VASILE MUSTEATA, MD, PhD, MPH,

associate professor;
Discipline of Hematology,
State University of Medicine
and Pharmacy “N. Testemitanu”

HODGKIN LYMPHOMA
NON-HODGKIN LYMPHOMAS

CHISINAU – 2020
WHO CLASSIFICATION OF MYELOID NEOPLASMS AND ACUTE LEUKEMIA
(VARDIMAN et al., BLOOD, 30 JULY 2009 VOLUME 114, NUMBER 5)

MYELOPROLIFERATIVE NEOPLASMS (MPN)

Chronic myelogenous leukemia, BCR-ABL1–positive
Chronic neutrophilic leukemia
Polycythemia vera
Primary myelofibrosis
Essential thrombocythemia
Chronic eosinophilic leukemia, not otherwise specified
Mastocytosis
Myeloproliferative neoplasms, unclassifiable

MYELOID AND LYMPHOID NEOPLASMS ASSOCIATED WITH EOSINOPHILIA AND

ABNORMALITIES OF PDGFRA, PDGFRB, OR FGFR1
Myeloid and lymphoid neoplasms associated with PDGFRA rearrangement
Myeloid neoplasms associated with PDGFRB rearrangement
Myeloid and lymphoid neoplasms associated with FGFR1 abnormalities

MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN)

Chronic myelomonocytic leukemia
Atypical chronic myeloid leukemia, BCR-ABL1–negative
Juvenile myelomonocytic leukemia
Myelodysplastic/myeloproliferative neoplasm, unclassifiable
Provisional entity: refractory anemia with ring sideroblasts and
thrombocytosis
WHO CLASSIFICATION OF MYELOID NEOPLASMS AND ACUTE LEUKEMIA
(VARDIMAN et al., BLOOD, 30 JULY 2009 VOLUME 114, NUMBER 5)
MYELODYSPLASTIC SYNDROME (MDS)
Refractory cytopenia with unilineage dysplasia
Refractory anemia
Refractory neutropenia
Refractory thrombocytopenia
Refractory anemia with ring sideroblasts
Refractory cytopenia with multilineage dysplasia
Refractory anemia with excess blasts
Myelodysplastic syndrome with isolated del(5q)
Myelodysplastic syndrome, unclassifiable
Childhood myelodysplastic syndrome
Provisional entity: refractory cytopenia of childhood

ACUTE MYELOID LEUKEMIA AND RELATED NEOPLASMS

Acute myeloid leukemia with recurrent genetic abnormalities
AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
APL with t(15;17)(q22;q12); PML-RARA
AML with t(9;11)(p22;q23); MLLT3-MLL
AML with t(6;9)(p23;q34); DEK-NUP214
AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1
AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1
Provisional entity: AML with mutated NPM1
Provisional entity: AML with mutated CEBPA
WHO CLASSIFICATION OF MYELOID NEOPLASMS AND ACUTE LEUKEMIA
(VARDIMAN et al., BLOOD, 30 JULY 2009 VOLUME 114, NUMBER 5)

Acute myeloid leukemia with myelodysplasia-related changes

Therapy-related myeloid neoplasms
Acute myeloid leukemia, not otherwise specified
AML with minimal differentiation
AML without maturation
AML with maturation
Acute myelomonocytic leukemia
Acute monoblastic/monocytic leukemia
Acute erythroid leukemia
Pure erythroid leukemia
Erythroleukemia, erythroid/myeloid
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis

Myeloid sarcoma

Myeloid proliferations related to Down syndrome

Transient abnormal myelopoiesis
Myeloid leukemia associated with Down syndrome

Blastic plasmacytoid dendritic cell neoplasm

WHO CLASSIFICATION OF MYELOID NEOPLASMS AND ACUTE LEUKEMIA
(VARDIMAN et al., BLOOD, 30 JULY 2009 VOLUME 114, NUMBER 5)

ACUTE LEUKEMIAS OF AMBIGUOUS LINEAGE

Acute undifferentiated leukemia
Mixed phenotype acute leukemia with t(9;22)(q34;q11.2); BCR-ABL1
Mixed phenotype acute leukemia with t(v;11q23); MLL rearranged
Mixed phenotype acute leukemia, B-myeloid, NOS
Mixed phenotype acute leukemia, T-myeloid, NOS
Provisional entity: natural killer (NK) cell lymphoblastic leukemia/lymphoma

B LYMPHOBLASTIC LEUKEMIA/LYMPHOMA
B lymphoblastic leukemia/lymphoma, NOS
B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities
B lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2); BCR-ABL 1
B lymphoblastic leukemia/lymphoma with t(v;11q23); MLL rearranged
B lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22) TEL-AML1
(ETV6-RUNX1)
B lymphoblastic leukemia/lymphoma with hyperdiploidy
B lymphoblastic leukemia/lymphoma with hypodiploidy
B lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32) IL3-IGH
B lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); TCF3-PBX1

T LYMPHOBLASTIC LEUKEMIA/LYMPHOMA
WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES
(Swerdlow S.H., Campo E, Harris NL et al, eds. Lyon: IARC Press, 2008)
MATURE B-CELL NEOPLASMS
Chronic lymphocytic leukemia/small lymphocytic lymphoma
B-cell prolymphocytic leukemia
Splenic B-cell marginal zone lymphoma
Hairy cell leukemia
Splenic lymphoma/leukemia, unclassifiable (provisional)
Splenic diffuse red pulp small B-cell lymphoma (provisional)
Hairy cell leukemia-variant (provisional)
Lymphoplasmacytic lymphoma
Waldenström macroglobulinemia
Heavy chain diseases
α Heavy chain disease
γ Heavy chain disease
µ Heavy chain disease
Plasma cell myeloma
Solitary plasmacytoma of bone
Extraosseous plasmacytoma
Extranodal marginal zone lymphoma of mucosa-associated lymphoid
tissue (MALT lymphoma)
Nodal marginal zone lymphoma
Pediatric nodal marginal zone lymphoma (provisional)
Follicular lymphoma
Pediatric follicular lymphoma (provisional)
WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES
(Swerdlow S.H., Campo E, Harris NL et al, eds. Lyon: IARC Press, 2008)

Primary cutaneous follicle center lymphoma

Mantle cell lymphoma
Diffuse large B-cell lymphoma (DLBCL), not otherwise specified
T-cell/histiocyte-rich large B-cell lymphoma
Primary DLBCL of the CNS
Primary cutaneous DLBCL, leg type
EBV-positive DLBCL of the elderly (provisional)
DLBCL associated with chronic inflammation
Lymphomatoid granulomatosis
Primary mediastinal (thymic) large B-cell lymphoma
Intravascular large B-cell lymphoma
ALK-positive DLBCL
Plasmablastic lymphoma
Large B-cell lymphoma arising in HHV8-associated multicentric
Castleman disease
Primary effusion lymphoma
Burkitt lymphoma
B-cell lymphoma, unclassifiable, with features intermediate between
diffuse large B-cell lymphoma and Burkitt lymphoma
B-cell lymphoma, unclassifiable, with features intermediate between
diffuse large B-cell lymphoma and classic Hodgkin lymphoma
WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES
(Swerdlow S.H., Campo E, Harris NL et al, eds. Lyon: IARC Press, 2008)
MATURE T-CELL AND NK CELL NEOPLASMS
T-cell prolymphocytic leukemia
T-cell large granular lymphocytic leukemia
Chronic lymphoproliferative disorder of NK cells (provisional)
Aggressive NK cell leukemia
Systemic EBV-positive T-cell lymphoproliferative disease of childhood
Hydroa vacciniforme-like lymphoma
Adult T-cell leukemia/lymphoma
Extranodal NK/T-cell lymphoma, nasal type
Enteropathy-associated T-cell lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Mycosis fungoides
Sézary syndrome
Primary cutaneous CD30+ T-cell lymphoproliferative disorders
Lymphomatoid papulosis
Primary cutaneous anaplastic large cell lymphoma
Primary cutaneous g/d T-cell lymphoma
Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell
lymphoma (provisional)
Primary cutaneous CD4+ small/medium T-cell lymphoma (provisional)
Peripheral T-cell lymphoma, not otherwise specified
Angio-immunoblastic T-cell lymphoma
Anaplastic large cell lymphoma, ALK positive
Anaplastic large cell lymphoma, ALK negative (provisional)
WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES
(Swerdlow S.H., Campo E, Harris NL et al, eds. Lyon: IARC Press, 2008)
HODGKIN LYMPHOMA
Nodular lymphocyte-predominant Hodgkin lymphoma
Classic Hodgkin lymphoma
Nodular sclerosis classic Hodgkin lymphoma
Lymphocyte-rich classic Hodgkin lymphoma
Mixed cellularity classic Hodgkin lymphoma
Lymphocyte-depleted classic Hodgkin lymphoma

HISTIOCYTIC AND DENDRITIC CELL NEOPLASMS

Histiocytic sarcoma
Langerhans cell histiocytosis
Langerhans cell sarcoma
Interdigitating dendritic cell sarcoma
Follicular dendritic cell sarcoma
Fibroblastic reticular cell tumor
Indeterminate dendritic cell tumor
Disseminated juvenile xanthogranuloma

POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDERS (PTLD)

Early lesions
Plasmacytic hyperplasia
Infectious mononucleosis-like PTLD
Polymorphic PTLD
Monomorphic PTLD (B- and T/NK cell types)
Classic Hodgkin lymphoma type PTLD
B-CELL DEVELOPMENT AND THE CORRESPONDING LYMPHOMAS
DERIVED AT EACH STAGE
(American Society of Hematology, New Approaches to Lymphoma Diagnosis. Hematology 2001)
 HODGKIN LYMPHOMA

HODGKIN LYMPHOMA (HL) is a clinicopathologically aggressive B-cell

lymphoma, which is one of the most curable of all haematological malignancies. The
annual incidence of HL ranges between 1.47 – 2.8 cases per 100.000 population.
This malignancy occurs mostly in population with the age of 5 – 9, 40 – 49, 60 – 69
years old in males and 20 – 29, 60 – 69 years old in females. Male : female ratio may
reach 1.4-1.5 : 1.

The demonstration of clonal rearrangements of the immunoglobulin heavy-

and light-chain loci has confirmed their B-cell origin. The presence of somatic
hypermutation within the immunoglobulin heavy and light chain loci suggest that
HRS cells are derived from B-lymphocytes with germinal centre exposure. Despite
their B-cell ontogenesis, HRS cells have lost most of the normal B-cell lineage gene
expression program (including the expression of immunoglobulin) through
numerous aberrant genetic mechanisms, such as epigenetic silencing at B-cell gene
promoter regions.
Source: Postgraduate Haematology, Seventh Edition. Edited by A Victor Hoffbrand, Douglas R Higgs, David M
Keeling and Atul B Mehta. © 2016 JohnWiley & Sons, Ltd. Published 2016 by JohnWiley & Sons, Ltd.
 HODGKIN LYMPHOMA

MOLECULAR PATHOGENESIS. Genes involved in normal B-lymphocyte

growth and differentiation are suppressed in HRS cells. Instead, numerous aberrant
intracellular signalling pathways contribute to the malignant phenotype of HRS cells
including the following:
HRS cells show constitutive activation of the NF-κB pathway, which is
associated with apoptosis resistance. The basis for constitutive NF-κB activation in
at least a proportion of cases is the result of inactivating mutations in TNFAIP3 and
NFKBIA, which encode inhibitors of the NF-κB pathway.
The JAK-STAT signalling pathway is overactive in HRS cells, resulting in
uncontrolled growth and proliferation. Mechanisms of JAK-STAT over-activity
include chromosomal gains at 9p24.1-24.3 (which includes the JAK2 locus) and
inactivating mutations in PTPN1 (leading to increased phosphorylation of JAK-STAT
pathway members).
HRS cells have been shown to have deacetylated histones (H3), increased
H3K27 trimethylation and DNA methylation patterns, leading to silencing of tumour-
suppressor genes and the extinction of the normal B-lymphocyte expression profile.
High-throughput sequencing studies have detected deleterious mutations in
β2M which could potentially contribute to immune evasion by HRS cells through
decreased β2M expression.
Source: Postgraduate Haematology, Seventh Edition. Edited by A Victor Hoffbrand, Douglas R Higgs, David M
Keeling and Atul B Mehta. © 2016 JohnWiley & Sons, Ltd. Published 2016 by JohnWiley & Sons, Ltd.
CLINICAL EXAMINATION OF PATIENT WITH HODGKIN LYMPHOMA:
CERVICAL LYMPH NODE ENLARGEMENT
 X-RAY EXAMINATION IN HODGKIN LYMPHOMA

Thorax survey demonstrates mediastinal lymph node enlargement

 PET scan images of patient with stage III HL showing FDG-avid
cervical, mediastinal, mesenteric and retroperitoneal
lymphadenopathy

Source: Postgraduate Haematology, Seventh Edition. Edited by A Victor Hoffbrand, Douglas

R Higgs, David M Keeling and Atul B Mehta. © 2016 JohnWiley & Sons, Ltd. Published 2016 by JohnWiley
& Sons, Ltd.
 ANATOMIC REGIONS FOR STAGING OF HODGKIN LYMPHOMA
(Pazdur R., Coia L.R., Hoskins W.J. et al., Cancer Management: A Multidisciplinary Approach. 8th Edition.
New York: CMP Healthcare Media)
 STAGING CLASSIFICATION OF HODGKIN LYMPHOMA:
(Pazdur R., Coia L.R., Hoskins W.J. et al., Cancer Management: A Multidisciplinary Approach. 8th Edition.
New York: CMP Healthcare Media)

Elevated levels of fibrinogen (>5.0 g/l), α2-globulin (>10 g/l), erythrocyte

sedimentation rate (> 30mm/h), haptoglobin (>1.5mg%) are considered the
signs of biological activity of Hodgkin lymphoma (if present, designation b is
used).
PROGNOSTIC SCORING STAGING SYSTEM FOR HODGKIN LYMPHOMA:
(Pazdur R., Coia L.R., Hoskins W.J. et al., Cancer Management: A Multidisciplinary Approach. 8th Edition.
New York: CMP Healthcare Media)
EARLY STAGES

ADVANCED STAGES
 HODGKIN LYMPHOMA

Touch preparation: binucleated large R-S cells.

May-Giemsa staining, x 200.
 HODGKIN LYMPHOMA

Touch preparation: binucleated large R-S cells.

May-Giemsa staining, x 1000.
 HODGKIN LYMPHOMA

Lymph node.
Hematoxylin and eosin stain, x1000
 HODGKIN LYMPHOMA

Immune phenotyping: large R-S cells positive for CD30.

May-Giemsa staining, x 1000.
FIRST--LINE CHEMOTHERAPY REGIMENS FOR HODGKIN LYMPHOMA
FIRST
(Byrne B.J., Gockerman J.P. The Oncologist 2007;12:156–167)
 EXTENDED RADIATION FIELDS USED FOR TREATMENT
OF CLASSIC HODGKIN LYMPHOMA
(Pazdur R., Coia L.R., Hoskins W.J. et al., Cancer Management: A Multidisciplinary Approach. 8th Edition.
New York: CMP Healthcare Media)
 NON-HODGKIN’S LYMPHOMAS

NON-HODGKIN’S LYMPHOMAS (HL) are a heterogenous group of neoplastic

disorders originating from the extramedullary hematopoietic lymphoid cells.
The incidence of NHL in Republic of Moldova constitutes 4.1 per 100 000
population. Age–adjusted incidence rate are somewhat higher in males (4.7) than in
females (3.6). Age–specific incidence rates show a logarithmic rise with increasing
age. The mean age at diagnosis is 45 to 55 years. Considerable geographic and racial
variations in overall incidence as well as histologic and immunologic subtypes are
found worldwide, with a lower incidence of follicular lymphomas in China and Japan.
Pathogenesis. The heterogenity of NHL suggests that a variety of factors
including genetic abnormalities, immune disturbances, infectious agents, and other
events interact in their pathogenesis. While morphology correlates with immunologic
cell type (immunophenotyping), cells of identical appearance may be of types as
disparate as T and B cells. Each of histologic types of NHL has its own prototype of
normal cell, which NHL develop from after malignant transformation.
The development of NHL is unifocal. The morphological composition of tumour
determines the clinical course of NHL. Under certain conditions, low-grade histologic
types can turn into high-grade histologic types and nodular forms of tumour gowth –
in those diffuse. In spite of the tumour progression, a number of neoplastic cells may
retain initial caryotypical and immunologic markers.
Source: Postgraduate Haematology, Seventh Edition. Edited by A Victor Hoffbrand, Douglas R Higgs, David M
Keeling and Atul B Mehta. © 2016 JohnWiley & Sons, Ltd. Published 2016 by JohnWiley & Sons, Ltd.
MULTI--STEP TRANSFORMATION OF LYMPHOID CELLS
MULTI
 EVENTS IN B-CELL DEVELOPMENT
(American Society of Hematology, New Approaches to Lymphoma Diagnosis. Hematology 2001)
 EVENTS IN B-CELL DEVELOPMENT
(American Society of Hematology, New Approaches to Lymphoma Diagnosis. Hematology 2001)
MULTI--STEP TRANSFORMATION OF LYMPHOID CELLS
MULTI
 NON--HODGKIN LYMPHOMAS
LOCALIZATIONS OF PRIMARY TUMOR FOCUS IN NON
 NON--HODGKIN LYMPHOMA
PRIMARY CUTANEOUS NON
 NON--HODGKIN LYMPHOMA
PRIMARY EYELID NON
 NON--HODGKIN LYMPHOMA
PRIMARY EYELID NON
NON--HODGKIN LYMPHOMA, BURKITT TYPE
NON

Obstruction lesion in ileum, a common presenting

clinical feature in sporadic Burkitt lymphoma
 NON--HODGKIN LYMPHOMA, BURKITT TYPE
NON

Cytology showing deeply basophilic vacuolated cytoplasm - vacuoles contain lipid.

May-Giemsa staining, x 1000.
 NON--HODGKIN LYMPHOMA, BURKITT TYPE
NON

Bone marrow aspirate with admixture of Burkitt lymphoma cells.

May-Giemsa staining, x 1000.
 B--CELL NON
DIFFUSE LARGE B NON--HODGKIN LYMPHOMA, ANAPLASTIC TYPE

Lymph node biopsy.

Hematoxylin and eosin stain, x1000.
 NON--HODGKIN LYMPHOMA
FOLLICULAR NON

May-Giemsa staining, x 100

 NON--HODGKIN LYMPHOMA
BONE MARROW SMEAR IN NON

May-Giemsa staining, x 1000

 T--CELL NON
CUTANEOUS T NON--HODGKIN LYMPHOMA

Hematoxylin and eosin stain, x400

 T--CELL NON
CUTANEOUS T NON--HODGKIN LYMPHOMA

Clot section.
Hematoxylin and eosin stain, x400.
 T--CELL NON
CUTANEOUS T NON--HODGKIN LYMPHOMA

Immunostain_antibody CD3(Leu4), x400

 T--CELL NON
CUTANEOUS T NON--HODGKIN LYMPHOMA

Blood smear.
May-Giemsa stain, x1000.
IMMUNOPHENOTYPIC AND GENETIC FEATURES OF COMMON B-CELL NEOPLASMS
(American Society of Hematology, New Approaches to Lymphoma Diagnosis. Hematology 2001)
IMMUNOPHENOTYPIC AND GENETIC FEATURES OF COMMON T-CELL NEOPLASMS
(American Society of Hematology, New Approaches to Lymphoma Diagnosis. Hematology 2001)
INTERNATIONAL PROGNOSTIC INDEX AND AGE-ADJUSTED INDEX FOR AGGRESSIVE
LYMPHOMA PATIENTS TREATED WITH DOXORUBICIN-CONTAINING
COMBINATION CHEMOTHERAPY
(Pazdur R., Coia L.R., Hoskins W.J. et al., Cancer Management: A Multidisciplinary Approach. 8th Edition.
New York: CMP Healthcare Media)
 CHEMOTHERAPY REGIMENS,
COMMONLY USED IN NON-HODGKIN LYMPHOMAS
(Williams M.E., Kahn M.J., American Society of Hematology Self-Assessment Program. Blackwell Publishing: 2005)
COMBINATION CHEMOTHERAPY IN NON-HODGKIN LYMPHOMAS:
REGIMENS, MODE OF ADMINISTRATION AND DOSES
(Pazdur R., Coia L.R., Hoskins W.J. et al., Cancer Management: A Multidisciplinary Approach.
8th Edition. New York: CMP Healthcare Media)
COMBINATION CHEMOTHERAPY IN NON-HODGKIN LYMPHOMAS:
REGIMENS, MODE OF ADMINISTRATION AND DOSES
(Pazdur R., Coia L.R., Hoskins W.J. et al., Cancer Management: A Multidisciplinary Approach.
8th Edition. New York: CMP Healthcare Media)