Answer: Serous cystadenoma of the pancreas.

 

Final diagnosis:  

Serous cystadenoma of the pancreas

Discussion

Serous cystadenomas (SCAs) are benign epithelial neoplasms which account for 1-2% of all pancreatic tumors. They are usually solitary and most frequently involve the pancreatic body or tail. There is a female predominance (3:1) and they are usually discovered incidentally by imaging performed for other reasons. SCAs may be associated with Von Hippel-Lindau syndrome. VHL- associated SCAs develop multiple microcystic and macrocystic serous cystadenomas which are indistinguishable from sporadic SCAs. Sporadic SCAs often carry somatic VHL gene alterations.  Serous cystadenocarcinoma based on the presence of metastasis to other organ(s) has been reported, but it is extremely rare.  The cysts can involve the entire pancreas if associated with germline alteration in VHL gene.  The classic radiologic finding is a well-circumscribed, multilocular microcystic lesion with central scar, sometimes with a “sunburst” calcification pattern due to calcifications involving the thin septa. On EUS, it appears as an echogenic mass with numerous cysts producing a characteristic honeycomb appearance. Histologically, the cysts are lined by a single layer of cuboidal to flat epithelial cells with clear cytoplasm, well defined cell border, and small round nuclei with inconspicuous nucleoli, and without any pleomorphism or atypia. Underlying the epithelium is an interweaving network of capillaries. The central scar consists of hyalinized stroma with fewer clusters of tiny cysts.   Due to presence of glycogen, the clear cells are positive for cytoplasmic granules on PAS which are sensitive to diastase. SCA may bleed spontaneously or after FNA/biopsy, which may lead to extensive scar and degenerative changes with only minimal remaining cystic epithelium.

 

As previous studies have demonstrated, the diagnosis of SCA can be very challenging on cytology and small biopsy. Cytology/biopsy specimens are usually paucicellular. Without knowledge of the characteristic imaging findings and chemical analysis of the cyst fluid, serous cystadenomas are not always recognized preoperatively. Scant cellular yield on fine-needle aspiration or biopsy often leads to a nondiagnostic or nonspecific benign diagnosis unless attention is paid to the subtle findings (1-2). The hint for diagnosis on low power lies in the hyalinized stroma which on high power can show embedded small cysts lined by flattened /clear cuboidal cells, sometimes mimicking vascular proliferation, especially since these cysts are also associated with a prominent capillary network. At other times, failure to recognize the cyst lining can be interpreted as non-diagnostic stroma of a pseudocyst. Judicious use of PAS histochemical stain with or without digestion, along with, immunohistochemical stains such as CK7 and inhibin can help in confirming the diagnosis. (Caveat: reportedly, α-inhibin sensitivity by immunohistochemistry was observed to be 80% in resected cases, but only 59% in cell block/biopsy specimens (3). GLUT-1 immunostaining may also be useful to highlight the epithelium of SCA. However, PanINs/IPMNs and ductal adenocarcinoma can also show variable expression, based on grade of lesion (4), and staining must be taken in context. Cyst fluid analysis of SCAs typically shows low CEA levels (typically <5 ng/mL) and amylase levels (typically <250 U/L). Presence VHL mutation on molecular analysis of cystic fluid also help to confirm the diagnosis of SCA.

Differential diagnosis:

Acinar Cystic Transformation of the Pancreas:

Acinar cystic transformation of the pancreas is a rare cystic lesion arising from dilatation of an acinar-ductal unit, with fewer than 100 cases have been described in literature (5). Currently, WHO classifies acinar cystic transformation as a non-neoplastic cystic lesion (6).  Cases are divided into two categories: clinically recognized macroscopic multilocular lesions and incidental unilocular microscopic findings. They have female predominance of 3:1 and have been associated with random X-chromosome inactivation (7). The multilocular cyst can diffusely involve the pancreas and rarely communicate with the main pancreatic duct. Histologically they consist of variably sized cysts with incomplete septa, surrounded by pancreatic parenchyma. Unilocular lesions have underlying thin or thick hyalinized walls. The cysts are lined by pale ductal epithelium with interspersed acinar cells with granular apical cytoplasm and basally oriented nuclei. No nuclear atypia or mitotic activity has been reported. Immunohistochemically, these cysts are diffusely positive for CK7 with patchy staining for CK19 in ductal cells; and trypsin, chymotrypsin, and BCL10 staining the acinar component. Acinar cystic transformation is regarded as a benign process, and there has been no reports of malignant transformation (8).  Acinar cystic transformation lacks the glycogen rich epithelium of serous cystadenomas. These lesions may be difficult to differentiate on small biopsy.

Hemangioma:

Pancreatic hemangiomas are extremely rare, especially in adults, and is considered a benign vascular tumor. To date, about 20 cases have been reported in the English literature (9). In difficult cases, vascular markers (CD34, CD31, ERG) and CK7 can be used to distinguish vascular spaces from small cysts of SCA.

Clear cell renal cell carcinoma (ccRCC):

Secondary neoplasms affecting the pancreas are uncommon, accounting from 2% to 5% of all malignancies in the pancreas. The most common metastases to the pancreas include renal cell carcinoma, melanomas, colorectal carcinomas, lung carcinomas, breast carcinomas, and sarcomas. ccRCC should always be considered when encountering pancreatic lesions with “clear” cytoplasm. Approximately 55% of patients with metastatic renal cell carcinoma to pancreas are asymptomatic, and the disease may manifest after a mean time intervals of > 10 years during which the patient may be disease free. Cytologic atypia, positivity for PAX-8 and CD10, along with the patient remote history of RCC, are helpful clues that can distinguish renal cell carcinoma from solid form of serous cystadenoma (10).

Well differentiated clear cell neuroendocrine tumor of the pancreas:

Well differentiated clear cell neuroendocrine tumors of the pancreas may be sporadic or associated with VHL syndrome or multiple endocrine neoplasia type I. The solid area of SCAs shares similar morphologic features of a well differentiated clear cell neuroendocrine tumors. Positive staining for neuroendocrine markers: chromogranin, synaptophysin and INSM1 would confirm the diagnosis of a well differentiated clear cell neuroendocrine tumor.

References:

1. Huang P, Staerkel G, Sneige N, Gong Y. Fine-needle aspiration of pancreatic serous cystadenoma: cytologic features and diagnostic pitfalls. Cancer. 2006 Aug 25;108(4):239-49. doi: 10.1002/cncr.21911. PMID: 16691573.
2. Salomao M, Remotti H, Allendorf JD, Poneros JM, Sethi A, Gonda TA, Saqi A. Fine-needle aspirations of pancreatic serous cystadenomas: improving diagnostic yield with cell blocks and α-inhibin immunohistochemistry. Cancer Cytopathol. 2014 Jan;122(1):33-9. doi: 10.1002/cncy.21347. Epub 2013 Aug 12. PMID: 23939868.
3. Steel M, Rao S, Ho J, et al. Cytohistological diagnosis of pancreatic serous cystadenoma: a multimodal approach. J Clin Pathol 2019; 72:615–621.
4. Basturk O, Singh R, Kaygusuz E, Balci S, Dursun N, Culhaci N, Adsay NV. GLUT-1 expression in pancreatic neoplasia: implications in pathogenesis, diagnosis, and prognosis. Pancreas. 2011 Mar;40(2):187-92. doi: 10.1097/MPA.0b013e318201c935. PMID: 21206329; PMCID: PMC3164314.
5. Rift CV, Hasselby JP, Hansen CP, Federspiel B. Acinar cystic transformation of the pancreas: report of a case and a review of the literature. Pathol Res Pract. 2020;216(6):152928)
6. WHO classification of tumors series, 5th ed.; vol. 1). http://publications.iarc.fr/579.2019
7. SongM.-Z., SuC.-H., & HsiaoC.-H. (2015). Acinar Cell Cystadenoma of Retroperitoneum: A Case Report and the Literature Review. JOP. Journal of the Pancreas, 16(3), 307-309. https://doi.org/10.6092/1590-8577/3002
8. Luchini C, et al. Acinar Cystic Transformation of the Pancreas: Histomorphology and Molecular Analysis to Unravel its Heterogeneous Nature. Am J Surg Pathol. 2023 Mar 1;47(3):379-386. Epub 2023 Jan 16. PMID: 36649476
9. Jin C, Mo JG, Jiang H, Wang LZ, Zou H, Wang KP. Adult pancreatic hemangioma: a rare case report and literature review. BMC Surg. 2020 Jun 3;20(1):118. doi: 10.1186/s12893-020-00779-8. PMID: 32493358; PMCID: PMC7268514.
10. Cheng SK, Chuah KL. Metastatic Renal Cell Carcinoma to the Pancreas: A Review. Arch Pathol Lab Med. 2016 Jun;140(6):598-602. doi: 10.5858/arpa.2015-0135-RS. PMID: 27232353.

Case contributed by:

Sara Alexandria Sherman, MD – PGY-1, Baylor College of Medicine, Houston TX
Shilpa Jain, MD – Associate Professor, Gastronintestinal and Liver Pathology, Baylor College of Medicine, Houston TX

Acknowledgment:

Special thanks to Deyali Chatterjee, MD at MD Anderson Cancer Center for her consultative expertise.

Conflict of Interest: No

Answer: Intracholecystic Tubular Non-mucinous Neoplasm (ICTN) with high-grade dysplasia.

 

Final diagnosis:  

Intracholecystic Tubular Non-mucinous Neoplasm (ICTN) with high-grade dysplasia.

Discussion

Intracholecystic Tubular Non-mucinous Neoplasm (ICTN) is an unusual type of intracholecystic neoplasm of the gallbladder, recently described as having distinct histologic findings from those of ICPN [1]. Pehlivanoglu et al. [1] analyzed 28 cases of ICTN. Demographic data revealed female/male ratio of 0.9, mean age of 51 years, and mean tumor size of 1.6 cm. The tumors presented as mass-forming lesions comprised of tightly packed, back-to-back, small tubule/glands with areas of cribriform architecture. The tubules/glands were lined by cuboidal, non-mucinous epithelium with high nuclear:cytoplasmic ratio and eosinophilic cytoplasm.

Nuclei were overlapping, round or ovoid with occasional nucleoli and clearing of the chromatin, reminiscent of the nuclear features seen in papillary thyroid carcinoma (Figure 3). The levels of nuclear atypia and architectural changes qualified as high-grade dysplasia in all cases. Squamoid morules were frequently noted. Amorphous amyloid-like hyalinization was sometimes present in the stroma. Immunohistochemical findings [1] showed diffuse positivity of MUC6 (about 70% of cases), scattered positivity of CDX2 (50%), particularly within squamoid morules and labeling for MUC5AC (10%). β-catenin showed diffuse nuclear expression in the tumor cells as well as the morular cells in two (2) cases.

The background gallbladders were without chronic inflammation/injury. Cholesterolosis/cholesterol polyps were commonly seen. However, there was no dysplasia in the background gallbladders and no association with invasive carcinoma. The authors also reviewed >600 gallbladder carcinomas in association with the initial characterization of ICTN and found no residual or associated lesions with similar features to the described cases of ICTN.

The pathogenesis of ICTN has not been fully elucidated but may be associated with alteration of Wnt/β-catenin pathway. Lesions with similar morphology have previously been considered as either a pyloric type of ICPN or as a type of PGA [3].  In summary, cases similar to the one presented here appear to have distinct features from ICPN, occurring in gallbladders with largely normal mucosa and without an associated invasive carcinoma. Further investigation with additional cases is needed to follow to fully establish these features, relationships to other biliary neoplasms and clinical behavior.

Differential diagnosis:

ICPN is a precancerous lesion of the gallbladder. Grossly it forms a distinct polypoid/exophytic intraluminal mass and microscopically shows papillary and/or tubular configuration with dysplasia, which can have four major morphological patterns, e.g., biliary, intestinal, gastric, oncocytic, or combination of these morphologically patterns [2, 4]. Regarding the molecular characteristics of ICPN, mutations in STK11 and CTNNB1 have been identified [3]. Surrounding mucosal epithelium may be associated with dysplasia as well.  About 50% of ICPNs are associated with invasive adenocarcinoma, but it has a better clinical outcome compared to conventional gallbladder adenocarcinomas.

PGA of the gallbladder is a polypoid neoplasm consisting of uniform, back-to-back mucinous glands with pyloric or Brunner gland features.  Positive β-catenin by IHC and mutation of CTNNB1 were identified in 60% of PGAs [2]. They also show diffuse and strong positivity of MUC6. 20% of PGAs contain squamoid morules. PGAs may also have variation in the amount of cytoplasmic mucin, with mucin-poor variants identified, although this is not the typical morphology [3]. Similar to ICTN, multifocality (field effect) is not a feature of PGAs [2]. Taken together, ICTNs are considered to have overlapping pathologic features with PGAs, but the recent characterization of ICTN suggests that they should be considered separate entity from mucinous PGAs [3].

BilIN is a microscopic, non-invasive, flat or (micro)papillary neoplastic lesion, usually not grossly visible.  KRAS mutations were identified in about 40% of cases as an early molecular event of carcinogenesis. It is often present in the mucosa adjacent to the carcinomas. BilIN is graded as low-grade and high-grade according to the degree of cytologic atypia and architectural changes. Low grade is of no clinical significance but high grade warrants extensive sampling to detect an occult invasive carcinoma [2].

References:

1. Pehlivanoglu B, Balci S, Basturk O, Bagci P, Erbarut Seven I, Memis B, Dursun N, Jang KT, Saka B, Ohike N, Tajiri T, Roa JC, Sarmiento JM, Reid MD, Adsay V. Intracholecystic tubular non-mucinous neoplasm (ICTN) of the gallbladder: a clinicopathologically distinct, invasion-resistant entity. Virchows Arch. 2021 Mar;478(3):435-447. 
2. Basturk O, Aishima S, Esoposito I. World Health Organization Classification of Tumours. Intracholecystic papillary neoplasm. In: Digestive System Tumours. 2019, IARC, Lyon.
3. Fukumura Y, Rong L, Maimaitiaili Y, Fujisawa T, Isayama H, Nakahodo J, Kikuyama M, Yao T. Precursor Lesions of Gallbladder Carcinoma: Disease Concept, Pathology, and Genetics. Diagnostics (Basel). 2022 Jan 28;12(2):341.
4. 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. 

Case contributed by:

Goo Lee, MD- University of Alabama at Birmingham.

Acknowledgment:

Special thanks to Volkan Adsay, MD, Koc University Hospitals, Turkey, for his consultative expertise.

Conflict of Interest: No

Answer: Well-differentiated pancreatic neuroendocrine tumor (Pan-NET), lipid rich variant.

 

Final diagnosis:  

Well-differentiated pancreatic neuroendocrine tumor (Pan-NET), lipid rich variant.

Educational Objectives and Discussion

Educational Objectives

1. Identify and describe the histologic features of lipid rich variant of PanNET
2. Review the clinical implications of a diagnosis of lipid rich variant of PanNET
3. Discuss the differential diagnosis for lipid rich variant of PanNET

Discussion
Immunohistochemical stains were performed on the biopsy material. The neoplastic cells were positive for pan-CK (strong and diffuse), synaptophysin (strong and diffuse) [Figure 2], chromogranin (strong but focal) and inhibin (strong and diffuse) while negative for CK7, RCC, PAX-8, S-100, Melan-A (MART-1), and beta catenin. A MIB-1 (Ki-67) stain showed a low proliferation index (<3%). A diagnosis of well-differentiated pancreatic neuroendocrine tumor, Grade 1, lipid rich variant was rendered.

The patient subsequently underwent surgical resection (pancreaticoduodenectomy). Sectioning of the pancreas revealed a tan-white to tan-yellow, stellate, firm, fibrous mass measuring 4.0 cm in greatest dimension. The microscopic and immunophenotypic features of the tumor in the resection specimen mirrored those of the biopsy material. Sections showed neoplastic cells arranged in nests/clusters and cords, surrounded by marked collagenized/fibrotic stroma [Figure 3]. The tumor cells demonstrated clear/foamy vacuolated cytoplasm and small uniform nuclei with finely dispersed chromatin [Figure 4]. Mitotic figures were virtually absent. The MIB-1 (Ki-67) stain was repeated on the resection specimen and showed a proliferation index of 5-7% in hot spots. A final diagnosis of well-differentiated pancreatic neuroendocrine tumor, Grade 2, lipid rich variant was rendered

PanNET with vacuolated, lipid rich cytoplasm was first described in 1997 by Ordonez and Silva [1]. Singh et al and Xue et al’s series on PaNET variant cases both offered additional valuable contributions to the literature [2,3]. The lipid rich variant affects both men and women and can occur in the head or tail of the pancreas, ranging in size from 2-11 cm. Microscopically, this variant represents a diagnostic challenge (see differential diagnosis section). The prototypical neuroendocrine growth pattern may be absent. The cytologic features are deceptively bland; tumor cells are characterized by round to pyknotic nuclei with fine chromatin and inconspicuous nucleoli. The classic stippled “salt and pepper” chromatin may not be evident. Nuclear “endocrine” atypia is also not identified. The cytoplasm is not only clear but also finely vacuolated; lipid droplets and neuroendocrine secretory granules can be identified ultrastructurally with electron microscopy. Mitotic activity is absent to low and MIB-1 (Ki-67) staining usually does not exceed 5% based on published data [2,3]. Given how unusual these histologic features are compared to a typical low grade neuroendocrine tumor, immunohistochemical stains are an essential adjunct aid. The neoplastic cells routinely express pan-cytokeratin and neuroendocrine markers chromogranin and synaptophysin (focal to diffuse staining). Inhibin and HIF-1α staining can be seen in a subset of tumors, while Melan-A (MART-1) and MUC6 expression is absent [2].
Xue et al. include the lipid rich variant in the “aggressive variant group” alongside hepatoid, oncocytic, plasmacytoid, and discohesive variants due to propensity for greater tumor size, T-stage, metastases, and progression rates [3]. Furthermore, patients with lipid rich PanNET fall into one of two categories: younger patients with familial/functional/syndromic tumors (rare) and older patients with non-functioning/sporadic tumors (common). While inhibin, HIF-1α, and Melan-A (MART-1) expression by immunohistochemistry in clear cell PanNET has a strong association with von Hippel Lindau (VHL) disease, this correlation is less robust in lipid rich PaNET [2,4]. Regardless, it may still be prudent for clinicians to exclude VHL disease or MEN1 (multiple endocrine neoplasia type 1) syndrome as lipid rich PaNETs have rarely been reported in these patients [2].

Differential diagnosis:

The pathologist should keep a broad differential diagnosis in mind when approaching a low-grade pancreatic lesion with clear/vacuolated cytoplasm:
Clear cell PanNET:
PanNET with clear cell change are not uncommon and have a strong association with VHL disease, particularly when HIF-1α, inhibin, and/or Melan-A (MART-1) expression by immunohistochemistry is seen in addition to traditional neuroendocrine markers. VHL-associated clear cell PanNETs usually occur in younger women and are non-functioning tumors [4-7]. While the cytoplasm is clear, it lacks the vacuolated/microvesicular appearance of lipid rich PanNET.
Solid pseudopapillary neoplasm (SPN):
SPNs are uniquely characterized by pseudopapilla, nuclear grooves, and hyaline globules. SPNs can exhibit clear cytoplasm and frequently contain foamy macrophages, and therefore could appear similar to lipid rich PanNET in small biopsy specimens. While SPNs can express synaptophysin, chromogranin is usually negative. More importantly, nuclear staining of the neoplastic cells with beta catenin is a key diagnostic clue for the diagnosis of SPN, reflecting underlying mutations in CTNNB1 [8]. Additionally, these tumors most commonly occur in adolescent girls/young women under the age of 35 and arise most frequently in the body or tail of the pancreas.
Perivascular epithelioid cell tumor (PEComa or so called “sugar tumor”):
PEComas are rare mesenchymal neoplasms with myomelanocytic differentiation. The tumors grow in sheets or nests and are characterized by epithelioid cells with clear to eosinophilic, granular cytoplasm, which has a moth-eaten appearance (“spider cells”) with a spindle cell component present in a minority of cases. Co-expression of smooth muscle markers (SMA, desmin, h-caldesmon) and melanoma markers (e.g. Melan-A/MART-1, HMB45) is characteristic. Neuroendocrine labeling and strong and diffuse keratin expression is notably absent [8].
Morphologic patterns of pancreatic ductal adenocarcinoma:
While pancreatic ductal carcinoma typically shows significant cytologic atypia and has a uniquely infiltrating gland-forming growth pattern accompanied by a desmoplastic stromal response, certain morphologic patterns can appear deceptively bland and lack gland formation. The foamy gland and clear cell patterns of invasive ductal adenocarcinoma of the pancreas both are included in this category. Helpful distinguishing characteristics from lipid rich PanNET include gland formation, possible presence of mucin and the lack of neuroendocrine marker expression. Additionally, PanNETs most often present as well-circumscribed lesion on imaging/EUS/gross examination, as opposed to the poorly-defined, infiltrative growth pattern seen with ductal adenocarcinomas [8].
Adrenal cortical tissue/neoplasm:
Adrenal cortical tissue/neoplasms share many overlapping histopathologic features with lipid rich PanNET and immunohistochemistry can be a helpful aid. Adrenal cortical lesions mark with antibodies to SF-1, calretinin, inhibin, Melan-A (MART-1), and CD68 [9]. Adrenal cortical lesions however lack keratin and neuroendocrine marker positivity. Please note, that inhibin expression (as in our case) can be seen in a subset of lipid rich PanNET; therefore, a broad panel of stains is essential.
Clear cell renal cell carcinoma (ccRCC):
ccRCC should always be considered when encountering pancreatic lesions with “clear” cytoplasm. Renal cell carcinoma is in fact the most common reason for a metastasis to the pancreas. While PAX-8 is a helpful ancillary screening marker used for renal cell carcinoma, it is important to note that PanNET can also express PAX-8 [10]. Therefore, additional antibodies such as RCC and CD10 (for renal cell carcinoma) and synaptophysin and chromogranin (for PaNET) should be included as part of the larger panel of stains.

References:

[1] Ordonez NG, Silva EG. “Islet cell tumor with vacuolated, lipid rich cytoplasm: a new histologic variant of islet cell tumor.” Histopathology 1997; 31:157-160.
[2] Singh R, Reid MD et al. “Lipid-rich variant of pancreatic endocrine neoplasms.” Am J Surg Pathol 2006; 30:194-200.
[3] Xue Y. et al “Morphologic variants of pancreatic neuroendocrine tumors: clinicopathologic analysis and prognodtic stratification.” Endocr Pathol 2020 31:3, 239-253.
[4] Hoang MP, Hruban RH et al. “Clear cell endocrine pancreatic tumor mimicking renal cell carcinoma: a distinctive neoplasm of von Hippel Lindau disease.” Am J Surg Pathol 2001; 25:602-609.
[5] Guarda LA, Silva EG et al. “Clear cell islet cell tumor.” Am J Surg Pathol 1983; 79:512-517.
[6] Mount SL, Weaver DL et al. “Von Hippel Lindau disease presenting as a pancreatic neuroendocrine tumor.” Virchows Arch 1995; 426:523-528
[7] Musso C, Paraf F. et al. “Pancreatic neuroendocrine tumors and von Hippel Lindau disease” Ann Pathol. 2000; 20:130-133.
[8] Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, Washington KM, Carneiro F, Cree IA; WHO Classification of Tumours Editorial Board. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020 Jan; 76(2):182-188. doi: 10.1111/his.13975. Epub 2019 Nov 13. PMID: 31433515; PMCID: PMC7003895.
[9] Sangoi A., Fujiwara M et al. “Immunohistochemical Distinction of Primary Adrenal Cortical Lesions from Metastatic Clear Cell Renal Cell Carcinoma: A Study of 248 Cases.” Am J Surg Pathol 2011; 35(5): 678-686.
[10] Bellizi AM “Immunohistochemistry in the diagnosis and classification of neuroendocrine neoplasms: wat can brown do for you?” Hum Pathol 2020; 96:8-33.

Case contributed by:

Susanne K. Jeffus, MD – University of Arkansas for Medical Sciences
Camila Simoes, MD – University of Arkansas for Medical Sciences
Felicia D. Allard, MD – University of Arkansas for Medical Sciences

Acknowledgment:

Special thanks to David Klimstra, MD, of Memorial Sloan Kettering Cancer Center for his consultative expertise.

Conflict of Interest: No

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