Category: Case of the Quarter

Case 2: Quarter 3, 2022

Case 2: Quarter 3, 2022

Clinical History

A 55-year-old female presented with right upper quadrant abdominal pain and fatigue. She reports a history of a pancreatic tail tumor status-post distal pancreatectomy and splenectomy approximately 25 years ago. The slides from her prior resection were no longer available for review, but per report demonstrated a large (8 cm), “centrally-necrotic” islet cell tumor with negative margins and no lymph node involvement. She had undergone 10 years of surveillance following the distal pancreatectomy with no evidence of recurrence or metastasis. The patient underwent an abdominal CT scan which demonstrated an 8.4 cm mass within the right lobe of the liver with occlusion of the right hepatic vein. The mass was described as mixed cystic and solid and radiologically the concern was for a mucinous cystic neoplasm with an associated invasive carcinoma. Per the radiologist, the findings were not typical of metastatic neuroendocrine tumor. A somatastatin receptor tracer Ga-68 Dotatate PET/CT scan showed no uptake in the liver lesion. As she had no evidence of other liver lesions or extra-hepatic disease, she was recommended to undergo an extended right hepatectomy.

Figure 1. Representative image of the tumor, H&E stain.
Figure 2. Representative image of the tumor/liver interface, H&E stain.
Figure 3. Areas with myxoid stroma in tumor, H&E stain.
Figure 4. Abundant eosinophilic hyaline globules in the tumor cells, H&E stain.

Macroscopic Description
The resection specimen showed a large, centrally necrotic, cystic, and solid mass in the superior aspect of the right hepatic lobe measuring 11.5 cm in greatest dimension. The mass abutted the liver parenchymal resection margin and was grossly suspicious for the involvement of vascular margins.

Histologic/Cytologic Features 

The H&E sections from the liver resection show a cellular neoplasm with poorly-cohesive cells adhering loosely to delicate branching blood vessels, imparting the appearance of papillary architecture without true fibrovascular cores (Figure 1). The tumor was clearly centered in liver parenchyma (Figure 2) and in areas there was myxoid stroma intermixed with solid nests of tumor cells (Figure 3). While the tumor is grossly cystic and solid, no true neoplastic lining was identified and the cystic areas were predominantly derived from the discohesive nature of the cells and central degeneration. Abundant brightly, eosinophilic hyaline globules were identified (Figure 4). Cytologically, the cells were polygonal with eosinophilic to focally clear cytoplasm with round to oval nuclei with scattered nuclear grooves (Figure 5). Mitoses were not easily identified. Immunohistochemical stains showed that the tumor cells labeled for synaptophysin (scattered, focal, Figure 6) and were negative for chromogranin (Figure 7). Cytokeratin AE1/3 was also focally positive in the tumor. The tumor cells were positive for PR and CD10. An immunohistochemical stain for beta-catenin showed an abnormal nuclear and cytoplasmic labeling pattern in the tumor cells.

Figure 5. High power view of tumor cytology, H&E stain.
Figure 6. Representative image of immunohistochemical stain for synaptophysin
Figure 7. Representative image of immunohistochemical stain for chromogranin
Figure 8. Representative image of immunohistochemical stain for beta-catenin

Please select your diagnosis in the poll, then see the answer and the discussion in the links below.


What is the correct diagnosis?

  • Metastatic solid pseudopapillary neoplasm of the pancreas (96%, 44 Votes)
  • Hepatocellular carcinoma (0%, 0 Votes)
  • Metastatic acinar cell carcinoma (4%, 2 Votes)
  • Metastatic well-differentiated neuroendocrine tumor (0%, 0 Votes)

Total Voters: 46

Loading ... Loading ...


Click Here To See The Answer

Answer: Metastatic solid-pseudopapillary neoplasm  of the pancreas

 


Click Here To See The Discussion

Final diagnosis:  

Metastatic solid-pseudopapillary neoplasm  of the pancreas after a 25 year interval

Discussion

This patient’s case is a rare example of metastatic solid pseudopapillary neoplasm of the pancreas to the liver after a long interval. While the presence of a primary solid-pseudopapillary neoplasm of the pancreas was not able to be definitively verified histologically in this case, multiple features of the patient’s history point to a potential misdiagnosis of her original tumor. The description of a “centrally necrotic” islet cell tumor is unusual. While necrosis can certainly be seen in well-differentiated neuroendocrine tumors, it is more commonly seem in higher grade tumors, which in turn, would be unlikely to show such indolent behavior over 25 years. The reported size of her original tumor, over 8 cm, is also somewhat unusual in terms of risk of progression over such a long time interval. Mostly likely, the original tumor represented a solid pseudopapillary neoplasm of the pancreas where large tumor size and necrosis are very common and the vast majority of tumors demonstrate very indolent behavior, as will be discussed in more detail below.

Solid-pseudopapillary neoplasms (SPN) of the pancreas are rare neoplasms, representing 1-2% of all pancreatic tumors. They are most commonly seen in younger women (90% female predominance) with a mean age at diagnosis of 29 years. For reference, our patient would have been 30 at the time of her original pancreatic surgery. Radiologically they are circumscribed to encapsulated heterogenous lesions, often with cystic degeneration. Grossly, SPN recapitulate this radiographic appearance and are variably mixed solid and cystic tumors with abundant necrosis/degenerative changes and hemorrhage (Figure 9, representative image). SPN can be located anywhere in the pancreas, but are most typically seen in the body/tail.

Figure 9. Gross and radiographic images of representative primary solid-pseudopapillary neoplasm of the pancreas

Histologically, tumors are comprised of loosely cohesive cells surrounding a delicate network of blood vessels, often with associated myxoid stromal change. Pseudopapillae form as the discohesive tumor cells fall apart around the blood vessels, creating the appearance of fibrovascular cores. Intracytoplasmic eosinophilic hyaline globules as well as cytoplasmic clearing and/or intracytoplasmic vacuoles can be seen. Degenerative changes with foamy macrophages, cholesterol clefts, hemorrhage and necrosis are very common in SPN. “Insidious invasion,” where the tumor extends into adjacent pancreas without generating significant stromal reaction is also common, despite an overall circumscribed appearance. Cytologically, the tumor cells of SPN are polygonal with eosinophilic cytoplasm and round to oval nuclei with nuclear grooves. Mitotic figures are rare, but degenerative atypia with pleomorphic nuclei and dark, “smudgy” chromatin and multinucleated atypical giant cells can be seen.

While the morphology of SPN is often very distinctive, there are overlapping features with other cellular neoplasms of the pancreas, most notably well-differentiated neuroendocrine tumors and acinar cell carcinomas.Immunohistochemistry can be very useful in sorting out these differentials. SPN are variably cytokeratin positive and characteristically label for CD56, CD10, and CD99 (perineuclear dot-like staining) as well as AR, PR, TFE3 and LEF1. Variable labeling with synaptophysin is typical, which can be misleading, particularly on a small biopsy, however, SPN should be negative for chromogranin, in contrast with well-differentiated neuroendocrine tumors of the pancreas, which are typically positive for chromogranin. Over 90% of SPN have a point mutation in exon 3 of CTNNB1, the gene encoding for beta catenin, leading to aberrant nuclear and cytoplasmic labeling with beta catenin antibodies. Immunohistochemical stains for E-cadherin and p120 catenin will also show the loss of membranous expression of these proteins in SPN.

While all SPN are considered to have low malignant potential, overall, the vast majority of cases are cured with surgical resection. Metastatic behavior is rare and can occur after a fairly long time interval from original diagnosis. Liver is the most common site of metastasis. Definitive evidence of clinical and histologic features predicting aggressive behavior and/or future metastases are lacking, although male sex, vascular invasion and perineural invasion, and the presence of metastasis among others, have been proposed. The degenerative atypia described above can be associated with increased Ki67 labeling but does not seem to track with metastatic behavior. Rare cases of SPN with diffuse growth, marked nuclear atypia with sarcomatoid features and markedly elevated mitotic rates have been described and were associated with highly aggressive clinical behavior.

Differential diagnosis:

The differential diagnosis of SPN primarily includes other cellular neoplasms of the pancreas: well-differentiated neuroendocrine tumors, acinar cell carcinoma and pancreatoblastoma. For the rare occurrence of metastatic SPN to the liver, primary liver tumors would also enter the differential, particularly if there was no known history of SPN or a previous pancreas resection.

Of the cellular neoplasms of the pancreas, the majority of morphologic and immunohistochemical overlap with SPN is seen with well-differentiated neuroendocrine tumors. More solid SPN with less cystic degeneration are also more likely to mimic neuroendocrine tumors morphologically. Neuroendocrine tumors can also form some pseudopapillae. Cytologically, the features of these two tumors is fairly distinct with neuroendocrine tumors having finely stippled “salt and pepper” chromatin and eosinophilic to amphophilic cytoplasm. As mentioned above, a major diagnostic pitfall is the combination of keratin, CD56, and synaptophysin reactivity in SPN. Despite these overlaps, SPN are almost uniformly chromogranin negative and neuroendocrine tumors should not show abnormal nuclear staining for beta-catenin. As long as one thinks of the diagnosis of SPN, Immunohistochemical studies can usually distinguish the two entities easily.

Cellular neoplasms with acinar differentiation including acinar cell carcinoma and pancreatoblastoma can be separated from SPN via distinct morphologic, cytologic and Immunohistochemical features. Acinar cell carcinomas have characteristically granular eosinophilic cytoplasm with a single, prominent nucleolus and label with antibodies against exocrine enzymes including trypsin and chymotrypsin. They also show strong granular, cytoplasmic labeling with BCL-10. Acinar cell carcinomas can show aberrant nuclear labeling with beta-catenin due to underlying molecular alterations, however SPN will not show reactivity with exocrine enzymes or BCL-10. Pancreatoblastoma has characteristic squamous morules in addition to acinar and variable neuroendocrine and ductal differentiation. These squamous morules will also show nuclear beta-catenin labeling, however their distinct morphology and areas of acinar differentiation on H&E and by immunohistochemistry will distinguish them from SPN.

While there is less morphologic overlap with primary liver tumors, this differential may arise when SPN metastasize to the liver. Hepatocellular carcinoma can be identified by labeling for Hep-Par1, arginase and glypican3. Intrahepatic cholangiocarcinoma can be identified by gland formation and strong, uniform keratin labeling. Both tumors will also show positivity for in situ hybridization for albumin.

References:

Hruban RH, Pitman MB, Klimstra DS. Tumors of the pancreas. Atlas of tumor pathology. Fourth Series, Fascicle 6 ed. Washington, DC: American Registry of Pathology and Armed Forces Institute of Pathology, 2007.

Abraham SC, Klimstra DS, Wilentz RE, Wu T-T, Cameron JL, Yeo CJ et al. Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations. Am J Pathol. 2002; 160(4):1361-1369.

Klimstra DS, Wenig BM, Heffess CS. Solid-pseudopapillary tumor of the pancreas: a typically cystic carcinoma of low malignant potential. Semin Diagn Pathol. 2000; 17(1):66-80.

Tang LH, Aydin H, Brennan MF, Klimstra DS. Clinically aggressive solid pseudopapillary tumors of the pancreas: a report of two cases with components of undifferentiated carcinoma and a comparative clinicopathologic analysis of 34 conventional cases. Am J Surg Pathol. 2005;29 (4):512-9.

La Rosa S, Bongiovanni M. Pancreatic Solid-pseudpapillary Neoplasm: Key Pathologic and Genetic Features. 2020; 144(7):829-37.

Li L, Othman M, Rashid A, Wang H, Li Z, Katz MH, Lee JE, Pisters PW, Abbruzzese JL, Fleming JB, Wang H. Solid pseudopapillary neoplasm of the pancreas with prominent atypical multinucleated giant tumour cells. Histopathology 2013; 62(3):465-71

Estrella JS, Li L, Rashid A, Wang H, Katz MH, Fleming JB, Abbruzzese JL, Wang H. Solid Pseudopapillary neoplasm of the pancreas: clinicopathologic and survival analyses of 64 cases from a single institution. Am J Surg Pathol 2014; 38(2):147-57.

Case contributed by:

Elizabeth Thompson, MD, PhD, Assistant Professor of Pathology and Oncology

Main submitter’s email: ethomp36@jhmi.edu

Main submitter’s institution: The Johns Hopkins University School of Medicine

Second submitter’s name and title:

Huili Li, MD, Surgical Pathology Assistant

Second submitter’s institution: The Johns Hopkins University School of Medicine

Conflict of Interest: No

Case 1: Quarter 3, 2022

Clinical History

A 50-year-old female presented with left upper quadrant pain, difficulty eating, and weight loss. An ultrasound showed a 3.0 cm mass in the head of the pancreas with a markedly dilated pancreatic duct. A subsequent CT scan demonstrated a solid mass involving the pancreatic head/neck and body. Laboratory studies showed a serum CA 19-9 of 13.4 U/ml. Endoscopic ultrasound with biopsy was performed and showed a 3.8 cm mass in the body of the pancreas with extension to the neck and associated dilatation of the main pancreatic duct. Core biopsies showed a predominantly tubular proliferation with small, anastomosing papillary fronds and significant nuclear atypia (Figures 1-4). Intracellular mucin was not apparent. Focal areas of necrosis were present. The proliferation was predominantly seen in detached tissue fragments and there was no clear evidence of stromal invasion. Immunohistochemical stains were performed and the lesional cells labeled for cytokeratin AE1/3, CK7 and MUC1 with no labeling seen for CDX2, GATA3, MUC2, synaptophysin, chromogranin, INSM1, BCL10 and trypsin. The lesional cells showed a normal, membranous labeling pattern for β-catenin. DPC4/SMAD4 expression was retained. The patient was referred for surgical resection.

Figure 1. Low-power view of biopsy, H&E stain.
Figure 2. Additional low-power view of biopsy, H&E stain.
Figure 3. Higher-power view of biopsy, H&E stain.
Figure 4. Higher-power view of biopsy, H&E stain.

Macroscopic Description
A Whipple resection was attempted, however, an intraoperative frozen section of the pancreatic neck margin showed extensive tumor involving the main pancreatic duct with expansion into multiple side-branch ducts and a decision was made to proceed with a completion total pancreatectomy. Grossly, both the Whipple resection and distal pancreatectomy were involved by a multi-nodular, intraductal mass spanning 4.0 cm in total with multiple adjacent ill-defined solid lesions.

Histologic/Cytologic Features 

Sections from the resection specimens showed marked expansion of the native ducts by a complex proliferation of tubular glands lined with cuboidal cells with minimal cytoplasm and significant atypia forming a tubular and cribriform growth pattern with anastomosing papillae and areas of central necrosis (Figures 5,6). There was no obvious intracellular mucin. In multiple areas, often expansile in nature, there are irregular, infiltrative nests with associated desmoplastic stroma (Figures 7,8,9).

Figure 5. Low-power view of intraductal proliferation, H&E stain.
Figure 6. Higher-power view of same field shown in Figure 5, H&E stain.
Figure 7. Complex, irregular nests with desmoplastic stroma, H&E stain.
Figure 8. Complex, irregular nests with desmoplastic stroma, H&E stain.
Figure 9. Complex, irregular nests with desmoplastic stroma, H&E stain.

Please select your diagnosis in the poll, then see the answer and the discussion in the links below.


What is the correct diagnosis?

View Results

Loading ... Loading ...


Click Here To See The Answer

Answer: Intraductal tubulopapillary neoplasm with associated invasive carcinoma.

 


Click Here To See The Discussion

Final diagnosis:  

Intraductal tubulopapillary neoplasm with associated invasive carcinoma.

Discussion

Intraductal tubulopapillary neoplasms (ITPN) are rare intraductal neoplasms of the pancreas, comprising about 3% of all intraductal lesions. Originally described in 2004 and termed “intraductal tubular carcinomas,” the term “intraductal tubulopapillary neoplasm was proposed in 2009 and incorporated into the last two editions of the WHO Classification.


The mean patient age is 55 years, fairly evenly split between male and female patients. About half of ITPN are located in the head of the pancreas with a much smaller percentage (about 15%) in the tail and about 30% are more diffuse, as seen in our case, involving both head and body/tail and sometimes the entire gland. Radiologically, ITPN can mimic more common intraductal lesions such as intraductal papillary mucinous neoplasms. However, their often solid appearance, as was seen in the current case, can also mimic ductal adenocarcinomas and other solid neoplasms of the pancreas. It can be challenging on cross-sectional imaging to determine the extent of intraductal versus invasive components in an ITPN.


Grossly, ITPN manifest as multinodular mixed cystic and solid masses (Figure 10) (Image is a representative ITPN, but not the specific tumor from this case), although the confluent intraductal growth often yields an overall solid, fleshy appearance of the tumors with a polypoid growth pattern to the intraductal component. Microscopically, ITPN show confluent growth of back-to-back tubules and anastomosing papillae often markedly expanding native ducts. Cytologically, the tubules and papillae are lined by cuboidal cells with a moderate amount of eosinophilic cytoplasm without appreciable mucin and moderate to marked nuclear atypia. Intracytoplasmic vacuoles and/or clear cell changes can be seen. Luminal secretions and central necrosis are common, often imparting a similar appearance to ductal carcinoma in situ of the breast. There is no specific immunohistochemical staining profile, however certain patterns are supportive. ITPN characteristically label with antibodies for cytokeratins 7 and 19 as well as MUC1 and MUC6. Overall, however, the diagnosis is based predominantly on morphology with immunohistochemistry mainly serving to rule out other possibilities (see Differential Diagnosis, below).

Associated invasive carcinomas are very common, seen in approximately 70% of cases. Given the expansile, nodular growth pattern of ITPN, it can be difficult to ascertain exactly how much of the tumor is invasive, but the presence of small, angulated glands and nests with an infiltrative pattern and desmoplastic stroma are useful in the identification of invasive carcinoma. Interestingly, ITPN with an associated invasive carcinoma still display fairly indolent behavior, with a 70% 5-year survival, dramatically improved relative to IPMN-associated carcinomas and ductal adenocarcinomas.


Molecular analysis demonstrates that ITPN harbor distinct alterations from other intraductal neoplasms of the pancreas. Notably, ITPN lack mutations in KRAS and GNAS commonly seen in IPMNs. Mutations in chromatin remodeling genes and in the phosphatidylinositol (PI3K) pathway have been reported as well as a subset of tumors with FGFR2 fusions. Work is ongoing in further unraveling the molecular underpinnings of ITPN and may ultimately contribute both to pre-operative diagnoses via molecular analysis of cyst fluid or fine needle aspiration specimens and to our understanding of the relatively indolent behavior of ITPN-associated invasive carcinomas.

Figure 10. Gross image of ITPN showing mixed cystic and solid lesion.

Differential diagnosis:

The main differential diagnosis is with other intraductal neoplasms of the pancreas and with solid cellular neoplasms of the pancreas that sometimes show intraductal growth within native pancreatic ducts, such as acinar cell carcinoma (ACC) and neuroendocrine neoplasms, predominantly well-differentiated neuroendocrine tumors (NET). Both ACC and NET may show morphologic features (acini and small tubules/pseudoglandular structures) that may mimic the growth patterns of ITPNs.


Among the intraductal neoplasms, ITPN most resemble pancreatobiliary-type IPMN. Intestinal- and gastric-type IPMN are easily distinguished by their distinct and abundant apical mucinous cytoplasm, which is lacking in ITPN. Pancreatobiliary-type IPMNs do have cuboidal cells with less abundant mucin, similar to ITPN, however, in general all IPMN have longer, more well-developed papillary fronds than ITPN, which are often more dominated by a tubular pattern, with papillae being more blunted and/or anastomosing. Glycoprotein expression varies in IPMN depending on histologic differentiation. While pancreatobiliary-type IPMNs may share MUC1 and MUC6 expression with ITPN, they may also label for MUC5AC, which should be absent in ITPN. MUC2 and MUC5AC expression in intestinal-type IPMNs and MUC5AC expression in gastric-type IPMNs can also help distinguish them from ITPN.


ITPN can usually be distinguished from intraductal oncocytic papillary neoplasms (IOPN) by the unique cytologic features of the latter: abundant pink, granular cytoplasm and a single prominent nucleolus. IOPN also have characteristic delicate, arborizing papillae and typically do not show tubular morphology. Approximately 60% of IOPN will show diffuse labling for HepPar1, which is typically rare and focal in ITPN.


Acinar cell carcinomas with an intraductal component can be separated from ITPNs based on their classic cytologic features: granular eosinophilic cytoplasm and single prominent central nucleolus as well as characteristic labeling for exocrine enzymes (trypsin, chymotrypsin) and BCL10. Similarly, the differential between ITPN and a neuroendocrine neoplasm showing intraductal growth can be resolved based on the cytologic features of neuroendocrine tumors (salt and pepper chromatin, eosinophilic to amphophilic cytoplasm) and labeling with neuroendocrine makers (synaptophysin, chromogranin).

References:

Tajiri T, Tate G, Inagaki T, et al. Intraductal tubular neoplasms of the pancreas: histogenesis and differentiation. Pancreas. 2005; 30:115-21.
Yamaguchi H, Shimizu M, Ban S, et al. Intraductal tubulopapillary neoplasms of the pancreas distinct from pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol. 2009; 33:1164-72.
Yamaguchi H, Kuboki Y, Hatori T, at al. Somatic mutations in PIK3CA and activation of AKT in intraductal tubulopapillary neoplasms of the pancreas. Am J Surg Pathol. 2011; 35:1812-7.
Basturk O, Adsay V, Askan G, et al. Intraductal tubulopapillary neoplasm of the pancreas: a clinicopathologic and Immunohistochemical analysis of 33 cases. Am J Surg Pathol. 2017; 41:313-25.
Basturk O, Berger MF, Yamaguchi H, et al. Pancreatic intraductal tubulopapillary neoplasm is genetically distinct from intraductal papillary mucinous neoplasm and ductal adenocarcinoma. Mod Path. 2017; 30:1760-772.

Case contributed by:

Elizabeth Thompson, MD, PhD. The Johns Hopkins University School of Medicine

Zahra Maleki, MD. The Johns Hopkins University School of Medicine

Conflict of Interest: No

Case 5: Quarter 4, 2021

Case 5: Quarter 4, 2021

Clinical History

A 63-year-old male with past medical history that includes hyperparathyroidism presented with ongoing left hip pain. Evaluation of the etiology of his pain revealed an incidental mid-abdominal mass on lumbar spine MRI. A dedicated CT scan confirmed the presence of a solid, well-demarcated ovoid peripancreatic mass measuring 11 cm. A CT-guided needle biopsy was performed.

Macroscopic Description
N/A

Histologic/Cytologic Features 

Microscopic pictures of the biopsy are shown in Figures 1-3. The histologic examination revealed numerous dilated and thin-walled angulated vascular channels distributed in myxoid matrix. Nested around these vessels are clustered epithelioid to spindle- shaped cells with pale, amphophilic cytoplasm and somewhat atypical, vesicular nuclei. Mitotic figures are scarce and there is no necrosis or significant pleomorphism. Immunohistochemical (IHC) analysis was performed on the biopsy. The neoplastic cells were entirely negative for pan-keratin, CAM 5.2, S100, HMB45, Melan-A, SOX10, MDM2, CDK4, ERG, CD34, CD31, SMA, desmin and MITF.

Figure 1. Biopsy, low to moderate power, H&E.
Figure 2. Biopsy, low to moderate power, H&E.
Figure 3. Biopsy, high power, H&E.

Please select your diagnosis in the poll, then see the answer and the discussion in the links below.


What is the best diagnosis?

View Results

Loading ... Loading ...


Click Here To See The Answer

Answer: Paraganglioma

 


Click Here To See The Discussion

Final diagnosis:  

Paraganglioma

Educational Objectives and Discussion:

Educational Objectives

  1. Identify and describe a rare case of peripancreatic paraganglioma, a rare neoplastic disease that presents considerable diagnostic difficulty.
  2. Review the clinicopathological characteristics of peripancreatic paragangliomas.
  3. Discuss differential diagnosis of peripancreatic paragangliomas.

Discussion

Peripancreatic paragangliomas can be diagnostically challenging on small biopsies due to morphologic overlap with other primary pancreatic tumors (1, 2). In this case, an initial diagnosis of atypical epithelioid and spindle cell neoplasm was made on the biopsy and decision was made to proceed with surgery. Grossly, the resection specimen showed a 11.8 cm purple-red, ovoid, well-circumscribed peripancreatic mass surrounded by a thin fibrous capsule. Cut surface displayed a tan-pink to dark red, variegated focally nodular cut surface with multiple dilated vessels and focal areas of hemorrhage (Figure 4). Microscopic examination of the resection specimen showed neoplastic cells arranged in nests and trabeculae within a prominent vascular network (Figure 5-7). The cells were predominantly round to oval with some spindling and moderate to abundant eosinophilic granular cytoplasm. Additional IHC on the resection specimen showed that the tumor cells labeled with synaptophysin (strong), chromogranin (patchy) and S100 (patchy) and were negative for cytokeratin (Figures 8-10). In areas the S100 labeled in a sustentacular pattern (Figure 10). Succinate dehydrogenase (SDH) A and B were intact. A final diagnosis of paraganglioma was made. Subsequent blood work showed elevated plasma and urine catecholamines and molecular testing showed no targetable mutations. While the tumor was initially described radiographically as being located in the pancreatic head, subsequent imaging demonstrated a peri-pancreatic localization, much more typical of this entity. It can be critical to consider paraganglioma from both the radiographic and pathologic standpoint as repeated needle biopsies may trigger catecholamine surges and care must be taken during surgical interventions.

Figure 4. Gross appearance of resection specimen.
Figure 5. Resection, low power, H&E
Figure 6. Resection, medium power, H&E
Figure 7. Resection, high power, H&E
Figure 8. Cytokeratin immunostain, resection specimen
Figure 9. Synaptophysin immunostain, resection specimen
Figure 10. S100 immunostain, resection specimen


The classic microscopic features of paragangliomas are similar irrespective of location and include round-to-polygonal-shaped cells containing amphophilic-to-eosinophilic cytoplasm with stippled, often pleomorphic nuclei containing small inconspicuous nucleoli. In certain cases, cytoplasmic clear cell change, multinucleation, vesicular nuclei, and prominent nucleoli can also be observed (1). The tumor cells usually adopt a nested or organoid (“Zellballen”) pattern separated by highly vascularized fibrous septa. Cases with diffuse growth pattern with only focal areas of nested architecture have been reported (1). In areas of parenchymal invasion, the Zellballen growth pattern can be replaced by irregularly spaced nests of discohesive neoplastic cells. The tumor cells are synaptophysin and chromogranin positive while the surrounding sustentacular cells, label for S100. GATA3 and PHOX2B also show frequent immunoreactivity in extra-adrenal paragangliomas (3-5). Keratin is almost always negative, but rare cases have focal staining. In contrast, paragangliomas in the sacral region are typically keratin positive.


The genetic profile of paraganglioma is similar to that described for pheochromocytomas. Mutations in VHL, RET, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX have been reported (6). Knowledge of these mutations may have significant impact on clinical management and patient outcome. For instance, studies have reported germline mutations in SDHB in up to 30% of patients with metastatic disease arising from sporadic paragangliomas and an association with shorter survival (1, 7, 8). Complete surgical resection of primary and
metastatic disease, when possible provides the highest chance for symptom control. Currently, there are no reliable markers to predict malignancy, except the presence of metastases. Increasing tumor size (>5 cm), increasing Ki-67 proliferation rate, SDHB mutation, and MAX mutation have been reported as risk factors for metastatic behavior (9, 10). Various scoring systems (PASS, GAPP), have been developed to predict risk in pheochromocytomas and paragangliomas (11, 12). Patients with paragangliomas ultimately require follow-up as metastatic disease can appear years after diagnosis.

Differential diagnosis:

The differential diagnosis of peripancreatic paragangliomas includes pancreatic neuroendocrine tumor (PanNET), acinar cell carcinoma (ACC), spindle cell neoplasms, PEComas, and metastatic renal cell carcinoma (RCC).Peripancreatic paragangliomas and PanNET are both neuroendocrine neoplasms thus sharing many of the same characteristics. PanNETs often show distinctive plasmacytoid morphology, usually display round and uniform nuclei and are generally positive for AE1/AE3 and CAM 5.2 while peripancreatic paragangliomas are distinctly negative. Prominent nucleoli typically seen in ACC can be present in peripancreatic paragangliomas. However, the characteristic stippled chromatin of peripancreatic paraganglioma is absent in ACC. The presence of spindle cell morphology/nuclear pleomorphism in peripancreatic paragangliomas can mimic spindle cell neoplasms. These possibilities can usually be distinguished on the basis of immunohistochemistry. Further, the nuclear pleomorphism in paragangliomas typically has a degenerative appearance. Peripancreatic paragangliomas can show cytoplasmic clear cell change thus mimicking metastatic RCCs. However, metastatic RCCs will express PAX8 and are negative for S100 and neuroendocrine
markers.

References:

  1. Singhi AD, Hruban RH, Fabre M, Imura J, Schulick R, Wolfgang C, Ali
    SZ. Peripancreatic paraganglioma: a potential diagnostic challenge in
    cytopathology and surgical pathology. Am J Surg Pathol. 2011
    Oct;35(10):1498-504. doi: 10.1097/PAS.0b013e3182281767.
    https://pubmed.ncbi.nlm.nih.gov/21921779/
  2. Zeng J, Simsir A, Oweity T, Hajdu C, Cohen S, Shi Y. Peripancreatic paraganglioma mimics pancreatic/gastrointestinal neuroendocrine tumor on fine needle aspiration: Report of two cases and review of the literature. Diagn Cytopathol. 2017 Oct;45(10):947-952. doi: 10.1002/dc.23761. https://pubmed.ncbi.nlm.nih.gov/28560856/
  3. Miettinen M, McCue PA, Sarlomo-Rikala M, Rys J, Czapiewski P, Wazny K, Langfort R, Waloszczyk P, Biernat W, Lasota J, Wang Z. GATA3: a multispecific but potentially useful marker in surgical pathology: a systematic analysis of 2500 epithelial and nonepithelial tumors. Am Surg Pathol. 2014 Jan;38(1):13-22. doi: 10.1097/PAS.0b013e3182a0218f. https://pubmed.ncbi.nlm.nih.gov/24145643/
  4. Lee JP, Hung YP, O’Dorisio TM, Howe JR, Hornick JL, Bellizzi AM. Examination of PHOX2B in adult neuroendocrine neoplasms reveals relatively frequent expression in phaeochromocytomas and paragangliomas. Histopathology. 2017 Oct;71(4):503-510. doi: 10.1111/his.13243. https://pubmed.ncbi.nlm.nih.gov/28464318/
  5. So JS, Epstein JI. GATA3 expression in paragangliomas: a pitfall potentially leading to misdiagnosis of urothelial carcinoma. Mod Pathol. 2013 Oct;26(10):1365-70. doi: 10.1038/modpathol.2013.76. https://pubmed.ncbi.nlm.nih.gov/23599157/
  6. Gimenez-Roqueplo AP, Dahia PL, Robledo M. An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Horm Metab Res. 2012 May;44(5):328-33. doi: 10.1055/s-0031-1301302. https://pubmed.ncbi.nlm.nih.gov/22328163/
  7. Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Linehan WM, Pacak K. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab. 2006 Nov;91(11):4505-9. doi: 10.1210/jc.2006-0423. https://pubmed.ncbi.nlm.nih.gov/16912137/
  8. Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J, Bertagna X, Schlumberger M, Jeunemaitre X, Gimenez-Roqueplo AP, Plouin PF. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab. 2007 Oct;92(10):3822-8. doi: 10.1210/jc.2007-0709. https://pubmed.ncbi.nlm.nih.gov/17652212/
  9. Kimura N, Takayanagi R, Takizawa N, Itagaki E, Katabami T, Kakoi N, Rakugi H, Ikeda Y, Tanabe A, Nigawara T, Ito S, Kimura I, Naruse M; Phaeochromocytoma Study Group in Japan. Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocr Relat Cancer. 2014 May 6;21(3):405-14. doi: 10.1530/ERC-13-0494. https://pubmed.ncbi.nlm.nih.gov/24521857/
  10. Assadipour Y, Sadowski SM, Alimchandani M, Quezado M, Steinberg SM, Nilubol N, Patel D, Prodanov T, Pacak K, Kebebew E. SDHB mutation status and tumor size but not tumor grade are important predictors of clinical outcome in pheochromocytoma and abdominal paraganglioma. Surgery. 2017 Jan;161(1):230-239. doi: 10.1016/j.surg.2016.05.050. https://pubmed.ncbi.nlm.nih.gov/27839933/
  11. Kimura N, Takekoshi K, Naruse M. Risk Stratification on Pheochromocytoma and Paraganglioma from Laboratory and Clinical Medicine. J Clin Med. 2018. Sep; 7(9): 242. https://pubmed.ncbi.nlm.nih.gov/30150569/
  12. Thompson LD. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol. 2002 May;26(5):551-66. doi: 10.1097/00000478-200205000-00002. https://pubmed.ncbi.nlm.nih.gov/11979086/


Case contributed by:

Oluwaseyi Olayinka, MD, MSc, Danbury Hospital

Ramapriya Vidhun, MD, Danbury Hospital

Conflict of Interest: NO

 

Case 4: Quarter 3, 2021

Clinical History

A 2-year-old-baby presented as a transfer from an outside hospital (OSH) due to concerns for possible acute cholecystitis. The patient has a history of abdominal pain for the last 2 weeks. The laboratory tests from the OSH were notable for leukocytosis. An abdominal CT scan showed a thickened gallbladder wall with numerous polypoid, non-mobile lesions. Eventually, the patient underwent laparoscopic cholecystectomy.

Macroscopic Description
On gross examination, the gallbladder measured 8.8 x 1.5 x 1.2 cm, with multiple, scattered polypoid mucosal lesions mainly in the body and fundus. The largest lesion measured 2 cm in the greatest dimension (arrows) (Figure 1). No cholelithiasis was present.

Figure 1. Gross photograph of the gallbladder showing polypoid exophytic lesions on the mucosa.

Histologic/Cytologic Features 

Microscopic pictures of the gallbladder lesions are shown in Figures 2-4. As shown in Figure 2, The lesions had an intraluminal exophytic (mass-forming) growth pattern and papillary architecture (black arrows). Adjacent mucosa (white arrows) is also involved by papillary overgrowth of epithelium. Figure 3 showed that the neoplastic epithelial lining is composed of a combination of biliary (black arrow), gastric foveolar-type (white arrow), and intestinal-type epithelium with goblet cells (blue arrow). No high grade cytologic atypia or architectural abnormalities were identified. A higher-power image is shown in Figure 4 and highlights a collection of the lamina propria macrophages (black arrows).

Figure 2. Low-power view of the exophytic lesion, H&E stain.
Figure 3. Medium-power view of the exophytic lesion, H&E stain.
Figure 4. High-power view of the lamina propria of the lesion, H&E stain.

[line]

Please select your diagnosis in the poll, then see the answer and the discussion in the links below.

[line]

What is the diagnosis of the lesion?

View Results

Loading ... Loading ...

[line]

Answer: Intracholecystic papillary neoplasm

Final diagnosis:  

Intracholecystic papillary neoplasm

Educational Objectives and Discussion:

Educational Objectives

  1. To understand the definition of intracholecystic papillary neoplasm
    (ICPN) of the gallbladder by 2019 WHO Digestive System Tumours.
  2. To recognize the gallbladder lesions associated with metachromatic
    leukodystrophy (MLD), an unusual neurologic disease in pediatric patients.
  3. To discuss the differential diagnosis of ICPN.

Discussion

Intracholecystic papillary neoplasm (ICPN) is a precancerous lesion of the gallbladder. Per the 2019 WHO Digestive System Tumours [1], ICPN encompasses/replaces the previous terminologies, including biliary
adenoma, tubulopapillary adenoma, intracystic papillary neoplasm, and papillomatosis. Grossly, these tumors form distinct polypoid/exophytic intraluminal masses that are grossly visible. Microscopically, these tumors show papillary and/or tubular configuration with varying degrees of epithelial dysplasia. There are four morphologic patterns recognized: biliary, intestinal, gastric, oncocytic, or combination of these. These morphologic patterns contrast with classifications of intraductal papillary mucinous neoplasms (IPMN) of the pancreas in which oncocytic lesions (intraductal oncocytic papillary neoplasms (IOPN)) have been separated from IPMN due to distinct molecular findings. Mucosa surrounding ICPN may demonstrate dysplasia as well. About 50% of ICPNs are associated with invasive adenocarcinoma, but they have a better clinical outcome than conventional gallbladder adenocarcinomas [1, 2].

Our case exhibited low-grade ICPN with combined biliary, gastric, and intestinal differentiation. Adjacent mucosa also showed diffuse low-grade dysplasia. No high-grade dysplasia or invasive carcinoma was identified in extensively submitted sections. The aforementioned unusual findings in the gallbladder from a 2-year-old baby triggered further work-up since there is a well-known association between ICPN (previously called gallbladder papillomatosis) and metachromatic leukodystrophy (MLD) [3-5]. Genetic analysis was performed and the results revealed homozygous deletion of pathogenic variant c.1283C>T (p.Pro428Leu) in ARSA gene, which is associated with MLD. Brain MRI findings were non-specific and she has no history of developmental delay, neurologic symptoms, or regression.

MLD is a lysosomal storage disease caused by a deficiency of arylsulfatase A (ASA) with autosomal recessive inheritance in most cases. The ASA deficiency leads to the accumulation of sulfatides in the central and peripheral nervous system, which results in the destruction of the myelin sheath and eventually leads to neurologic symptoms such as seizures, loss of motor functions, and peripheral neuropathy [6]. Sufatide accumulation is also detected in other organs, e.g., the gallbladder, kidney, lymph nodes, liver, and bone marrow. The gallbladder epithelial cells and macrophages contain cytoplasmic inclusions on electron microscopic examination, consistent with sulfatide accumulation [3, 7]. Almost all case reports described the presence of collections of the lamina propria macrophages in the gallbladder [3, 4, 7, 8], as seen in our case (Figure 4). This accumulation of macrophages could show histologic overlap with cholesterolosis, a more common finding in the gallbladder. In MLD, Giemsa and toluidine blue stains will show metachromasia of the cytoplasm of macrophages, consistent with the accumulation of sulfatide deposits. In contrast, the accumulation of cholesterol esters and triglycerides can be highlighted on frozen tissue with Oil red O or Sudan black stains.

According to the age of disease onset, there are three clinical subtypes of MLD, including late infantile-onset, juvenile-onset, and adult-onset. Our patient showed no neurologic symptoms but was homozygous for mutation of the ARSA gene, which encodes ASA. Numerous mutations in the ARSA gene have been identified, and c.1283C_T mutation in our case is usually seen in juvenile or adult-onset phenotype [6]. That may explain the neurologic symptom-free status of our patient. A possible treatment for MLD so far is hematopoietic stem cell transplantation for selected cases [4]. MLD-associated gallbladder abnormalities occasionally appear before the onset of neurologic symptoms or an MLD diagnosis [3]. One case series with 34 patients reported that 76% of MLD patients showed gallbladder involvement [4]. The gallbladder abnormalities consist of benign and malignant conditions, e.g., cholecystitis, cholelithiasis, mucosal hyperplasia, polypoid lesions (now most lesions are under the category of ICPN), and adenocarcinoma [3-5]. In conclusion, gallbladder abnormalities, in particular polypoid lesions, are rare during childhood. This condition can be seen in cases with MLD, Peutz-Jeghers’ syndrome, and pancreaticobiliary malunion [8]. Pathologists should pay close attention to unusual gallbladder abnormalities in pediatric and adolescent patients to consider the above-mentioned possibilities and associated risk of malignancy.

Differential diagnosis:

Pyloric gland adenoma is composed of lobules of small, tightly packed, bland-looking glands that are morphologically similar to pyloric or Brunner glands. The uninvolved gallbladder mucosa is mostly devoid of dysplasia or pyloric gland metaplasia. Of note, pyloric gland nodules <0.5 cm arising in a background of pyloric gland metaplasia should not be designated as pyloric gland adenoma [9].
Reactive epithelial hyperplasia, commonly due to secondary causes (e.g., cholelithiasis, chronic cholecystitis, inflammatory bowel disease, primary sclerosing cholangitis), shows focal or diffuse papillary-shaped and elongated mucosal folds lined by bland epithelial cells with or without metaplastic changes. The presence of significant inflammation and no discrete, grossly visible mass-forming lesion, may help distinguish reactive hyperplasia from ICPN [1,10].
Invasive adenocarcinoma is present in about 50% of the ICPN cases at the time of diagnosis [2]. Gallbladder adenocarcinoma arising in ICPN is more commonly associated with papillary growth patterns, biliary epithelial lineage, and high-grade dysplasia. The invasive component is often a tubular adenocarcinoma, although other types, such as mucinous, adenosquamous, or neuroendocrine carcinoma, have also been reported. Extensive sampling is warranted because approximately 60% of ICPN with carcinoma showed ≤ 5mm of invasive focus, and the carcinoma may also occur away from the main ICPN lesion. Some patients with non-invasive ICPN can also die of new primary carcinoma in the biliary tract, typically long after the diagnosis of ICPN, possibly due to the field cancerization phenomenon. This observation supports long-term surveillance of these patients with ICPN even after resection [1, 2].

References:

  1. Basturk O, Aishima S, Esoposito I. World Health Organization Classification of Tumours. Intracholecystic papillary neoplasm. In: Digestive System Tumours. 2019, IARC, Lyon.
  2. Adsay V, Jang KT, Roa JC, Dursun N, Ohike N, Bagci P, Basturk O, Bandyopadhyay S, Cheng JD, Sarmiento JM, Escalona OT, Goodman M, Kong SY, Terry P. Intracholecystic papillary-tubular neoplasms (ICPN) of
    the gallbladder (neoplastic polyps, adenomas, and papillary neoplasms that are ≥1.0 cm): clinicopathologic and immunohistochemical analysis of 123 cases. Am J Surg Pathol. 2012 Sep;36(9):1279-301.
  3. McFadden K, Ranganathan S. Pathology of the gallbladder in a child with metachromatic leukodystrophy. Pediatr Dev Pathol. 2015 May-Jun;18(3):228-30.
  4. van Rappard DF, Bugiani M, Boelens JJ, van der Steeg AF, Daams F, de Meij TG, van Doorn MM, van Hasselt PM, Gouma DJ, Verbeke JI, Hollak CE, van Hecke W, Salomons GS, van der Knaap MS, Wolf NI. Gallbladder
    and the risk of polyps and carcinoma in metachromatic leukodystrophy. Neurology. 2016 Jul 5;87(1):103-11.
  5. Kim J, Sun Z, Ezekian B, Schooler GR, Prasad VK, Kurtzberg J, Rice HE, Tracy ET. Gallbladder abnormalities in children with metachromatic leukodystrophy. J Surg Res. 2017 Feb;208:187-191.
  6. Cesani M, Lorioli L, Grossi S, Amico G, Fumagalli F, Spiga I, Filocamo M, Biffi A. Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy. Hum Mutat. 2016 Jan;37(1):16-27.
  7. Rodriguez-Waitkus PM, Byrd R, Hicks J. Metachromatic leukodystrophy and its effects on the gallbladder: a case report. Ultrastruct Pathol. 2011 Dec;35(6):271-6.
  8. Garavelli L, Rosato S, Mele A, Wischmeijer A, Rivieri F, Gelmini C, Sandonà F, Sassatelli R, Carlinfante G, Giovanardi F, Gemmi M, Della Giustina E, Amarri S, Banchini G, Bedogni G. Massive hemobilia and
    papillomatosis of the gallbladder in metachromatic leukodystrophy: a life-threatening condition. Neuropediatrics. 2009 Dec;40(6):284-6.
  9.  Basturk O, Aishima S, Esoposito I. World Health Organization Classification of Tumours. Pyloric gland adenoma of the gallbladder. In: Digestive System Tumours. 2019, IARC, Lyon.
  10. Umudum H, Gunbatili E, Sanal M, Ceyhan K. Primary diffuse papillary hyperplasia of the gallbladder. Pathology. 2006 Dec;38(6):591-2.

[line] 

Case contributed by:

Goo Lee, MD, PhD. University of Alabama at Birmingham

Rong Li, MD, PhD. Children’s of Alabama Benjamin Russell Hospital For Children

Conflict of Interest: NO

Case 4: Quarter 3, 2021

Case 4: Quarter 3, 2021

Clinical History

A 2-year-old-baby presented as a transfer from an outside hospital (OSH) due to concerns for possible acute cholecystitis. The patient has a history of abdominal pain for the last 2 weeks. The laboratory tests from the OSH were notable for leukocytosis. An abdominal CT scan showed a thickened gallbladder wall with numerous polypoid, non-mobile lesions. Eventually, the patient underwent laparoscopic cholecystectomy.

Macroscopic Description
On gross examination, the gallbladder measured 8.8 x 1.5 x 1.2 cm, with multiple, scattered polypoid mucosal lesions mainly in the body and fundus. The largest lesion measured 2 cm in the greatest dimension (arrows) (Figure 1). No cholelithiasis was present.

Figure 1. Gross photograph of the gallbladder showing polypoid exophytic lesions on the mucosa.

Histologic/Cytologic Features 

Microscopic pictures of the gallbladder lesions are shown in Figures 2-4. As shown in Figure 2, The lesions had an intraluminal exophytic (mass-forming) growth pattern and papillary architecture (black arrows). Adjacent mucosa (white arrows) is also involved by papillary overgrowth of epithelium. Figure 3 showed that the neoplastic epithelial lining is composed of a combination of biliary (black arrow), gastric foveolar-type (white arrow), and intestinal-type epithelium with goblet cells (blue arrow). No high grade cytologic atypia or architectural abnormalities were identified. A higher-power image is shown in Figure 4 and highlights a collection of the lamina propria macrophages (black arrows).

Figure 2. Low-power view of the exophytic lesion, H&E stain.
Figure 3. Medium-power view of the exophytic lesion, H&E stain.
Figure 4. High-power view of the lamina propria of the lesion, H&E stain.

[line]

Please select your diagnosis in the poll, then see the answer and the discussion in the links below.

[line]

What is the diagnosis of the lesion?

View Results

Loading ... Loading ...

[line]

Click Here To See The Answer

Answer: Intracholecystic papillary neoplasm

 

[line]

Click Here To See The Discussion

Final diagnosis:  

Intracholecystic papillary neoplasm

Educational Objectives and Discussion:

Educational Objectives

  1. To understand the definition of intracholecystic papillary neoplasm
    (ICPN) of the gallbladder by 2019 WHO Digestive System Tumours.
  2. To recognize the gallbladder lesions associated with metachromatic
    leukodystrophy (MLD), an unusual neurologic disease in pediatric patients.
  3. To discuss the differential diagnosis of ICPN.

Discussion

Intracholecystic papillary neoplasm (ICPN) is a precancerous lesion of the gallbladder. Per the 2019 WHO Digestive System Tumours [1], ICPN encompasses/replaces the previous terminologies, including biliary
adenoma, tubulopapillary adenoma, intracystic papillary neoplasm, and papillomatosis. Grossly, these tumors form distinct polypoid/exophytic intraluminal masses that are grossly visible. Microscopically, these tumors show papillary and/or tubular configuration with varying degrees of epithelial dysplasia. There are four morphologic patterns recognized: biliary, intestinal, gastric, oncocytic, or combination of these. These morphologic patterns contrast with classifications of intraductal papillary mucinous neoplasms (IPMN) of the pancreas in which oncocytic lesions (intraductal oncocytic papillary neoplasms (IOPN)) have been separated from IPMN due to distinct molecular findings. Mucosa surrounding ICPN may demonstrate dysplasia as well. About 50% of ICPNs are associated with invasive adenocarcinoma, but they have a better clinical outcome than conventional gallbladder adenocarcinomas [1, 2].

Our case exhibited low-grade ICPN with combined biliary, gastric, and intestinal differentiation. Adjacent mucosa also showed diffuse low-grade dysplasia. No high-grade dysplasia or invasive carcinoma was identified in extensively submitted sections. The aforementioned unusual findings in the gallbladder from a 2-year-old baby triggered further work-up since there is a well-known association between ICPN (previously called gallbladder papillomatosis) and metachromatic leukodystrophy (MLD) [3-5]. Genetic analysis was performed and the results revealed homozygous deletion of pathogenic variant c.1283C>T (p.Pro428Leu) in ARSA gene, which is associated with MLD. Brain MRI findings were non-specific and she has no history of developmental delay, neurologic symptoms, or regression.

MLD is a lysosomal storage disease caused by a deficiency of arylsulfatase A (ASA) with autosomal recessive inheritance in most cases. The ASA deficiency leads to the accumulation of sulfatides in the central and peripheral nervous system, which results in the destruction of the myelin sheath and eventually leads to neurologic symptoms such as seizures, loss of motor functions, and peripheral neuropathy [6]. Sufatide accumulation is also detected in other organs, e.g., the gallbladder, kidney, lymph nodes, liver, and bone marrow. The gallbladder epithelial cells and macrophages contain cytoplasmic inclusions on electron microscopic examination, consistent with sulfatide accumulation [3, 7]. Almost all case reports described the presence of collections of the lamina propria macrophages in the gallbladder [3, 4, 7, 8], as seen in our case (Figure 4). This accumulation of macrophages could show histologic overlap with cholesterolosis, a more common finding in the gallbladder. In MLD, Giemsa and toluidine blue stains will show metachromasia of the cytoplasm of macrophages, consistent with the accumulation of sulfatide deposits. In contrast, the accumulation of cholesterol esters and triglycerides can be highlighted on frozen tissue with Oil red O or Sudan black stains.

According to the age of disease onset, there are three clinical subtypes of MLD, including late infantile-onset, juvenile-onset, and adult-onset. Our patient showed no neurologic symptoms but was homozygous for mutation of the ARSA gene, which encodes ASA. Numerous mutations in the ARSA gene have been identified, and c.1283C_T mutation in our case is usually seen in juvenile or adult-onset phenotype [6]. That may explain the neurologic symptom-free status of our patient. A possible treatment for MLD so far is hematopoietic stem cell transplantation for selected cases [4]. MLD-associated gallbladder abnormalities occasionally appear before the onset of neurologic symptoms or an MLD diagnosis [3]. One case series with 34 patients reported that 76% of MLD patients showed gallbladder involvement [4]. The gallbladder abnormalities consist of benign and malignant conditions, e.g., cholecystitis, cholelithiasis, mucosal hyperplasia, polypoid lesions (now most lesions are under the category of ICPN), and adenocarcinoma [3-5]. In conclusion, gallbladder abnormalities, in particular polypoid lesions, are rare during childhood. This condition can be seen in cases with MLD, Peutz-Jeghers’ syndrome, and pancreaticobiliary malunion [8]. Pathologists should pay close attention to unusual gallbladder abnormalities in pediatric and adolescent patients to consider the above-mentioned possibilities and associated risk of malignancy.

Differential diagnosis:

Pyloric gland adenoma is composed of lobules of small, tightly packed, bland-looking glands that are morphologically similar to pyloric or Brunner glands. The uninvolved gallbladder mucosa is mostly devoid of dysplasia or pyloric gland metaplasia. Of note, pyloric gland nodules <0.5 cm arising in a background of pyloric gland metaplasia should not be designated as pyloric gland adenoma [9].
Reactive epithelial hyperplasia, commonly due to secondary causes (e.g., cholelithiasis, chronic cholecystitis, inflammatory bowel disease, primary sclerosing cholangitis), shows focal or diffuse papillary-shaped and elongated mucosal folds lined by bland epithelial cells with or without metaplastic changes. The presence of significant inflammation and no discrete, grossly visible mass-forming lesion, may help distinguish reactive hyperplasia from ICPN [1,10].
Invasive adenocarcinoma is present in about 50% of the ICPN cases at the time of diagnosis [2]. Gallbladder adenocarcinoma arising in ICPN is more commonly associated with papillary growth patterns, biliary epithelial lineage, and high-grade dysplasia. The invasive component is often a tubular adenocarcinoma, although other types, such as mucinous, adenosquamous, or neuroendocrine carcinoma, have also been reported. Extensive sampling is warranted because approximately 60% of ICPN with carcinoma showed ≤ 5mm of invasive focus, and the carcinoma may also occur away from the main ICPN lesion. Some patients with non-invasive ICPN can also die of new primary carcinoma in the biliary tract, typically long after the diagnosis of ICPN, possibly due to the field cancerization phenomenon. This observation supports long-term surveillance of these patients with ICPN even after resection [1, 2].

References:

  1. Basturk O, Aishima S, Esoposito I. World Health Organization Classification of Tumours. Intracholecystic papillary neoplasm. In: Digestive System Tumours. 2019, IARC, Lyon.
  2. Adsay V, Jang KT, Roa JC, Dursun N, Ohike N, Bagci P, Basturk O, Bandyopadhyay S, Cheng JD, Sarmiento JM, Escalona OT, Goodman M, Kong SY, Terry P. Intracholecystic papillary-tubular neoplasms (ICPN) of
    the gallbladder (neoplastic polyps, adenomas, and papillary neoplasms that are ≥1.0 cm): clinicopathologic and immunohistochemical analysis of 123 cases. Am J Surg Pathol. 2012 Sep;36(9):1279-301.
  3. McFadden K, Ranganathan S. Pathology of the gallbladder in a child with metachromatic leukodystrophy. Pediatr Dev Pathol. 2015 May-Jun;18(3):228-30.
  4. van Rappard DF, Bugiani M, Boelens JJ, van der Steeg AF, Daams F, de Meij TG, van Doorn MM, van Hasselt PM, Gouma DJ, Verbeke JI, Hollak CE, van Hecke W, Salomons GS, van der Knaap MS, Wolf NI. Gallbladder
    and the risk of polyps and carcinoma in metachromatic leukodystrophy. Neurology. 2016 Jul 5;87(1):103-11.
  5. Kim J, Sun Z, Ezekian B, Schooler GR, Prasad VK, Kurtzberg J, Rice HE, Tracy ET. Gallbladder abnormalities in children with metachromatic leukodystrophy. J Surg Res. 2017 Feb;208:187-191.
  6. Cesani M, Lorioli L, Grossi S, Amico G, Fumagalli F, Spiga I, Filocamo M, Biffi A. Mutation Update of ARSA and PSAP Genes Causing Metachromatic Leukodystrophy. Hum Mutat. 2016 Jan;37(1):16-27.
  7. Rodriguez-Waitkus PM, Byrd R, Hicks J. Metachromatic leukodystrophy and its effects on the gallbladder: a case report. Ultrastruct Pathol. 2011 Dec;35(6):271-6.
  8. Garavelli L, Rosato S, Mele A, Wischmeijer A, Rivieri F, Gelmini C, Sandonà F, Sassatelli R, Carlinfante G, Giovanardi F, Gemmi M, Della Giustina E, Amarri S, Banchini G, Bedogni G. Massive hemobilia and
    papillomatosis of the gallbladder in metachromatic leukodystrophy: a life-threatening condition. Neuropediatrics. 2009 Dec;40(6):284-6.
  9.  Basturk O, Aishima S, Esoposito I. World Health Organization Classification of Tumours. Pyloric gland adenoma of the gallbladder. In: Digestive System Tumours. 2019, IARC, Lyon.
  10. Umudum H, Gunbatili E, Sanal M, Ceyhan K. Primary diffuse papillary hyperplasia of the gallbladder. Pathology. 2006 Dec;38(6):591-2.

[line] 

Case contributed by:

Goo Lee, MD, PhD. University of Alabama at Birmingham

Rong Li, MD, PhD. Children’s of Alabama Benjamin Russell Hospital For Children

Conflict of Interest: NO

Case 3: Quarter 2, 2021

Case 3: Quarter 2, 2021

Clinical History

A 50-year-old woman with no significant past medical history presented with abdominal pain and a syncopal episode. Abdominal MRI showed a multicystic mass with a significant solid component in the pancreatic tail, measuring 2.2 cm in the greatest dimension. A fine-needle biopsy of the lesion was performed.

Histologic/Cytologic Features 

Microscopic pictures of the biopsy are shown in Figures 1-5. The histologic examination revealed a spindle cell lesion. The cells had relatively uniform and elongated nuclei, and some had vesicular chromatin with conspicuous nucleoli; others appeared wavy and hyperchromatic. No significant nuclear atypia or mitotic activity was present. Background normal pancreatic parenchyma was also identified.

Figure. 1-3. 1. H&E stain of the tumor, 4X; 2. H&E stain of the tumor, 10X; 3. H&E stain of the tumor, 10X
Figure. 4-5. 4. H&E stain of the tumor, 20X; 5. H&E stain of the tumor, 20X

[line]

Please select your diagnosis in the poll, then see the answer and the discussion in the links below.

[line]

What is the diagnosis of the lesion?

View Results

Loading ... Loading ...

[line]

Click Here To See The Answer

Answer: Mucinous cystic neoplasm

 

[line]

Click Here To See The Discussion

Final diagnosis:  

Mucinous cystic neoplasm

Educational Objectives and Discussion:

Educational Objectives

  1. Discuss spindle cell lesions of the pancreas.
  2. Review the clinicopathological characteristics of mucinous cystic neoplasms of the pancreas.
  3. Identify an unusual presentation of mucinous cystic neoplasms with stromal overgrowth.

Discussion

Immunohistochemistry stains were performed, and the spindle cells were positive for estrogen and progesterone receptors (Figures 6-7) and focally positive for inhibin. The spindle cells were negative for CD117, DOG1, S100, pan-cytokeratin, and beta-catenin. The proliferation index assessed with Ki-67 was approximately 1%. Based on the lesion’s morphology and immunoprofile, the case was diagnosed as mucinous/non-mucinous cystic neoplasm with ovarian-type stroma.

Figure. 6-7. 6. Immunohistochemical stain for estrogen receptor, 20X; 7. Immunohistochemical stain for progesterone receptor, 20X

After the diagnosis, distal pancreatectomy and splenectomy were performed. Grossly, there was a 2.2 x 1.6 x 1.6 cm partially cystic well-circumscribed mass in the pancreatic tail containing thick clear fluid (Figure 8). Serial sections showed a 60% cystic and a 40% solid component. The mass showed no communication with the pancreatic ductal system.

Figure. 8. Gross photograph of the cystic lesion at the tail of the pancreas

Microscopic pictures of the resection are shown in Figures 9 – 11. The histologic examination revealed multiple cysts lined by a single layer of cuboidal cells that lacked mucin and had abundant eosinophilic cytoplasm. A prominent densely packed spindle cell-rich stroma was identified. The spindle cells had elongated nuclei with fine chromatin and inconspicuous nucleoli. No malignant features were present.

9-11. 9. H&E stain of the tumor in resection specimen, 10X; 10. H&E stain of the tumor in resection specimen, 10X; 11. H&E stain of the tumor in resection specimen,

Pancreatic mucinous/non-mucinous cystic neoplasm (MCN) is an epithelial tumor typically associated with ovarian-type stroma. The majority of these lesions are found in the body or tail of the pancreas, occur in women, and have a mean age at diagnosis of 48 years old (1). Clinically, patients with MCN present with abdominal discomfort or epigastric pain, while others may be asymptomatic, and the tumor is found incidentally (2).

The histogenesis of these lesions is still in debate. Some proposed hypotheses suggest that the mesenchymal component derives from ectopic ovarian stroma incorporated during embryogenesis in the pancreas or represents persistent fetal periductal mesenchyme under hormonal stimulation (1).

Grossly, MCN usually presents with large unilocular or multilocular cysts, filled with thick gelatinous material, and lacks communication between the cyst and the pancreatic ductal system (3). Microscopically, the cysts are lined by mucin-producing columnar cells with varying degrees of cytologic and architectural atypia. However, cuboidal cells with no mucin can also occur. Based on the level of atypia, MCNs are further categorized as MCN with low- or high-grade dysplasia. The stromal component, called “ovarian-type stroma,” forms bands of densely packed spindle cells amongst the cysts, and its presence is required for the diagnosis. Typically, the stroma represents a smaller constituent of the lesion, and in some cases, it is difficult to identify as it can become hypocellular and replaced by hyalinized tissue (3). The epithelial cells stain positive with CK7 and MUC5AC. The ovarian-type stroma expresses PR (60-90%), ER (30%), SMA, and desmin. Luteinized cells can stain for inhibin and calretinin (1).

Molecularly, most MCN epitheliums carry activating mutations in codon 12 of KRAS (50-66%), some can carry loss-of-function mutations in RNF43 (1).

The case reported here has a very unusual presentation, given the fact that the stroma represents the predominant component of the lesion. The subepithelial stroma in this lesion was cellular and composed of cytologically bland spindle cells mimicking ovarian-type stroma without any malignant features. To our knowledge, this rare presentation of MCN has only been reported twice in the literature (4-5).

Molecular studies have shown frequent mutations in ID3, ARID1A, APC, and CDKN2A tumor suppressor genes in ACC (5-7). TP53 mutation or deletion has been identified in 12-24% of ACC (5,6). About 23% of ACC harbor gene fusion involving BRAF and RAF1 with the most common fusions being SND1-BRAF and HERPUD1-BRAF (5). These tumors are more sensitive to MEK inhibitors. In addition, microsatellite instability has been found in 8-14% of ACC (8,9).

Differential diagnosis:

The specimen was composed predominantly of bland-looking stroma on the initial biopsy, lacking a prominent epithelial component. Hence the initial differential diagnosis of this case comprises MCNs with sarcomatous stroma, carcinosarcoma, and benign mesenchymal tumors.

MCNs with sarcomatous stroma are infrequent and have been reported more frequently in the tail of the pancreas (6). The sarcomatous component is hypercellular, contains mitotic figures, and shows atypia and pleomorphism, in contrast with the bland looking stroma of the typical MCN.

Carcinosarcoma of the pancreas is a neoplasm composed of malignant mixed epithelial and mesenchymal elements (7). The sarcomatous component is composed of highly cellular areas with pleomorphic spindle cells containing abundant cytoplasm, hyperchromatic nuclei, and prominent nucleoli. Occasional bizarre cells can be identified. The histogenesis of this tumor remains unclear.

Benign mesenchymal tumors of the pancreas are extremely rare; some examples include inflammatory myofibroblastic tumor, extra gastrointestinal stromal tumor (GIST), schwannoma, and solitary fibrous tumor (SFT). Very few cases of pancreatic SFT have been reported in the literature. In the present case, the stroma did not show prominent staghorn-like vascularization, or a short storiform arrangement of the spindle cells, characteristics of SFT (8). Inflammatory myofibroblastic tumors could also be excluded based on the absence of a significant chronic inflammatory cell component. Primary GIST of the pancreas has been reported, showing the typical morphologic characteristics of the uniform spindle or epithelioid cells arranged in short fascicles or whorls (9). Differential diagnosis between MCN stroma and these mesenchymal tumors is based on histology and immunohistochemistry findings. The immunoprofile of the ovarian-type stroma of MCNs, showing positivity for inhibin, calretinin, estrogen and progesterone receptors, is not shared by these benign mesenchymal lesions. GIST is positive for c-kit and DOG1, schwannoma for S100, and SFT for STAT6 and CD34.

Finally, in the resection specimen, intraductal papillary mucinous neoplasms (IPMNs) should be considered in the differential diagnosis. IPMNs are characterized by cystic dilatation of pancreatic ducts in which an intraductal proliferation of neoplastic mucin-producing cells is arranged in a papillary pattern. IPMNs do not contain the ovarian-type stroma that characterizes the MCN (10).

References:

  1. Basturk O, Esposito I, Fukushima N et al. Pancreatic mucinous cystic neoplasm. In: Board WCoTE, ed. WHO Classification of Tumours: Digestive System Tumours. 5th ed. Lyon, France: IARC Press; 2019:319-321.
  2. Fukushima N, Fukayama M. Mucinous cystic neoplasms of the pancreas: pathology and molecular genetics. J Hepatobiliary Pancreat Surg. 2007;14(3):238-42.
  3. Jang KT, Park SM, Basturk O, Bagci P, Bandyopadhyay S, Stelow EB, Walters DM, Choi DW, Choi SH, Heo JS, Sarmiento JM, Reid MD, Adsay V. Clinicopathologic characteristics of 29 invasive carcinomas arising in 178 pancreatic mucinous cystic neoplasms with ovarian-type stroma: implications for management and prognosis. Am J Surg Pathol. 2015;39(2):179-87.
  4. Handra-Luca A, Couvelard A, Sauvanet A, Fléjou JF, Degott C. Mucinous cystadenoma with mesenchymal over-growth: a new variant among pancreatic mucinous cystadenomas? Virchows Arch. 2004;445(2):203-
  5. Lee WA. Mucinous cystadenoma of the pancreas with predominant stroma creating a solid tumor. World J Surg Oncol. 2005; 3:59.
  6. Van den Berg W, Tascilar M, Offerhaus GJ, Albores-Saavedra J, Wenig BM, Hruban RH, Gabrielson E. Pancreatic mucinous cystic neoplasms with sarcomatous stroma: molecular evidence for monoclonal origin with subsequent divergence of the epithelial and sarcomatous components. Mod Pathol. 2000;13(1):86-91.
  7. Farbod Darvishian, James Sullivan, Saul Teichberg, Kevin Basham; Carcinosarcoma of the Pancreas: A Case Report and Review of the Literature. Arch Pathol Lab Med. 2002; 126 (9):1114–1117.
  8. Baxter AR, Newman E, Hajdu CH. Solitary fibrous tumor of the pancreas. J Surg Case Rep. 2015; (12): rjv144.
  9. Trabelsi A, Yacoub-Abid LB, Mtimet A, et al. Gastrointestinal stromal tumor of the pancreas: A case report and review of the literature. N Am J Med Sci. 2009;1(6):324-326.
  10. Basturk O, Esposito I, Fukushima N et al. Pancreatic intraductal papillary mucinous neoplasm. In: Board WCoTE, ed. WHO Classification of Tumours: Digestive System Tumours. Lyon, France: IARC Press; 2019:310-314.

[line] 

Case contributed by:

Julia A. Gallardo, M.D.

Sadhna Dhingra, M.D.

Department of Pathology and Immunology, Baylor College of Medicine

Conflict of Interest: NO

Case 2: Quarter 2, 2021

Case 2: Quarter 2, 2021

Clinical History

A 63-year-old man with a history of mixed hyperlipidemia and gallstones underwent cholecystectomy for recurrent episodes of pancreatitis. A follow-up computed tomography (CT) scan revealed an interval increase in the size of an ill-defined, mass-like lesion in the pancreatic head with peripheral enhancement and central necrosis, concerning for malignancy (Figure 1). Endoscopic ultrasound with fine needle aspiration documented a solid/cystic mass and acinar cells on cytology. He underwent pancreaticoduodenectomy.

Figure-1. CT demonstrating a mass in the head of the pancreas

Macroscopic Description

Grossly, the resection specimen was remarkable for a 10 cm, well-circumscribed, tumor in the head of the pancreas, which had yellow and pink cut surfaces and areas of hemorrhage (Figure 2).

Figure-2. Gross photograph of the pancreaticoduodenectomy specimen showing a large mass in the head of the pancreas)

Histologic/Cytologic Features 

Microscopic pictures of the tumor are shown in Figures 3-6. Sections revealed a highly cellular tumor with a delicate vascular network, scant intervening stroma, and foci of tumor necrosis. Neoplastic cells exhibited a prominent acinar pattern of growth with basally located nuclei. Some acini showed minute lumina. Individual tumor cells had moderate amounts of granular eosinophilic cytoplasm and uniform nuclei. Some neoplastic cells exhibited prominent nucleoli. There were scattered mitotic figures but no cellular pleomorphism. Tumor cells were immunoreactive for pancytokeratin AE1/AE3. Rare cells showed weak reactivity for synaptophysin. They were negative for chromogranin and nuclear β-catenin.

Figure-3. Interface between pancreas (upper left) and tumor (right), H&E stain (4x)
Figure-4. Tumor, H&E stain (10x)
Figure-5. Tumor necrosis, H&E stain (10x)
Figure-6. Tumor, H&E stain (40x)

[line]

Please select your diagnosis in the poll, then see the answer and the discussion in the links below.

[line]

What is the diagnosis of the lesion?

View Results

Loading ... Loading ...

[line]

Click Here To See The Answer

Answer: Acinar cell carcinoma

 

[line]

Click Here To See The Discussion

Final diagnosis:  

Acinar cell carcinoma

Educational Objectives and Discussion:

Educational Objectives

  1.  Know the key histologic and immunohistochemical findings required for a diagnosis of acinar cell carcinoma.
  2.  Recognize the most common gross findings and clinical presentation of acinar cell carcinoma.
  3. Review the differential diagnosis and necessary workup to exclude histologically similar tumors.

Discussion

Acinar cell carcinoma (ACC) accounts for about 1-2 % of adult pancreatic neoplasms. The average age of adult patients is approximately 60 years. Some patients develop lipase hypersecretion and associated paraneoplastic syndrome. These tumors are generally well-circumscribed, at least partially encapsulated, solid, and large (average diameter 8-10 cm) with a homogenous pink to tan cut surface. They can arise in any part of the pancreas and are more common in the head region.

Microscopically, these tumors are typically denselycellular with minimal stroma. They may have different architectural patterns, solid and acinar patterns being the most prevalent. Less common patterns include a glandular and trabecular pattern. Individual tumor cells have striking eosinophilic cytoplasm, uniform nuclei, and a characteristic large central nucleolus. The mitotic rate is variable, ranging from 5 to 20 (mean 14) per 10 high power fields. Vascular invasion within the capsule of the neoplasm is common. The eosinophilic cytoplasm reflects the presence of cytoplasmic zymogen granules. However, in some cases, the cytoplasmic granularity is not well developed, and special stains are required to document their presence.

A cystic variant of ACC has been described as typically large, circumscribed tumors with cysts lined by single or multiple layers of neoplastic acinar cells. In these cystic lesions, there are areas of solid nests of acinar cells, areas of necrosis, and mitotic figures, which support a malignant process.

The finding of granular Periodic Acid-Schiff (PAS)/diastase positivity in the apical cytoplasm may be enough to confirm a diagnosis of acinar cell carcinoma (Figure 7). The butyrate esterase stain detects the presence of enzymatically active lipase in the neoplastic cells and is highly specific for acinar differentiation. Trypsin (Figure 8), chymotrypsin, and BCL10 (clone 331.1) (Figure 9) antibodies are the most sensitive, and simultaneous use of any two of them allows the detection of nearly 100% of acinar cell carcinomas. Of these, BCL10 is the most sensitive and specific. They have a favorable prognosis compared to the more common pancreatic ductal adenocarcinoma. (1-4)

Figure-7. Tumor, PAS/diastase stain (40x)
Figure-8. Tumor, immunohistochemical stain for trypsin (20x)
Figure-9. Tumor, immunohistochemical stain for BCL 10 (20x)

 

Molecular studies have shown frequent mutations in ID3, ARID1A, APC, and CDKN2A tumor suppressor genes in ACC (5-7). TP53 mutation or deletion has been identified in 12-24% of ACC (5,6). About 23% of ACC harbor gene fusion involving BRAF and RAF1 with the most common fusions being SND1-BRAF and HERPUD1-BRAF (5). These tumors are more sensitive to MEK inhibitors. In addition, microsatellite instability has been found in 8-14% of ACC (8,9).

Differential diagnosis:

Well-differentiated pancreatic neuroendocrine tumor, previously called islet cell tumors/islet cell carcinomas, are the pancreatic counterparts of APUDomas (Amine Precursor Uptake and Decarboxylation tumors) or carcinoids. They can be functional or non-functional (more common), are composed of monotonous cells with typical coarse nuclear chromatin, and express general markers of neuroendocrine differentiation (diffuse/intense synaptophysin and usually also chromogranin staining). They are the most important differential diagnosis of acinar cell carcinoma. Similarities between the two include a solid, acinar, or glandular architecture, relatively minimal stroma, and nuclear uniformity. Features favoring the diagnosis of well-differentiated pancreatic neuroendocrine tumor include hyalinized or amyloid-like stroma between nests of neoplastic cells (indicative of insulinoma), trabecular or gyriform growth patterns (particularly when arranged in single cell-thick cords), central nuclear localization, a coarsely clumped “salt and pepper” chromatin pattern, paler cytoplasm with less granularity and diffuse rather than focal positivity for synaptophysin and chromogranin. (1,10)

Mixed acinar-neuroendocrine carcinomas are malignant epithelial neoplasms with both acinar and neuroendocrine differentiation. They are defined as having > 30% of each line of differentiation by immunohistochemistry. They are best regarded as a subtype of acinar cell carcinoma because they share its clinical behavior and genomic features. (1,10)

Mixed acinar-ductal carcinomas are malignant epithelial neoplasms with both acinar and ductal differentiation. They are defined as having > 30% of each line by immunohistochemistry. These tumors may present with extensive extracellular colloid-like pools of mucin or nests of columnar or signet ring cells with cytoplasmic mucin or individual gland pattern of infiltration with an associated desmoplastic stromal response. Ductal differentiation is based on immunohistochemical reactivity for glycoproteins such as CEA (using monoclonal antibodies), CA19-9, or B72.3. Treatment is like that of ACC. (1,11)

Pancreatoblastomas are malignant epithelial neoplasms of the pancreas, principally affecting children in the first decade of life. However, it can rarely occur in adults. These are very cellular tumors and typically have more prominent lobules separated by cellular stromal bands. They are predominantly composed of solid sheets and acini of uniform cells with characteristic squamoid nests or corpuscles. Lesser amounts of a neuroendocrine component, ductal component, and/or primitive round blue cell component may be seen. Though acinar differentiation is the most common and predominant pattern in most cases, careful microscopic examination and additional sampling may help reveal ductal and/or neuroendocrine components as well as squamoid nests and cellular stromal bands. The age of the patient helps suggest the right diagnosis as pancreatoblastoma. (1)

Solid pseudopapillary neoplasm (SPN) are low grade malignant pancreatic tumors composed of poorly cohesive epithelial cells forming solid and pseudopapillary structures that lack a specific line of pancreatic epithelial differentiation. SPN displaying a predominantly solid growth pattern without foamy cells or eosinophilic globules could be confused with ACC. However, SPN never exhibits true lumen formation, so the presence of an acinar or glandular pattern would
exclude this entity. In contrast to ACC, SPN does not label with specific acinar markers (trypsin and chymotrypsin) and consistently shows diffuse nuclear β-catenin staining. (1,12)

References:

  1. International Agency for Research on Cancer. (2019). WHO Classification of Tumours of the Digestive System. Lyon: International Agency for Research on Cancer.
  2. Klimstra DS, Heffess CS, Oertel JE, Rosai J. Acinar Cell Carcinoma of the Pancreas. Am J Surg Pathol. 1992;16(9):815-837.
  3. Wood LD, Klimstra DS. Pathology and Genetics of Pancreatic Neoplasms with Acinar Differentiation. Semin Diagn Pathol. 2014;31(6):491-497.
  4. Matos JM, Schmidt CM, Turrini O, Agaram NP, Niedergethmann M, Saeger HD, Merchant N, Johnson CS, Lillemoe KD, Grützmann R. Pancreatic Acinar Cell Carcinoma: A Multi-institutional Study. J Gastrointest Surg. 2009;13(8):1495-502.
  5. Chmielecki J, Hutchinson KE, Frampton GM, Chalmers ZR, Johnson A, Shi C, Elvin J, Ali SM, Ross JS, Basturk O, Balasubramanian S, Lipson D, Yelensky R, Pao W, Miller VA, Klimstra DS, Stephens PJ. Comprehensive genomic profiling of pancreatic acinar cell carcinomas identifies recurrent RAF fusions and frequent inactivation of DNA repair genes. Cancer Discov. 2014;4(12):1398-405.
  6. Jiao Y, Yonescu R, Offerhaus GJ, Klimstra DS, Maitra A, Eshleman JR, Herman JG, Poh W, Pelosof L, Wolfgang CL, Vogelstein B, Kinzler KW, Hruban RH, Papadopoulos N, Wood LD. Whole-exome sequencing of pancreatic neoplasms with acinar differentiation. J Pathol. 2014;232(4):428-35.
  7. Jäkel C, Bergmann F, Toth R, Assenov Y, van der Duin D, Strobel O, Hank T, Klöppel G, Dorrell C, Grompe M, Moss J, Dor Y, Schirmacher P, Plass C, Popanda O, Schmezer P. Genome-wide genetic and epigenetic analyses of pancreatic acinar cell carcinomas reveal aberrations in genome stability. Nat Commun. 2017;8(1):1323.
  8. Liu W, Shia J, Gönen M, Lowery MA, O’Reilly EM, Klimstra DS. DNA mismatch repair abnormalities in acinar cell carcinoma of the pancreas: frequency and clinical significance. Pancreas. 2014;43(8):1264-70.
  9. La Rosa S, Sessa F, Capella C. Acinar Cell Carcinoma of the Pancreas: Overview of Clinicopathologic Features and Insights into the Molecular Pathology. Front Med (Lausanne). 2015;2:41.
  10. Ulich T, Cheng L, Lewin KJ. Acinar-endocrine cell tumor of the pancreas. Report of a pancreatic tumor containing both zymogen and neuroendocrine granules. Cancer. 1982;50(10):2099-105.
  11. Stelow EB, Shaco-Levy R, Bao F, Garcia J, Klimstra DS. Pancreatic Acinar Cell Carcinomas with Prominent Ductal Differentiation: Mixed Acinar Ductal Carcinoma and Mixed Acinar Endocrine Ductal Carcinoma. Am J Surg Pathol. 2010;34(4):510-8.
  12. Notohara, Kenji, Hamazaki, Shuji, Tsukayama, Choutatsu, et al. Solid-Pseudopapillary Tumor of the Pancreas: Immunohistochemical Localization of Neuroendocrine Markers and CD10. Am J Surg Pathol. 2000;24(10):1361-1371.

[line] 

Case contributed by:

Pragya Jain, MD

Saryn Doucette, MD

Department of Pathology and Laboratory Medicine
Medical College of Wisconsin

Conflict of Interest: NO

Case 4: Quarter 4, 2020

Case 4: Quarter 4, 2020

Clinical History

A 58-year-old woman with no significant past medical history developed left abdominal pain. An abdominal MRI showed an irregular enhancing 4.5 x 4.0 cm pancreatic tail mass that was inseparable from vessels in the splenic hilum. Endoscopic ultrasound-guided fine-needle aspiration showed rare malignant cells, favoring adenocarcinoma. The patient subsequently underwent neoadjuvant therapy with Gemcitabine/Abraxane followed by a distal pancreatectomy, splenectomy, partial omentectomy and removal of surrounding lymph nodes.

Histologic/Cytologic Features 

Figures 1-4 are representative photomicrographs of the tumor. The histologic examination revealed a small component of invasive ductal adenocarcinoma involving pancreatic parenchyma. Malignant glands were admixed with prominent nests of cells with cribriform/microcystic architecture containing intermingled epidermoid cells, mucin secreting cells, and intermediate/clear cells (the latter features resemble mucoepidermoid carcinoma of the salivary gland). The proportion of different cell types and microcystic architecture varied in different areas. Focal high grade pancreatic intraepithelial neoplasia (formerly PanIN-3) and pancreatic atrophy were also noted.

Figure-1. H&E stain of the tumor, 2X
Figure-2. H&E stain of the tumor, 4X
Figure-3. H&E stain of the tumor, 20X
Figure-4. H&E stain of the tumor, 20X

[line]

Please Select Your Diagnosis in the Poll, Then See the Answer and the Discussion in the Links Below

[line]

What is the diagnosis of the lesion?

View Results

Loading ... Loading ...

[line]

Click Here To See The Answer

Answer: Pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features

 

[line]

Click Here To See The Discussion

Final diagnosis:  

Pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features

Educational Objectives and Discussion:

Educational Objectives

1. Review the clinicopathologic features of pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features
2. Understand the molecular alterations of pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features
3. Discuss pertinent differential diagnosis for pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features

Discussion

The current tumor demonstrated that tumor cells were positive for pan-cytokeratin. p40, p63, and CK5 highlighted epidermoid tumor cells. CDX2 and CK20 highlighted luminal cells and mucin-producing cells. Synaptophysin, chromogranin, and CD56 stains were negative. Intracytoplasmic and luminal mucinous secretions were highlighted by mucicarmine stain (Figures 5-7). Molecular study showed mutations in KRAS, CDKN2A, SF3B1, and TP53 genes.

Figure-5. P40 immunohistochemical stain, 40X
Figure-6. CDX2 immunohistochemical stain, 40X
Figure-7. Mucicarmine stain, 40X

Pancreatic mucoepidermoid carcinoma (PAN-MEC, more appropriately termed as pancreatic adenosquamous carcinoma with mucoepidermoid carcinoma-like features) has been proposed as one of the histologic subtypes of pancreatic adenosquamous carcinoma because of their
clinicopathologic and molecular similarities (1). To date, approximately 20 PAN-MEC cases have been documented (1-6). This tumor is more frequently located at the pancreatic body/tail and is significantly larger in size and more aggressive than those of the conventional pancreatic ductal adenocarcinomas (1). 

Similar to salivary gland MECs, three intermingled cell types, including mucin-producing cells, epidermoid cells, and intermediate cells, are usually present in varying proportions in PAN-MEC. Mucin-producing cells (mucocytes) produce mucin (and are positive for mucin stains such as mucicarmine). These cells may have a vacuolated, columnar, or goblet cell-like appearance (Figure 8). Mucocytes often form the lining of microcysts or duct-like structures.

Figure-8. H&E stain of the tumor, 20X

Epidermoid cells are polygonal and squamoid in appearance with dense eosinophilic cytoplasm, which can be highlighted by immunohistochemical stains such as p40, p63, or CK5/6. Epidermoid cells commonly have nested, or sheet-like growth pattern and are often located at the periphery of the nests or cribriform/microcystic structures. While intercellular bridges may be found, keratin pearl formation, overt keratinization, or dyskeratosis is not typically seen. Intermediate cells are less differentiated, and are morphologically not mucous or fully epidermoid cells. Their appearance may vary from small clear cells to small basaloid cells with scant basophilic cytoplasm or intermediate oval cells with pale eosinophilic cytoplasm. The intermediate cells are often admixed with epidermoid cells or mucocytes (Figure 9).

Figure-9. H&E stain of the tumor, 40X

Despite morphologic similarity, PAN-MEC appears not to be a counterpart of MEC of the salivary gland. In the salivary gland, a high proportion of MECs have been reported to harbor an oncogenic CRTC1/3MAML2 gene fusion; whereas in the pancreas, these gene fusions were not detected by PCR in a study involving 16 PAN-MEC cases (all cases were classified as high-grade based on the salivary gland MEC grading system) (1). In addition, PAN-MEC has been reported to harbor KRAS and TP53 mutation, which is similar to the most common molecular signature found in pancreatic ductal adenocarcinomas (4)

Differential diagnosis:

Due to morphologic similarity, metastatic mucoepidermoid carcinoma or clear cell carcinoma of the salivary gland should be one of the first differentials to consider. However, the lack of clinical history of a salivary gland tumor, the presence of a pancreatic precursor lesion (high grade pancreatic intraepithelial neoplasia), and a component of conventional  invasive ductal adenocarcinoma would support this tumor being a primary pancreatic carcinoma with MEC features as opposed to a metastasis from salivary gland. Goblet cells and microcystic structures are generally not seen in clear cell carcinoma of the salivary gland, although squamous differentiation and mucinproduction are not uncommon (7).

Conventional pancreatic adenosquamous carcinoma is also in the differential diagnosis. By definition, this tumor has at least a 30% squamous cell carcinoma component with coexisting ductal adenocarcinoma. Apparent keratinization and squamous pearl formation, as well as focal nuclear anaplasia, are often noted. Low-grade mucoepidermoid carcinoma-like features are generally absent.

Neoadjuvant therapy has been reported to induce squamous metaplasia of ductal columnar cells. However, there was no squamous metaplasia identified in the background pancreatic tissue of the present case. Although focal squamous transdifferentiation from the small ductal adenocarcinoma component induced by neoadjuvant therapy (8) cannot be completely excluded, the diffuse squamoid cells intermingled with other cell types and predominant cribriform/microcystic architecture are difficult to be explained by focal squamous transdifferentiation changes.

Pancreatoblastoma is an uncommon malignant epithelial neoplasm characterized by multilineage differentiation including at least prominent acinar differentiation and focal squamoid morules that exhibit nuclear beta-catenin immunopositivity. Tumors are commonly seen in children but can occur in adults. Ductal/glandular or neuroendocrine differentiation can also be seen but are generally focal (9-10).

References:

  1. Saeki K, Ohishi Y, Matsuda R, et al. “Pancreatic Mucoepidermoid Carcinoma” Is not a Pancreatic Counterpart of CRTC1/3-MAML2 Fusion Gene-related Mucoepidermoid Carcinoma of the Salivary Gland, and May More Appropriately be Termed Pancreatic Adenosquamous Carcinoma With Mucoepidermoid Carcinoma-like Features. Am J Surg Pathol. 2018;42:1419-1428.
  2. Onoda N, Kang SM, Sugano S, Yamashita Y, Chung YS, Sowa M. Mucoepidermoid carcinoma of the pancreas: report of a case. Surgery. 1995;25:843-847.
  3. Ma R, Yu YQ, Li JT, Peng SY. Mucoepidermoid carcinoma of the pancreas: a case report and a review of literature. Journal of research in medical sciences: the official journal of Isfahan University of Medical Sciences. 2012;17:886-889.
  4. Kardon DE, Thompson LD, Przygodzki RM, Heffess CS. Adenosquamous carcinoma of the pancreas: a clinicopathologic series of 25 cases. Mod Pathol. 2001;14:443-451.
  5. Hu HJ, Zhou RX, Liu F, Wang JK, Li FY. You cannot miss it: Pancreatic mucoepidermoid carcinoma: A case report and literature. Medicine. 2018;97:e9990.
  6. Boecker J, Feyerabend B, Tiemann K, et al. Adenosquamous Carcinoma of the Pancreas Comprise a Heterogeneous Group of Tumors With the Worst Outcome: A Clinicopathological Analysis of 25 Cases Identified in 562 Pancreatic Carcinomas Resected With Curative Intent. Pancreas. 2020;49:683-691.
  7. Hsieh MS, Wang H, Lee YH, Ko JY, Chang YL. Reevaluation of MAML2 fusion-negative mucoepidermoid carcinoma: a subgroup being actually hyalinizing clear cell carcinoma of the salivary gland with EWSR1. Hum Pathol. 2017;61:9-18.
  8. Marcus R, Maitra A, Roszik J. Recent advances in genomic profiling of adenosquamous carcinoma of the pancreas. The Journal of pathology. 2017;243:271-272.
  9. Klimstra DS, Wenig BM, Adair CF, Heffess CS. Pancreatoblastoma. A clinicopathologic study and review of the literature. Am J Surg. 1995;19:1371-1389.
  10. Tanaka Y, Kato K, Notohara K, et al. Significance of aberrant (cytoplasmic/nuclear) expression of beta-catenin in pancreatoblastoma. The Journal of pathology. 2003;199:185-190.

[line] 

Case contributed by:

Wei Zheng, Assistant Professor

Alyssa M. Krasinskas, Professor

Department of Pathology and Laboratory Medicine

Emory School of Medicine

Conflict of Interest: NO

Case 3: Quarter 3, 2020

Case 3: Quarter 3, 2020

Clinical History

A 38-year-old female with a history of hypertension presented to the emergency department with complaints of nausea, vomiting, and back pain. MRI showed a T1 hypointense, T2 hyperintense, nonenchancing cystic lesion at the tail of the pancreas, which caused mass effect upon the spleen and stomach. A distal pancreatectomy was subsequently performed. The patient is currently being followed with no evidence of recurrence or malignant transformation.

Macroscopic Description
Grossly, there was a well-circumscribed 11.5 x 10 x 3.7 cm cyst at the tail of the pancreas containing cloudy, milky fluid (Figure 1). The lining of the cyst was smooth, without papillary projections or solid areas. There was no communication between the cyst and the main pancreatic duct.

Figure-1. Gross photograph of the cystic lesion at the tail of the pancreas

 Histologic/Cytologic Features 
Microscopic pictures of the cyst wall are shown in Figures 2 – 4. Sections show a unilocular cyst lined by 1-2 cell layers of bland cuboidal epithelium with abundant eosinophilic granular apical cytoplasm and basally oriented nuclei consistent with acinar differentiation. There was  little intervening ductal differentiation (mucin-containing ductal epithelium). No substantial nuclear atypia or mitotic activity was present. The cyst was surrounded by a thick fibrous pseudocapsule, which was composed of dense collagen with scattered fibroblasts. No ovarian type stroma was identified.

Figure-2. H&E stain low power view of the cyst wall
Figure-3. H&E stain median power view of the cyst wall
Figure-4. H&E stain high power view of the cyst wall
 

[line]

Please Select Your Diagnosis in the Poll, Then See the Answer and the Discussion in the Links Below

[line]

What is the diagnosis of the lesion?

View Results

Loading ... Loading ...

[line]

Click Here To See The Answer

Answer: Acinar cystic transformation of the pancreas

[line]

Click Here To See The Discussion

Final diagnosis:  

Acinar cystic transformation of the pancreas

Educational Objectives and Discussion:

Educational Objectives

  1. To understand the clinicopathologic features of the acinar cystic transformation of the pancreas.
  2. To understand the molecular alterations of the acinar cystic transformation of the pancreas.
  3. To discuss the differential diagnoses of the acinar cystic transformation of the pancreas.

Discussion

Acinar cystic transformation of the pancreas, also called acinar cell cystadenoma, is currently considered a non-neoplastic cystic pancreatic lesion that is lined by benign-appearing acinar and ductal epithelium. These lesions can occur throughout the pancreas, but they are more common in the pancreatic head. Some examples may diffusely involve the entire organ. Acinar cystic transformation commonly occurs in adults (mean age 43 years old) and shows female predominance (F:M=3:1) (1-9). Clinically it can present as recognized macroscopic lesions or incidental microscopic lesions. Patients can present with abdominal pain, dyspepsia or palpable mass. Some cases are completely asymptomatic. The etiology is unknown, but some cases may be related to obstruction. The size of these lesions can range from 1.5 cm – 19.7 cm (mean 5.8 cm) and cysts may be unilocular or multilocular with a smooth cyst lining and rare communication with the main pancreatic duct.

Microscopically, acinar cystic transformation is characterized by cysts of variable sizes lined by bland cuboidal eosinophilic epithelium with both acinar and ductal differentiation, cytoplasmic zymogen rich granules and without significant nuclear atypia, mitotic figures, necrosis, or infiltrative growth pattern.

The apical zymogen granules stain positively for the periodic acid-Schiff (PAS) stain and are resistant to diastase (Figures 5 & 6). Immunohistochemical labeling for the pancreatic enzymes trypsin (Figure 7), chymotrypsin, and lipase is seen in the lining epithelial cells, and cytokeratins (such as cytokeratin 7) are also detectable in the lining epithelium.

Molecular studies have been done on a few cases with one showing chromosomal gains of 1p, 3p, 5q, 6p, 7q, 8, 10q, 11, 14, 20, and X by array comparative genomic hybridization (10). However, another study performed X-chromosome inactivation analysis on 5 cases and showed that these lesions have a random X-chromosome inactivation pattern (11), supporting a non-neoplastic process.

Figure-5. PAS stain of the cyst wall
Figure-6. PAS-D stain of the cyst wall
Figure-7. Immunohistochemical stain for trypsin

Differential diagnosis:

Serous cystadenoma of the pancreas is a benign epithelial cystic neoplasm that is composed of uniform cuboidal, glycogen-rich pale pink to clear cells that often form cysts containing serous fluid. Immediately underlying the clear epithelium is an interweaving network of capillaries that is challenging to see on H&E but can be highlighted by CD31 stain. A central scar can be present, which consists of hyalinized stroma. Owing to the presence of abundant intracytoplasmic glycogen, PAS staining is positive in tumor cells but PAS-D staining is negative. Serous epithelium is immunoreactive for inhibin and Glut-1.

Mucinous cystic neoplasm (MCN) is another differential that is also characterized by pancreatic cysts of the body/tail that do not communicate with pancreatic duct. Cysts are characteristically lined by mucinous/non-mucinous epithelium with underlying entity defining ovarian-type stroma. Acinar epithelial lining is not a feature of MCN.

Squamoid cysts of the pancreatic duct are not neoplastic and are lined by epithelium with squamous or transitional differentiation instead of acinar and ductal differentiation.

Acinar cell cystadenocarcinoma is exceedingly rare. The epithelium of acinar cell cystadenocarcinoma is more complex than that of acinar cystic transformation and the acinar cells are less well polarized, and show significant nuclear atypia, including pleomorphism and prominent nucleoli. Areas of necrosis, solid nests of neoplastic cells, easily identifiable mitoses, and infiltration into the surrounding stroma support a malignant diagnosis.


References:

1. Zamboni G, Terris B, Scarpa A, et al. Acinar Cell Cystadenoma of
the Pancreas: A New Entity? Am J Surg Pathol. 2002, 26(6): 698-704.
2. Albores-Saavedra J. Acinar Cystadenoma of the Pancreas: A
Previously Undescribed Tumor. Ann Diagn Pathol. 2002, 6(2): 113-5.
3. Chatelain D, Paye F, Mourra N, et al. Unilocular Acinar Cell
Cystadenoma of the Pancreas an Unusual Acinar Cell Tumor. Am J Clin
Pathol. 2002, 118(2): 211-4.
4. G Klöppel. Pseudocysts and Other Non-Neoplastic Cysts of the
Pancreas. Semin Diagn Pathol. 2000 Feb; 17(1); 7-15.
5. McEvoy MP, Rich B, Klimstra D, et al. Acinar Cell Cystadenoma of
the Pancreas in a 9-year-old Boy. J Pediatr Surg. 2010, 45(5): e7-9.
6. Wolf AM , Shirley LA, Winter JM, et al. Acinar Cell Cystadenoma of
the Pancreas: Report of Three Cases and Literature Review. J
Gastrointest Surg. 2013l,17(7): 1322-6.
7. Singhi AD, Norwood S, Liu TC, et al. Acinar Cell Cystadenoma of the
Pancreas: A Benign Neoplasm or Non-Neoplastic Ballooning of Acinar and
Ductal Epithelium. Am J Surg Pathol. 2013, 37(9): 1329-35.
8. Wang G, Ji L, Qu FZ, et al. Acinar Cell Cystadenoma of the
Pancreas: A Retrospective Analysis of Ten-Year Experience From a
Single Academic Institution. Pancreatology, 2016, 16(4): 625-31.
9. Zhang X, Zhu H, Yang X, et al. Post-obstructive Cyst Formation in
Pancreas and Cystic Acinar Transformation: Are They Same? Pathol Res
Pract 2017, 213(8): 997-1001.
10. Khor TS, Badizadegan K, Ferrone C, et al. Acinar cystadenoma of
the pancreas: a clinicopathologic study of 10 cases including
multilocular lesions with mural nodules. Am J Surg Pathol.
2012;36(11):1579‐1591.
11. Singhi AD, Norwood S, Liu TC, et al. Acinar cell cystadenoma of
the pancreas: a benign neoplasm or non-neoplastic ballooning of acinar
and ductal epithelium? Am J Surg Pathol. 2013;37(9):1329‐1335.

[line] 

Case contributed by:

Yue Xue, MD, PhD

Rebecca C. Obeng, MD, PhD

Department of Pathology and Laboratory Medicine

Northwestern University, Chicago, IL 60611, USA

Conflict of Interest: NO

Case 2: Quarter 2, 2020

Case 2: Quarter 2, 2020

Clinical History

A 24-year-old female presented to the emergency department with severe left-sided abdominal pain. CT abdomen/pelvis showed a heterogeneous mass in the tail of the pancreas with multiple metastatic liver lesions and lymphadenopathy. Liver lesion biopsies were attempted and yielded necrotic debris with outlines of atypical cells that were positive for pancytokeratin (AE1/AE3). The patient next underwent a distal pancreatectomy.

Fig. 2
Figure-2.-HE-stain-of-tumor-20X
Figure-3.-HE-stain-of-tumor-40X
Figure-4.-PAS-Diastase-stain-40X
Figure-5.-CK-AE1AE3-immunohistochemical-stain-20X
 

[line]

Please Select Your Diagnosis in the Poll, Then See the Answer and the Discussion in the Links Below

[line]

What is the diagnosis of the lesion?

View Results

Loading ... Loading ...

[line]

Click Here To See The Answer

Answer: Undifferentiated carcinoma, sarcomatoid type with rhabdoid features

[line]

Click Here To See The Discussion

Microscopic description:
The tumor had a predominantly solid architecture and was primarily composed of loosely cohesive sheets of large ovoid-to-polygonal tumor cells. Focal glandular architecture was also seen. The tumor cells had large atypical vesicular nuclei, prominent nucleoli, and
eosinophilic to amphophilic cytoplasm with abundant intracytoplasmic eosinophilic globules, which displaced the tumor nuclei peripherally, creating a rhabdoid appearance. Multifocal lymphovascular and perineural invasion, abnormal mitoses, and areas of necrosis were also present.

Immunohistochemistry and special stains:
The tumor cells were positive for pancytokeratin (AE1/AE3), vimentin, and EMA. Ki-67 immunostain was positive in 60% of tumor cells. Intracytoplasmic eosinophilic globules were positive for PAS and were resistant to diastase digestion. Tumor cells showed diffuse loss of INI1 immunostain not only in solid areas, but also in areas of glandular differentiation. The tumor cells were negative for CK7, CD10, synaptophysin, chromogranin, and CD34.

Molecular analysis:
SMARCB1 gene mutation was detected.

Final diagnosis:  

Undifferentiated carcinoma, sarcomatoid type with rhabdoid features

Educational Objectives and Discussion:

Educational Objectives
1. Review undifferentiated carcinoma of pancreas and its subtypes

2. Discuss the clinicopathologic features of a recently described entity, pancreatic undifferentiated rhabdoid carcinoma

3. Understand pertinent differential diagnosis for undifferentiated carcinoma, sarcomatoid type with rhabdoid features

Discussion

Undifferentiated carcinoma is one of the histologic subtypes of pancreatic ductal adenocarcinoma. Tumors are usually hypercellular and composed of poorly cohesive tumor cells which often coexpress cytokeratin and vimentin. Osteoclast-like giant cells are typically lacking. Perineural and vascular invasion are also frequent findings. The current (5th) edition of WHO Classification of Tumors (Digestive System Tumors) recognizes three subtypes of undifferentiated carcinoma based on the tumor’s morphological patterns. These include anaplastic, sarcomatoid, and carcinosarcoma (1).

Sarcomatoid type undifferentiated carcinoma is composed of poorly cohesive atypical spindle-shaped tumor cells resembling a sarcoma. Tumors may contain admixed heterologous elements including bone and cartilage. At least 80% of the tumor typically shows spindle cells, with or without heterologous differentiation (1). A more specific morphologic type of sarcomatoid undifferentiated carcinomas with rhabdoid features has also been described, as with the case illustrated here (2). These are composed of sheets of dishesive rhabdoid cells with myxoid stroma. Pleomorphic giant cells, spindling and tubular components may also be seen and loss of nuclear positivity for SMARCB1 (INI1) is characteristic. SMARCB1/INI1 is known to encode for a tumor suppressor gene located on chromosomal band 22q11.2 (3, 4), and is a core subunit of a group of chromatin-modeling complexes, the SWI/SNF family. Biallelic inactivation of this gene is associated with highly malignant tumors with prominent rhabdoid morphology, including malignant rhabdoid tumor (both renal and “pure” extrarenal), atypical teratoid/rhabdoid tumor, epithelioid sarcoma and renal medullary carcinoma, among others. (3, 5, 6, 7).

Agaimy et al. recently described a group of pancreatic undifferentiated carcinomas with prominent rhabdoid morphology, which they named pancreatic undifferentiated rhabdoid carcinoma (PURC) (8). The authors described 14 such cases from their home institution as well as an additional 46 cases discovered on review of the literature. There were 44 males and 16 females (male-to-female ratio=2.8:1) of mean age 65 years (range 30 -96 years). Patients had an extremely poor prognosis with 45 of 49 (92%) with available follow-up information reportedly dying of disease within 1-19 months.

Agaimy et al also described two distinct subtypes of pancreatic undifferentiated rhabdoid carcinoma based both on the histomorphologic features and molecular profiles. One subtype is the pleomorphic giant cell subtype which shows highly pleomorphic neoplastic cells with abundant eosinophilic cytoplasm frequently containing rhabdoid inclusions. Molecular studies have shown this particular subtype to have a strong association with KRAS alteration and intact SMARCB1 gene. The second subtype, which is similar to the current case, is the monomorphic anaplastic subtype. This subtype shows uniformly atypical rhabdoid cytological features without significant pleomorphism. The tumor cells in the monomorphic anaplastic subtype have medium to large vesicular nuclei, prominent nucleoli, and eosinophilic cytoplasm which frequently contains rhabdoid cytoplasmic inclusions. This subtype shows diffuse loss of SMARCB1 nuclear immunostain as well as SMARCB1 gene mutation. However, no KRAS alterations are detected in these tumors (8).

Figure-6.-INI1-immunohistochemical-stain-20X

Differential diagnosis:

The morphologic features of undifferentiated carcinoma, sarcomatoid type with rhabdoid features raises several differential diagnoses one of which is poorly differentiated neuroendocrine carcinoma, particularly the large cell variant. The large cell variant of neuroendocrine carcinoma is often composed of round to polygonal cells which can have vesicular nuclei and prominent nucleoli. Glandular differentiation can rarely be present. However, unlike pancreatic undifferentiated carcinomas with rhabdoid morphology neuroendocrine carcinoma almost always expresses at least one neuroendocrine marker (synaptophysin and chromogranin) and shows intact INI1 (9).

Solid pseudopapillary neoplasm (SPN) is another differential to consider. The presence of a pancreatic neoplasm in a female in her 20’s should always raise the possibility of SPN as a
differential diagnosis. The presence of PAS-positive and diastase resistant intracytoplasmic globules is also characteristic of SPN. However, SPN often has a “pseudo-papillary” morphology, with nuclear beta-catenin labeling and is negative or focally positive for cytokeratin (1,10).

Melanomas can also display rhabdoid morphology, and can lose HMB45 and Melan-A expression. However, melanoma with rhabdoid morphology is often is positive for S100, shows intact INI1 staining and is cytokeratin negative (11).

Proximal-type epithelioid sarcoma is another neoplasm that can have predominant rhabdoid features with negative INI1 staining/INI1 loss. Differentiating undifferentiated carcinoma with rhabdoid features and SMARCB1 (INI1) loss from proximal-type epithelioid sarcoma can be very difficult. However, the presence of glandular architecture in this case makes this entity less likely. CD34 immunostain is positive in approximately 50% of epithelioid sarcoma (8,12).


References:

1.WHO Classification of Tumours Editorial Board, World Health Organization., International Agency for Research on Cancer. Digestive system tumours. 5th ed. Lyon: IARC Press; 2019.
2. Alguacil-Garcia A, Weiland LH. The histologic spectrum, prognosis, and histogenesis of the sarcomatoid carcinoma of the pancreas. Cancer 1977;39:1181-1189.
3. Kohashi K, Oda Y. Oncogenic roles of SMARCB1/INI1 and its deficient tumors. Cancer Sci. 2017;108(4):547-552.
4. Cho YM, Choi J, Lee OJ, et al. SMARCB1/INI1 missense mutation in mucinous carcinoma with rhabdoid features. Pathol Int 2006;56:702-706.
5.Fuller CE. All things rhabdoid and SMARC: An enigmatic exploration with Dr. Louis P. Dehner. Semin Diagn Pathol. 2016;33(6):427‐440.
6. Donner LR, Wainwright LM, Zhang F, et al. mutation of the INI1 gene in composite rhabdoid tumor of the endometrium. Hum Pathol 2007;38:935–939.
7. Fuller CE, Pfeifer J, Humphrey P, et al. Chromosome 22q dosage in composite extrarenal rhabdoid tumors:clonal evolution or a phenotypic mimic? HumPathol 2001;32:1102–8.
8. Agaimy A, Haller F, Frohnauer J, et al. Pancreatic undifferentiated rhabdoid carcinoma: KRAS alterations and SMARCB1 expression status define two subtypes. Mod Pathol. 2015;28(2):248‐260.
9. Basturk O, Tang L, Hruban RH, et al. Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. Am J Surg Pathol. 2014;38(4):437‐447.
10. Odze RD, Goldblum JR. Odze and Goldblum surgical pathology of the GI tract, liver, biliary tract, and pancreas. Third edition. ed. Philadelphia, PA: Saunders/Elsevier; 2015:xix, 1612 pages.
11. Abbott JJ, Amirkhan RH, Hoang MP. Malignant Melanoma With a Rhabdoid Phenotype: Histologic, Immunohistochemical, and Ultrastructural Study of a Case and Review of the Literature. Arch Pathol Lab Med. 2004;128(6):686-8
12. Sullivan LM, Folpe AL, Pawel BR, et al. Epithelioid sarcoma is associated with a high percentage of SMARCB1 deletions. Mod Pathol 2013;26:385-392.

[line] 

Case contributed by:

Aaron Sohn, M.D.
Anatomic and Clinical Pathology Resident, PGY-4
Baylor University Medical Center, Dallas, TX

Atin Agarwal, M.D.
Staff Pathologist
Baylor University Medical Center, Dallas, TX

Conflict of Interest: NO