Answer: Metastatic solid-pseudopapillary neoplasm  of the pancreas

 

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.

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