 protein, DNA aneuploidy,
proliferative activity.

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Salivary Duct Carcinoma and hormone receptors.

Clinical outcome depending on hormone receptor
and HER2 status.

Williams et al. AJSP 2007; 31: 1645-1652.

Salivary duct carcinoma: treatment.

________________________________________________________________________________________________________________________________________________________________________________

At present, the best hope for long term survival is

complete surgical excision with radical neck
dissection followed by radiotherapy to the
dissection,
tumour bed and chemotherapy.
Possible future avenues for investigation include:
• Herceptin.
• Anti
Anti-androgen
androgen therapy.
therapy
• Anti-EGFR.

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Salivary Duct Ca: patient with a partial response to

anti-androgen therapy.
April 2010 – April 2013

Very few published studies, but one from Milan showed

some promise (Locati et al. Ann Oncol 2006; 16: iii 38.).

Salivary Duct Ca: HER2+ case successfully treated.

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Salivary Carcinomas: those diagnosed

mainly by their morphological appearance.

Low Grade Cribriform Cystadenocarcinoma;

(Low grade salivary duct carcinoma).

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB
ChB, MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Low grade salivary duct carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

Synonym (WHO 2005):

Low Grade Cribriform Cystadenocarcinoma.
Figures from the three studies:
Number:….. 29.
Sex:……….. M:F=13:15.
Age:………. 64 (range 32-93).
Site:
Site:………. Par 28
28, SMand 11.
Outcome:… 22 NED (follow up to 12 years).
1 neck LN mets (high grade change).
6 lost to follow up.

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LGSDC: Solid and cystic growth pattern.

LGSDC: Cytologically bland cells, regular nuclei.

Very few mitotic figures.

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LGSDC: proliferating epithelium – papillae, cribriform.

Fine yellow-brown pigment, resembling lipofuschin.

LGSDC: in situ pattern predominates.

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LGSDC: Immunohistochemistry.

Usual type (high grade) SDC: typical IHC pattern.

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LGSDC: Markers typically + in high grade SDC.

Low grade cribriform

cystadenocarcinoma
(LG salivary duct carcinoma): what is its
relationship with purely in situ salivary
duct carcinoma?
________________________________________________________________________________________________________________________________________________________________________________

1. A spectrum of cytological grades

within a single
g entity
y of
salivary DCIS, OR......
2. Two separate entities.

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Low grade salivary duct carcinoma: 3rd series.

Slide courtesy of Drs. Weinreb and Perez-Ordonez.

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Slide courtesy of Drs. Weinreb and Perez-Ordonez.

What proportion of SDCs arise in a PA?

No of cases of SDC: 44
Obvious PA: 8
Hyalinized nodule: 10
Molecular evidence of PA in “de novo” SDC: 5*
 evidence of PA in SDC: 23/44 (52%) ?55-60%.
________________________________________________________________________________________________________________________________________________________________________________

Molecular evidence of PA.

PLAG1 or HMGA2 rearrangement in
i 50-70%
50 70% off PAs.*
PA *
________________________________________________________________________________________________________________________________________________________________________________

Low grade CCC/SDC in high grade SDCs: 6/44

________________________________________________________________________________________________________________________________________________________________________________

CONCLUSION: Most SDCs arise in a PA.

Bahrami et al. Histopathology 2013; 63: 250-262.

395
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What proportion of SDCs arise in a PA?

No of cases of SDC: 44
Obvious PA: 8
Hyalinized nodule: 10
Molecular evidence of PA in “de novo” SDC: 5*
 evidence of PA in SDC: 23/44 (52%) ?55-60%.
________________________________________________________________________________________________________________________________________________________________________________

Molecular evidence of PA.

PLAG1 or HMGA2 rearrangement in
i 50-70%
50 70% off PAs.*
PA *
________________________________________________________________________________________________________________________________________________________________________________

Low grade CCC/SDC in high grade SDCs: 6/44

________________________________________________________________________________________________________________________________________________________________________________

CONCLUSION: Most SDCs arise in a PA.

Bahrami et al. Histopathology 2013; 63: 250-262.

Low grade cribriform

cystadenocarcinoma
(LG salivary duct carcinoma): what is its
relationship with purely in situ salivary
duct carcinoma?
________________________________________________________________________________________________________________________________________________________________________________

1. A spectrum of cytological grades

within a single
g entity
y of
salivary DCIS, OR......
2. Two separate entities.
2014 favour Option 1.

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Salivary Carcinomas: those diagnosed

mainly by their morphological appearance.

Oncocytic Carcinoma.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB
ChB, MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Salivary Carcinoma: oncocytic cell with ↑mitochondria.

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Oncocytic Carcinoma: important points.

________________________________________________________________________________________________________________________________________________________________________________

Synonyms: malignant oncocytoma, oncocytic adenoca.

Definition: “A very rare tumour composed of malignant
oncocytic cells”.
y
Criteria: 1. Tumour cells identified as oncocytes.
2. Local/nerve/vascular invasion or metastasis.
My 3. Not an oncocytic variant of another ca.
____________________________________________________________________________________________________________________________________________________________

Oncocytic carcinoma in the AFIP Fascicle 17.

Sex: “male predominance in reported cases”.
Age: about 63 (range 2929-91).
91).
Site: most in parotid, few in submandibul, minor glands.
Clinical: pain/paralysis in 1/3 patients, rapid growth;
nodes±.
Progn: “evidence for considering it high-grade neoplasm”.

Oncocytic Carcinoma: important points.

________________________________________________________________________________________________________________________________________________________________________________

Synonyms: malignant oncocytoma, oncocytic adenoca.

Definition: “A very rare tumour composed of malignant
oncocytic cells”.
y
Criteria: 1. Tumour cells identified as oncocytes.
2. Local/nerve/vascular invasion or metastasis.
My 3. Not an oncocytic variant of another ca.
____________________________________________________________________________________________________________________________________________________________

Oncocytic carcinoma in the AFIP Fascicle 17.

Sex: “male predominance in reported cases”.
Age: about 63 (range 2929-91).
91).
Site: most in parotid, few in submandibul, minor glands.
Clinical: pain/paralysis in ⅓ of patients, rapid growth;
nodes±.
Progn: “evidence for considering it high-grade neoplasm”.
However, is it a genuine single entity?

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Oncocytic Salivary Duct Carcinoma.

Oncocytic Salivary Duct Carcinoma: mitochondria ++.

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Oncocytic salivary duct carcinoma: immuno.

Acinic cell carcinoma: cell types. Rare oncocytic variant.

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Salivary Oncocytic Carcinoma.

________________________________________________________________________________________________________________________________________________________________________________

Most salivary carcinomas include uncommon

variants composed largely of cells with plentiful
mitochondria (oncocytes).
(oncocytes)
My personal view is that I doubt the existence of
“oncocytic carcinoma” as a separate tumour entity.

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Salivary Carcinomas: those diagnosed

mainly by their morphological appearance.

Hybrid carcinomas.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB
ChB, MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

Hybrid Tumours.
____________________________________________________________________________________________________________________________________________________________

Definition:
• Single lesion arising at a single site.
• Composed of two or more entities.
• Each entity conforms to a defined tumour type.
Incidence:
<0.1% of neoplasms in Hamburg salivary registry.
Various combinations: e.g. EMCa and AdCCa.
Possible precursor lesions:
Intercalated duct lesions (adenomas and
hyperplasia) may have a role in some cases.

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Hybrid ca: tongue tumour. Biopsy. EMCa area.

Hybrid ca: tongue tumour. Resection. AdCCa area.

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IDLs: possible explanations for hybrid tumours.

Salivary Carcinomas: those diagnosed

mainly by their morphological appearance.

Metastases.

Roderick H
H.W.
W Simpson
Simpson, BSc
BSc, MB ChB
ChB, MMed
(Anat Path), FRCPath.
University of Calgary, Alberta, Canada.

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SALIVARY TUMOURS IN EXETER,

UK 1978-1998:- Malignant.
Primary carcinoma (all types) 87
Metastases 24
Malignant lymphoma 29 .
TOTAL 140
All salivary tumours (benign & malignant) 608
_________________________________________________________________________________________________________________

NB: Studies from Australia:

Metastases from skin primaries
(sq ca, melanoma) much commoner.

Metastases to the parotid gland:

____________________________________________________________________________________________________________________________________________________________

Location of primary Number of tumours (n=785)

Skin of head and neck (mostly squam ca, melanoma) 422 (53.8%).
Upper aero-digestive tract (mouth, nose, sinuses, pharynx) 63
Eye (conjunctiva, lacrimal gland) 6
Thyroid 5
Head, NOS 4
Central nervous system 4
Submandibular salivary gland 1
Lung 28}
Kidney 23}
Breast 19}
Colorectal 7}
Prostate 4}
Skin, distant 3}
Stomach 2}
Uterus 1} Total, distant
Pancreas 1} sites 88 (11.2%).
Skin, NOS 108
Unknown primary site 84
Gnepp DR. in Ellis GL, Auclair PL,Gnepp DR..Surgical Pathology of the Salivary Glands.1991.

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Parotid-metastatic squamous ca and melanoma from skin.

Parotid metastases: from outside head and neck region.

________________________________________________________________________________________________________________________________________________________________________________

Location of primary Number of tumours (n=785)

Skin of head and neck (mostly squam ca, melanoma) 422 (53.8%).
Upper aero-digestive tract (mouth, nose, sinuses, pharynx) 63
Eye (conjunctiva, lacrimal gland) 6
Thyroid 5
Head, NOS 4
Central nervous system 4
Submandibular salivary gland 1
Lung 28}
Kidney 23}
Breast 19}
Colorectal 7}
Prostate 4}
Skin, distant 3}
Stomach 2}
Uterus 1} Total, distant
Pancreas 1} sites 88 (11.2%).
Skin, NOS 108
Unknown primary site 84
Gnepp DR. in Ellis GL, Auclair PL,Gnepp DR..Surgical Pathology of the Salivary Glands.1991.

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HI81-08194 Metastatic breast lobular carcinoma.

2º from breast Mrs. Lochrie
pics

Clear cell Ca: differential diagnosis –

Metastatic renal cell carcinoma.

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Parotid: metast renal cell ca. Cytokeratin 7, CD10.

Renal cell carcinoma: presented as a parotid mass.

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Exeter 04-03543 Metastatic prostate carcinoma.

Exeter 04-03543 Metastatic prostate carcinoma.

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Salivary Carcinomas: those diagnosed mainly by

their morphological appearance.
Summary.
• Several salivary carcinomas are now recognized to
harbour specific genetic alterations, but....
• Morphology still has a role in the diagnosis of many.
• Acinic cell carcinoma can be differentiated from MASC
in most cases.
• PLGA characterized by y morphological
p g diversity y and
cytological uniformity.
• EMCa composed of 2 cell types throughout the tumour.
• Salivary duct carcinoma: a molecular approach may
point the way to new therapies.

The value of pattern recognition.

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"Molecular classification" of
salivary gland carcinomas
Prof. Alena Skalova, MD, PhD

Disclosure
Dr. Prof.
Dr Prof Alena Skalova
Skalova, MD
MD, PhD
has nothing to disclose.

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

• Mucoepidermoid carcinoma
• Adenoid cystic carcinoma
• Hyalinizing
y g clear cell carcinoma
• Mammary analogue secretory
carcinoma (MASC)
• Carcinoma ex pleomorphic adenoma
• PLAG1 or HMGA2 genes
• Salivary duct carcinoma
• Rearrangements in PLAG1 or HMGA2 genes
• HER-2/neu gene amplification

Oncogenic translocations in salivary
gland carcinomas
Translocation Fusion genes
Mucoepidermoid
p t(11;19)
( ; ) CRTC1--MAML2
CRTC1
carcinoma t(11;15) CRTC3--MAML2
CRTC3

Adenoid cystic t(6;9) MYB

MYB--NFIB
carcinoma

Hyalinizing
y g clear cell t(12;22)
( ; ) EWSR1--ATF1
EWSR1
carcinoma

Mammary analogue t(12;15) ETV6--NTRK3

ETV6
secretory ca (MASC)

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Translocation generated network of oncogenic fusions in salivary gland tumors 

MUCOEPIDERMOID
CARCINOMA

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Mucoepidermoid carcinoma
• common salivary gland tumor
• occurs in broad age range and can appear both in major
and minor glands
• translocation t(11;19) fuses MECT1 (mucoepidermoid
carcinoma translocated-1) at 19p13 with MAML2 (mastermind-like
gene family) at 11q21
• also known as CRTC1/MAML2
• Tonon et al. 2003. Nat Genet 33:208-213.
• Behboudi et al. 2006. Genes Chromosomes Cancer 45:470-481.

Mucoepidermoid carcinoma low grade

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Mucoepidermoid carcinoma
• Highly variable clinical prognosis
• Grading of MEC
– WHO 2005, AFIP, Brandwein-Gensler system,
modified Healey grading system, etc.
• CRTC1/MAML2 t(11;19) fusion positive
patients have better outcomes
– Less local recurrences, metastases and
tumor-related deaths

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

• Fusion positive cases of MEC have better

outcome even in high grade morphology

Fehr et al, 2008, Genes Chromosomes Cancer

CRTC1-MAML2 translocation can be used

in differential diagnosis

Am J Surg Pathol 2009:33:409‐416

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

A                                                             B                            C
1    2     3    4    5    6      1     2  3   4     5    6

D CRTC1              MAML2

E CRTC3              MAML2

• these studies indicate that molecular

genetic analysis can be useful adjunct to
histological scoring of MEC
– development
d l t off new guidelines
id li f
for
management of patient and new therapeutic
strategies
• HG translocation-negative MEC may
represent different entity (SDC or
adenosquamous cell ca)
– MAML2 FISH test has dif. dg value, but its
clinical utility has yet to be proven

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

ADENOID CYSTIC
CARCINOMA

Adenoid cystic carcinoma

• both minor and major SG
• relentless clinical course with late
recurrences and distant metastases
• causes significant morbidity
• Perineural and intracranial invasion

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Adenoid cystic carcinoma

• Recurrent t(6;9) translocation in AdCC of both
head and neck (salivary,
(salivary lacrimal,
lacrimal ceruminal
glands) and breast
• Translocation fuses MYB oncogene with
transcription factor gene NFIB
– Leads to chimeric MYB-NFIB fusion transcript
– MYB activation through gene fusion is a major
oncogenic event in AdCCa of many sites

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Adenoid cystic carcinoma

• Differential diagnosis
g
– MYB-NFIB fusion- in 30-100% cases
– All anatomic locations
• prognosis
– MYB-NFIB fusion- positive cases show tendency
toward higher local relapse rate
• MYB-NFIB fusion is a candidate
therapeutic target

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HYALINIZING
HYA INIZING CLEAR
C EAR CELL
CE
CARCINOMA OF MINOR
SALIVARY GLANDS

Hyalinizing clear cell carcinoma of

minor salivary glands
• considered a diagnosis of exclusion
• D
Despiteit its
it very di
distinctive
ti ti appearance it was
labeled as “not otherwise specified “ by WHO
2005
• Dif
Dif.. Dg.
– clear epithelial-
epithelial-myoepithelial ca
ca,, mucoepidermoid
carcinoma
carcinoma,, myoepithelial ca
– metastatic renal cell ca
– clear cell odontogenic ca

Simpson et al: Histopathology 1990: 17:433-438

Milchgrub et al. Am J Surg Pathol 1994:18:74-92

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Hyalinizing clear cell carcinoma of minor salivary glands

Antonescu CR, et al. - EWSR1-ATF1 fusion is a novel and consistent finding in

hyalinizing clear-cell carcinoma of salivary gland.

Genes Chromosomes Cancer 2011: 50:559-70.

FISH detects break in gene EWSR1

translocation t(12;22) (EWSR1-ATF1)

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EWSR1-ATF1 translocation

• EWSR1 ATF1 fusion gene in soft tissue tumors (also

EWSR1-ATF1
with other fusion partners, such as CREB1, etc.)
• EWSR1-ATF1 fusion has been characterized by
Antonescu et al. as a consistent finding in HCCCa
• Recently seen in clear cell odontogenic carcinoma
(CCOCa)
• HCCC can be distinguished from its mimics, such as
epithelial-myoepithelial carcinoma and
mucoepidermoid carcinoma
• Molecular and biological link between HCCCa and
CCOCa

MAMMARY ANALOGUE
ANA OGUE
SECRETORY CARCINOMA (MASC)

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Mammary analogue secretory

carcinoma (MASC)
• akin to secretory carcinoma of the breast, MASC
expresses S S-100
100 protein and mammaglobin and
harbours a t(12;15)(p13;q25) translocation that
results in an ETV6/NTRK3 fusion product
• presence of t(12;15) has not been demonstrated
in any other salivary gland tumour so far

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Mammary analogue secretory carcinoma of salivary glands

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MASC

Secretory ca breast

MASC

Secretory ca of breast

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breast secretory carcinoma

• recurrent balanced chromosomal translocation
t(12;15) (p13;q25) ETV6
ETV6-NTRK3
NTRK3
• fusion gene between the ETV6 gene on
chromosome 12 and the NTRK3 gene on
chromosome 15
• resultant fusion gene protein has transforming
activity
– in congenital fibrosarcoma, AML, etc.
– in breast pathology restricted to secretory carcinoma
not present in IDC, ILC etc.

Tognon et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human breast
secretory carcinoma. Cancer Cell 2002:2:367-376.

Mammary analogue secretory carcinoma of salivary glands

1     2       3    4      5    6

ETV6                    NTRK3

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S-100

CK18

positive
S-100+, CK7+,CK8+,CK18+,CK19+
VIM+, EGFR, MMG

negative
CK14, CK5, CK5/6, P63 protein,
Calponin,, ASMA, SMA, DOG1
Calponin CK7

Differential diagnosis of MASC

• „zymogen granules poor“ AciCC
• cystadenocarcinoma NOS
• Low grade cribriform cystadenocarcinoma
(LG SDC)
• Mucoepidermoid carcinoma

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ACINIC CELL CARCINOMA

Acinic cell carcinoma

• AciCC is the most common ‘named’

named entity
mimicked by MASC
• Classic AciCC shows intact ETV6!!!
• MASC has characteristic IHC profile
(CK7+,S-100+,VIM+,
(CK7 ,S 100 ,VIM , MMG+,
MMG , STAT5
STAT5+))
• No PAS+ zymogen granules in MASC
• DOG1 possible novel marker of AciCC

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Acinic cell carcinoma

Adenocarcinoma NOS
• Adenocarcinoma NOS poorly defined
category,
t representt dg.
d off exclusion
l i
• Ductal cellular component
• ETV6-NTRK3 negative

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Low grade cribriform

cystadenocarcinoma (LG SDC)
• Low grade morphology, S-100+
• LG SDC shows intact ETV6!!!
• IHC evidence of p63 protein+ in some
cases of MASC
– not as extensive as in “low-grade cribriform
cystadenocarcinoma” (LGCCC)
cystadenocarcinoma
– it could represent ductal extension of tumor
akin to “cancerization of ducts” in the breast

p63

MUCOEPIDERMOID
CARCINOMA

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Mucoepidermoid carcinoma
• Focal expression of HMWCK and presence
isolated mucinous cells in MASC
• lack of a cobblestone-like appearance with
intercellular bridges, true squamoid areas and
intermediate cells
• MASC usually lacks p63 staining and shows
diffuse S100 positivity
• t(11;19) translocation coding for a CRTC1-
MAML2 fusion protein in MEC

Clinicopathological characterization
of MASC
• MASC have a slight male predilection
• MASC is noted more commonly in non-
parotid sites
• higher incidence of LN mets
• No statistically significant difference in
disease free survival
disease-free

Chiosea et al. Histopathology 2012:61:387-394.

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In conclusion MASC
• MASC is more common than currently
recognized
• molecular proof of the ETV6-NTRK3
fusion for exact diagnosis of MASC is
necessary
• Testing for ETV6 translocation may be of
potential
t ti l value
l ini patient
ti t treatment
t t t
• presence of ETV6-NTRK3 translocation
may represent therapeutic target in MASC

CARCINOMA EX PLEOMORPHIC
P EOMORPHIC
ADENOMA

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Carcinoma ex pleomorphic
adenoma CXPA
• CXPA in the revised WHO classification
published
bli h d in
i 2005 is
i defined
d fi d as: a
pleomorphic adenoma in which an
epithelial malignancy is derived
• Three subtypes should be recognised
– non
non-invasive
invasive (in situ,
situ intracapsular)
– Minimally invasive (less than 1.5 mm)
– invasive carcinoma XPA (more than 1.5 mm)

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Carcinoma ex pleomorphic adenoma in situ (intracapsular)

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Invasive CXPA
• it occurs mainly in men over 60 y
• Most cases (81.7%)
(81 7%) involve the parotid gland
• submandibular in 18% and the sublingual in
0.3%;
• minor salivary glands, particu-larly in the
palate, can also be affected
• typical
t i l presentation
t ti is
i a long
l hi t
history off a
salivary gland nodule that suddenly increases
in size

Invasive CXPA
• Demonstration of both a carcinoma and a
PA is necessary for the diagnosis
• history of a long-standing parotid tumour is
not suf-ficient evidence for a pre-existing
PA
• previously excised PA at the site of a
carcinoma
i i acceptable
is t bl
• scarring, dystro-phic calcification, necrosis
and haemorrhage

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HER‐2/neu score 3+

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PLAG1 and HMGA2 gene fusion

in pleomorphic adenoma
• PA is the most common benign tumor of the
salivary glands
• histological diversity with epithelial, myoepithelial
and mesenchymal-type cells arranged in a variety
of architectural and differentiation patterns
• PLAG1 gene consistently rearranged in PA, and in
CXPA
• is
i activated
ti t d by
b chromosomal
h l translocations
t l ti
involving 8q12
• much less frequent target gene in PA is HMGA2

PLAG1 and HMGA2 gene fusion

in CXPA
• CXPA is diverse with malignant components
that can resemble distinct types of salivary
gland carcinomas
• including heterologous mesenchymal
elements in some instances
• malignant component of CXPA often overruns
the preexisting PA
• Presence of a precursor PA may only be
suggested by extensive areas of tumor
hyalinization

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PLAG1 and HMGA2 gene fusion

in CXPA
• histologic diversity of CXPA increases the
lik lih d off misclassification
likelihood i l ifi ti
• both as other salivary and non-salivary
malignancies, in small biopsy specimens.
Therefore, defining a specific IHC or
genetic marker for CXPA has practical
diagnostic implications
• PLAG1 gene alterations common in CXPA

PLAG1 immunohistochemistry
• PLAG1 protein is a nuclear oncoprotein
• transcriptional upregulation of PLAG1
results in a high level of protein expression
• antibody against the PLAG1 protein is
commercially available
•

spindle Hyaline /plasmacytoid

Myoepithelial cells

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SALIVARY DUCT CARCINOMA

Precursor lesions of SDC

• SDC often arises in PA
• Putative
P t ti precursor lesions
l i i l d LG
include
cribriform cystadenocarcinoma (LG SDC)
• In situ SDC (DCIS)
• PLAG1 or HMGA2 in precursor
lesions/intraductal proliferations of SDC

• Simpson et al. Salivary duct carcinoma in situ. Histopathology, 2008;53:416‐25

• Bahrami et al. An analysis of PLAG1 and HMGA2 rearrangements in SDC… 
Histopathology 2013;63:25‐262

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Salivary duct carcinoma ex PA

• CXPA with features of SDC demostrates
positive
iti staining
t i i for
f PLAG1
• PLAG1 IHC is a specific and reliable
marker of PA and CXPA

CLEAR
C EAR CELL
CE VARIANT OF HIGH
GRADE MYOEPITHELIAL
CARCINOMA

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Myoepithelial carcinoma

Clear cell variant 
cell variant of
of high grade 
grade myoepithelial
myoepithelial carcinoma

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MIB1 index 45%

Clear cell variant 
cell variant of
of high grade 
grade myoepithelial
myoepithelial carcinoma

S100

actin

CC myoepithelial
CC  myoepithelial carcinoma

CK14

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EWSR1 positive HG clear cell

myoepithelial carcinoma

FISH analysis using EWSR1 dual color, break apart probe. Visualization under Triple Band Pass filter. 
Yellow signals indicate intact EWSR1 gene region, separated green and red signals represent 
rearrangered EWSR1 gene region.  Several nuclei positive for EWSR1 break are shown. 

Abstract at 2014 Annual
2014 Annual Meeting, USCAP, San Diego, March
Meeting, USCAP, San Diego, March 1‐7, 2014

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Conclusions
• Four salivary carcinomas have unique
oncogenic translocations
• Diagnostic markers (HCCC, MASC)
– Identify as yet not discovered tumor types or
reclassify (MASC)
• Some may be prognostic (MAML2 in
MEC)
• May serve as targets for therapy (MYB-
NFIB? ETV6/NTRK3?)

Thank you for attention

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Review-consensus talk on
salivary gland tumors
malignant
Prof. Alena Skalova, MD, PhD

Disclosure
Dr Skalova has nothing to disclose
Dr. disclose.

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Salivary gland carcinomas

• Rare tumors with heterogenous morphology
• Newly described entities and reclassification
of other salivary gland ca
• Genetic alterations, some of them specific
– CRTC1/MAML2, ETV6/NTRK3, PLAG1,etc
• Immunohistochemistry
– MIB1 and
d prognosis
i (AciCC,
(A iCC MEC,
MEC AdCCa)
AdCC )
• Chalenging both for pathologists and
clinicians

Incidence, etiology and risk factors

• about 0.5% of all malignancies and less
th t 5% off allll h
that head
d and
d neckk cancers
• Risk factors are largely unknown
– Ionising radiation
– Endogenous hormones (AR in SDC)
– Hereditary origin in basal cell carcinoma and
acinic cell carcinoma

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Oncogenic translocations in salivary
gland carcinomas
Translocation Fusion genes
Mucoepidermoid
p t(11;19)
( ; ) CRTC1--MAML2
CRTC1
carcinoma t(11;15) CRTC3--MAML2
CRTC3

Adenoid cystic t(6;9) MYB

MYB--NFIB
carcinoma

Hyalinizing
y g clear cell t(12;22)
( ; ) EWSR1--ATF1
EWSR1
carcinoma

Mammary analogue t(12;15) ETV6--NTRK3

ETV6
secretory ca (MASC)

Tumor histology
• 2005 WHO
classification
recognises 23
subtypes of
salivary gland
cancer

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WHO 2005

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Grading
• different concepts of grading the
h t
heterogenous group off SG tumors
t have
h
been proposed but there is no consensus
to date
• grading of SG cancers is an important
predictor of survival

Low-grade category
• LG mucoepidermoid carcinoma
• A i i cellll carcinoma
Acinic i
• Basal cell adenocarcinoma
• PLGA
• MASC
• Cystadenocarcinoma
• Clear cell carcinoma
• Epithelial-myoepithelial carcinoma

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Intermediate-grade category
• Grade 2 mucoepidermoid carcinoma
• Tubular and cribriform adenoid cystic
carcinoma
• Myoepithelial carcinoma
• Mucinous adenocarcinoma

High-grade category
• High grade mucoepidermoid carcinoma
• Solid (basaloid) adenoid cystic carcinoma
• SDC
• Carcinoma ex pleomorphic adenoma
• Carcinosarcoma
• HG clear cell myoepithelial carcinoma

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High-grade transformation
• Acinic cell carcinoma
• MASC
• Adenoid cystic carcinoma
• Basal cell adenocarcinoma
• Epithelial-myoepithelial carcinoma

High-grade tranformation in
salivary gland carcinomas
• High grade transformation (originally
called
ll d “d
“dedifferentiation”)
diff ti ti ”) iis d
defined
fi d as th
the
histologic progression of a low grade
malignant neoplasm to a high grade one,
within which the original line of
differentiation is lost
• always associated with tumor progression
• Aggressive behavior and poor outcome

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HG transformation of MASC

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HG transformation of MASC

MIB1

Diagnostics and staging

• SG carcinomas are staged according to
th recommendation
the d ti off th
the A
Am JJoint
i t
Committee on Cancer (AJCC) or the UICC
(International Union against Cancer)
• distinct TNM classification exists for major
salivary glands
• minor salivary gland tumors are staged as
oral squamous cell carcinoma

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Prognosis
• Histologic type
• A (high
Age (hi h age is
i worse))
• Stage and grade
• Gender (male worse)
• Site (submandibular gland worse)
• facial nerve involvement
• MIB1 proliferation activity
• CRTC1/MAML2 translocation (better)

"Molecular classification" of salivary

gland carcinomas
• Mammary analogue secretory carcinoma
(MASC)
• adenoid cystic carcinoma
• mucoepidermoid carcinoma
• hyalinizing clear cell carcinoma

OAKSTONE COMPREHENSIVE  PATHOLOGY SEMINARS
Prof. Alena Skalova, MD 1

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„Conventional“ classification of
salivary gland carcinomas
• Acinic cell carcinoma
• PLGA
• Epithelial-myoepithelial carcinoma
• Oncocytic carcinoma
• Salivary duct carcinoma
• Carcinoma ex pleomorphic adenoma (PA)
• Metastasizing PA
• Hybrid and metastic tumors
OAKSTONE COMPREHENSIVE  PATHOLOGY SEMINARS
Prof. RHW Simpson, MD, 1

Rare salivary gland carcinoma

• Myoepithelial carcinoma
• carcinosarcoma
• Cystadenocarcinoma
• Mucinous adenocarcinoma
• Basal cell adenocarcinoma
• Cribriform adenocarcinoma of tongue and
other minor salivary glands (CATS)

OAKSTONE COMPREHENSIVE  PATHOLOGY SEMINARS
Prof. Alena Skalova, MD 2

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MYOEPITHELIAL CARCINOMA

• Most cases arise in parotid gland

• but
b t they
th also
l occur iin submandibular
b dib l andd
minor glands, usually the palate
• they rarely may arise in the base of
tongue, maxillary sinus and larynx
• may arise de novo, but at least half of
them develop in pre-existing pleomorphic
adenomas (PA) or benign
myoepitheliomas particularly in recurrence

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• mean age of patients at presentation is

about
b t 55 years ((range 14
14-86
86 years))
• sex incidence is approximately equal in
most studies
• It accounts for about 2-5 percent of
malignant salivary neoplasms
neoplasms, but it may
not be as rare as supposed earlier

Macroscopy
• unencapsulated but may be well-defined
with
ith nodular
d l surfaces
f
• cut surface is grey-white and can be
glassy
• some tumors reveal areas of hemorrhage,
necrosis and pseudocystic degeneration

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ASMA

p63 protein

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Prognosis of myoepithelial
carcinoma
• one third of patients die of disease
• another third have multiple recurrence
• remaining third are disease free
• Myoepithelial carcinomas ex recurrent PAs
may persue a prolonged clinical course
• marked cellular pleomorphism, high mitotic
rate and high proliferative activity (MIB1
index) correlate with poor prognosis

Differential diagnosis
• salivary duct carcinoma
• spectrum of clear cell tumors
• mucoepidermoid carcinoma
• soft tissue sarcomas
• variety of clear cell neoplasms primary and
metastatic, including epithelial-myoepithelial
carcinoma,
i clear
l cellll carcinoma
i NOS
NOS,
hyalinizing clear cell carcinoma and
metastatic renal cell carcinoma

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• immunohistochemistry is helpful in
excluding
l di th
these neoplasms
l
• myoepithelial carcinomas are defined by
co-expression of wide spectrum
cytokeratins and myoepithelial markers

CARCINOSARCOMA

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Carcinosarcoma
• Very rare biphasic salivary gland tumor
composed d off sarcomatous
t andd
carcinomatous component
• Variable histomorphology
• Arise ex pleomorphic adenoma or de novo
• Aggressive,
Aggressive high grade malignancy

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AE1‐AE3

HER‐2/neu

AR

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MIB1 proliferative activity

CYSTADENOCARCINOMA

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Cystadenocarcinoma
• rare malignant tumor of salivary glands
characterized by invasive growth and multiple
cystic structures lined with epithelium
• grossly, the tumours are cystic or multicystic,
well circumscribed unencapsulated lesions
that usually range in size from 0.4 to 10 cm in
greatest dimension
• cystadenocarcinoma represents malignant
counterpart of cystadenoma

Cystadenocarcinoma
• rare neoplasm accounting for 0.5 to 2.0%
off malignant
li t salivary
li gland
l d tumors
t
• Although the age range is broad (5 to 87
years), more than 70 % of patients are
over 50 years of age
• no sex predilection,
predilection men and women are
affected equally

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Site and treatment

• In AFIP series about 60 percent occur in
major salivary glands
glands, most of these were
located in parotid gland
• minor glands are affected in descending
order in frequency in palate, buccal mucosa,
lips, floor of mouth and tongue
• majority are low
low-grade
grade or intermediate-grade
intermediate grade
neoplasms
• treatment should be relevant to grade and
stage of the tumor

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MUCINOUS
ADENOCARCINOMA

Mucinous adenocarcinoma
• According to WHO 2005 - a malignant
epithelial tumor composed of epithelial
clusters within large pools of extracellular
mucin
• mucin component occupies the majority of
the tumor
• Signet-ring cell carcinoma - characterized
by presence of isolated tumor cells with
intracytoplasmic mucus vacuoles

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• Mucinous (colloid) adenocarcinoma of

major and minor salivary glands is an
extremely rare neoplasm
• Most tumors arise in minor salivary glands
– namely in the glands of palate
– buccal mucosa
– floor
f off the mouth, and base off the tongue
– few cases have been described in the parotid
gland

• tumor is often nodular and ill defined

• cut surface is whitish-grey with multiple
cystic spaces containing gelatinous
secretory material
• Mucinous (colloid) adenocarcinoma of
salivary glands is histologically identical
with breast and colorectal analogues

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Differential diagnosis
• mucinous cystadenoma
• mucinous cystadenocarcinoma
• mucoepidermoid carcinoma (MEC)
• mucin-rich salivary duct carcinoma
• metastic tumors
• mucin extravasation phenomenon

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BASAL CELL
ADENOCARCINOMA

Basal cell adenocarcinoma

• rare malignant epithelial tumor of major
andd minor
i salivary
li glands
l d composed d off
predominantly basaloid cells
• cytologically and morphologically similar to
basal cell adenoma
• but has invasive growth and potential to
develop metastases

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Site and gross appearance

• Over 90% of BCAC occur in parotid gland
• occurs over a wide age range with
average age of 60
• most are well defined nonencapsulated
lesions
• on cut section
section, they are mostly
homogenous, some of them partly cystic

Microscopy
• 4 main growth patterns – tubular, trabecular,
solid and membranous
solid,
• BCAC is composed of basaloid cells with
large round to oval nuclei and little cytoplasm
• most tumors have a limited mitotic activity
and nuclear and celllular polymorphism
• diagnosis of BCAC is based on invasive
growth into the adjacent tissues and
identification of perineural or vascular
invasion

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Vážený pane docente,

chtěla bych Vás požádat o přidání termínů na zkoušky z Farmakologie. Ve zkouškovém období byl vypsán sice dostatečný počet míst pro studenty 4. ročníku, boh

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Basal cell carcinoma

Invasive growth

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Treatment and prognosis

• low-grade malignancy
• cumulative
l ti ddata
t from
f the
th literature
lit t reveall a
local recurrence rate of about 37%,
locoregional metastatic rate of 8% and
very low risk of distant metastasis
• Optimal treatment includes wide surgical
resection
ti with
ith ffree margins,
i additional
dditi l
radiotherapy or elective neck dissection
are not warranted

SIALOBLASTOMA

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Sialoblastoma-definiton
• low-grade malignant neoplasm usually present at
birth or shortly thereafter
• composed of epithelial basaloid and myoepithelial cells
that recapitulate primitive salivary gland anlage
• Sialoblastoma was first reported in 1996 by Vawter
and Tefft who used the term embryoma
• approximately 40 tumors, that fit into a definition of
sialoblastoma, were reported under different names
– congenital basal cell adenoma
– congenital hybrid basal cell adenoma/adenoid cystic
carcinoma
– sialoblastoma

Sialoblastoma-grossly
• arises almost exclusively in perinatal
period with rare cases presenting after 2
years of age
• tumors range up to 15 cm in greatest
dimension and are well circumscribed and
even partly encapsulated
• they
th may be b locally
l ll iinvasive
i with
ith
extension to adjacent soft tissues and
bone

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Sialoblastoma-microscopy
• It recapitulates embryonic development of
majorj salivary ygglands
• variable histological patterns, composed of
variably sized nests and solid sheets of basaloid
cells with focal ductal differentiation and cystic and
microcystic change
• cells are fairly uniform with minimal cytoplasm and
round to oval nuclei with only slight polymorphism
• Mitoses
Mit are frequently
f tl found
f d andd may bbe
numerous, atypical mitoses are not present
• Neural and occasionally vascular invasion may be
found

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Differential diagnosis
• Pleomorphic adenoma
– is exceedingly rare in neonatal age group and is
distinguished by chondromyxoid stroma and combination
of epithelial and myoepithelial cells with duct formation and
metaplastic changes.
• Basal cell adenoma
– is very rare in neonatal population, and it consists of
uniform basaloid cells without mitoses and polymorphism
• Adenoid cystic carcinoma
– iis exceedingly
di l rare iin neonatal
t l age group
– it is characterized by invasive growth and formation of
abundant extracellular matrix presenting with cribriform
and pseudocystic patterns

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CRIBRIFORM ADENOCARCINOMA
OF TONGUE (CATS)

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Possible variant of PLGA is CAT, but it is not yet clear

whether this represents a genuine entity or just an
unusual growth pattern in PLGA……….

WHO Classification of Tumours: Pathology and Genetics

Head and Neck Tumours, IARC Press, 2005

• About 39 cases of CAT have been

described in English literature so far
• originally designated as CAT and
considered to be restricted to tongue
• Tongue is not exclusive site of the cancer
• may also arise from the minor salivary
glands of soft palate, buccal mucosa, area
of the palatine tonsils and the upper lip
• renamed as “cribriform adenocarcinoma of
minor salivary gland origin” (CAMSG)

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Clinico-pathological findings:
review of the published cases
• CATS ( ) is a malignant but not a
CAMSG

highly aggressive neoplasm

• infiltrative, poorly circum
circum--
scribed sub
submucosal
mucosal tumor
• in adults wide range of age
– 21
21--85y
– no sex predilection

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• More than half of patients (23 cases)

revealed
l d cervical
i l llymph
h node
d metastasis
t t i
at the time of diagnosis and one as a
recurrent disease
• 4/23 patients developed bilateral
metastasis
• early metastasis to cervical lymph
nodes is a consistent clinical finding

• follow up ranged from 2 months to 13

years
• None of patients has developed distant
metastasis
• If positive surgical margins, the patients
have greater chance to develop
recurrences

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• Most patients with positive surgical

margins and/or cervical lymph node
metastasis received complementary
radiotherapy
• Only one patient received adjuvant
chemotherapy with cisplatin
• treatment of CATS ((CAMSG
CAMSG)) should aim
to ard complete s
toward surgical
rgical e
excision,
cision
supplemented by lymphadenectomy if
dissemination is evident

Intact mucosa

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Cribriform growth pattern

Tubules lined by single cell layer

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Solid mass divided by fibrous septa into irregularly shaped nodules

Tumor nests detached from the surrounding stroma

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Peripheral palisading and arteficial clefts

Cribriform growth pattern

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Solid growth pattern

Ground-glass nuclei („Orhan Annie eyes“)-resemble papillary ca of thyroid

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TTF1, Thyreoglobulin neg

Papillary growth pattern, ground-glass nuclei

CK7, S-100, actin+

Ground glass nuclei in LN metastasis

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S-100 protein +/ thyreoglobulin and TTF1 always negative

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MIB1 index

Infiltration of muscle of tongue

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Lymphovascular invasion

D2-40

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Laco et al. Virchows Arch 2012 Nov; 461(5):531-40

Immunohistochemical Findings
• +in all cells- S-100, VIM, AE1-3, p63, CK7, CK8
• +in ll with
i mostt cells, ith enhanced
h d expression
i in
i
peripheral cells- CK18, CK5, CK5/6, CK14
• focal +stain- c-kit, SMA, MSA, p53 protein
• MIB1 <3%
• +few cells- CK19
• negative in all cases- EGFR, HER2, TTF1,THG

Skalova et al: Am J Surg Pathol 2011

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Molecular Findings
• positive expression of galectin-
galectin-3, CK19,
and
d HBME
HBME--1 1, but
b t nott off thyroglobulin
th l b li andd
TTF-
TTF-1
• No somatic mutations of RET, BRAF, K- K-
RAS, H RAS, and N-RAS proto
H--RAS, proto--
oncogenes were detected

Skalova et al: Am J Surg Pathol 2011

Laco et al; Virchows Arch 2012

DIFFERENTIAL
DIAGNOSIS

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CATS versus PLGA

• CATS is not a polymorphous tumor
• PLGA wideid range off architectural
hit t l
appearances, such as streaming columns
of single file or narrow trabeculae of cells
forming concentric whorls
• extensive nuclear ground-glass change in
CATS withith overlapping
l i clear
l “O
“Orphan
h
Annie eye–like nuclei”

CATS versus PLGA

• a novel and recurrent ARID1A-PRKD1
f i in
fusion i CATS was recentlytl detected
d t t d
• first molecular evidence of a difference
between CATS and "classic" PLGA
– Weinreb, et al, Abstract at USCAP 2014

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CATS versus PLGA- clinical

behavior
• PLGA only rarely metastasizes
• CATS had lymph node metastases in
most cases already at the time of the
presentation of the primary tumor
• Cervical LN metastases present even
extralingual cases

Adenoid cystic carcinoma versus

CATS
• Cribriform pattern, pseudocystic spaces,
andd stromal
t lh
hyaline
li collagen
ll d
deposits
it
• adenoid cystic carcinoma is characterized
by angulated hyperchromatic nuclei and
biphasic pattern
• CATS - monophasic growth pattern and
vesicular clear often overlapping nuclei

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CATS versus metastatic thyroid

cancer
• CATS stain strongly for S-100 protein
and p16 protein
• focal myoepithelial differentiation with
calponin and actin positivity in CATS
• CATS is always thyroglobulin and TTF1
negative, colloid absent

In conclusion: CATS is distinctive

entity
• Location in tongue, tonsils, palate
• Characteristic histology different from
PLGA
• Clinical behavior
– neck lymph node metastasis at diagnosis
– good prognosis,
prognosis no tumor related death
– Radiotherapy is currently of unproven benefit
in PLGA, CATS seem to be radiosensitive

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Thank you for attention

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Fine Needle Aspiration

Cytology of Salivary Gland

Fang Fan, MD, Ph.D

Department of Pathology and Laboratory Medicine
University of Kansas Medical Center

Disclosure
Dr Fan has nothing to disclose
Dr. disclose.

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Salivary Gland
• Normal
• Non-neoplastic lesions
• Neoplastic lesions

Salivary Gland
• Normal
• Major salivary gland: parotid (exclusively serous),
submandibular (mixed with serous predominance),
and sublingual (mixed with mucinous
predominance)

• Minor salivary gland: lips, gingiva, floor of mouth,

cheek, hard and soft palates, tongue, tonsillar areas
and oropharynx

• Histology: acini and ducts

• Scattered lymphocytes in the connective tissue

around the acini and ducts-MALT

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Normal Salivary Gland

Normal Salivary Gland

• Normal acinar cells

are grouped in
rounded lobules
admixed with
adipose tissue and
ductal cells
• Cells have small
round nuclei and
abundant vacuolated
cytoplasm.

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Normal Salivary Gland

Salivary Gland
• Non neoplastic lesions
• Sialadenitis
– Scant cellularity
– Scattered lymphocytes, benign salivary gland ducts

• Lmphoepithelial sialadenitis (LESA)

– Synonyms: Mikulicz’s disease (localized), Sjogren’s
syndrome (clinical syndrome), benign lymphoepithelial lesion
(BLEL), and myoepithelial sialadenitis (MESA)
– An
A autoimmue
t i di
disorder
d
– Cytologic features:
• Mixed lymphoid population, plasma cells, germinal
center fragments
• Lymphoepithelial islands

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Salivary Gland
Non neoplastic cysts
• Squamous-lined
q cysts
y
– Congenital cyst
– Sporadic simple lymphoepithelial cyst (not
related to HIV)
– HIV associated cystic lymphoepithelial lesion
• Multiple and bilateral
• Cytologic features:
• Cyst contents debris,
debris histiocytes
• Keratin debris and anucleated squames
• Benign squamous cells and/or columnar cells
• Mixed population of lymphocytes
• Germinal center fragments
• Lymphoepithelial islands

Benign squamous-lined cyst

Be careful and not over-diagnose as cystic squamous cell carcinoma!!!

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Salivary Gland
• Non neoplastic cysts
• Mucin-containing cysts
– Mucin, mucinphages, epithelial elements
– Differential diagnosis includes a mucocele,
mucus retention cyst, chronic sialadenitis with
mucinous metplasia, and a mucoepidermoid
carcinoma
– Caution should be taken in evaluating mucinous
cysts especially in the parotid and
cysts,
submandibular glands and when there is a
residual mass after aspiration

Mucous-containing cyst

Be cautious in interpreting mucous-containing cyst!

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Low-grade mucoepidermoid carcinoma

Salivary Gland
• Neoplastic lesions
• Benign
– Pleomorphic adenoma
– Basal cell adenoma
– Warthin’s tumor
– Oncocytoma
• Malignant
– Adenoid cystic carcinoma
– Mucoepidermoid carcinoma
– Acinic cell carcinoma
– Polymorphous low grade
– Salivary duct carcinoma

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Pleomorphic Adenoma
• Clinical features
• Most common neoplasm of salivary gland
• Asymptomatic, slow growing mass
• Female>male, 4th to 5th decade

• Pathologic features
• Well-circumscribed mass with white tan, sometimes
gelatinous cut surface
• Three components histologically
– Epithelial groups (positive for keratin)
– Myoepithelial cells (positive for SMA, S100, GFAP)
– Mesenchymal stroma-myxoid, chondroid, osseous, fatty

Pleomorphic Adenoma

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Pleomorphic
Adenoma

•Epithelial
E ith li l cells
ll
•Myoepithelial cells
•Fibrillary
Chondromyxoid matrix

Pleomorphic Adenoma

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Pleomorphic Adenoma

Pleomorphic Adenoma
• Differential diagnoses
• Scant or absent matrix
– Basal cell adenoma or myoepithelioma

• Cylindromatous (matrix-producing) area

– Adenoid cystic carcinoma

• Focal cytologic atypia or squamous metaplasia

– Carcinomas

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Basal Cell Adenoma

• Clinical features
• 2% of salivary gland tumors
• Most within parotid gland, peak incidence in 6th decade

• Pathologic features
• Well-circumscribed and encapsulated
• Characteristic feature is the peripheral palisading around
nests of basaloid cells
• Four
F basic
b i architectural
hit t l patterns:
tt solid,
lid tubular,
t b l
trabecular, and membranous
– The membranous type has a “jig-saw” puzzle pattern,
tumor nodules surrounded by dense basement membrane
material resembling eccrine cylindroma-”dermal analogue
tumor”

Basal Cell
Adenoma

•Clusters
Cl t off lloosely
l
cohesive cells
•Cell groups surrounded
by dense stroma

Note: The distinction between basal cell adenoma and basal cell
adenocarcinoma can not be made based on cytologic material.

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Basal Cell Adenoma

Small and intermediate-sized cells form crowded groups with

peripheral palisading

Basal Cell Adenoma

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Basal Cell Adenoma

• Often diagnosed as “basaloid
neoplasm
neoplasm”
• Differential diagnoses include
• Basal cell adenoma
• Basal cell adenocarcinoma
• Solid variant of adenoid cystic
carcinoma
• Metastatic carcinoma (be aware of
clinical history)

Oncocytoma
• Clinical features
• 1% of all parotid gland neoplasm
• 7th to 8th decade of life
• Asymptomatic slow growing mass

• Pathologic features
• Soft, well-circumscribed tan-brown nodule
• Polygonal cells with abundant eosinophilic finely
granular
l cytoplasm,
t l uniform
if round
d centrally
t ll placed
l d
nuclei

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Oncocytoma

•Sheets or clusters
of oncocytes in a clean
background

Oncocytoma

No lymphocytes or naked nuclei in the background

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Oncocytoma
• Differential diagnosis
• Acinic cell carcinoma
– Abundant naked nuclei and granular background

• Warthin tumor
– Abundant lymphocytes in the background
– Cystic debris in the background

Acinic cell carcinoma Oncocytoma

Warthin tumor

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Warthin Tumor
(papillary cystadenoma lymphomatosum)

• Clinical features
• Second most common tumor of parotid gland
• More frequently bilateral
• Associated with cigarette smoking

• Pathologic features
• Circumscribed cystic, brown mass
• Cysts with papillary infoldings
• Double layer of oncocytic epithelium
• Dense lymphocytes underneath the epithelium with
germinal centers

Warthin tumor

•Sheets of oncocytes
•Lymphocytes
•Degenerated debris
in the background

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Warthin Tumor

Salivary Gland
• Neoplastic lesions
• Benign
– Pleomorphic adenoma
– Basal cell adenoma
– Oncocytoma
– Warthin’s tumor
• Malignant
– Mucoepidermoid carcinoma
– Adenoid cystic carcinoma
– Acinic cell carcinoma
– Polymorphous low grade
– Salivary duct carcinoma

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Mucoepidermoid Carcinoma
• Clinical features
• The most common malignant salivary gland tumor
• Also the most common salivary gland malignancy in
children

• Pathologic features
• Circumscribed or infiltrative, solid and cystic
• Three types of cells: mucus, intermediate and
epidermoid cells
• Tumors separate into low, intermediate and high grade

Mucoepidermoid
carcinoma

•Three
Th ttypes off cells
ll
•Mucus cells
•Epidermoid cells
•Intermediate cells

•Extracellular mucin

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Mucoepidermoid carcinoma, low-grade

Mucoepidermoid carcinoma, high-grade

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Mucoepidermoid Carcinoma
• Differential diagnosis for low-grade MEC
• M
Mucocelel or retention
t ti cystt
• Necrotizing sialometaplasia
• Be very careful with mucinous cysts in major
salivary glands

• Differential diagnosis for high-grade MEC

• Squamous cell carcinoma
• Salivary gland duct carcinoma

Adenoid Cystic Carcinoma

• Clinical features
• Slow growing but highly malignant
• Most common malignant tumor of minor salivary gland
• Less common than mucoepidermoid carcinoma and
acinic cell carcinoma in parotid

• Pathologic features
• Comprised of epithelial cells and myoepithelial cells
• Main patterns are cribriform, tubular and solid
• The typical cribriform pattern is composed of islands of
myoepithelial cells containing rounded pseudocysts.
• The pseudocysts are filled with eosinophilic PAS positive
basement membrane material or granular basophilic material.

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Adenoid Cystic Carcinoma

• Pathologic features
• Small true glandular lumina are also seen
seen.
• Identification of both pseudocysts and true glandular lumina is
required to make a diagnosis of adenoid cystic carcinoma.
• Perineural invasion is almost always present.
• IHC: two cell populations, positive for keratin, S100, CD117

Adenoid Cystic
Carcinoma

•Variable sized hyaline

globules surrounded
by basaloid tumor
cells (cylindromatous
pattern)
•The matrix material
has smooth sharp
borders

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Adenoid Cystic Carcinoma

Adenoid Cystic Carcinoma

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Adenoid Cystic Carcinoma

Hyperchromatic nuclei

Adenoid Cystic Carcinoma

• Differential Diagnoses
• Pleomorphic adenoma
– Fibrillary matrix and embedded cells
• Basal cell adenoma
– Forming strands not spheres
• Polymorphous low grade adenocarcinoma
– Uniform cell population, bland morphology, nuclei not
hyperchromatic

• Some suggest only making this

diagnosis with clinical evidence of
malignancy

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Adenoid cystic carcinoma Pleomorphic adenoma

Acinic Cell Carcinoma

• Clinical features
• Slow growing,
growing mobile or fixed

• Pathologic features
• Serous acinar cells with pale to basophilic cytoplasmic
granules (PAS positive, diastase resistant zymogen granules)
• Small gland-like spaces and microcysts may be seen.
• May have focal heavy lymphocytic infiltrate.
infiltrate

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Acinic cell carcinoma

•Sheets
Sheets and single cells
•Abundant vacuolated
or granular cytoplasm
•Indistinct cytoplasm
•Bland nuclei

•Granular background

•Naked nuclei

Acinic cell carcinoma

•Sheets and single cells

•Abundant vacuolated
or granular cytoplasm
•Indistinct cytoplasm
•Bland nuclei

•Granular background

•Naked nuclei

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Acinic Cell Carcinoma

• Differential Diagnosis
• Normal salivary gland
• Oncocytoma
O t
• Warthin tumor
Normal salivary gland Acinic cell carcinoma

Acinic cell carcinoma Oncocytoma

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Polymorphous Low-Grade Adenocarcinoma

• Clinical features
• Almost exclusively in minor salivary gland
• The most common site is the palate, especially at the
junction of the hard and soft palates
• Painless slow growing mass

• Pathologic features
• Circumscribed but not encapsulated
• Cytologically
C t l i ll bl bland
d and
d uniform,
if architecturally
hit t ll
polymorphous
• Concentric targeting around nerves and blood vessels
• Mitoses and necrosis uncommon
• Rarely encountered in FNA

PLGA

•Uniform cells with

normochromatic nuclei

•Cells adhering to
fibrovascular stroma forming
A pseudopapillary pattern

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Salivary Duct Carcinoma

• Clinical features
• Rapidly growing mass with ulceration and facial nerve
palsy

• Pathologic features
• Resemble high grade breast ductal carcinoma with
comedo necrosis
• May arise ex pleomorphic adenomas
• Strongly positive for androgen receptor,
receptor most show Her-
Her
2/neu over expression, negative for ER, PR

Salivary duct
carcinoma

•High-grade malignant
morphology

•Prominent nucleoli,
granular or vacuolated
cytoplasm

•Necrotic background

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Salivary Duct Carcinoma

• Differential Diagnoses
• Metastatic breast carcinoma
carcinoma, squamous cell carcinoma

• Prognosis
• The most aggressive salivary gland tumor

Salivary Gland FNA

Summaries

• Cystic neoplasms
• Warthin tumor
• Mucoepidermoid carcinoma
• Acinic cell carcinoma

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Warthin tumor Mucoepidermoid carcinoma

Acinic cell carcinoma

Salivary Gland FNA

Summaries
• Basaloid neoplasms
• Basal cell adenoma/adenocarcinoma
• Solid variant of adenoid cystic carcinoma
• Metastatic carcinoma

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Solid variant of ACC Basal cell adenoma/carcinoma

Metastatic BCC

Salivary Gland FNA

Summaries
• Cylindromatous (matrix-producing)
neoplasms
• Pleomorphic adenoma
• Adenoid cystic carcinoma

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Adenoid cystic carcinoma Pleomorphic adenoma

Salivary Gland FNA

Summaries
• With background
g lymphocytes
y y
• Warthin tumor
• Lymphoepithelial cyst
• Acinic cell carcinoma
• Lymphoma

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Salivary Gland FNA

Summaries
• Oncocytic
y neoplasm
• Warthin tumor
• Oncocytoma
• Acinic cell carcinoma

Acinic cell carcinoma Oncocytoma

Warthin tumor

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Thyroiditis, Goiter and Related

Conditions
Ivan Damjanov, MD,PhD
Professor of Pathology
The University of Kansas School of
Medicine,,
Kansas City, Kansas

Disclosure Statement

Dr.Ivan
Dr Ivan Damjanov reports no relevant
financial relationships with commercial
interests.

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Abbreviations used
CL:Clinical TPO:thyroid
Dx:Diagnosis peroxidase
Ddx:Differential Tg:thyroglobulin
diagnosis TSH:-thyroid
E:Etiology stimulating hormone
MA: Macrosocopic TSHR:TSH receptor
MI:Microscopic MØ, Ly,Pls:
M:F=male female macrophages,lymph-
ratio ocytes,plasma cells

Thyroiditis –Definition and

Classifications
Thyroiditis-inflammation of the thyroid
Classification criteria
1.Etiology—infection, autoimmune,
secondary to other pathology, unknown
2.Onset/duration-acute, subacute, chronic
3 Clinically-subclinical
3.Clinically subclinical, euthyroid
euthyroid,
hypothyroid, hyperthyroid-with/without goiter
4.Histopathology-types of cells infiltrating the
thyroid + related changes

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Acute Thyroiditis
Infectious inflammation, A.k.a suppurative
thyroiditis-infiltrates of neutrophils
RARE-usually secondary to infections
f locally
on the neck or in systemic bacteremia
Etiology: Streptococcus, Staphylococcus,
mixed bacterial infections, fungi
Risk factors: Tracheostomy,
Tracheostomy neck surgery
surgery,
neck cancer, sepsis, immunosuppression
In children-developmental remnants- pyriform
sinus fistula ( remnant of thymopharyngeal
duct) or thyroglossal duct (rarely in thyroid )

Subacute granulomatous
thyroiditis

Fritz de Quervain
Swiss physician, 1868-1940

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Subacute granulomatous
thyroiditis
A.k.a. de Quervain thyroiditis, giant cell
th iditi struma
thyroiditis, t granulomatosa
l t etc.
t
MIDDLE AGED FEMALES, F:M= 4:1
THE MOST COMMON PAINFUL THYROID
Etiology: Presumably viral (not
proven) summer months(!)
proven),summer
Antiviral therapy-(e.g. interferon)
Etanercept (anti-TNF alpha)
Genetics--HLA-B35 predispose (twin studies)

Subacute granulomatous
thyroiditis
MA: Asymmetric enlargement
enlargement, painful
MI: Temporal variation-damaged follicles,
loss of epithelium, inflammation : acute
(PMNs),chronic( MØ, Ly,Pls), granulomas
(with multinucleated cells), and fibrosis.
CLINICAL: Acute onset, pain, after URI,
summer, hyperthyroidism- transient (weeks,
months),spontaneous recovery in most
cases-steroid treatment-good prognosis

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Subacute granulomatous
thyroiditis-differential Dx
Other forms of thyroid granulomas
P l ti th
Palpation thyroiditis-
iditi a.k.a.multifocal
k ltif l
granulomatous folliculitis-single follicles or
small groups, limited, no acute inflammation
or necrosis
Sarcoidosis-stromal
Sarcoidosis stromal (not folliculocentric!),
may coexist with Hashimoto thyroiditis
Fungal infections(Histo,coccidiod).Aspergillus
the most common fungal inf.-no granulomas
Tuberculosis-rare.Caseating granulomas

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Chronic thyroiditis
Variable clinically ,immunologically and
pathologically-correlation not always evident
evident.
Problems with diagnosis and classification:
• High prevalence of anti-thyroid antibodies
in general population , especially women
• Subclinical nature of thyroiditis –common
common
• Hypothyroidism develops over a long
period of time, difficult to establish etiology

Chronic thyroiditis
Classification of pathologic findings is not
precise criteria not well defined
precise,
Etiology and pathogenesis –poorly defined
Lymphocytic infiltrates seen in up to 50%
thyroids examined histologically
Age related
related, more common in women
Significance of pathologic findings often
questionable

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Chronic lymphocytic thyroiditis

Hakaru Hashimoto
Japanese surgeon 1881-1934

Chronic lymphocytic thyroiditis

A.k.a. Hashimoto thyroiditis
Autoimmune thyroiditis--
y lymphocytic
y p y
infiltrates and destruction of follicles
Antibodies to TPO(95%), Tg (65%)
MOST COMMON CAUSE OF
HYPOTHYRODISM
F:M=6:1, genetic factors predispose
Peak in 5th decade, but occurs at any age
Rare in children and adolescents, still the
MOST COMMON THYROIDITIS under 20 y

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Chronic lymphocytic thyroiditis-

associations
Other autoimmune diseases COMMON:
autoimmune gastritis(pernicious anemia),
primary biliary cirrhosis, diabetes mellitus 2,
Sjögren disease, myasthenia gravis
================================
Autoimmune polyendocrine syndrome II—
(genetic) includes lymphocytic thyroiditis and
goiter, adrenalitis and diabetes mellitus 1,
Early onset but delayed Dx~30 years of age!

Chronic lymphocytic thyroiditis-

pathogenesis
Not entirely known-presumably immune
activation of CD4+ T-helper cells (genes+
environment).Many suggested mechanisms:
Iodine intake, drugs like amiodarone, INF-α,
homogy of antigens on Borrelia burgdorferi
and Yersinia enterocolitica
enterocolitica, low expression of
CTLA-4 ( a suppressor of T-cell activation)
Antibodies to TPO and Tg may play a role in
ADCC and NK cell effect. IgG4-RSD??

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Chronic lymphocytic thyroiditis-

pathology
Enlarged (~40
( 40 gm)
gm).Normal
Normal =15g(F)
15g(F),18g
18g (M)
Diffuse or nodular, cross section of variable
color:brown, yellow-tan, gray, motled, nodular
MI: Infiltrates of Ly,Pls,lymphoid follicles, loss
of thyroid
y cells, oncocytic
y metaplasia,
p foci of
fibrosis. Occasional multinucleated giant cells
Lymphocytes T>B, CD4:CD8=7:1,B-cell
polyclonal, in fibrous type↑ IgG4++

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Chronic lymphocytic thyroiditis-

thyroid cell-METAPLASIA
1.Oncocytic
1 Oncocytic metaplasia
(a.k.a.oxyphilic, Hϋrthle, Askanazy cells)
Cells enlarged, red granular cytoplasm
Nucleus may be enlarged nucleolus, and
even show prominent atypia !
By EM numerous mitochondria, defects in
cytochrome C oxidase,↓ respiratory chain
2.Squamous metaplasia (in fibrous variant!!)

Oncocyte (Hurthle cell)

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Chronic lymphocytic thyroiditis-

pathology-oncocytes
Nuclear changes-enlarged
changes enlarged and clear
clear,may
may be
confused with papillary carcinoma cells
Dd: in oncocytes nuclear changes most
prominent in area of inflammation gradually
merge with normal--PC-sharp transition from
tumor to benign thyroid
Cytoplasm of oncocytes may be clear-due to
swelling of mitochondria

Nuclei enlarged,clearing of
chromatin,most prominent in
areas of chronic inflammation

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Nuclear atypia

Chronic lymphocytic thyroiditis-

variants
Fibrous variant-(10%)
variant (10%),older
older patients
patients,
enlarged thyroid, firm, lobulated
Fibrous atrophy variant-small gland(1-6 g),
elderly, loss of follicles,titer ↑anti-TPO,-Tg
Juvenile variant- yyoungsters,
g less
destruction, but similar to adult Hashimoto
Cystic variant-with branchial cleft like cysts
Hashitoxicosis-Hashimoto with Graves
disease

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Chronic lymphocytic thyroiditis-

fibrous variant
Characterized by massive fibrosis replacing
thyroid follicles-clinically faster course
Fibrosis →lack of follicles.Limited to thyroid!
Infiltrates of Ly,Pls,lymphoid follicles,
Metaplasia
p oncocytic
y and squamous(!!)
q ( )
IgG4+ count allows subdivision in two groups
1. > 20/HPF, and IgG/IgG4 ratio >30%
2. < 20/HPF, and IgG/IgG4 ratio <20%

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Broad fibrous strands

and oncocytic metaplasia

Squamous metaplasia

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Squamous metaplasia and cyst

Squamous metaplasia-
clear cells

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Chronic lymphocytic thyroiditis-

fibrous atrophy
Small thyroid (5
(5-6
6 g).Small
g) Small thyroid follicles
remain
in fibrous
tissue

Chronic lymphocytic thyroiditis-

risk factor for neoplasia
Lymphoma incidence increased
Most lymphomas are marginal zone
lymphomas (MALT) or diffuse large B cell
lymphomas,20 to MALToma or de-novo.
Papillary carcinoma-?incidence controversial
NOTE: Lymphocytic thyroiditis is part of the
rare PTEN-hamartoma tumor syndrome
(multiple adenomas/hyperplasia, papillary
carcinoma and follicular carcinoma)

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Invasive fibrous thyroiditis

Bernhard Moritz Carl Ludwig Riedel

German surgeon, 1846-1916

Invasive fibrous thyroiditis

(Riedel)
A.k.a. fibrosing (invasive) thyroiditis,
sclerosing thyroiditis,
thyroiditis Riedel thyroiditis
• Association--30% have some other
fibroinflammatory disease such as
mediastinal or retroperitoneal fibrosis,
sclerosing cholangitis or pancreatitis,
orbital pseudotumor
• -IgG4 associated disease??
• Related to eosinophilia?

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Invasive fibrous thyroiditis

(Riedel)
Unknown etiology
etiology, suspected to be a form of
the IgG4-related sclerosing disease (RSD)
Peak age 50 years but may occur earlier
F:M=3:1
Fibrosis extending outside the thyroid
compression of trachea, larynx, esophagus.
Serum antibodies to TPO and Tg in 50% but
in lower titer than in Hashimoto
Corticosteroid therapy may give good results

Invasive fibrous thyroiditis

(Riedel)-pathology
MA: Thyroid firm fixated to surrounding
structures. Cut surface gray-white. Thyroid
involved diffusely or partially.
MI: Fibrosis and chronic inflammation extend
beyond thyroid. Infiltrates of Ly, Pls,
occasional Eo and PMN. Veins and venules
contain in their walls infiltrates of Ly and Pls.
Immuno:IgG4+ cells vary from 10-50%HPF,
but only 0.2-0.8% of all. IgG4 RDS ???

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Invasive fibrous thyroiditis

(Riedel) vs. fibrous Hashimoto
Features favoring Riedel:
1.Fibrosis extends beyond thyroid
2.Loss of lobulation of thyroid tissue
3.Absence of lymphoid follicles
4 Loss of thyroid follicles and no evidence of
4.Loss
oncocytic or squamous metaplasia
5.Venulitis-lymphocytic and or occlusive

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Common and uncommon forms

of chronic thyroiditis
Peritumoral thyroiditis —localized
localized ,especially
especially
common around papillary carcinoma
Silent thyroiditis (“painless thyroiditis with
hyperthyroidism”)-resembles de Quervain
thyroiditis but only infiltrates of lymphocytes,
no granulomas-viral, drug-induced?
Postpartum thyroiditis resembles clinically
silent thyroiditis, but occurs after pregnancy

Diffuse toxic hyperplasia of the

thyroid

Robert James Graves

Irish physician , 1796-1853

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Diffuse toxic hyperplasia of the

thyroid

A.k.a
A k a Graves disease
disease, Basedow disease in
Germany, diffuse toxic goiter
Common autoimmune disease,0.5-1% in US
F:M=3-5:1,peak 40-60 years, rare before
adolescence
Etiology:??- stress, pregnancy, smoking↑
Genetic- identical twin concordance= 35%
HLA-DR3 is risk factor (3-4x)

Diffuse toxic hyperplasia of the

thyroid-pathogenesis
Autoantibodies to thyroid stimulating
hormone receptor (THSR)on thyroid cells
Activate second messenger pathways
including cAMP transmission of signal to
gene for thyroid hormone synthesis.
Thyroid contains CD4
CD4+TTh1,CD4
1,CD4+T Th2,
CD4Treg (CD25+).
CD4+Th2 (autoantibody production) play key
role!!

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Diffuse toxic hyperplasia of the

thyroid-multiple genes

HLA DR3 on chromosome 6p21 plays a key

HLA-DR3
role in Caucasian populations
CTLA-4 (CD152) cytotoxic T lymphocyte
antigen 4 ,acts↓↓ T-cell mediated response
CD40 g gene on chr.20q—its
q protein belongs
p g
to the TNFR superfamily expressed on B
cells and antigen presenting cells
Protein tyrosine phosphatase 2 (PTPN2) acts
as inhibitor of T-cell activation

Diffuse toxic hyperplasia of the

thyroid-clinical

Signs and symptoms of hyperthyroidism:

Hyperactivity,anxiety,perspiration and heat
sensitivity,nervousness, fatigue, polyphagia
and loss of weight.
Warm moist skin, tremor, tachycardia,
hypertension, exophthalmus

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Diffuse toxic hyperplasia of the

thyroid-laboratory
Free T4 ↑in most cases, some only free T3↑
TSHR-two tests
1.anti TSHR antibodies--thyroid binding
inhibitory immunoglobulins (TBII)
2.Thyroid stimulating immunoglobulin(TSI)
Nonspecific thyroid antibodies in serum: anti-
TPO(90%),anti-Tg(50%)-not diagnostic
diagnostic value, but titer reflects activity of
disease, and is thus valuable in follow up

Diffuse toxic hyperplasia of the

thyroid-pathology
MA: Diffuse enlargement of thyroid,50-150 g
Nodularity seen in 10-20% cases
Spongy to firm, dark red to pale (treated)
MI: Diffuse hyperplasia- columnar cells, pale,
form papillary projections, narrowing lumen
Nuclei vesicular
vesicular, some hyperchromatic
Colloid stains lighter, peripheral scalloping
Lymphocyte infiltrates variable(CD8+>CD4+),
B cells in germinal centers

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Colloid pale and peripheral scalloping

Colloid –reduced amounts.Follicles have reduced lumen

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Reduced colloid-solid appearance of follicles

Papillary hyperplasia

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Diffuse toxic hyperplasia of the

thyroid-post treatment pathology

Radioactive iodine reduces the signs of

hyperplasia , causes atrophy of follicles.
Remain: oncocytic metaplasia, nuclear
atypia, residual hyperplastic nodules.
Fibrosis may be prominent
Lymphoid follicles persist-differential
diagnosis Hashimoto!
Papillary microcarcinoma,rare, 2-4%

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Differential diagnosis-Graves
vs papillary carcinoma
Graves Papillary carcinoma
Diffuse papillary Localized papillary
Papillae simple, contain Papillae complex with
no vascular cores vascular cores
Nuclei , enlarged ↑, Enlarged ↑↑ , nuclei not
basal polarized
Nuclear feature of PC DIAGNOSTIC PC
not prominent or focal NUCLEAR FEATURES
Cytoplasm vacuolated Cytoplasm scant, dense
Colloid scalloped, pale Colloid dark red, dense,
not scalloped

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Graves disease-
papillary hyperplasia

Nodular hyperplasia of the

thyroid

A.k.a.
A k a goiter
Clinical-pathologic classification
Multinodular
Endemic
Dyshormonogenetic
Toxic multinodular
Amyloid goiter

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Multinodular hyperplasia(goiter)

Etiology multifactorial -no

Etiology-multifactorial no single cause!
Smoking, goitrogenic foods,lack of iodine,
certain drugs (e.g. lithium,iodine containing
compounds),genetic factors
SINGLE GENE onlyy identified in PTEN-
hamartoma tumors syndrome(PHTS)
More common in women than men (5-10x)
NOTE:Almost all enlarged thyroids become
nodular over time!

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Multinodular hyperplasia(goiter)-
is it neoplasia or not?
No definitive answer
answer-work
work to be done!
Clonal analysis of X chromosome inactivation
show that many nodules have the same
pattern of inactivation=monoclonality!?
Cytogenetic—most
y g goiters have normal
g
karyotype but some show trisomy or
tetrasomy of Chr.7
Some nodules show autonomous growth

Multinodular hyperplasia(goiter)-
pathology
MA:Enlarged thyroid
thyroid-on
on average 200 g
Nodules vary in size, number, appearance
Secondary changes common-cystic,
hemorrhage, fibrosis,calcification
MI: Colloid nodules vs cellular nodules
(“adenomatous nodule”).Cells vary in size
and shape.
Sometimes form papillae structures(nuclei
dark), or so called Sanderson polsters.

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Dyshormonogenetic goiter

Enlargement of thyroid due to genetic defect

in the synthesis of thyroid hormone(50-250g).
Autosomal recessive inheritance
Symptoms appear before 25 years of age
Accounts for 15% of all cases of congenital
hypothyroidism, which has a rate of 1:4000
May resemble goiter treated with antithyroid
drugs or even follicular carcinoma

Dyshormonogenetic goiter-
pathology
Multinodular shows marked hyperplasia
Multinodular-shows
Very cellular, follicles contain scant colloid,
and are classified as solid or microfollicular
Less common: trabecular of insular
Nuclei enlarged, irregular shape, atypia often
in some nodules and surrounding thyroid.
Extensive fibrosis-DDx: follicular carcinoma
invading capsule!!

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Dyshormonogenetic goiter-
vs. follicular carcinoma
Dyshormonog.goiter Follicular carcinoma
Nodules resemble Nodular cells distinct
perinodal thyroid from normal thyroid
Colloid minimal Colloid minimal
Secondary changes rare Secondary change-yes
but variable
Fibrosis usuallyy mild, but Thick fibrous capsule
may be↑, thin fibers around most of tumor
No vascular invasion Tumor strands penetrate
capsule, or cells invade
blood vessels

Thank you for your attention!

THE END

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Common Lesions in the

Thyroid
Kyle Perry, MD

Disclosure
Dr Kyle Perry has nothing to disclose
Dr. disclose.

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Introduction
• Sometimes not a popular specimen
• Well documented variability
• Amongst individuals and likely institutions
• Difficult to characterize clinical behavior
• More frequently encountered
– More aggressive imaging/staging
• Molecular studies hold promise

Objectives
• Discuss frequent causes of “thyroid nodule”
– Specific histologic criteria
– Key histological variants
– Primary differential diagnosis
– Ancillary studies

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Follicular multinodular disease

• Frequent lesion in the thyroid
• Thought to represent dysfunction
– Found more frequently in areas lacking iodine
– Medications can interfere
– Most cases likely multifactorial
• Compensatory hyperplasia?
• 70% show clonal proliferation

Follicular multinodular disease

– Follicles of varying shape and size
– Colloid
C ll id usually
ll iis apparentt ((varying
i amounts)
t )
– Small bland nuclei
– Degenerative changes
• Hemosiderin deposition
• Fibrosis
– Reactive endothelial hyperplasia
– Squamous metaplasia, adipose metaplasia,
osseous metaplasia

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Multinodular goiter

Multinodular goiter

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Multinodular Goiter

Differential: Follicular adenoma

• Follicular adenoma
– Usually more encapsulated
– Follicles are more homogenous, smaller
– Distinct from extranodular parenchyma

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Differential: Papillary thyroid

carcinoma
• Papillary thyroid carcinoma
– Adenomatoid nodules can have papillary
projections (Sanderson's polsters)
• But they lack complexity
• Nuclear features are not present
– No peripheral chromatin condensation
– Longitudinal grooves
– No intranuclear cytoplasmic psuedoinclusions

Treatment
• Clinical monitoring
– FNA can almost exclude malignant entities
– If significant growth
• Radiodine ablation
– Can be gradual
• Subtotal thyroidectomy
– Allows
All assessmentt off th
the actual
t l nodule
d l
• T4 medical therapy
– Better for smaller goiters

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Follicular adenoma
• Benign follicular tumor
• Relatively
R l ti l common (3 (3-5%)
5%)
• Associated with iodine deficiency/radiation
exposure
• Genetic disorders
– Carneyy complex
p ((nevi, atrial myxoma,
y myxoid
y
neurofibromas, ephelides “freckles”)
– Cowden’s syndrome (intestinal
hamartomatous polyps, trichilemmomas, etc)

Follicular adenoma
• Microfollicular architecture
• Thin fibrous capsule
• Minimal colloid
• Bland appearing nuclei
• No angiolymphatic invasion
• No capsular invasion
– Need to see the entire lesion

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Follicular adenoma

Follicular adenoma

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Follicular adenoma variants

• Oncocytic adenoma
– Oncocytic (“Hurthle cells”) with granular
cytoplasm
– Central nuclei and prominent nucleoli
– Can have occasional hyperchromatic nuclei
– Acute hemorrhageg and infarction
– Emphasize benign

Follicular adenoma variants

• Adenolipoma
• Follicular adenoma with clear cells
• Follicular adenoma with signet ring cells

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Ancillary studies
• Will stain for usual follicular markers (TTF-
1 P
1, Pax-88 andd Th
Thyroglobulin)
l b li )
• Usually negative for galectin-3, HBME-1
and CITED1
• Often positive for mutations in RAS gene
(encodes GTPase)
– Not specific (follicular carcinomas can have)

Differential: Adenomatoid nodule

• Difficult on histology (and cytology)
• Not a well defined capsule
• Variable follicles
• Typically more colloid
• Good news-both with similar follow up

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Differential: Follicular carcinoma

• Often in differential diagnosis
– Similar microfollicular architecture
• Minimally invasive follicular carcinoma
– Defined by strict criteria for
• Capsular and/or
• Angiolymphatic
g y p invasion
– Good idea to submit the entire capsule

Differential: Follicular variant of

papillary thyroid carcinoma
• Diagnosis based on nuclear features
– Nuclear clearing
– Grooves
– Intranuclear pseudoinclusions
– Thresholds can be difficult (how clear is clear)
– HBME1,
HBME1 CK19,
CK19 galectin
galectin-3
3
– Molecular studies (BRAF(K601E), RET/PTC)
could prove helpful

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Treatment
• Lobectomy is usually performed (for
di
diagnosis)
i )
• Sometimes will clinical follow
– Patient put on levothyroxine

Follicular thyroid carcinoma

• 10% of thyroid malignancies
– (2nd most common)
• Decreasing in relative incidence
– Iodine deficiency (a frequent cause) is
decreasing
• Other risk factors
– Ionizing radiation
– Benign thyroid disease (eg goiter)

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Follicular thyroid carcinoma

• Slowly enlarging, solitary nodule
– Usually without symptoms
– Can be fixed to surrounding tissues
• Can sometimes present as distant met
– Pathological fracture

Follicular thyroid carcinoma

• Gross examination:
– Round
Ro nd nodule
nod le with
ith thick fibrotic caps
capsule
le
– Widely invasive tumors can be grossly id’d
• Microscopic examination:
– Small monomorphic microfollicles
– Nuclei without significant atypia
– Critical to define
• Angiolymphatic invasion
• Capsular Invasion

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Capsular invasion
• Widely invasive-> grossly evident
• Minimally invasive can be difficult

Follicular thyroid carcinoma

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Minimal capsular invasion

From CAP Cancer Reporting Protocol: Thyroid (Updated June 15, 2012)

Angiolymphatic invasion
• Lymphovascular invasion
– Capsular vessels/Extracapsular vessels
• Should be of venous caliber
• With attachment, thrombi, or endothelial lining
• Can’t be just free floating

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Lymphovascular invasion
– Capsular
vessels/Extracapsular
vessels
• Should be of venous
caliber
• With attachment,
thrombi, or endothelial
lining
• Can’t be just free
floating

From CAP Cancer Reporting Protocol: Thyroid (Updated June 15, 2012)

Angiolymphatic invasion

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Angiolymphatic invasion
– Focal=less than 4 vessels
– Extensive=4
E t i 4 or more vessels
l

Minimally Invasive
• Controversial terms and still evolving
• Possible definitions
– No capsular invasion but angiolymphatic
– Capsular invasion but not angiolymphatic
• CAP recommends report on components
and extent of invasion
– Accommodate various definitions of minimally
invasive

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Immunohistochemistry
• Can confirm follicular origin
– CK 7, Cam 5.2, AE1/AE3 positive
– TTF-1, PAX-8 (nuclear staining)
– CK 20 negative
– Calcitonin, CEA, chromogranin,
y p p y , CD56,, NSE negative
synaptophysin, g
– CD34/CD31 can confirm vascular invasion

Genetics
• PPARy-PAX8 fusion
– Younger patients, smaller tumors
– Possibly not specific (found in follicular
adenoma)
• RAS abnormal in up to 50%
– Not specific
• Follicular adenoma
• Follicular variant of papillary thyroid carcinoma

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Immunohistochemistry
• Galectin-3, HBME-1, CITED1
– Not specific (follicular adenoma)
– Two of three more specific
– Papillary thyroid carcinoma in differential

Oncocytic variant
• Similar criteria for malignancy
– Over 75% of cells oncocytic (Hurthle cells)
• Granular cytoplasm
• Variably sized nuclei
• Conspicuous nucleoli
– Does not respond well to post operative
i di
iodine

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Other variants
• Clear cell variant of follicular carcinoma
– Over 75% clear cytoplasm
• Mucinous variant of follicular carcinoma
• Follicular carcinoma with signet ring cells

Differential:Follicular adenoma
• Criteria for angiolymphatic/capsular
i
invasion
i

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Differential: Follicular variant of

papillary thyroid carcinoma (FVPTC)

• Can have predominantly follicular

architecture (follicular variant)
• Nuclear features most helpful
– Enlarged nuclei
– Intranuclear cytoplasmic pseudoinclusions
– Grooves

Differential: Medullary carcinoma

• Tumors composed of thyroid C-cells
• Lacks colloid
• Amyloid present
• Insular/nested architecture
• Immunohistochemical stains
– Synaptophysin positive
– Chromogranin positive
– Calcitonin positive

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Differential: Poorly differentiated

carcinoma
• Solid/trabecular patterns
• Mitotic figures and necrosis

Treatment
• Total thyroidectomy
• If minimally invasive, completion debatable
• Radioiodine therapy
• External RT if not possible to resect

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Prognosis
• 20 year survival
– 97% minimally invasive
– 50% widely invasive
• Over 45 years poorer prognosis
• Metastasizes to soft tissue (not lymph
nodes)

Papillary thyroid carcinoma

• Vast majority of thyroid malignancies
– In iodine “sufficient” areas
• Incidence has been increasing
– Increasingly picked up by scans
– Lower threshold for diagnosis?

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Etiologic factors
• Ionizing radiation major risk factor
• Iodine rich diet
• Thyroid disease
– Goiter
– Possibly Hashimoto’s and Grave’s

Papillary thyroid carcinoma

• Architecture can vary
– So
S nott necessarily
il papillary
ill
• Nuclear overlapping
• Loss of basal oriented nuclei
• Nuclear grooves
• Enlarged nuclei (3 times size of RBC)
• Peripheral nuclear chromatin condensation
• Peripheral nucleoli

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Intranuclear cytoplasmic
pseudoinclusions
• Strict criteria
– Defined border
– Material in inclusion similar
color to cytoplasm
– Inclusion must be 25% of
overall nuclear size
• Most specific but not
entirely specific
– Nonspecific
p vacuolization
– C cells/Medullary
carcinoma
– Reactive changes
(Hashimoto’s thyroiditis)

Other (nonspecific) features?

• Squamous metaplasia
• Giant cells
• Psammamotous calcifications

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Papillary thyroid carcinoma

Papillary thyroid carcinoma

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Papillary thyroid carcinoma

Papillary thyroid carcinoma

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Variants
• Tall cell variant
– Height three times width
– More aggressive
• Columnar cell variant
– Stratified, hyperchromatic cells
• Hurthle cell variant
– Nuclear features of PTC
• Warthin cell variant
– Oncocytic cytoplasm and associated lymphocytes

Oncocytic papillary thyroid

carcinoma

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Oncocytic papillary thyroid

carcinoma

Variants
• Cribiform-Morular Variant
– Variable architecture with whorled spindle
tumor cells
– Associated with familial adenomatous
polyposis
• Papillary
p y Carcinoma with Fasciitis-Like
Stroma
• Cystic papillary carcinoma

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Follicular variant of papillary thyroid

carcinoma (FVPTC)
• Predominantly follicular architecture
• Usually well circumscribed
• Scalloped, “bubble gum” colloid
• Distinct nuclei
– Large vesicular nuclei
– Chromatin clearing
– Irregular contour
– Pseudoinclusions less common

Follicular variant of PTC

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Follicular variant of PTC

“On the fence” lesions

• Nuclear enlargement
• Irregular
I l contours
t
– Irregular follicles
– Abortive papilla
– Irregular spaced nuclei
– Fibrosis
– Dense “bubble gum” colloid
• Inflammation?
• Adjacent parenchyma?

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Immunohistochemistry
• Confirm follicular origin
– CK 7, Cam 5.2, AE1/AE3 positive
– TTF-1, PAX-8 (nuclear staining)
– CK 20 negative
– Calcitonin, CEA, chromogranin,
y p p y , CD56,, NSE negative
synaptophysin, g
– CD34/CD31 can confirm vascular invasion

Immunohistochemistry
• Galactin-3
– Staining lower in follicular variant
• HBME-1
– Staining lower in follicular variant
• CK19
– Generally diffusely positive
– Not very specific
• CITED-1
– Nuclear protein involved in transcription
regulation

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Immunohistochemistry
• In combination, better specificity
• Strong staining in more than one helpful

Molecular studies
• BRAF-Most frequent in PTC
– BRAF (V600E)
• 99% specificity
• Possibly indicates more aggressive behavior
• Greater percentage in high risk variant (tall cell)
• Watch out for metastasis (colonic/lung primary).
– BRAF (K601E)
• 1-2% of cases
• Follicular or microfollicular growth pattern (FVPTC)

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Molecular studies
• RET/PTC
–CCommon iin radiation
di ti PTC
– Favorable prognosis and usually do not progress
• RAS
– Predominantly in FVPTC
• NTRK
– Rearrangements involving the NTRK1 gene
– Small minority of cases (approximately 5%)
– Uncertain clinical significance

Differential: Hyperplastic nodule

• Can have focal Sanderson’s polsters
• Lack nuclear features

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Differential: Follicular adenoma

• Particularly problematic with FVPTC
• Careful nuclear evaluation

Differential: Poorly differentiated

carcinoma
• Shouldn’t have PTC nuclear changes

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Prognosis
• Generally excellent
• Prognostic factors for survival
– Age: older than 45 years poorer (strongest)
– Tumor size
– Distant metastases
– Extrathyroidal extension
• Prognostic factors for recurrence
– Lymph node involvement

Treatment
• Total or near total thyroidectomy
– Possibly
Possibl dissection of central llymph
mph nodes
– Except those less than 1.0 cm (papillary
microcarcinoma)
• Radioactive iodine for Stage II-IV disease
• Long term disease monitoring
– Serum thyroglobulin
– Neck ultrasound
– Sometimes other imaging

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Treatment
• Future potential with molecular targeted
therapy
th
– Such as BRAF inhibitors

Summary
• Thyroid can be intimidating
• Strict diagnostic criteria are important
• Immunohistochemistry should be used
with caution
• Molecular studies could prove helpful

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Rare (But Important) Thyroid

Lesions
Dr. Kyle Perry, MD

Disclosure
Dr Kyle Perry has nothing to disclose
Dr. disclose.

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 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Objectives
• Discuss rare (but important) thyroid
l i
lesions
– Specific histologic criteria
– Histological variants
– Key differential diagnosis
– Relevant ancillary studies

Medullary thyroid carcinoma

• 3-4% of thyroid malignancies
– Most cases are sporadic
– Familial in 15-30% of cases
• Younger age
• Autosomal dominant

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Medullary thyroid carcinoma

• MEN 2A
– Medullary thyroid carcinoma (90-100%)
• Usually
U ll fifirstt manifestation
if t ti
– Pheochromocytoma
– Primary parathyroid hyperplasia
• MEN 2B
– Medullary thyroid carcinoma (100% risk)
– Pheochromoctyoma (50%)
– Mucosal neuromas, GI ganglioneuromatosis, marfanoid habitus
• Familial medullary thyroid carcinoma
– No evidence of pheochromocytoma, hyperparathyroidism
– Multiple carriers or family members
– More than 10 carriers

Clinical presentation
• Painless solitary nodule
• 5th-6th decade of life
• Hoarseness, stridor, dysphagia
• Approximately 50% will have metastasis
• Can have paraneoplastic syndromes
– Diarrhea
– Rarely Cushing syndrome

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Gross examination
• Range in size
– Microcarcinomas are less than 1 cm
• Often in mid lateral lobes
– Highest density of C cells
• Can be bilateral (if hereditary)

Microscopic
• Various architecture patterns
– Sheets and nests of cells separated by stroma
• Trabecular
• Insular
• Linear
– Round, oval or spindled nuclei, fine chromatin
– Amphophilic cytoplsm
– Background
g fibrous stroma
• Variable and thickness
• Can have calcifications
– Amyloid is often present
• Likely from calcitonin

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Microscopic
• Usually rare mitosis
• Can
C h have nuclear
l pseudoinclusions
d i l i
– “Great mimicker”
• Less common features
– Mucin
– Clear cytoplasm
• Focal calcifications
• Less than 1 cm = medullary
microcarcinoma

Medullary thyroid carcinoma

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Medullary thyroid carcinoma

Medullary thyroid carcinoma

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Medullary thyroid carcinoma

Medullary thyroid carcinoma

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Microscopic variants
• Oncocytic variants
– Oncocytic cytoplasm
– Will stain for calcitonin
• Glandular variant
– Tubular structure with “colloid like” material
• Papillary variant
– Papillary architecture from cell drop out

Microscopic variants
• Spindle cell variant
– Entirely composed of spindle cells
• Squamous cell variant
• Clear cell variant
• Small cell variant
• Paraganglioma variant
• Giant cell variant
• Melanin producing variant
• Angiosarcoma like variant

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Immunohistochemistry
• Positive for calcitonin (can be variable)
• Positive for synaptophysin, chromogranin
• Other peptides can be positive
– Gastrin releasing peptide
– Insulin
– ACTH
– Somatostatin
– Glucagon

Molecular Studies
• Familial medullary carcinomas associated
with
ith gain
i off function
f ti RET mutations
t ti
(codes for tyrosine kinase)

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Molecular Studies
• Sporadic medullary thyroid carcinoma
– Somatic RET mutations in 30-66%
• Higher frequency of metastasis
– Lymph nodes and distal

Molecular studies
• Useful for establishing germline mutation
• Peripheral blood drawn for RET mutation
– Location of the mutation identified
– Family members can then be tested

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Differential: C-cell hyperplasia

• C-cell hyperplasia
– Precursor of hereditary medullary carcinoma
– Greater than 50 cells/10 hpf
• Somewhat arbitrary designation
– Lacks destructive growth
• Lacks fibrosis

Differential: Papillary carcinoma

• Both can have intranuclear inclusions
• Medullary can have pseudopapillary
architecture
• Calcitonin can be helpful

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Differential: Follicular carcinoma

• Medullary can also have tubular
architecture
hit t (glandular/tubular
( l d l /t b l variant)
i t)
– “Intratubular material” can mimic colloid
• However
synaptophysin/chromogranin/calcitonin is
positive in medullary
– Not in follicular carcinoma.

Differential: Poorly differentiated

carcinoma
• Poorly differentiated carcinoma
– Insular architecture
– Both can have solid or nodular architecture
– Calcitonin can help discriminate

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Differential: Anaplastic carcinoma

• Spindle cells can lead to misdiagnosis
– Calcitonin will help

Treatment
• Total thyroidectomy
• Central neck dissection
• Possible ipsilateral modified radial neck
dissection.
• Prophylactic thyroidectomy
– Those
Th with
ith germline
li RET mutations
t ti

633
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Treatment
• Post operative treatment variable
– External RT
– Radioiodine therapy
– Radiofrequency ablation
– Potential RET directed therapy
• Prophylactic thyroidectomy
– Family members with germline mutations

Poorly differentiated carcinoma

• Aggressive malignancy
• Loss of thyroid differentiation
• Intermediate between follicular/papillary
and anaplastic thyroid carcinoma

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Poorly differentiated carcinoma

• Less than 1% of thyroid malignancies
• Patients tend to present older
– 5th to 6th decades
• Evolve from preexisting malignancy
– Follicular or papillary carcinoma
• Can
C also
l occur as a primary
i

Prognosis
• 50% will have metastasis at diagnosis
• Prognostic indicators
– Extrathyroidal extension
– Lymph node metastasis

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Poorly differentiated
carcinoma(insular carcinoma)
• Mass
– Often chronically present with recent increase

Microscopic
• Solid/insular/trabecular architecture
• No nuclear features of papillary carcinoma
• One of following:
– Convoluted nuclei
– Tumor necrosis (in at least a group of cells)
– Increased mitosis (3 or more per 10 hpf)

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Poorly differentiated carcinoma

Poorly differentiated carcinoma

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Poorly differentiated carcinoma

Immunohistochemistry
• Diffuse positivity for TTF-1 present
• Only focal thyroglobulin staining
• PAX8 present
• AE1/AE3, CK7 strong and diffuse
• Ki-67 usually 10-30%

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Differential: Follicular Carcinoma

• Follicular carcinoma can have solid pattern
• Should not have significant mitosis or
necrosis

Differential: Papillary thyroid

carcinoma
• Solid PTC can be mistaken for poorly
diff
differentiated
ti t d thyroid
th id carcinoma.
i
• Nuclear features helpful in differentiating

639
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Differential: Medullary thyroid

carcinoma
• Both usually lack follicular architecture
• Immunohistochemical stains
(synaptophysin, chromogranin, calcitonin)
can help exclude

Differential: Anaplastic Carcinoma

• More nuclear atypia
• Greater amount of necrosis
• Anaplastic carcinoma
– AE1/AE3 only focally retained
– Lost TTF-1 and thyroglobulin

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Prognosis
• Between well differentiated neoplasm and
anaplastic
l ti ththyroid
id carcinoma
i
• Approximately 5 year survival of 65%
• Approximately 10 year survival of 35%

Treatment
• Less consistent treatment regimens
• Total thyroidectomy and lymph node
dissection
• Many advocate radioactive iodine
• Also external beam RT for higher stage
tumors.
tumors

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Anaplastic thyroid carcinoma

• Highly aggressive thyroid malignancy
– Thyroid follicular cell origin
• 1-2% of thyroid malignancy
• Goiter is a risk factor
• Many originate from existing malignancy
which
hi h progresses
• Often originates in older adults

Anaplastic thyroid carcinoma

• Prexisting thyroid malignancy
• Preexisting benign disease
– Goiter
• Iodine deficiency
• Radiation exposure

642
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Clinical presentation
• Clinical correlation important
• Rapidly growing neck mass
• Grossly replaces the thyroid gland
• Extends into soft tissue and muscle
• 50% with extrathyroidal extension

Gross examination
• Often replaces the thyroid gland
• Extends into the adjacent soft tissue

643
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Microcopic
• Variable patterns
– Necrosis (extensive)
– Widely invasive growth
– Mitosis
– Nuclear pleomorphism
• Irregular
g nuclei with coarse chromatin

Microscopic patterns
• Spindle cells
– Fibrosarcoma like or MFH like
• Squamoid (nonkeratinizing)
• Pleomorphic giant cells
– Multiple hyperchromatic nuclei
• C
Can h
have rhabdoid
h bd id cells
ll
• Can be hypocellular

644
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Anaplastic thyroid carcinoma

Anaplastic thyroid carcinoma

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Anaplastic thyroid carcinoma

Anaplastic thyroid carcinoma

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Anaplastic thyroid carcinoma

Immunohistochemistry
• Negative markers don’t mean much
• AE1/AE3-over
AE1/AE3 80%
– But focal and weak
– Spindle cell histology least likely to stain
• EMA is less sensitive
• TTF-1 rarelyy expressed
p
• PAX8 in 79% of anaplastic carcinoma
• Ki-67 (about 50%)

647
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Differential: Poorly differentiated

thyroid carcinoma
• Significant prognostic difference
• Anaplastic with more nuclear
pleomorphism
– More necrosis
– TTF-1 usually not expressed

Differential: Riedel Thyroiditis

• Paucicellular anaplastic thyroid carcinoma
can mimic
i i Riedel
Ri d l
– TP53 will highlight anaplastic cells
– Look for atypical cells in a fibrous stroma

648
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Differential: Medullary thyroid

carcinoma
• Can rarely dedifferentiate and lose
calcitonin
l it i
– Be wary of anaplastic carcinoma if history of
MEN 2a/2b
– Medullary with RET mutation
– Anaplastic
p with BRAF, RAS, RET/PTC

Hyalinizing trabecular tumor

• Very rare thyroid tumor
• Patient’s predominantly female
• Often in lymphocytic thyroiditis or goiter
• Presents as palpable nodule

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Clinical presentation
• Palpable nodule
• Can be incidentally found on goiter
resection

Microscopic
• Well circumscribed
• Cords
C d off ffusiform
if cells
ll with
ith elongated
l t d
nuclei
• Background stroma often hyalinized
• Minimal colloid
• Grooves/intranuclear pseudoinclusions
• Yellow cytoplasmic granules
• Background inflammation or hypertrophy

650
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Hyalinizing trabecular tumor

Hyalinizing trabecular tumor

651
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Hyalinizing trabecular tumor

Hyalinizing trabecular tumor

652
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Immunohistochemistry
• Positive for TTF-1, thyroglobulin
• Negative for calcitonin
• Ki-67
– Membranous/peripheral cytoplasmic staining

Differential: Papillary carcinoma

• Similar nuclear features
– Grooves
– Intranuclear inclusions
• Granules, background hyalinization can
help
• Ki-67
Ki 67 staining pattern helpful

653
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Differential: Follicular adenoma

• Follicular adenoma contains bland nuclei
• Doesn’t usually have atypical nuclear
features
• Lacks unique Ki-67 staining
• Lacks intratrabecular hyalinization

Differential: Medullary Carcinoma

• Hyalinizing trabecular tumor
– Possibly may show chromogranin positivity
• Calcitonin will differentiate

654
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Molecular studies
• Possibly RET/PTC (still unclear)
– Positive reports of this translocation were not
quantiative
• Negative for BRAF and RAS mutations

Prognosis/Treatment
• Extremely low malignant potential
• Lobectomy generally curative

655
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Metastases to thyroid
• Mass in thyroid gland
• Often can be initial sign of malignancy
• Can be solitary or multiple nodules

Microscopic
• Generally resembles the primary lesion
• Distinct from thyroid parenchyma
• Common Sources
– Kidney
– Lung
– Breast

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Metastatic RCC

Metastatic RCC

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Finding the primary

• Primary thyroid follicular tumors
– TTF-1
TTF 1
– Thyroglobulin
– PAX8
– CK7
• Primary C-cell tumors
– Synpatophysin
– Chrommogranin
Ch i
– Calcitonin
• Clinical history can be most helpful

Differential: Clear cell variant of

follicular adenoma
• Can be confused for renal clear cell
carcinoma
i
– RCC has more vascularity
– RCC will stain positive with CD10, EMA, RCC
antigen

658
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Differential: Primary SCC of thyroid

• Clinically exclude direct extension
• Exclude direct metastases

Summary
• Rare entities can still occur in everyday
practice.
ti
• Exclusion is critical to avoid misdiagnosis
• Ancillary studies can be helpful

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Soft tissue lesions of

head/neck
Dr. Kyle Perry, MD

Disclosure
Dr Kyle Perry has nothing to disclose
Dr. disclose.

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Objectives
• Common soft tissue tumors of head/neck
– Key clinical presentations
– Histologic diagnosis
– Differential diagnosis

Spindle cell/pleomorphic lipoma

• Shoulder and posterior neck common site
– In addition to back
• Predominantly in older middle age men

661
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Gross examination
• Fatty lesion with myxoid or fibrous features
• Usually well circumscribed

Microscopic
• Varying amounts of
– Adipose tissue
– Spindled cells
• Bland oval cells
• Vague areas of parallel orientation
– Myxoid background
– Floret cells
• Peripheral hyperchromatic nuclei
• Eosinophilic cytoplasm

662
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Spindle cell lipoma

Spindle cell lipoma

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Spindle cell lipoma

Spindle cell lipoma

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Spindle cell lipoma

Immunohistochemical stain
• Spindle cells are positive for CD34
• Floret cells also stain for CD34
• Negative for active or desmin

665
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Differential:Neurofibroma
• “Adipose poor” spindle cell lipoma
– Neurofibroma can have CD34 positive cells
– Neurofibroma with “buckled nuclei”
– Spindle cell lipoma not positive for S-100
– NF should be negative in spindle cell lipoma

Differential:Neurofibroma

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Differential:Neurofibroma

Differential:Well differentiated
liposarcoma
• Both can have “floret like cells”
• WDL usually does not have ropey collagen
• MDM/CDK4 FISH studies will differentiate
• CD34 staining usually not seen in WDL

667
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Differential:Well-Differentiated
Liposarcoma

Differential:Well-Differentiated
Liposarcoma

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Differential:Well-Differentiated
Liposarcoma

Differential:Spindle cell liposarcoma

• Spindle cell liposarcoma
– Contains highly atypical vacuolated lipoblasts

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Nodular fasciitis
• Young adults to middle age
• Generally limited in size (less than 3 cm)
• Head and neck second most common site
– Upper extremity most common
• Usually subcutaneous/can arise in muscle

Histology
• Frequently a difficult lesion given variation
– Irregular fascicles
– Whirls of fibroblasts/myofibroblasts
• Rare giant cells
• Peripheral microcyst architecture and rbc
• Can
C b be myxomatous,
t cellular
ll l or fib
fibrous
– Depending on age
– Older with increased collagen deposition

670
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Nodular fasciitis

Nodular fasciitis

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Nodular fasciitis

Immunohistochemistry
• Myofibroblast like pattern
– Variable staining with smooth muscle actin
– Desmin limited to none
– Negative for caldesmon

672
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Molecular
• Clonal proliferation detected
• MYH9-USP6

Differential:Neurofibromatosis
• Both can have myxoid background
• Neurofibroma with “shredded carrot”
• NF with mast cells
• NF is S-100 reactive

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Differential:Leiomyosarcoma
• Can be superficial with spindled cells
• Generally more organized fascicles
• Blunt ended nuclei
• Typically positive for desmin, caldesmon
• Both will have positivity for actin

Differential:Leiomyosarcoma

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Differential:Leiomyosarcoma

Differential-Malignant Fibrous
Histiocytoma
• Both can have significant mitosis
• MFH usually with pleomorphic nuclei
• MFH usually larger
– Not well circumscribed

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Treatment-Nodular Fasciitis
• Conservative excision
• Very rarely recur (if incompletely excised)

Schwannoma
• Nerve sheath tumor, predominantly
composedd off S
Schwann
h cells
ll
• Common in adults (30-50)
• Can be associated with neurofibromatosis
type II

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Schwannoma
• Fascicles of plump spindle cells
• T
Tapering
i nuclei l i
• Abundant eosinophilic cytoplasm
• Areas of hyper and hypocellularity.
• Indistinct cell borders
• Palisading
• Perivascular hyalinization
• Hemosiderin deposition

Schwannoma

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Schwannoma

Schwannoma

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Schwannoma

Schwannoma

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Schwannoma-
Immunohistochemistry
• S-100 positivity
• Positive for GFAP
• EMA stains capsule

Schwannoma-Differential Diagnosis
• Melanocytic lesion
– MART-1 negative.
• Reactive fibroblastic proliferation
• Malignant peripheral nerve sheath tumor
– Strong S-100 staining should be assuring

680
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Palisaded encapsulated neuroma

• Spontaneous proliferation of nerve sheath
elements
l t
• Small asymptomatic nodule
– Face of adult patients

Palisaded encapsulated neuroma

• Solid proliferation of Schwann cells
• Intermixed with axons
• Well circumscribed
• Can see pre-existing nerve at base
• Can also see clefting in the lesion

681
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Palisaded encapsulated neuroma

Palisaded encapsulated neuroma

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Palisaded encapsulated neuroma-

Differential
• Schwannoma
– Antonia A and B areas,
areas no neurofilament
ne rofilament
axons
• Perineuroma
– Perineural cells will demonstrate EMA
positivity
– No neurofilament axons
• Pilar leiomyoma
– Will demonstrate desmin positivity

Epithelioid hemangioma
• Angiolymphoid hyperplasia with
eosinophilia
i hili
• Benign vascular tumor with characteristic
features
• Dermal or subcutaneous nodules
• Commonly in head and neck region
– Particularly around the ear

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Epithelioid hemangioma
• Aggregate of capillaries with lobular
arrangementt
– Often surrounding a central vessel
• Focal solid areas of endothelial cells
• Endothelial cells with epithelioid features
– This feature can be “patchy”
patchy
• Background eosinophils

Epithelioid hemangioma

684
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Epithelioid hemangioma

Epithelioid hemangioma

685
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Differential:Epithelioid
angiosarcoma
• Angiosarcoma
– Nuclear atypia and mitosis
– Usually lacks eosinophils

Differential: Epithelioid
angiosarcoma

686
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Differential: Epithelioid
angiosarcoma

Differential:Epithelioid
Hemangioendothelioma
• Epithelioid hemangioendothelioma
– Background myxoid matrix
– Usually doesn’t have eosinophils

687
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Differential-Kimura Disease
• Also occurs in head and neck region
• Also with eosinophils
• Kimura disease
– Infiltrative margins
– Lymphoid follicles
– Eosinophilic microabscesses
– Lymphadenopathy
• Peripheral eosinophilia or elevated IgE

Prognosis
• Benign
• Can have local recurrence (approximately
33%)

688
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Paraganglioma
• Arises from the paraganglia (hence the
name)
• More frequent in head and neck
– Carotid body
• Mostly adults
• Associated with
– Carney triad (GIST, pulmonary chondroma,
paraganglioma)
– Others (MEN2, NF)

Clinical presentation
• Painless mass
• Can be associated with vagal symptoms
(such as syncope)

689
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Paraganglioma
• Nested pattern (Zellballen)
• Mix of clear and granular cells
• Sustentacular cells around nests
• Fibrosis can be present
• Atypical nuclear features can be present

Paraganglioma

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Paraganglioma

Paraganglioma

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Immunohistochemistry
• Chromogranin, CD56 positive
• S-100 positive in sustentacular cells
• AE1/AE3, EMA negative

Differential:Melanoma
• S-100 can be positive in both (different
patterns)
tt )
– Additional melanocytic markers can help

692
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Differential:Metastatic RCC
• Both entities can have clear cells
• RCC will be AE1/AE3

Differential: Metastatic RCC

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Differential: Metastatic RCC

Paraganglioma:Prognosis
• Mostly benign but can recur
• Rarely will have malignant tumors which
will metastasize to other sites
– Bone
– Lung
– Lymph nodes

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Paraganglioma: Treatment
• Surgical excision

Embryonal Rhabdomyosarcoma
• Malignant sarcoma with skeletal muscle
diff
differentiation
ti ti
• Majority in young children.
• Head and neck common site

695
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Embryonal Rhabdomyosarcoma
• Small, hyperchromatic round or spindle cells
• Scattered cells with eosinophilic cytoplasm
• Myxoid or fibrous background
• Varying cellularity
• Necrosis
• About 50% will show striated cytoplasm
– (Strap cells)
– More apparent after chemotherapy

Embryonal Rhabdomyosarcoma

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Immunohistochemistry
• Desmin (diffusely positive)
• Myogenin and MyoD1
– Not diffusely positive
– These are nuclear stains

Molecular genetics
• Loss of heterozygocity at 11p15
• No consistent, definitive translocation

697
 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Differential: Ewing Sarcoma

• Ewing sarcoma
– Negative for myogenic markers
– CD99 diffusely positive
– Usually EWSR1-FLI1/ERG

Ewing Sarcoma

698
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Differential: Poorly Differentiated

Synovial Sarcoma
• At least focal keratin or EMA expression
• Negative myogenin experssion
• SYT-SSX1/2 fusion

Differential: Alveolar
Rhabdomyosarcoma
• Molecular cytogenetics can help
diff
differentiate
ti t
– T(1;13) or T(2;13)

699
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Prognosis
• 5 year survival about 73%
• Localized disease does well
• Distant metastatic disease poor prognosis

Alveolar rhabdomyosarcoma
• High grade sarcoma with skeletal muscle
diff
differentiation
ti ti
• Can arise in head and neck
• Median age in adolescence

700
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Histology
• Poorly differentiated oval/round cells
• Central loss of cells forms “alveolar”
architecture
• Fibrous septa can be present
• Can have (and be predominant) solid
• Rare rhabdomyoblasts
• Giant cells can be present

Alveolar rhabdomyosarcoma

701
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Alveolar rhabdomyosarcoma

Alveolar rhabdomyosarcoma

702
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Immunohistochemistry
• Desmin (Diffusely positive)
• Myogenin (diffuse) and MyoD1 positive
• Smooth muscle actin can be positive
• CD56 positive

Molecular cytogenetics
• t(2;13)(q35;q14)->PAX3-FOX01A
• t(1;13)(p36;q14)->PAX7-FOX01A
• Approximately 20% negative for fusion

703
 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Differential:Embryonal
Rhabdomyosarcoma
• Molecular confirmation can be helpful
• Myogenin not as strong in Embryonal
Rhabdomyosarcoma

Prognosis
• Usually worse than Embryonal
Rh bd
Rhabdomyosarcoma

704
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Treatment
• Chemotherapy
– In conjunction with surgery or/and RT

Rhabdomyoma
• Adult type
– 6th to 7th decades
• Fetal type
– Childhood

705
 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Microscopic
• Adult rhabdomyoma
– Large eosinophilic cells
– Scattered vacuolated cells
– Bland nuclei (some nucleoli)
• Fetal rhabdomyoma
– Spindled eosinophilic cells
– Occasional striations

Rhabdomyoma

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Immunohistochemistry
• Desmin
• Myogenin
• MyoD1

Differential:Hibernoma
• Usually more multivacuolated cells
• Nuclei are more central

707
 Copyright © The Oakstone Institute, 2014. All Rights Reserved.

Differential: Rhabdomyosarcoma
• Rhabdomyosarcoma usually not as
diff
differentiated
ti t d
• Rhabdomyosarcoma will usually have
– Mitosis
– Necrosis
– More atypia

Differential:Granular Cell Tumor

• Granular rather than fibrillary cytoplasm
• S-100 positive

708
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Summary
• Variety of soft tissue lesions that involve
h d and
head d neckk
• Ancillary diagnostics can be helpful
• Histologic context is important

709
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Fine Needle Aspiration

Cytology of Thyroid
The New Bethesda Reporting System

Fang Fan, MD, Ph.D

Department of Pathology and Laboratory Medicine
University of Kansas Medical Center

Disclosure
Dr Fan has nothing to disclose
Dr. disclose.

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Thyroid FNA
Introduction

The Bethesda System for Reporting Thyroid

Cytopathology
– Nondiagnostic or Unsatisfactory
– Benign
– Atypia of Undetermined Significance or Follicular Lesion of
Undetermined Significance
– Follicular Neoplasm or Suspicious for a Follicular Neoplasm
– Suspicious for Malignancy
– Malignant

The role of molecular markers

Thyroid FNA

Thyroid nodules are common

Most
M t off th
these nodules
d l are benign
b i
FNA is a safe, cost-
cost-effective, and
accurate means of evaluating a thyroid
nodule
– Decrease number of patients needing
i
surgery, increase i ld off malignancies
yield li i att
thyroidectomy
– Decrease cost of managing thyroid nodules

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Challenges

Often done by y radiology

gy
Lots of slides - bloody
Combination of features
Diagnostic categories

Thyroid FNA

NCI Thyroid FNA State of the Science

Conference, Bethesda, MD, October 22-
22-
23, 2007

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Thyroid FNA

Indications for thyroid FNA

Training
Technique
Ancillary testing
Diagnostic terminology
Patient management

Thyroid FNA
Indications
– Any nodule with sonographically
suspicious features should be considered
for FNA
– Lesions with a maximum diameter greater
than 1.0
1.0--1.5 cm should be considered for
FNA

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Thyroid FNA
Technique
– Palpation and ultrasound are acceptable for
guidance
– Smears and cell blocks are acceptable
preparation methods; liquid-
liquid-based
preparation is still controversial

Specimen Processing
Direct smears → DQ, pap
Rinse needle in CytoLyt →
– Thin-Layer preparation
– Cell block
Ancillary:
Flo Cytometry
– Flow C tometr (rinse needle in RPMI)
– IHC
– Special Stains

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Direct Smears
DQ (Romanowsky)
– Rapid, on-site evaluation
– Better for extracellular features: colloid,
amyloid, cytoplasmic detail (granules)

Pap
– Better for nuclear features: inclusions,
grooves, chromatin

Thyroid FNA
Introduction

The Bethesda System for Reporting Thyroid

Cytopathology
– Nondiagnostic or Unsatisfactory
– Benign
– Atypia of Undetermined Significance or Follicular
Lesion of Undetermined Significance
– Follicular Neoplasm or Suspicious for a Follicular
Neoplasm
– Suspicious for Malignancy
– Malignant

Patient Management

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Bethesda Terminology for Reporting

Thyroid FNA Results

I Nondiagnostic or Unsatisfactory
I.
II. Benign
III. Atypia of Undetermined Significance or
Follicular Lesion of Undetermined
Significance
IV F
IV. Follicular
lli l N Neoplasm
l or Suspicious
S i i for
f a
Follicular Neoplasm
V. Suspicious for Malignancy
VI. Malignant

Bethesda Terminology for Reporting

Thyroid FNA Results

I Nondiagnostic or Unsatisfactory
I.
II. Benign
IV. Follicular Neoplasm or Suspicious for a
Follicular Neoplasm
V. Suspicious for Malignancy
VI. Malignant
III. Atypia of Undetermined Significance or
Follicular Lesion of Undetermined
Significance

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Bethesda Terminology for Reporting

Thyroid FNA Results
Nondiagnostic or Unsatisfactory
– Specimen processed and examined, but
non-
non-diagnostic due to
Limited cellularity
– require at least 6 groups, each with at least 10 well-
well-
visualized follicular cells
y fluid only
Cyst y ((or fewer than 6 g p of ten
groups
follicular cells)

Exceptions: Thyroiditis, abundant colloid, any

atypia

Cyst
Contents

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Bethesda Terminology for Reporting

Thyroid FNA Results

I Nondiagnostic or Unsatisfactory
I.
II. Benign
IV. Follicular Neoplasm or Suspicious for a
Follicular Neoplasm
V. Suspicious for Malignancy
VI. Malignant
III. Atypia of Undetermined Significance or
Follicular Lesion of Undetermined
Significance

Follicular lesions

Nodular hyperplasia (nodular goiter) Follicular adenoma

Follicular neoplasm
on FNA

Follicular carcinoma

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Demay, The Arts and Science of Cytopathology

Bethesda Terminology for Reporting

Thyroid FNA Results
Benign
– Includes
Nodular goiter (colloid nodule)
Hyperplastic nodule/adenomatoid nodule
Chronic lymphocytic thyroiditis

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Bethesda Terminology for Reporting

Thyroid FNA Results
Benign
– Colloid nodule
Abundant colloid
Follicular cells small, arranged in monolayer
sheets
– Hyperplastic nodule/adenomatoid nodule
Cellular
C ll l specimen
i with
ith a b
background
k d off watery
t
colloid and macrophages
Cells arrange in a macrofollicular pattern
(evenly spaced honeycomb arrangement, in
spheres and fragments)

Colloid Nodule

H&E

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DQ
Colloid

DQ
Colloid

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PAP
Colloid

PAP
Colloid

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Follicular Sheet

DQ

Intact Macrofollicle

DQ

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Bethesda Terminology for Reporting

Thyroid FNA Results
Benign
– Lymphocytic thyroiditis
Cellular specimen
Abundant mixed lymphocytes, plasma cells,
and germinal center fragments
Scant colloid, follicular cells with oncocytic
features (Hurthle cells) and variable nuclear
atypia

Chronic Lymphocytic Thyroiditis

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Bethesda Terminology for Reporting

Thyroid FNA Results

I Nondiagnostic or Unsatisfactory
I.
II. Benign
V. Follicular Neoplasm or Suspicious for a
Follicular Neoplasm
V. Suspicious for Malignancy
VI. Malignant
III. Atypia of Undetermined Significance or
Follicular Lesion of Undetermined
Significance

Bethesda Terminology for Reporting

Thyroid FNA Results
Follicular Neoplasm or Suspicious for a
Follicular Neoplasm
– Includes follicular adenoma and follicular
carcinoma
– The distinction between FA and FC is not
possible by FNA
– The diagnosis of FC is only based on the
demonstration of capsular and/or vascular
invasion
– Surgery is needed for definitive diagnosis

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Bethesda Terminology for Reporting

Thyroid FNA Results
Follicular Neoplasm or Suspicious for a
Follicular Neoplasm
– Hypercellularity
– Scant colloid, in small dense droplets
– Three cytoarchitectural patterns of
follicular cells
Microfollicular (<15 cells
cells, arranged in a ringlike
or wreathlike pattern)
Trabecular
Crowded, three-
three-dimensional groups and
dispersed cells

H&E

PAP

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DQ

PAP

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Follicular Neoplasm or Suspicious for a Follicular Neoplasm

Architecture FNA Dx Histologic Dx

Predominantly Benign-
Benign- adenomatoid
macrofollicular adenomatoid nodule nodule

Predominantly Suspicious Follicular adenoma

microfollicular, for follicular neoplasm or follicular carcinoma
t b
trabecular,
l or
three--dimensional
three

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Bethesda Terminology for Reporting

Thyroid FNA Results

I Nondiagnostic or Unsatisfactory
I.
II. Benign
IV. Follicular Neoplasm or Suspicious for a
Follicular Neoplasm
-specify if Hurthle cell type
V. Suspicious for Malignancy
VI. Malignant
III. Atypia of Undetermined Significance or
Follicular Lesion of Undetermined
Significance

Bethesda Terminology for Reporting

Thyroid FNA Results
Suspicious for Hurthle cell neoplasm
– Cellular aspirate comprising pure
population of Hurthle cells, mainly in
scattered single cells and loosely cohesive
groups, crowded three dimensional
groups can be seen
S
– Scantt colloid
ll id
– Absent lymphocytes and plasma cells

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DQ Pap

Hurthle cells:
Abundant dense granular cytoplasm
Enlarged round eccentrically located
nucleus
Prominent central nucleolus

Bethesda Terminology for Reporting

Thyroid FNA Results

I Nondiagnostic or Unsatisfactory
I.
II. Benign
IV. Follicular Neoplasm or Suspicious for a
Follicular Neoplasm
V. Suspicious for Malignancy
VI. Malignant
III. Atypia of Undetermined Significance or
Follicular Lesion of Undetermined
Significance

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Bethesda Terminology for Reporting

Thyroid FNA Results
Suspicious for malignancy
S i i
– Suspicious f papillary
for ill i
carcinoma
Patchy/incomplete nuclear changes, sparsely cellular
– Suspicious for medullary carcinoma
Limited specimen to perform IHC stains for calcitonin
Add a note in the cytology report to measure serum
calcitonin
– Suspicious
S i i for
f lymphoma
l h
Cellular monomorphic or scant atypical lymphocytes
Recommend repeat FNA with flow cytometry
– Suspicious for metastatic tumor to thyroid

Bethesda Terminology for Reporting

Thyroid FNA Results

I Nondiagnostic or Unsatisfactory
I.
II. Benign
IV. Follicular Neoplasm or Suspicious for a
Follicular Neoplasm
V. Suspicious for Malignancy
VI. Malignant
III. Atypia of Undetermined Significance or
Follicular Lesion of Undetermined
Significance

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Bethesda Terminology for Reporting

Thyroid FNA Results
Malignant
– Papillary carcinoma and its variants
– Medullary carcinoma
– Poorly differentiated carcinoma (insular
carcinoma)
p
– Anaplastic carcinoma
– Lymphoma
– Metastatic tumor

Bethesda Terminology for Reporting

Thyroid FNA Results
Papillary thyroid carcinoma
– Diagnosed on the basis of its nuclear
morphology
– Major diagnostic criteria
Enlarged oval and irregular nucleus
Eccentric and often multiple micro-
micro-nucleoli
Fine, pale chromatin
Longitudinal nuclear grooves
Intranuclar pseudo-
pseudo-inclusion

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Bethesda Terminology for Reporting

Thyroid FNA Results
Papillary thyroid carcinoma
Di
– Diagnosedd on the
h b i off iits nuclear
basis l h l
morphology
– Minor diagnostic criteria
Papillary cytoarchitecture
Syncytial monolayers
Dense squamoid cytoplasm
Bubble--gum colloid
Bubble
Psammoma bodies
Multinucleated giant cells
Histiocytoid cells
Cellular swirls

Papillary Thyroid Carcinoma

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Papillary Thyroid Carcinoma

Papillary Thyroid Carcinoma

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Bethesda Terminology for Reporting

Thyroid FNA Results
Medullary thyroid carcinoma
– Cellular aspirate consisting of round to
oval cells arranged mainly as single cells
or loosely cohesive groups
Plasmacytoid cells
Spindled cells
Polygonal
P l l cells
ll
– “Salt
“Salt--and
and--pepper” chromatin
– Background amyloid

Medullary Carcinoma

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Medullary Carcinoma

Medullary Carcinoma

Amyloid

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Bethesda Terminology for Reporting

Thyroid FNA Results
Anaplastic carcinoma
H percell lar
– Hypercellular
– Obvious malignant features
Nuclear pleomorphism
Clumped chromatin
Macronucleoli
yp
Atypical mitoses
– Three cell types: squamoid, spindled,
tumor giant cells
– Background necrosis

Anaplastic Carcinoma

DQ

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Anaplastic Carcinoma

PAP

H&E Cell Block

Anaplastic Carcinoma

Cam 5.2

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Bethesda Terminology for Reporting

Thyroid FNA Results

I Nondiagnostic or Unsatisfactory
I.
II. Benign
III. Atypia of Undetermined Significance or
Follicular Lesion of Undetermined
Significance
IV F
IV. Follicular
lli l N Neoplasm
l or Suspicious
S i i for
f a
Follicular Neoplasm
V. Suspicious for Malignancy
VI. Malignant

Bethesda Terminology for Reporting

Thyroid FNA Results
Atypia of Undetermined Significance or
Follicular Lesion of Undetermined
Significance
– Avoid overuse of this term
– Usually due to compromised specimen
Low cellularity, but microfollicles
Low cellularity, but atypical cells
Obscuring blood, poor fixation

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AUS/FLUS

Bethesda Terminology for Reporting

Thyroid FNA Results
Atypia of Undetermined Significance or
Follicular Lesion of Undetermined
Significance

Example:
ATYPIA OF UNDETERMINED SIGNIFICANCE
Sparsely cellular specimen comprised of follicular cells with
hit t
architecturall atypia.
t i
Note: A repeat aspirate after an appropriate interval of
observation may be helpful if clinically indicated.

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Thyroid FNA
Introduction

The Bethesda System for Reporting Thyroid

Cytopathology
– Nondiagnostic or Unsatisfactory
– Benign
– Atypia of Undetermined Significance or Follicular Lesion of
Undetermined Significance
– Follicular Neoplasm or Suspicious for a Follicular Neoplasm
– Suspicious for Malignancy
– Malignant

The role of molecular markers

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Cancer Cytopathology May 2013

Thyroid FNA
• The Bethesda System for Reporting
Thyroid Cytopathology
– Nondiagnostic or Unsatisfactory
– Benign
– Atypia of Undetermined Significance or
IndeterminateFollicular Lesion of Undetermined
Nodules Significance
(10-26%)
– Follicular Neoplasm or Suspicious for a
Follicular Neoplasm
– Suspicious for Malignancy
– Malignant

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Robbins and Cotran Pathologic Basis of Disease, eighth edition, chapter 24

BRAF mutation

BRAF V600E mutation

– ~50% of PTCs, associated with the classic and tall cell variants, rare in the
follicular variant
– Tumors with the mutation: aggressive, extrathyroidal extension, recur,
resistant to 131I therap
therapy

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Molecular diagnostic tests

Genetic tests (mutational analysis)
– BRAF, RET/PTC, PAX8/PPARG and RAS
– Stable DNA sample
– High specificity and PPV
However:
– 30
30--40% of cancers do not have mutations (low sensitivity)
– Additional passes needed
– Representative of the lesion?
– Expensive
p
Gene expression tests ((mRNAs or microRNAs))
– Simultaneous measure of many mRNAs or microRNAs
However:
– RNA instability
– Additional passes needed
– Representative of the lesion?
– Expensive

Commercial molecular diagnostic tests

miRInform
miRInform;; Asuragen Inc, Austin, Tex
– A panel of DNA mutation markers and RNA fusion transcripts
(including BRAF, RET/PTC, PAX8/PPARgamma
PAX8/PPARgamma and RAS)
– Test intended to diagnose malignancy
– High specificity and high positive predictive value

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Commercial molecular diagnostic tests

Afirma Gene Expression Classifier, GEC; Veracyte,

South San Francisco, CA
– Simultaneous measurement of many mRNAs (167 genes)
– Test intended to exclude malignancy
– High sensitivity and high negative predictive value

Limitations:

N Engl J Med 2012; 367;705-15

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Xing M, Haugen BR, Schlumberger M.

Lancet 2013;381:1058-69

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Summary
Thyroid nodules are common
Most are benign
FNA remains to be the most cost
cost--effective
way to triage thyroid nodules and reduce
unnecessary surgeries
Molecular tests have ggreat p
potential as an
ancillary test to FNA
An evidence-
evidence-based guideline is needed to
guide the appropriate use of these tests

References:
1. http://thyroidfna.cancer.gov
2. Douglas P. Clark, William C Faquin (eds.)
2005 Thyroid Cytopathology. Springer
Science+Business Media, New York.
3 Syed Z
3. Z. Ali
Ali, Edmund S.
S Cibas (eds.)
(eds ) 2010 The
Bethesda Reporting Thyroid Cytopathology.
Springer Science+Business Media, New
York.

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Lymphomas of the head and

neck

Anamarija M. Perry, M.D.

Disclosure
Dr. Anamarija Perry has nothing to
Dr
disclose.

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Outline
• Introduction
• O l adnexal
Ocular d l llymphomas
h
• Lymphomas of Waldeyer’s ring
• Lymphomas of the nasal cavity and
paranasal sinuses
• Lymphomas of the salivary glands
• Lymphomas of the oral cavity
• Thyroid lymphomas

Introduction
• Most lymphoma subtypes can occur in the
head and neck region
– Primary or secondary
• Histologic, immunophenotypic and genetic
features of the various lymphomas are
overall similar to those that arise in other
anatomic sites
• Some distinctive features of head and
neck lymphomas will be emphasized

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Ocular adnexal lymphomas

Ocular adnexal lymphomas

• L
Lymphomas
h th
thatt arise
i ini th
the ti
tissues and
d
structures surrounding the eye, including orbital
soft tissue (most common), conjuctiva, lacrimal
gland and sac, and eyelids
– 8% of all extranodal lymphomas
– Lymphoma is the most common orbital malignancy
• Epidemiology
– More common in women (M:F=3:4); median age 60s

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Ocular adnexal lymphomas

• Etiology
– Most patients have no predisposing condition
– Occasionally, clinical history of autoimmune disorder,
HIV infection, contact lens wearing, Hepatitis C
infection
– Chlamydia psittaci infection found in some patients
(some respond to antibiotics)
• Clinical presentation
– Palpable mass, exophthalmos, ptosis, diplopia,
nasolacrimal duct obstruction etc.
– “Salmon patch” lesion – conjunctival lymphoma

Ocular adnexal lymphomas -

subtypes
• Extranodal marginal zone lymphoma of
mucosa-associated
i t d llymphoid
h id titissue (MALT
lymphoma)
• Follicular lymphoma
• Diffuse large B-cell lymphoma
• Peripheral T T-cell
cell lymphoma
• Extranodal NK/T-cell lymphoma, nasal
type

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MALT lymphoma
• Histology
– Lymphoma
y p cells infiltrate around reactive B-cell follicles
(marginal zone distribution) and spread out; eventually
architecture is overrun
– Small to medium-sized, round to slightly irregular lymphoid cells
with scant to moderate pale cytoplasm
– Lymphoepithelial lesions uncommon
– In one third of cases abundant plasma cells seen – plasmacytic
differentiation; amyloid deposition rarely observed
• Immunohistochemistry
I hi t h i t
– Positive: CD20, CD79a, CD43 (25%), IgM (most common), IgG;
CD21 and CD23 – follicular dendritic cell (FDC) meshworks in
reactive follicles (CD21 will also stain MZL cells)
– Negative: CD5 (rare cases positive), CD10, CD23

MALT lymphoma
• Genetic features
– Site
S te spec
specific
c ge
genetic
et c cchanges
a ges
– t(14;18)(q32;q21) IGH-MALT – also found in marginal
zone lymphoma in the liver, skin, and salivary glands,
but very rare in other sites
– t(11;18)(q21;q21) API2-MALT1 – common in gastric,
not frequently seen in ocular MALT
• Prognosis
– Indolent lymphoma; in 8080-90%
90% of patients disease is
confined to the ocular adnexa (uni- or bilateral)
– Localized lymphomas treated with radiotherapy;
systemic spread-chemotherapy
– Overall survival rate very good, but relapses frequent

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CD20 CD3

CD43 BCL2

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Follicular lymphoma
• Histology
– Most have follicular p
pattern ((closely
yppacked follicles)) and are low
grade (1/2); sclerosis common
– Mixture of centrocytes and centroblasts
– Grading - counting number of centroblasts in 10 neoplastic
follicles, expressed per 40x high-power field
– Grade 1/2 – 0-15 centroblasts/hpf; Grade 3 - >15
centroblasts/hpf
• Immunohistochemistry
– Positive: CD20, CD10, BCL6, BCL2 (small subset negative)
– Negative: CD43
• Genetic features
– t(14;18)(q32;q21) IGH-BCL2

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CD20 CD10

BCL6 BCL2

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Lymphomas of Waldeyer’s
ring

Waldeyer’s ring
• Ring of organized
lymphoid tissue that
guards the entrance
to alimentary and
respiratory tracts

• Palatine tonsils,
tonsils the
nasopharynx, the
base of tongue

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Lymphomas of Waldeyer’s ring

• Most common primary site for lymphomas of the
upper aerodigestive tract (5-10%
(5 10% of all NHL
lymphomas)
• More than half of primary head and neck
lymphomas arise here
• Epidemiology
– Most commonly adults (median age 50s); children
rarely
l
• Etiology
– Few patients HIV positive or otherwise
immunosuppressed

Lymphomas of Waldeyer’s ring

• Clinical presentation
– Airway obstruction – dyspnea; sore throat,
throat neck mass
(lymph node involvement)
– Tonsil most frequently involved, followed by
nasopharynx and base of tongue
– Mass – unilateral, exophytic; may be polypoid,
fungating or ulcerated with invasion to adjacent
structures
t t
– Lymphoma most commonly localized to Waldeyer’s
ring and local lymph nodes (stage II)

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Lymphomas of Waldeyer’s ring -

subtypes
• Diffuse large B-cell lymphoma – 60-85% of
cases
• Mantle cell lymphoma
• MALT lymphoma
• Follicular lymphoma
• Burkitt lymphoma – usually in children
• Peripheral T-cell lymphoma
• NK/T-cell lymphoma, nasal type

Diffuse large B-cell lymphoma

• Histology
– Diffuse p
proliferation of large
g lymphoid
y p cells effacing
g the
architecture
– Common morphologic variants: immunoblastic, centroblastic,
anaplastic
• Immunohistochemistry/in situ hybridization
– Positive: CD19, CD20, CD22, CD79a, CD30 (occasionally), CD5
(10%), CD10 (30-60%), BCL6 (60-90%), MUM1 (35-65%)
– Proliferation index (Ki67) usually high (>40%)
– Cell-of-origin subgroups: germinal-centre like (GCB) (CD10+ or
BCL6+, CD10-, MUM1-); all other non-GCB
– EBER in situ hybridization for EBV – if + in patients over 50
years of age, consider EBV+ DLBCL of the elderly

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Diffuse large B-cell lymphoma

• Genetic features
– Usually complex karyotypes
– BCL6 (3q27) abnormalities – 30%
– BCL2 rearranged in 20-30%
– MYC rearranged in 10%
– Double-hit lymphoma – MYC + BCL2 or BCL6
• Prognosis
– With R-CHOP chemotherapy 60% of patients are cured
– Multiple prognostic factors have been identified
• Clinical – stage,
stage International Prognostic Index (IPI)
• Better survival reported for tonsillar lymphoma than elsewhere in the
Waldeyer’s ring
• Pathologic – GCB more favorable than non-GCB, double-hit
lymphomas very poor prognosis

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CD20 BCL6

BCL2 Ki67

Mantle cell lymphoma

• Clinical features
– Most cases widespread
p at diagnosis
g – involvement of
Waldeyer’s ring usually part of systemic disease
– Bone marrow and blood commonly involved
• Histology
– Growth patterns: nodular, diffuse, mantle zone
– Small to medium-sized lymphoid cells with irregular nuclei,
resembling centrocytes
– Hyalinized
y vessels and epithelioid
p “pink”
p histiocytes
y scattered
– Variants: blastoid and pleomorphic
• Immunohistochemistry
– Positive: CD20, CD5, CD43, surface IgM/IgD, BCL2, cyclin D1
– Negative: CD10 (very rarely +), BCL6 (very rarely +), CD23

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Mantle cell lymphoma

• Genetic features
– t(11;14)(q13;q32)
( ; )(q ;q ) IGH-CCND1 – p present in almost all cases,,
primary genetic event
– Cyclin D1 negative MCL – negative for t(11;14), but otherwise
indistinguishable from conventional MCL
• Cyclin D2 or D3 usually expressed in these cases
• Prognosis
– Aggressive and incurable, median survival 3-5 years
– Clinical prognostic factor – MCL International Prognostic Index
(MIPI)
– Pathologic prognostic factor – high Ki67 and
blastoid/pleomorphic morphology non-favorable
– Gene expression profiling – proliferation signature score
important prognostic factor

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Cyclin D1

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MALT lymphoma
• Morphology
– Similar features to MALT in other head and neck sites
– Parafollicular, interfollicular or diffuse proliferation of MZL cells
with slightly irregular nuclei and moderate amount of clear
cytoplasm
– Neoplastic cells invade crypt epithelium – lymphoepithelial
lesions (this feature also seen in non-neoplastic lymphocytes in
this site)
– Plasmacytic differentiation sometimes seen
– Differential diagnosis with reactive lymphoid hyperplasia
– MZL can progress/transform to DLBCL
• Immunohistochemistry – identical to MZL in other sites
• Prognosis
– Indolent disease, prognosis excellent
– Progression to DLBCL is adverse prognostic event

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Prominent plasmacytic differentiation

CD20 CD138

Kappa Lambda

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Lymphomas of the nasal

cavity and paranasal sinuses

Lymphomas of the nasal cavity and

paranasal sinuses
• In the sinonasal area, lymphoma is second in
frequency only to squamous cell carcinoma
– Fewer than 5% of extranodal lymphomas
• Two main lymphoma subtypes
– DLBCL – in paranasal sinuses most common
lymphoma; similar features to DLBCL in other sites
– NK/T
NK/T-cell
cell lymphoma,
lymphoma nasal type – most frequently in
nasal cavity
• Other lymphomas can uncommonly arise in this
area

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Extranodal NK/T-cell lymphoma,

nasal type
• Predominantly extranodal lymphoma characterized by
vascular damage, destruction, necrosis, cytotoxic
phenotype and association with EBV
• Epidemiology
– More prevalent in Asians, native American populations of
Mexico, Central and South America; rare in Western countries
• Etiology
– St
Strong association
i ti with
ith EBV irrespective
i ti off ethnic
th i origin
i i off th
the
patient
– Disease activity can be monitored by measuring circulating EBV-
DNA – high titer correlates with poorer outcome

Extranodal NK/T-cell lymphoma,

nasal type

• Clinical
Cli i l ffeatures
t
– Nasal cavity most common site of involvement, but
can involve other areas of upper aerodigestive tract
– Other body sites can also be involved (e.g. skin, GI-
tract, soft tissue)
– Extensive,, destructive midfacial lesion;; nasal
obstruction/epistaxis
– Often localized, can invade adjacent structures and
sometimes disseminate to distant sites

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Extranodal NK/T-cell lymphoma,

nasal type
• Histology
– Infiltrate diffuse and p
permeative,, necrosis common;;
angioinvasion and angiodestruction
– Cytologic spectrum broad, from small to large anaplastic cells;
irregular nuclei, inconspicuous nucleoli
– Heavy admixture of inflammatory cells can be present – may
mimic inflammatory process
• Immunohistochemistry and in situ hybridization
– Positive: CD2, CD56, cytoplasmic CD3 (surface CD3 neg),
cytotoxic markers (granzime, perforin, TIA1), CD7 (rare), CD30
(rare)
– Negative: CD4, CD5, CD8, TCRδ, betaF1, CD16, CD57
– EBER in situ hybridization – always positive (if negative,
diagnosis should be reconsidered)

Extranodal NK/T-cell lymphoma,

nasal type

• Molecular studies
– T-cell receptor and immunoglobulin clonality studies
negative in most cases
– In small number of cases T-cell receptor genes show
clonal rearrangement – cytotoxic T-cell derivation
• Prognosis
– Hi
Historically
t i ll poor, b
butt iimproved
d iin recentt years d
due tto
treatment with new chemotherapy regimens (e.g.
SMILE regimen) +/- radiation
– Poor prognostic factors – disseminated disease, high
circulating EBV DNA levels

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EBER

Lymphomas of the salivary

glands

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Lymphomas of the salivary glands

• Lymphoma accounts for 2-5% of all salivary gland
malignancies
g
– 5% of extranodal lymphoma are primary in the salivary glands
• Parotid most commonly involved (70%), followed by
submandibular (15-25%) and minor salivary glands
(10%)
– 25% lymphomas in major salivary glands can be bilateral
• Clinical – enlarging painless mass, sometimes with
lymphadenopathy
– Facial nerve paralysis can occur
• MALT lymphoma, follicular lymphoma and DLBCL are
three main subtypes

Lymphomas of the salivary glands

– risk factors
• Sjögren’s syndrome
– Risk of salivary gland lymphoma greatly
increased (up to 250-fold)
– Risk of MALT lymphoma 1000-fold increased
• Hepatitis C
– Controversial
– HCV involved in lymphoma pathogenesis in
some patients with lymphoepithelial
sialadenitis (LESA)

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MALT lymphoma

• Most common salivary gland lymphoma

• Epidemiology
– Middle-aged and older adults (median age 60)
– Women affected twice as common - Sjögren’s
syndrome also more common in women
• Histology
– Usually arises in the background of LESA

MALT lymphoma
• LESA
– Nearly
ea y aall pat
patients
e ts with
t Sjög
Sjögren’s
e s sy
syndrome
d o e have
a e
LESA, but about half of the people with LESA have
Sjögren’s syndrome
– Histology
• Multifocal or diffuse lymphoid proliferation
• Lymphoepithelial lesions in ductal structures, surrounded by
reactive follicles, small lymphocytes, plasma cells, and
immunoblasts
• Loss of ductal lumen
• In the lymphoepithelial lesions monocytoid B-cells (oval or
indented nuclei and abundant pale cytoplasm) – monocytoid
cells confined to the lymphoepithelial lesion or form a narrow
halo

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MALT lymphoma
• Histology of MALT lymphoma
– LESA vs. MALT – in MALT large g haloes,, broad strands and
sheets of monocytoid B-cells
– Lymphoepithelial lesions and obliteration of salivary parenchyma
– Scattered reactive lymphoid follicles and plasma cells
(sometimes plasmacytic differentiation)
– In salivary glands other than parotid lymphoepithelial lesions
may be less pronounced
– Transformation to DLBCL can rarely occur
• Immunohistochemistry
– Positive: CD20, CD79a, CD43 (subset), BCL2
– Negative: CD5, CD10, BCL6, cyclin D1

MALT lymphoma
• Molecular and genetic features
– Clonal IGH rearrangement
g usually
yp present
– Note: cases of LESA can also have clonal IGH rearrangement –
morphology very important to distinguish from MALT
– t(14;18) IGH-MALT1 sometimes encountered (up to 20% of
cases)
• Prognosis
– Disease localized in most cases, can spread to local lymph
nodes
– Occasionally staging will reveal MALT in other sites
– Overall survival excellent, relapses common
– Progression to DLBCL – poorer prognosis

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MALT
lymphoma

Lymphoepithelial lesion

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CD20 CD3

BCL6 BCL2

Follicular lymphoma
• Primary follicular lymphoma of the salivary gland
is controversial entity
y
– Many claim that these lymphomas involve peri- or
intraparotid lymph nodes and extend to salivary gland
– Others maintain that subset are truly salivary gland
follicular lymphomas
• Histology
– Similar to other sites, most low grade
– In
I few
f cases lymphoepithelial
l h ith li l lesions
l i can b
be seen
– Cases of Warthin tumor in which lymphoid stroma of
the tumor is composed of follicular lymphoma have
been described

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Follicular lymphoma

• Prognosis
– Behave similar to follicular lymphomas in
other sites
– Staging typically shows widespread disease,
p
relapses common
– If truly extranodal and localized to salivary
gland, prognosis is excellent

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CD20

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CD10 BCL6

BCL2 CD21

Lymphomas of the oral cavity

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Lymphomas of the oral cavity

• Overall rare (2% of all extranodal
lymphomas)
• Include lymphomas of palate, gingiva,
tongue, buccal mucosa, floor of the mouth,
lips, and lymphomas that arise in jaw
bones and protrude into the oral cavity
• Many
M llymphoma
h subtypes
bt can occur here
h
and most are not distinct oral cavity
entities, except plasmablastic lymphoma

Lymphomas of the oral cavity

• Epidemiology
– Mostlyy middle-aged
g and older adults in 6th or 7th decade
– Men and women equally affected
• Etiology
– Most patients immunocompetent
– Increased incidence of oral cavity lymphomas in HIV+ individuals
• Almost all males, median age 40
– Oral lymphomas reported in transplanted patients too
• Clinical presentation
– Soft tissue swelling, mass, pain, mucosal ulceration, gingival
thickening, loosening of teeth
– Palate (bone or soft tissue), maxilla and gingiva most commonly
affected, other sites less common

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Plasmablastic lymphoma
• Diffuse proliferation of large neoplastic cells most of
which resemble B immunoblasts, but in which all tumor
cells
ll h
have th
the iimmunphenotype
h t off plasma
l cells
ll
• Originally described in oral cavity, but may occur in other
sites
• Epidemiology
– Uncommon
– Median age 50 years
• Etiology
– Immunodeficiency (HIV-mostly males, iatrogenic
immunosuppression)
– Advanced age
– Cells EBV-infected in majority of cases

Plasmablastic lymphoma
• Clinical presentation
– Mass in oral cavity; can involve other sites (particularly mucosal)
– Rarely involves lymph nodes
– Most patients are at advanced stage
• Histology
– Diffuse proliferation of cells resembling immunoblasts or having
more obvious plasmacytic differentiation (may resemble
plasmablastic plasma cell myeloma)
• Immunohistochemistry and in situ hybridization
– Positive: CD138,
CD138 CD38,
CD38 MUM1,
MUM1 CD79a (portion of cases)
cases), EMA
EMA,
CD30,cytoplasmic IgG (50-70%), kappa or lambda light chains
– Negative: CD45 (can be focally +), CD20, PAX5
– EBER in situ hybridization + in 60-75% of cases (in oral cavity in
HIV+ patients 100% positive)

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Plasmablastic lymphoma
• Molecular and genetic features
– Clonal IGH chain gene rearrangement
– Some cases have t(8;14) MYC-IGH
• Prognosis
– Clinical course very aggressive, patients
usually die in the first year after diagnosis
– Outcome somewhat improved with better
management of HIV infection

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CD138 CD45

CD79a

Other oral lymphomas associated

with HIV infection
• Most lymphomas are high grade
– DLBCL – most common
– Burkitt lymphoma
– Peripheral T-cell lymphoma
– Anaplastic large T-cell lymphoma
• Most cases (T- and B- NHL) are EBER +
– EBV may be important player in pathogenesis
of HIV-associated lymphomas

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Other oral lymphomas in

immunocompetent patients

• Variety or low- and high-grade lymphomas

can occur
• Almost all B-cell lymphomas, at least half
DLBCL
• Follicular lymphomas and marginal zone
lymphomas also common

Thyroid lymphomas

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Thyroid lymphomas

• 1-5% of all thyroid malignancies

• Most common subtypes
– MALT lymphoma
– Diffuse large B-cell lymphoma

MALT lymphoma and diffuse large

B-cell lymphoma
• Discussed together as they share many clinical features
– Subset of DLBCL represents
p transformation from MALT
– Together they account for nearly all thyroid lymphomas
• Epidemiology
– Mostly older adults (60 to 70 years of age); striking female
predominance
• Etiology
– Hashimoto’s thyroiditis – almost all MALT patients and subset of
DLBCL patients have evidence of Hashimoto’s
Hashimoto s thyroiditis
– Patients with Hashimoto’s have 70-fold increase in risk for
thyroid lymphoma
– Rarely lymphomas develop in patients with Graves’ disease

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MALT lymphoma and diffuse large

B-cell lymphoma
• Clinical features
– Mass, swelling, dysphagia, cough, dyspnea, hoarseness, stridor,
d
dysphonia,
h i pain i
– Symptoms usually more severe in DLBCL – growing more
rapidly than MALT
• Histology
– Up to half of DLBCL have MALT lymphoma component,
suggesting large cell transformation
– Histology of DLBCL and MALT similar to other sites
– MALT – characteristic lymphoepithelial lesion with round
aggregates
t off MZL cellsll filli
filling th
the llumens off th
thyroid
id ffollicles
lli l –
“MALT ball”
– MALT can colonize reactive follicles mimicking follicular
lymphoma
– Changes of Hashimoto’s often seen adjacent to lymphoma

MALT lymphoma vs. Hashimoto’s

• Hashimoto’s
Hashimoto s
– Lymphoid infiltrate extensively involving the thyroid
– Reactive lymphoid follicles and interfollicular infiltrate
of small lymphocytes and plasma cells
– Thyroid follicles – oxyphil metaplasia
– Lymphoepithelial lesions if present are small and focal
(and more often contain T-cells)
– Clonal
Cl l IGH gene rearrangementt can b be ffoundd iin
some cases – do not make diagnosis of lymphoma
based on clonality alone!

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MALT lymphoma vs. Hashimoto’s

• Histologic findings favoring MALT lymphoma
– Obliteration
Ob te at o of o thyroid
t y o d pa
parencyma
e cy a by lymphoid
y p od
infiltrate
– Interfollicular cells with morphology and
immunophenotype of MZL cells
– Large, prominent lymphoepithelial lesions (composed
of B-cells)
– Lymphoid follicles with follicular colonization by MZL
cells
– Plasma cells expressing monotypic immunoglobulin
– Flow cytometry - monotypic B-cell population can
often be found

MALT lymphoma and diffuse large

B-cell lymphoma
• Immunohistochemistry
– Same immunophenotypes like in other locations
• Genetic features
– MALT – t(3;14)(p14.1;q32) FOXP1-IGH in seen in some cases
• Prognosis
– Both MALT and DLBCL usually localized
– Patients with DLBCL have more frequent widespread disease
– MALT - treated with surgery +/- radiation; excellent prognosis
– DLBCL – treated with chemotherapy +/- radiation
• Localized disease – good prognosis
• Higher stage disease – poorer outcome

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cytokeratin

MALT lymphoma – “MALT ball” lesion

DLBCL

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CD20 CD3

Ki67

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