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GASTROINTESTINAL IMAGING |
Pancreatic Ductal Adenocarcinoma
and Its Variants: Pearls and Perils
Khoschy Schawkat, MD
Maria A. Manning, MD Pancreatic ductal adenocarcinoma (PDAC), an epithelial neoplasm
Jonathan N. Glickman, MD, PhD derived from the pancreatic ductal tree, is the most common his-
Koenraad J. Mortele, MD tologic type of pancreatic cancer and accounts for 85%–95% of
all solid pancreatic tumors. As a highly lethal malignancy, it is the
Abbreviations: ASqC = adenosquamous carci- seventh leading cause of cancer death worldwide and is responsible
noma, HC = hepatoid carcinoma, HCC = hepa- for more than 300 000 deaths per year. PDAC is highly resistant to

FROM THE RADIOLOGIC PATHOLOGY ARCHIVES

tocellular carcinoma, IPMN = intraductal pap-
illary mucinous neoplasm, MCP = medullary current therapies, affording patients a 5-year overall survival rate of
carcinoma of the pancreas, MSI+ = microsatellite only 7.2%. It is characterized histologically by its highly desmoplas-
instability, PDAC = pancreatic ductal adenocarci-
noma, SRCC = signet ring cell carcinoma, UC =
tic stroma embedding tubular and ductlike structures. On images,
undifferentiated carcinoma, UCOGC = UC it typically manifests as a poorly defined hypoenhancing mass, caus-
with osteoclast-like giant cells, WHO = World ing ductal obstruction and vascular involvement. Little is known
Health Organization
about the other histologic subtypes of PDAC, mainly because of
RadioGraphics 2020; 40:0000–0000
their rarity and lack of specific patterns of disease manifestation.
https://doi.org/10.1148/rg.2020190184
According to the World Health Organization, these variants include
Content Codes: adenosquamous carcinoma, colloid carcinoma, hepatoid carcinoma,
From the Division of Abdominal Imaging, De- medullary carcinoma, signet ring cell carcinoma, undifferentiated
partment of Radiology (K.S., K.J.M.), and De-
partment of Pathology (J.N.G.), Beth Israel Dea-
carcinoma with osteoclast-like giant cells, and undifferentiated car-
coness Medical Center, Harvard Medical School, cinoma. Depending on the subtype, they can confer a better or even
330 Brookline Avenue, Boston, MA 02115; Insti- worse prognosis than that of conventional PDAC. Thus, awareness
tute of Diagnostic and Interventional Radiology,
University Hospital Zurich, University of Zurich, of the existence and differentiation of these variants on the basis of
Zurich, Switzerland (K.S.); and American Insti- imaging and histopathologic characteristics is crucial to guide clini-
tute for Radiologic Pathology, Silver Spring, Md,
and MedStar Georgetown University Hospital,
cal decision making for optimal treatment and patient management.
Washington, DC (M.A.M.). Presented as an edu-
cation exhibit at the 2019 RSNA Annual Meeting.
Received July 25, 2019; revision requested March
2, 2020, and received March 12; accepted March
19. For this journal-based SA-CME activity, the Introduction
authors, editor, and reviewers have disclosed no On the basis of their histogenesis, pancreatic tumors are classified as
relevant relationships. Address correspondence
to K.S. (e-mail: kschawka@bidmc.harvard.edu). either epithelial or nonepithelial. Pancreatic ductal adenocarcinoma
K.S. supported by the Swiss National Science (PDAC), an epithelial neoplasm, is the most common malignant tu-
Foundation (grant 181917) and Swiss Society of mor of the pancreas and accounts for more than 85% of all pancre-
Radiology.
atic malignancies (1). PDAC is highly resistant to current therapies,
Supported by the American Institute for Radio-
logic Pathology, the Joint Pathology Center, and affording patients a 5-year overall survival rate of only 7.2% (2). This
Uniformed Services University of the Health Sci- makes PDAC the deadliest of all adult abdominal tumors. Because
ences. The views expressed in this article are those
of the authors and do not necessarily reflect the
of its sharply rising incidence, PDAC is anticipated to emerge as the
official policy or position of the Department of second leading cause of cancer-related death in the United States by
Defense or the U.S. Government. 2030, even surpassing breast cancer (3,4).
To a certain extent, all ductal pancreatic tumors are mucinous
SA-CME LEARNING OBJECTIVES because mucin production is a hallmark of ductal differentiation in
After completing this journal-based SA-CME pancreatic tumors (5). Distinct tumor types arise from the ductal
activity, participants will be able to: tree, exhibiting various degrees of mucin production, and the distri-
„ Describe the radiologic features of bution of intracellular and extracellular mucin accumulation varies
PDAC and its variants, with pathologic significantly. For instance, extracellular mucin accumulation is found
correlation.
in colloid carcinoma but not found in conventional PDAC, although
„ Identify the most important imaging
findings for differentiating PDAC from a certain degree of intracellular mucin is present in most PDAC
its variants to better formulate an accu- tumors (6). On the other hand, mucinous noncystic adenocarcinoma
rate differential diagnosis. (also referred to as colloid carcinoma), a histologic variant of PDAC,
„ Discuss the prognostic landscape of is defined by the accumulation of extracellular mucin, containing
PDAC and its variants. floating carcinoma cells.
See rsna.org/learning-center-rg. Rare histologic variants of PDAC are recognized in the literature
(7), some with superior overall survival, such as colloid carcinoma and
2  September-October 2020 radiographics.rsna.org

TEACHING POINTS Clinical Features

„ The typical imaging features of conventional PDAC include
PDAC is the most common pancreatic malig-
an indistinct, poorly enhancing focal mass that obstructs nancy, accounting for more than 85% of pancre-
nearby pancreatic and bile ducts, reflecting the underlying atic tumors. It is typically a disease of elderly pa-
abnormality. tients, with a mean age at presentation of 68 years
„ ASqC usually manifests with ring enhancement and high and a male-to-female ratio of 1.6:1. After colorec-
signal intensity at T2-weighted MRI. This tumor type is more tal cancer, it is the second most common cancer of
frequently located in the pancreatic tail compared with PDAC the digestive system in the United States, and its
and is usually larger than the hypoenhancing mass observed
in PDAC.
incidence is rising sharply (3). The development
„ Colloid carcinomas manifest as focal hypoenhancing masses
of pancreatic cancer is strongly related to smok-
with lobulated contours and indiscrete margins. The abun- ing, family history, obesity, long-standing diabetes,
dant mucinous content appears as high signal intensity on and chronic pancreatitis. Early stages of PDAC
T2-weighted MR images, with internal meshlike low signal in- are clinically silent. Abdominal pain is the most
tensities and hypointense foci, which are commonly mistaken frequently reported clinical symptom, even when
to be cystic lesions.
the tumor is small (<2 cm). Other symptoms
„ According to our own experience with HC of the pancreas,
include weight loss, pruritus, and jaundice, which
combined with a few case reports that briefly address imaging
features, the tumor is typically exophytic, well-delineated, and
are typically present when the tumor invades
hypoattenuating at CT and shows hyperenhancement during adjacent tissue or seeds distant organ metastases.
the arterial phase, with washout in the portal venous phase A hypercoagulable state frequently accompanies
and diffusion restriction. PDAC, leading to a high incidence of both venous
„ Contrary to PDAC findings, UCOGC is surrounded by a well- and arterial thromboembolism.
defined hypoenhancing and low-signal-intensity rim at T2- The majority of patients are diagnosed when
weighted MRI, reflecting a fibrous capsule.
their cancer is at an advanced stage (T3 or T4, in
approximately 80% of patients), and therefore,
these patients do not qualify for complete surgi-
undifferentiated carcinoma with osteoclast-like cal resection, which offers the only chance of a
giant cells (UCOGC). However, adenosquamous cure. T3 tumors extend beyond the pancreas but
carcinoma (ASqC) and signet ring cell carcinoma have no involvement of the celiac axis or superior
(SRCC) are associated with an even worse prog- mesenteric artery. T4 tumors affect the celiac axis
nosis. According to the World Health Organization or superior mesenteric artery. In patients who
(WHO), other relatively rare histopathologic vari- have borderline resectable PDAC (approximately
ants of PDAC include hepatoid carcinoma (HC), 50% of patients) with a high risk of positive
medullary carcinoma of the pancreas (MCP), and resection margins, neoadjuvant chemotherapy
UC (8). To our knowledge, few studies have inves- and radiation therapy are recommended. The
tigated their natural history and radiologic-patho- 5-year survival rate of this surgical patient group
logic features, many of which are entirely limited is 15%–25% (12,13).
to case reports and single-center studies (9–11).
This article reflects our combined experience Pathologic Features
with PDAC and its rare histologic variants and Approximately 60%–70% of PDACs are located in
is based on data from the Radiologic Pathology the head of the pancreas, with the remaining in the
Archives at the American Institute of Radiologic body and tail. PDAC is generally a solitary lesion.
Pathology and Beth Israel Deaconess Medical At gross pathologic examination, PDACs are
Center. We summarize the current literature by firm multinodular and sclerotic tumors with
reviewing the radiologic features in context with indistinct margins and a whitish cut surface (14).
clinical and pathologic data. The main emphasis The pathogenesis of PDAC follows a series of
is on specific radiologic and pathologic features stepwise mutations from normal pancreatic tissue
that may help to differentiate the rare histologic that first forms a precursor lesion and eventually
variants of PDAC, which have different prognos- mutates to an invasive malignancy (15). The most
tic landscapes from those of conventional PDAC. common neoplastic precursor lesions of PDAC
The Table provides a comprehensive overview of are pancreatic intraepithelial neoplasms, which
the information in this article. are microscopic tumors (<5 mm) that are not
directly visible at pancreatic imaging (16). Less
Pancreatic Ductal Adenocarcinoma frequently, PDAC can evolve from intraductal
papillary mucinous neoplasms (IPMNs) and
Definition mucinous cystic neoplasms (17).
Pancreatic ductal adenocarcinoma is a malignant At histopathologic evaluation, most tumors are
epithelial neoplasm with pancreatic ductal dif- well differentiated to moderately differentiated
ferentiation and mucin production. with infiltrating glandular and ductlike structures
Clinical, Pathologic, and Radiologic Features of Conventional PDAC and its Histologic Subtypes with their Differential Diagnosis
Histologic
Subtype Key Clinical Features Key Pathologic Features Key Radiologic Features Differential Diagnosis

Conventional Most common Infiltrating glandular and ductlike structures Indistinct, poorly enhancing Pancreatitis (focal, groove,
PDAC Older adults, male predominance Desmoplastic reaction 10% are isoattenuating autoimmune)
Most patients present at an advanced tumor stage SMAD4 protein is lost in approximately 55% Indirect signs of PDAC: ductal obstruction, Inflammatory pseudotumor
(T3–T4) of patients pancreatitis, segmental atrophy, contour Pancreatic acinar cell carcinoma
abnormalities Pancreatic neuroendocrine
tumors
Primary pancreatic lymphoma
ASqC 1%-4% of exocrine pancreatic malignancies Round lobulated tumor with clearly defined borders Smooth margins Metastatic squamous cell car-
RG  •  Volume 40  Number 5

Older adults, male predominance Large tumors Progressive ring enhancement cinoma to the pancreas
Less favorable outcome than that with PDAC Predilection for the pancreatic body and tail Extensive central tumor necrosis
Mixed tumor with glandular and at least 30% squamous High signal intensity at T2-weighted MRI
differentiation
Colloid carci- 1%-3% of exocrine pancreatic malignancies Extensive amount of mucin (at least 50%), containing Cystic imaging appearance Intraductal papillary mucinous
noma Older adults, male predominance floating neoplastic cells Lobulated contour neoplasm
More favorable long-term survival after surgical resection Predilection for the pancreatic head Indiscrete margins Mucinous cystic adenocarci-
compared to PDAC Typically associated with intestinal-type intraductal High T2 signal intensity with “salt and pep- noma
papillary mucinous neoplasm per” appearance
Patients usually present at an early T stage Poorly but gradually enhancing
HC Younger patient age than in conventional PDAC (mean Large tumors (6 cm) Exophytic, well-defined hypointense tumor Metastatic hepatocellular carci-
age, 56 y), male predominance Predilection for the pancreatic body and tail Arterial hyperenhancement and washout in noma to the pancreas
Early hematogenous metastasis and lymph node invasion Gray-greenish cut surface the portal venous phase
Resection of distant metastasis may be considered Antialbumin immunohistologic staining is most specific Intratumoral microscopic fat has been
reported
MCP Interlinked with hereditary nonpolyposis colorectal cancer Syncytial growth pattern of poorly differentiated cells No data Poorly differentiated conven-
MCP with microsatellite instability: better prognosis than Extensive necrosis with lymphocytic reaction tional PDAC
that of conventional PDAC Distinct borders Acinar cell carcinoma

SRCC <1% of exocrine pancreatic malignancies >50% signet ring cell contribution No data Metastatic extrapancreatic
Older adults, male predominance Frequent manifestation in the periampullary region SRCC to the pancreas
Unconventional sites of metastasis (bone, leptomeninges) Colloid carcinoma
UC 2%-7% of exocrine pancreatic malignancies No definite direction of differentiation May appear cystic in up to 50% of cases Conventional PDAC
Older adults, male predominance Firm to rubbery mass Aggressive mass with direct invasion to
Less favorable outcome than that with conventional Excessive necrosis with necrotic debris at gross patho- adjacent structures
PDAC logic examination Peripheral enhancement
Cystic degeneration
UCOGC Slight female predominance Pleomorphic mononuclear cells mixed with multilocu- Low signal intensity at T2- and T2*-weight- Conventional PDAC
Lymph node metastasis and perineural invasion are not lated osteoclast-like giant cells ed MRI due to hemorrhage Pancreatic neuroendocrine
common Focal osteoid formation Well-defined hypoenhancing and low- tumors
Treatment of choice: surgical en bloc resection Larger than conventional PDAC (5 cm) signal-intensity rim at T2-weighted MRI Cystic pancreatic tumors such
Hemorrhage and focal necrosis Calcifications as mucinous cystadenocar-
Fibrotic capsule cinoma
Schawkat et al  3
4  September-October 2020 radiographics.rsna.org

Figure 1.  Conventional PDAC in a 61-year-old man who presented at the emergency department after experiencing trauma.
(a, b) Axial contrast material–enhanced CT images of the abdomen show a left hepatic lobe hematoma (arrowhead in a) and a
small hypoattenuating pancreatic body mass (arrowhead in b) as an incidental finding that was missed. (c, d) Coronal (c) and
axial (d) contrast-enhanced CT images obtained 12 months later when the patient presented with right upper quadrant pain
and elevated liver function test results show a large pancreatic body and tail hypovascular mass (arrowhead in c and d) with
upstream obstruction of the main pancreatic duct. Furthermore, multiple hypoattenuating focal liver lesions are visible (arrows
in c) and are consistent with liver metastases. (e, f) Photomicrographs at histopathologic evaluation show an infiltrating tumor
with glandular and ductlike structures (arrowhead), which is typical for conventional PDAC. (Hematoxylin-eosin stain; original
magnification, 20 and 40, respectively.)

(Fig 1). Typically, a desmoplastic stromal reac- (sialo-type and sulfated) produced by PDAC. At
tion is associated with these tumors and cor- immunohistochemical analysis, the SMAD4 pro-
responds to the firm consistency, haphazard tein is lost in approximately 55% of PDACs, and
growth pattern, and obstructive features of the p53 is either overexpressed or completely absent
tumor. Alcian blue solution stains acid mucins in most cases.
RG  •  Volume 40  Number 5 Schawkat et al  5

Figure 2.  Conventional PDAC in a 72-year-old man with abnormal pancreatic function test results. (a) Axial contrast-enhanced
CT image of the abdomen shows a slightly prominent main pancreatic duct (MPD) in the pancreatic tail (arrow), without clear ev-
idence of a pancreatic mass. (b) Axial multiparametric fat-suppressed T2-weighted MR image shows a small mildly hyperintense
pancreatic head mass with irregular boundaries (arrowhead). (c, d) Axial diffusion-weighted MR images (b = 750 sec/mm2) show
high signal intensity (arrowhead in c), with a low apparent diffusion coefficient (arrowhead in d). The imaging findings are con-
sistent with an isoattenuating pancreatic mass displaying slight dilatation of the MPD at contrast-enhanced CT as an indirect sign,
with clear depiction of the mass at MRI. Histopathologic assessment (not shown) confirmed the diagnosis of conventional PDAC.

Radiologic Features kVp (20). Conventional PDAC is hypoenhancing

The typical imaging features of conventional relative to the normal pancreatic parenchyma,
PDAC include an indistinct, poorly enhancing because of hypovascularity of the intermixed
focal mass that obstructs nearby pancreatic and desmoplastic stroma and diminished vascularity
bile ducts, reflecting the underlying abnormal- of the tumoral tissue.
ity. The tumor is typically hypointense at T1- Ten percent of PDACs are isoattenuating and
weighted MRI, shows variable signal intensity at remain the main challenge in the detection of
T2-weighted MRI, and is restricted at diffusion- PDAC, even further limiting the diagnostic accu-
weighted MRI (18). racy of CT. Isoattenuating PDACs are believed to
High-quality imaging is crucial for the detec- have less desmoplastic stroma (3). Because these
tion and staging of PDAC. Multidetector thin- isoattenuating tumors are associated with a better
section multiphasic CT is the modality of choice prognosis, their detection is of the highest impor-
for initial assessment. The dedicated pancreatic tance (3). Indirect signs of PDAC such as up-
protocol includes a pancreatic (ie, delayed arte- stream pancreatic duct dilatation and dilatation of
rial) phase for optimal assessment of the pan- the common bile duct can also be associated with
creatic parenchyma and arterial structures and a pancreatitis, segmental atrophy, and abnormali-
portal venous phase for optimal assessment of the ties of the pancreatic contour (3) (Fig 2). Because
venous structures and the liver. The tumor con- of its better contrast resolution, MRI is useful in
spicuity is best in the pancreatic phase, because these cases, with up to 79% sensitivity for detec-
the attenuation grade of the usually hypoenhanc- tion of isoattenuating tumors at CT (21).
ing tumor (Fig 1) and healthy pancreatic tissue Because of overlapping imaging features, the
is greater (19). Newer techniques have been differentiation of PDAC from other mass-form-
introduced to increase tumor conspicuity, such ing focal lesions in the pancreas can be difficult
as dual-energy CT with low-energy acquisition and leads to false-positive rates in 2%–35% of
at 80 kVp instead of the frequently applied 120 patients, causing unnecessary surgery and risk
6  September-October 2020 radiographics.rsna.org

to patients (22). A broad range of nonneoplastic transformation of adenocarcinoma to squamous

and neoplastic abnormalities can mimic PDAC, carcinoma of the pancreas. Therefore, ASqC is con-
including focal acute and chronic pancreatitis, sidered a metaplastic tumor that follows a transition
groove or paraduodenal pancreatitis, autoim- from adenocarcinoma to squamous cell carcinoma
mune pancreatitis, inflammatory pseudotumors, (30). Squamous metaplasia is generally related to
pancreatic acinar cell carcinoma, pancreatic chronic inflammation of the pancreas (23).
endocrine tumors, and primary pancreatic At gross pathologic examination, the tumor
lymphoma. A comprehensive assessment with manifests with a round lobulated shape and a
evaluation of clinical manifestations, laboratory clearly defined border (31). It is frequently en-
data, and the superior contrast resolution of MRI capsulated by fibrous tissue and frequently shows
with varying sequences can facilitate the correct cystic components (28). Previous studies show
diagnosis of PDAC. that ASqC, when compared with PDAC tumors,
are larger and have a predilection for the pancre-
Differential Key Points atic body and tail (24,25,32).
PDAC manifests as a hypoenhancing mass with At histopathologic examination, ASqC is more
irregular margins that is frequently located in the likely to be poorly differentiated compared with
pancreatic head, causing obstruction of adjacent PDAC tumors (24). ASqC is defined pathologi-
pancreatic and bile ducts. cally as a mixed tumor with ductal and squamous
differentiation, with an at least 30% squamous
Adenosquamous Carcinoma component (23). However, the proportion of
squamous differentiation is not associated with
Definition median overall survival of the patient (27).
Adenosquamous carcinoma (ASqC) of the pancreas
is a malignant epithelial neoplasm, which is de- Radiologic Features
fined at pathologic examination as a mixed tumor The imaging features of ASqC tumors correlate
with ductal and squamous differentiation, with at with the pathologic features and are usually seen
least a 30% squamous component (23). as large round lobulated masses with extensive
central necrosis and progressive enhancement of
Clinical Features the fibrous capsule (Fig 3) (33). The presence of
ASqC is a rare and still poorly understood vari- extensive central tumor necrosis was suggested
ant of PDAC that accounts for only 1%–4% of by several reports to be a characteristic imaging
exocrine pancreatic malignancies (24). Clinical feature (28,34,35). The pronounced peripheral
presentation (jaundice, weight loss, anorexia, and enhancement, mostly described as ring enhance-
abdominal pain) and age and sex distribution of ment, is gradual progressive enhancement,
patients with ASqC are very similar to those of presumably reflective of progressive accumula-
PDAC (25). The mean age at presentation is 68 tion of contrast material in the interstitial space
years, with a male predominance (26,27). Previous of the fibrous tissue. In a case-control study (28),
studies suggest a less-favorable outcome for pa- the ring-enhancement pattern was described
tients with ASqC and more aggressive initial mani- as the most useful predictive factor for ASqC.
festation at imaging, with often simultaneous liver The overall degree of enhancement is reported
metastases and lymphadenopathy (24,28). ASqC to be greater than in PDAC (34). An important
is also associated with worse survival in patients advantage of MRI over CT is that it has the
with stage I or II disease who have undergone ability to depict differences in signal intensity on
resection (25). However, the strongest predictor of T2-weighted MR images. The signal intensity of
survival among patients with ASqC is the resection ASqC at T2-weighted MRI was also found to be
status. Surgical resection was shown to improve significantly higher in patients with ASqC com-
median patient survival from less than 6 months to pared with patients with PDAC, as reported in a
11–20 months in some studies (24,29). Adjuvant study by Ding et al (34). The overall higher signal
chemotherapy and radiation therapy were reported intensity at T2-weighted MRI may be attributed
to markedly improve survival rates in patients to mucoid or necrotic components that are more
with ASqC (23). Therefore, for the prediction of pronounced in AsqC (Fig 3) (33).
survival and therapy planning, the differentiation
of ASqC from PDAC is critical. Differential Key Points
ASqC usually manifests with ring enhancement and
Pathologic Features high signal intensity at T2-weighted MRI. This tu-
Regarding the development of ASqC, several patho- mor type is more frequently located in the pancre-
logic pathways have been assumed. At present, atic tail compared with PDAC and is usually larger
the dominant pathway is thought to be the direct than the hypoenhancing mass observed in PDAC.
RG  •  Volume 40  Number 5 Schawkat et al  7

Figure 3.  ASqC in a 40-year-old woman who pre-

sented with worsening left upper quadrant pain.
(a) Photomicrograph of the tumor shows both glan-
dular (arrowhead) and squamous differentiation.
(Hematoxylin-eosin stain; original magnification,
100.) (b) Axial contrast-enhanced CT image shows
a well-circumscribed exophytic tumor with minimal
enhancement in the pancreatic head and dilatation
of the main pancreatic duct (arrowhead). (c, d) Ax-
ial T2-weighted MR images of the focal pancreatic
head mass show moderate signal hyperintensity.
(e) Axial contrast-enhanced MR image shows
marked ring enhancement (arrowhead), with a pro-
nounced nonenhanced central part of the tumor.

Colloid Carcinoma (Mucinous Clinical Features

Noncystic Adenocarcinoma) Colloid carcinoma accounts for only 1%–3% of
all exocrine pancreatic malignancies and has a
Definition patient age and sex distribution similar to those
Colloid carcinoma of the pancreas is characterized of PDAC (36). It shows a slight male predomi-
by mucin-producing neoplastic ductal epithelial nance and is diagnosed at a mean age of 61
cells dispersed in an accumulation of extracellular years (6,37). However, the incidence of colloid
mucin. According to the definition by the WHO, carcinoma might be underestimated because
the mucinous component should comprise at of ambiguity of the classification of mucin-
least 50% of the tumor (8). producing pancreatic tumors and inconsistency
8  September-October 2020 radiographics.rsna.org

of terminology (38). Many synonyms for col- is expressed in colloid carcinoma but rarely in
loid carcinoma have been used, including but PDAC, which might also contribute to the bet-
not limited to mucinous noncystic carcinoma, ter prognosis for colloid carcinoma (46).
gelatinous adenocarcinoma, and mucoid car- Patients typically present with an early T
cinoma. Patients present with abdominal pain, stage tumor. A study (37) showed that, with in-
diarrhea, jaundice, light-colored stool, weight creasing stage, the long-term survival of patients
loss, and pancreatitis (39). Typically, the diag- with colloid carcinoma is comparable to that of
nosis of colloid carcinoma is based on surgical PDAC.
resection rather than on preoperative workup,
mainly because of the rarity of the diagnosis Radiologic Features
(40). Patients with colloid carcinoma can de- Although colloid carcinomas are not true cystic
velop migratory thromboembolism (ie, Trousseau tumors, the abundant mucin production leads
syndrome) after incisional biopsy of the tumor, to a cystic appearance at imaging (Fig 4). There-
with a fatal outcome, as shown in one case report fore, these tumors can be confused with mainly
(6). Previous studies described the capacity of cystic tumors, such as IPMNs or mucinous cystic
mucin to activate the coagulation cascade; during adenocarcinomas.
surgical intervention, release of mucin from this At imaging, colloid carcinomas manifest with
mucin-rich tumor into the circulation may cause a lobulated contour and indiscrete margins.
thromboembolism (41). Despite this phenom- The abundant mucin accumulation manifests as
enon, long-term survival after surgical resection high signal intensity on T2-weighted MR images
is significantly better for patients with colloid (higher intensity than that of the spleen) (38).
carcinoma than for those with PDAC: the 2-year On dynamic contrast-enhanced CT images, the
and 5-year survival rates are 70% and 28% and tumor appears as a low-attenuation and poorly
57% and 12%, respectively (P = .001) (6). The but gradually enhancing mass. Yoon et al (38)
development of pseudomyxoma peritonei has described in a case series of colloid carcinomas
also been described after a total pancreatectomy a “salt and pepper” appearance on T2-weighted
for IPMN with colloid carcinoma (42). MR images, with diffusely scattered small nodu-
lar high signal intensities, meshlike linear low
Pathologic Features signal intensities, and internal hypointense foci.
At histologic examination, colloid carcinomas
show extensive amounts of mucin with neoplas- Differential Key Points
tic cells floating within, forming stellate clusters, Colloid carcinomas manifest as focal hypoen-
and occasionally resembling signet ring cells (6). hancing masses with lobulated contours and
Well-differentiated cuboidal cells partially line the indiscrete margins. The abundant mucinous
large mucinous pools. content appears as high signal intensity on T2-
Most colloid carcinomas are located in weighted MR images, with internal meshlike low
the head of the pancreas and frequently also signal intensities and hypointense foci, which are
infiltrate the body and tail (43). The major- commonly mistaken to be cystic lesions.
ity of colloid carcinomas are associated with Typically observed IPMN characteristics such
invasive intestinal-type IPMN and account as a communication between the mass and the
for one-quarter of all cases of invasive IPMN pancreatic duct, downstream dilatation of the
(44). Their more favorable clinical course has pancreatic duct, or intraductal papillary compo-
been mainly attributed to two factors: First, the nents are not features of colloid carcinomas. MR
inverse polarization of the cellular layers pro- cholangiopancreatography (MRCP) is a helpful
vides a favorable environment in which the basal tool in assessment of these features and in dis-
epithelial cells develop secretory properties and tinguishing colloid carcinomas from IPMNs. At
deposit mucin into the cell-stroma interface, endoscopic retrograde cholangiopancreatography
which consecutively separates the cell from the (ERCP), the spillage of mucin from the ampulla
underlying stroma. Second, by surrounding the of Vater, a typical feature of IPMN, is not ob-
neoplastic cells, the mucin serves as a protect- served in colloid carcinoma. The differentiation
ing barrier and inhibits further invasion (45). of IPMN from mucinous cystadenocarcinoma
This distinct cellular structure is also reflected can be challenging, but most colloid carcinomas
with differential staining, which shows MUC1, are not cystic. Mucinous cystic carcinomas are
a surface glycoprotein, to be expressed on the large encapsulated unilocular or septated mac-
basal cell surface in colloid carcinoma compared rocystic lesions with intracystic enhancing soft
with on the luminal surface or throughout the tissue and have a different appearance than the
cell in PDAC (46). However, MUC2, a surface indistinct margin and gradual internal enhance-
glycoprotein with tumor suppressor activity, ment typical of colloid carcinomas.
RG  •  Volume 40  Number 5 Schawkat et al  9

Figure 4.  Colloid carcinoma in an 82-year-old man

who presented with anemia and weight loss. (a) Ax-
ial contrast-enhanced CT image shows a large cys-
tic-appearing mass that contains an enhancing solid
component in the pancreatic head (arrow). Of note
is the fistula (arrowhead) between the tumor and
duodenum (D). The tumor abuts the superior mes-
enteric artery (A) and the superior mesenteric vein
(V). (b) Photograph of the gross specimen shows a
mucinous tumor with a predominant solid compo-
nent. (c) Photomicrograph of the histologic surgical
specimen shows haphazard distribution of acellular
mucin with malignant epithelial cells. (Hematoxylin-
eosin stain; original magnification, 100.)

Hepatoid Carcinoma HC of the pancreas is considered to be an

aggressive tumor that shows early hematogenous
Definition metastasis to the liver and lymph node invasion,
Hepatoid carcinoma (HC) of the pancreas is a with a mean overall survival time of 18 months
primary extrahepatic epithelial malignancy that re- (9). One study (48) reported that pure HC has a
sembles hepatocellular carcinoma (HCC) in terms better prognosis than mixed-type HC, although
of morphologic and immunohistochemical proper- this is still debated (9).
ties. On histological specimens, HC is heteroge- To date, no standard therapeutic regimen has
neous, showing either pure hepatoid differentiation been established for the treatment of HC of the
or areas more common to pancreatic neoplasms pancreas because of the rarity of this tumor and a
such as PDAC or neuroendocrine tumors. lack of experience in treating it. Up-front radical
surgery is suggested, even for patients with locally
Clinical Features advanced tumors, and resection of distant metas-
HC of the pancreas is an extremely rare extra- tases may be considered.
hepatic neoplasm and, to date, only case reports
have been published, with the largest case series Pathologic Features
of 23 patients being reported by Kuo et al (9). The pathogenesis of HC of the pancreas is not
At presentation, the patients are younger than entirely understood, and two theories have been
patients with PDAC tend to be, with a mean age of proposed. First is the ectopic liver theory, which
56 years (range, 21–80 years) and a male pre- relies on the embryonic pathway of the foregut
dominance (70%) (9). The majority of patients are endoderm that gives rise to the liver and pan-
asymptomatic, and the tumors are usually inci- creas. The theory suggests the possibility that
dentally discovered. If present, clinical symptoms ectopic liver tissue rests in organs derived from
are nonspecific (weight loss, jaundice, nausea and the foregut endoderm, such as the pancreas,
vomiting, and epigastric and/or back pain). Serum gallbladder, stomach, and lung, where HC has
α-fetoprotein levels may be elevated. However, been equally reported, with the gallbladder be-
α-fetoprotein production is nonspecific and can be ing the most common site (49–51). Second is
found in nonhepatoid tumors such as PDACs, pan- the pancreas-to-liver transdifferentiation theory,
creaticoblastomas, and acinar cell carcinomas (47). which relies on an observation in animal models
10  September-October 2020 radiographics.rsna.org

Figure 5.  HC of the pancreas in a 52-year-old man who presented with a history of painless jaundice.
(a) Photograph of the cut surface of the pancreatic head shows a large (approximately 6 cm) well-
circumscribed homogeneous green mass (due to bile production). (b) Photomicrograph shows that the
tumor cells have a typical granular cytoplasmic appearance, confirming hepatocytic origin. (Hepatocyte
paraffin 1 monoclonal antibody stain; original magnification, 100.) (c) Photomicrograph shows that
the tumor cells have round nuclei with moderate nuclear pleomorphism and an abundant eosinophilic
granular cytoplasm, which is characteristic of hepatocellular lesions. (Hematoxylin-eosin stain; original
magnification, 100.) (d) Axial T2-weighted MR image of the exophytic well-delineated pancreatic head
mass shows homogeneous mild signal hyperintensity. (e, f) Axial contrast-enhanced MR images show
early arterial phase (e) enhancement of the mass with washout in the portal venous phase (f).

of a loss of pancreatic stem cell suppressor activ- located in the pancreatic body or tail region (in
ity. Pancreatic stem cells inhibit hepatocyte differ- approximately 60% of cases) (9). At gross patho-
entiation in the healthy pancreas. However, after logic examination, the appearance of the cut
exposure to carcinogens, their suppressor ability surface of the tumor is similar to that of HCC, in
is lost, which leads to hepatocellular differentia- that it is lobulated and gray to greenish, depend-
tion in pancreatic cells (9). ing on the amount of bile production (Fig 5).
Compared with PDAC, HC tumors are larger At histopathologic evaluation, pancreatic HC
(median tumor size, 6 cm) and more often typically manifests with islands of large tumor
RG  •  Volume 40  Number 5 Schawkat et al  11

Figure 6.  HC in a 65-year-old man who presented with abdominal pain and an elevated lipase level. (a) Duplex US image shows
a predominantly hypoechoic mass in the pancreatic tail, with evidence of mild internal perfusion. (b) Photomicrograph shows
positive immunostaining for cytokeratin 7. (Cytokeratin immunostaining; original magnification, 100.) (c) Photomicrograph of
the specimen shows the typical appearance of hepatocellular cells with moderate nuclear pleomorphism and abundant eosinophilic
granular cytoplasm. (Hematoxylin-eosin stain; original magnification, 200.) (d) Axial contrast-enhanced CT image shows a well-
circumscribed heterogeneous exophytic mass (maximum size, 1 cm) in the pancreatic tail. (e) Axial T2-weighted MR image shows a
complex solid and cystic mass in the pancreatic tail, with predominantly high signal intensity compared with the residual pancreatic
tissue. (f) Axial T1-weighted MR image of the mass shows inhomogeneous signal hypointensity, with a stripe of hyperintensity that
most likely reflects a hemorrhagic spot. (Case courtesy of Chris McKee, MD, Auckland, New Zealand.)

cells, with round prominent nuclei and abundant scientific study. According to our own experi-
eosinophilic cytoplasm. The polygonal sheets ence with HC of the pancreas, combined with
of neoplastic cells are organized in a trabecular a few case reports that briefly address imag-
or perisinusoidal pattern, occasionally with bile ing features, the tumor is typically exophytic,
formation and canaliculi (48). Pure hepatoid well-delineated, and hypoattenuating at CT and
histologic results are found in 59% of cases, and shows hyperenhancement during the arterial
the remaining 41% have synchronous, more phase, with washout in the portal venous phase
common, pancreatic tumor differentiations such and diffusion restriction (56). The signal inten-
as serous microcystic cystadenomas, PDACs, or sity at T2-weighted MRI is heterogeneous. In
neuroendocrine tumors (52–54). one case (9), lower signal intensity during the
Similar to the immunohistochemical findings out-of-phase gradient-recalled-echo sequence
of HCC, HC reveals hepatocellular differentia- than that of the in-phase sequence was reported,
tion and stains positively for hepatocyte paraffin corresponding to intratumoral microscopic
1 (Figs 5, 6), polyclonal carcinoembryonic anti- fat content. In another case report (57), HC
gen, cytokeratin, α-fetoprotein, and antialbumin showed characteristic contrast material enhance-
(55). Antialbumin immunohistologic staining is ment on dynamic CT images, with early arterial
the most specific of these, because many of the hyperenhancement and late portal venous wash-
other markers are found in several other tissue out similar to that of HCC (Fig 5).
types. However, albumin is exclusively expressed
by the liver, and positive staining discloses certain Differential Key Points
hepatic lineage (47). No standardized imaging criteria have been
established for pancreatic HC. On the basis of
Radiologic Features our observations, pancreatic HC seems to be well
To our knowledge, little is known about the delineated and arterially hypervascularized and
radiologic features of HC because of a lack of shows washout similar to that in HCC.
12  September-October 2020 radiographics.rsna.org

The differential diagnosis of pancreatic HC first clinical clue for an inherited cancer syn-
and metastatic HCC is particularly challenging drome, possibly warranting genetic counseling of
when the primary tumor is unknown, because patients and their relatives (10).
both share numerous clinical-pathologic features
and morphologic, histologic, immunohisto- Pathologic Features
chemical, and laboratory findings. Although the MCP manifests at gross pathologic examination
incidence of HCC metastasis to the pancreas is as a well-circumscribed tumor with intralesional
low (2.7%–5.6%) and it usually manifests late necrosis. As anticipated by the terminology
in the course of disease, the possibility of HCC medulla, which is Latin and has the implication
metastasis to the pancreas should be considered of the soft inner part of structures, MCP has a
(58). At immunohistochemical analysis, two spe- softer texture than does PDAC (62).
cific hepatocyte transporters, the bile salt export MCP tumors have several histologic character-
pump and multidrug-resistance protein 3, are istics, and these characteristics resemble those of
usually not expressed by HCC and can be helpful MSI+ colon cancer: MCP tumors are demarcated
to exclude metastatic HCC (59). by distinct borders, are poorly differentiated,
show at least focal areas of necrosis, have a growth
Medullary Carcinoma of the Pancreas pattern that is syncytial (Fig 7), and commonly
display an intratumoral lymphocytic reaction. The
Definition adjacent nonneoplastic surrounding pancreatic
Medullary carcinoma of the pancreas (MCP) is parenchyma inherits precursor lesions of conven-
characterized by a syncytial growth pattern of tional PDAC (pancreatic intraepithelial neoplasia)
poorly differentiated highly pleomorphic cells in almost one-half of cases of MCP (10).
that are accompanied by extensive necrosis. The Immunohistochemical analysis shows positiv-
tumor displays a lymphocytic reaction and clearly ity for cytokeratin. MSI+, because of inherited
defined borders. Microsatellite instability (MSI+) germline mutations, is shown by immunolabeling
is apparent with polymerase chain reaction. for MLH1 and MSH2, displaying loss of ex-
pression of at least one of these DNA mismatch
Clinical Features repair proteins (Fig 7). Similar to PDAC, most
To our knowledge, little is known about the MCPs show mutations in the KRAS genes.
clinical features of MCP, an extremely rare vari-
ant of PDAC. In a case series (10) of 18 pa- Radiologic Features
tients, three patients reported a medical history To date and to our knowledge, no data have been
of colonic cancer in a first-degree relative. The published on the radiologic features of MCP. On
same study interconnected hereditary nonpol- the basis of our experience, MCP manifests at
yposis colorectal cancer syndrome to MCP. One imaging as a well-circumscribed mass with cen-
patient in the study cohort presented with a syn- tral hypoenhancement at contrast-enhanced CT,
chronous pancreatic and colonic cancer, both corresponding to hyperintensity with a hypoin-
with MSI+, a feature linked to adenocarcinoma tense rim at T2-weighted MRI.
of the colon in patients with hereditary nonpol-
yposis colorectal cancer syndrome (10). Similar Differential Key Points
to the MSI+ colon cancer, MSI+ MCP is associ- Two entities can mimic MCP at histologic exami-
ated with an improved prognosis, and patients nation: poorly differentiated PDAC and acinar
with MSI+ MCP have a reported mean postsur- cell carcinoma. Poorly differentiated PDAC
gical survival time of 62 months compared with shows infiltrative borders but lacks the reactive
10 months for those with PDAC (60,61). Also, infiltrative lymphocytic infiltration of the tumor
a family history of cancer in general is more that is characteristic of MCP. Differentiation of
commonly observed in patients with MCP (10). poorly differentiated acinar cell carcinoma from
MCPs do not respond well to chemotherapy MCP based on histologic findings alone is a chal-
(61), making surgery the optional first-line lenge. However, immunolabeling in acinar cell
therapy for patients with MCP. carcinoma shows positivity for trypsin and intact
The distinction of MCP from conventional labeling for MLH1 and MSH2. MCP, on the
PDAC is not only crucial for the choice of treat- other hand, does not show labeling for trypsin.
ment of the individual patient but has more
far-reaching consequences. Because of the link Signet Ring Cell Carcinoma
between MCP and hereditary nonpolyposis
colorectal cancer syndrome and the higher fre- Definition
quency of any cancer in a first-degree relative, the The hallmark of signet ring cell carcinoma
diagnosis of MCP in a family member may be a (SRCC) of the pancreas is the appearance of
RG  •  Volume 40  Number 5 Schawkat et al  13

Figure 7.  MCP in a 38-year-old man with a pancreatic head mass. The family history revealed cancers of the pancreas, breast,
ovary, and colon in first-degree relatives at a young age. (a) Photomicrograph of the specimen shows a syncytial growth pattern.
(Hematoxylin-eosin stain; original magnification 200.) (b, c) Photomicrographs show MSI+ with MSH1 retention (b) and MSH2
and MSH6 loss (c). (Immunohistochemical stain; original magnification, 200.) (d) Axial contrast-enhanced CT image shows a well-
circumscribed heterogeneous mass in the pancreatic head with central hypoattenuation. (e) Axial T2-weighted MR image of the mass
shows central signal hyperintensity, with a hypointense rim. (Case courtesy of Christine O. Menias, MD, Phoenix, Arizona.)

round isolated cells filled with large intracyto- entiation and advanced stage at presentation.
plasmic mucin vacuoles that push the crescent- However, owing to the extremely rare num-
shaped nucleus to the periphery of the cells, ber of reported SRCC cases, the prognosis of
thereby forming the characteristic “signet patients with this disease cannot be estimated.
ring” configuration. Most SRCCs show a large Poor differentiation and the lack of expression
component of conventional tubular-type ductal of normal cellular markers are major limita-
adenocarcinoma on histologic evaluation. When tions to targeted therapy and thereby predis-
the signet ring cells contribute to greater than pose a patient to a poor outcome. On the basis
50% of the cellular composition, the lesion can of immunohistochemical patterns, SRCCs are
be classified as an SRCC. subdivided into intestinal (I) and pancreatobili-
ary (PB) types, with the I-type seemingly having
Clinical Features a better prognosis (65,66). Compared with
SRCC contributes to less than 1% of pancreatic PDAC, SRCC has been shown to metastasize to
cancers and occurs far more frequently in the unconventional sites such as the bone (11) and
stomach (>96% of cases) (63). Other rare loca- leptomeninges (67).
tions of SRCC have been reported, including the In the previously reported cases, the majority of
breast, gallbladder, bladder, cervix, prostate, and patients underwent a radical therapeutic approach
colon (64). and pancreatoduodenectomy with or without
According to a case series (11) of patients with gastrectomy, occasionally with extended lymphad-
SRCC of the periampullary regions, the mean enectomy. The efficacy of adjuvant chemothera-
age of patient presentation with the disease was peutic regimens has not yet been established (68).
59.5 years, and a higher incidence was found in
men. Patients present mostly with jaundice and Pathologic Features
abdominal pain. In the pancreas, a frequent site of disease mani-
Similar to SRCC in other sites of the body, festation appears to be the periampullary region,
SRCC of the pancreas has been suggested to with up to 40 cases reported in the literature
have a dismal prognosis due to poor differ- (11). The epithelium of the ampulla is composed
14  September-October 2020 radiographics.rsna.org

of three different types of epithelia derived from because it often contains individual signet ring
the duodenum, the pancreas, and the common cells in the large stromal mucin; however, there
bile duct. It is postulated that SRCC arises from are far fewer signet ring cells in colloid carcinoma
ectopic gastric mucosa in the periampullary re- than in SRCC.
gion. In support of this hypothesis, a small num-
ber of patients with SRCC have been reported to Undifferentiated Carcinoma
have areas of peritumoral ectopic gastric mucosa
(69,70). Another common theory is that gastric Definition
metaplasia in duodenal mucosa near the ampulla Undifferentiated carcinoma (UC) of the pancreas is
of Vater, occurring as a protective response to a malignant epithelial neoplasm with a significant
increased acidity, secondarily invades the periam- tumor component that shows no definitive direc-
pullary region and lays the foundation for SRCC tion of differentiation and is considered a variant
formation (70). of conventional PDAC with poor differentiation.
At histopathologic examination, SRCC is
composed of at least 50% characteristic cells with Clinical Features
abundant intracytoplasmic mucin. The nucleus is UC is a rare pancreatic tumor, representing
crescent shaped and eccentric in location, thereby 2%–7% of all exocrine pancreatic malignancies
forming the signet ring cells. (72). Synonyms include anaplastic carcinoma,
At immunohistochemical analysis, positive pleomorphic carcinoma, and giant cell carcinoma.
staining for MUC2, cytokeratin 20, and CDX2, In a case series (73) of 35 patients, the mean age
combined with no expression of cytokeratin 7, at presentation was 62.5 years, with a male pre-
signifies I-type SRCC that might have a better dominance (71%) . The presenting symptoms are
prognosis compared with the PB-type of SRCC, nonspecific and comparable to those of conven-
which has an inverted immunohistochemical tional PDAC (eg, weight loss, abdominal pain, and
staining pattern. nausea). The serum tumor markers CA 19–9 and
polyclonal carcinoembryonic antigen are found
Radiologic Features to be elevated in fewer than 20% of patients (72),
To date and to our knowledge, information on reflecting the poor differentiation of these tumors.
imaging of SRCC of the pancreas is limited to The reported median survival time of patients
a few case reports (67,71) that briefly address with UC is 5.7 months, whereas for PDAC, it
the radiologic appearance of SRCC without is 15.7 months. The duration of survival in UC
defining any specific features that might help to improves significantly after R0 or R1 resection
distinguish SRCC from conventional PDAC. In compared with surgery with palliative intent (72).
one case report (71), the SRCC was depicted
at contrast-enhanced CT as a diffuse mass in Pathologic Features
the head and tail of the pancreas, while other UC is located in the pancreatic head in 61% of
authors (67) described isolated dilatation of the patients, with a median tumor diameter of 4 cm as
common bile duct of 12.5 mm without evidence assessed in pathologic specimens (72).
of a mass. We illustrate a case of SRCC at con- On gross pathologic examination, UC appears
trast-enhanced CT and MRI with an exophytic mostly as a firm to rubbery mass and may have
mass in the pancreatic head that enhances ho- cystic or soft fleshy components. Some tumors
mogeneously after administration of intravenous yield macroscopically visible necrotic debris (73).
contrast material (Fig 8). UC displays a variety of histologic appearances
and is not defined by one direction of differen-
Differential Key Points tiation. In fact, the tumor is a conglomerate of
Metastasis to the pancreas from extrapancreatic growth patterns and coexisting cell differentiations
SRCC tumors (eg, gastric or mammary sites) including spindle cell, giant cell, pleomorphic cell,
are more common than primary pancreatic and round cell types (Fig 9) (73). Focal squamous
SRCCs and must be excluded. Another entity differentiation is seen in up to one-third of UCs.
that mimics SRCC at histopathologic evaluation The tumor contains extensive necrosis and cystic
is metastatic clear cell–type renal cell carcinoma. degeneration, with a surrounding dense wall of
But the cytoplasm of clear cells is filled with vital epithelial tumor cells.
glycogen, which can be easily distinguished from
signet ring cells with the use of periodic acid Radiologic Features
diastase staining, which stains the intracellular At contrast-enhanced CT and MRI, UC manifests
mucin in SRCCs. as an aggressive pancreatic mass with no specific
Colloid carcinoma of the pancreas is also im- features. In some case reports (72,74), UC is
portant to consider in the differential diagnosis, described as a large hypoattenuating lesion with
RG  •  Volume 40  Number 5 Schawkat et al  15

Figure 8.  SRCC in a 62-year-old woman with

a pancreatic head mass. (a) Axial contrast-en-
hanced CT image shows an exophytic hypoat-
tenuating pancreatic head mass (arrowhead),
with upstream dilatation of the main pancreatic
duct. (b, c) Diffusion-weighted MR images of the
mass (arrowhead) show diffusion restriction with
a low apparent diffusion coefficient. (d, e) Axial
T2-weighted MR images of the mass (arrowhead)
show homogeneous hyperintensity compared
with the remaining pancreatic parenchyma (d)
and homogeneous enhancement after administra-
tion of intravenous contrast media (e). (Case cour-
tesy of Christine O. Menias, MD, Phoenix, Arizona.)

peripheral enhancement that is more pronounced enhancement at contrast-enhanced imaging.

in the portal venous phase. The tumor may ap- The peripheral enhancement reflects the histo-
pear cystic in up to 50% of cases, with the cystic logic composition of densely packed epithelial
components better depicted at endoscopic US cells surrounding the degenerated center of the
compared with other imaging modalities (74). Be- tumor. Conventional PDAC, on the other hand,
cause of the extensive tumor size, direct invasion is composed of a marked desmoplastic stroma,
of adjacent structures and extrapancreatic tumor which contains sparse blood vessels and appears
spread are present in most cases. hypovascular at imaging compared with the sur-
rounding pancreatic parenchyma and compared
Differential Key Points with UC. Both UC and conventional PDAC dis-
UCs are usually large tumors with necrotic play aggressive imaging features, with UCs larger
areas and cystic degeneration, with peripheral at presentation.
16  September-October 2020 radiographics.rsna.org

Figure 9.  UC in a 35-year-old man with a history of recurrent heartburn and epigastric pain. (a) Photograph from gross patho-
logic examination shows an ill-defined pancreatic body and tail tumor with a whitish cut surface, measuring 6 cm. (b) Endoscopic
US image with fine needle aspiration shows a hypoechoic mass in the pancreatic body and tail with cystic structures (arrowhead).
(c, d) Photomicrographs from histopathologic evaluation show a variety of histologic appearances not defined by one direction
of differentiation, including pleomorphic cells and osteoclast-like giant cells (arrowhead in c) and spindle cells (d). (e) Photomi-
crograph of the remaining pancreatic parenchyma specimen shows chronic pancreatitis and pancreatic intraepithelial neoplasia
III lesions. (f–h) Axial contrast-enhanced CT images show an exophytic pancreatic body and tail mass (arrowhead) with direct
invasion into the liver and subcapsular hemorrhage (* in g and h).

UC with Osteoclast-like Giant Cells nomas (78). Many other terms have been used
to describe this tumor, including pleomorphic or
Definition osteoclastic giant cell tumor, giant cell carcinoma
Undifferentiated carcinoma with osteoclast-like giant of the pancreas, osteoclastoma, spindle cell carci-
cells (UCOGC) of the pancreas is a malignant epi- noma, and sarcomatoid carcinoma. Because of the
thelial neoplasm of the pancreas and a histologic plethora of names, the true incidence of UCOGC
variant of PDAC. Histopathologic evaluation re- remains unknown. Tumors with osteoclast-like gi-
veals at least two distinct but intermixed cell popu- ant cells have been reported in several extraskeletal
lations: pleomorphic neoplastic mononuclear cells sites, such as in the soft tissue, kidneys, breasts,
and large nonneoplastic multinucleated osteoclast- and thyroid and parotid glands (79–83). Patient
like giant cells (75,76). Focal intratumoral osteoid clinical presentation is nonspecific and similar
formation may be associated (77). to that of PDAC (eg, anorexia, fatigue, weight
loss, and jaundice). At presentation, patients are
Clinical Features typically aged 60–80 years, and they are slightly
UCOGC is a rare exocrine pancreatic tumor, ac- more likely to be women. The serum CA 19–9
counting for only 1.4% of total pancreatic carci- level is elevated in some patients. In the largest
RG  •  Volume 40  Number 5 Schawkat et al  17

Figure 10.  UCOGC in a 59-year-old asymptomatic woman with a pancreatic head mass that had increased in size and had
shown internal complexity at follow-up imaging. (a) Photograph of gross examination of the pancreatic head cut sections shows
a well-circumscribed multilocular cystic mass exhibiting internal hemorrhage and necrosis. (b) Photomicrograph of the specimen
shows a mixture of pleomorphic and bizarre mononuclear and multinucleated giant tumor cells with nonneoplastic osteoclast-like
multinucleated giant cells (arrowhead). (c) Axial contrast-enhanced CT image shows a well-circumscribed heterogeneous mass in
the pancreatic head. (d) Axial T2-weighted MR image shows a complex solid and cystic mass in the pancreatic head, with multiple
internal septa (arrowhead).

case series (78) of 38 patients, the survival rate shows heterogeneous reddish to brown areas due
was reported to be better than that of conven- to hemorrhage and focal necrosis (Fig 10a).
tional PDAC (78,84). Lymph node metastasis and At least two cell populations are found in
perineural invasion were less commonly observed UCOGC tumors at histologic evaluation: the
in UCOGC than in PDAC (78). In some cases, neoplastic cell line, which consists of round to
long-term survival beyond 10 years has been spindle-shaped mononuclear cells, and reactive
reported (78). The treatment of choice is surgical osteoclast-like giant cells (Fig 10), the histopath-
en bloc resection. Currently, because of a paucity ologic hallmark of this tumor. The osteoclast-like
of experience, the role of adjuvant therapy has not giant cells manifest without mitotic figures and
yet been determined, and there are no guidelines contain multiple small uniform nuclei within an
for chemotherapy or radiation therapy. abundant eosinophilic cytoplasm. Foci of osteoid
or bone differentiation have been described in a
Pathologic Features few cases (77,86). The osteoclast-like giant cells
Compared with PDAC, UCOGC tends to be may demonstrate phagocytic activity, with evi-
larger (80% are larger than 5 cm) and more often dence of phagocytosis of neoplastic mononuclear
located in the body and tail of the pancreas (85). cells and hemosiderin (87).
Regarding pathogenesis, consensus leads At immunohistochemical analysis, the os-
toward an epithelial-to-mesenchymal transition teoclast-like giant cells show positivity for the
model rather than a pure mesenchymal origin, histiomonocytic marker CD68. The lack of prolif-
because the atypical neoplastic mononuclear cells erative activity and mitosis suggests that they
show evidence of epithelial origin. The reactive originate from the fusion of mononuclear macro-
osteoclast-like giant cells are of histiocytic deriva- phages and histiocytes that are chemoattracted by
tion. Approximately 20% of UCOGCs arise ei- the neoplastic cells (77,88).
ther from IPMNs or mucinous cystic neoplasms.
Whether these neoplasms share a common path- Radiologic Features
way of pathogenesis is yet to be determined. At contrast-enhanced CT, UCOGC appears as
On gross pathologic examination, the cut a well-defined solid tumor with smooth margins
surface of the solid or partially cystic tumor often and low attenuation compared with the healthy
18  September-October 2020 radiographics.rsna.org

pancreatic parenchyma during the pancreatic and 6. Adsay NV, Pierson C, Sarkar F, et al. Colloid (mucinous
noncystic) carcinoma of the pancreas. Am J Surg Pathol
portal venous phases (75,88). 2001;25(1):26–42.
Low signal intensity at T2- and T2*-weighted 7. Pokrzywa CJ, Abbott DE, Matkowskyj KA, et al. Natural
MRI is described (75) and is consistent with History and Treatment Trends in Pancreatic Cancer Sub-
types. J Gastrointest Surg 2019;23(4):768–778.
hemosiderin deposition. Similar to findings 8. Bosman F, Carneiro F, Hruban R, Theise N. Faculdade
in PDAC, interruption of the main pancreatic de Filosofia da USP: lições inesquecíveis. Estud Av
duct with upstream duct dilatation is a common 2006;7(18):189–207.
9. Kuo PC, Chen SC, Shyr YM, Kuo YJ, Lee RC, Wang SE.
secondary sign (88) Contrary to PDAC findings, Hepatoid carcinoma of the pancreas. World J Surg Oncol
UCOGC is surrounded by a well-defined hy- 2015;13:185.
poenhancing and low-signal-intensity rim at T2- 10. Wilentz RE, Goggins M, Redston M, et al. Genetic, immuno-
histochemical, and clinical features of medullary carcinoma
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Some UCOGC tumors are almost entirely Am J Pathol 2000;156(5):1641–1651.
cystic, and thereby mimic cystic neoplasms of 11. Damania R, Weaver J, Cocieru A. Signet Ring Cell Car-
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findings have been attributed to UCOGC in case Malignancy. J Gastrointest Cancer 2016;47(1):89–92.
reports, such as venous tumor thrombi (89) and 12. Neoptolemos JP, Stocken DD, Dunn JA, et al. Influence of
resection margins on survival for patients with pancreatic
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Differential Key Points Surg 2001;234(6):758–768.
13. Rutter CE, Park HS, Corso CD, et al. Addition of ra-
The main differential diagnoses of UCOGC are diotherapy to adjuvant chemotherapy is associated with
PDAC, pancreatic neuroendocrine tumors, and improved overall survival in resected pancreatic adeno-
cystic pancreatic neoplasms such as mucinous carcinoma: an analysis of the National Cancer Data Base.
Cancer 2015;121(23):4141–4149.
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Conclusion 2016;9(4):547–560.
15. McGuigan A, Kelly P, Turkington RC, Jones C, Coleman
This review provides a comprehensive account HG, McCain RS. Pancreatic cancer: a review of clinical
of the variant clinical-pathologic and radiologic diagnosis, epidemiology, treatment and outcomes. World
characteristics of PDAC and its rare histologic J Gastroenterol 2018;24(43):4846–4861.
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variants to promote awareness of their existence consensus on the classification of pancreatic intraepithelial
and understanding of their natural history. Mainly neoplasia and intraductal papillary mucinous neoplasms.
because of their rarity, significant gaps remain in Am J Surg Pathol 2004;28(8):977–987.
17. Goh BKP, Tan YM, Chung YFA, et al. A review of mucinous
the understanding of these histologic variants, as cystic neoplasms of the pancreas defined by ovarian-type
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malignancy: value of arterial, pancreatic, and hepatic
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Acknowledgments.—We would like to thank Marion L. Hart- 20. Macari M, Spieler B, Kim D, et al. Dual-source dual-
ley, PhD, for her editing support; Chris McKee, MD, for energy MDCT of pancreatic adenocarcinoma: initial
providing a case of hepatoid carcinoma of the pancreas; and observations with data generated at 80 kVp and at simu-
Christine O. Menias, MD, for providing cases of medullary lated weighted-average 120 kVp. AJR Am J Roentgenol
carcinoma and signet ring cell carcinoma. 2010;194(1):W27–W32.
21. Kim JH, Park SH, Yu ES, et al. Visually isoattenuating
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