Case 2: Quarter 2, 2023

Case 2: Quarter 2, 2023

Clinical History

A 56-year -old female with chronic left upper quadrant abdominal pain of more than 10 years duration with multiple comorbidities including endometriosis, ovarian cyst, right renal stones, diverticulosis, and pancreatic cyst. The pancreatic cyst was incidentally discovered on abdominal MRI, located in the pancreatic head, measuring 2 cm in greatest dimension. EUS and CT scan showed a multilobulated cystic lesion (2.5 cm) with a solid component, not in communication with the main pancreatic duct. EUS guided fine needle aspiration (FNA) and biopsies were performed for 3 times to establish the diagnosis. All three FNA and biopsies were reported as negative for malignancy or atypical cells. Cyst fluid showed a low CEA (<2 ng/ml) and cyst fluid was negative for KRAS mutation. The patient continued to have chronic left upper quadrant pain and it was recommended that she undergo Whipple surgery for definitive management of her pancreatic cyst.

Macroscopic Description: The resection specimen showed a multiloculated cyst with a central scar and fibrosis

Histologic/Cytologic Features 

H&E sections showed a multiloculated cyst with hyalinized stroma. The cysts were lined by flat to cuboidal cells with clear cytoplasm and minimal cytologic atypia (Figure 1). Some cystic spaces were accompanied by hemorrhage and hemosiderin-laden macrophages (Figure 2). Immunohistochemical stain for CK7 highlighted the epithelial lining of the cystic spaces with weak, patchy labeling for inhibin (Figures 3 and 4). A PAS stain highlighted the cytoplasm of the cyst lining (Figure 5).

Figure 1: Multiloculated cyst with intervening hyalinized fibrous stroma, cystic spaces are lined by cuboidal to flattened cells with clear cytoplasm, without nuclear atypia.  (H&E; 20x)

Figure 2. There was accompanying hemorrhage and hemosiderin-laden macrophages with associated surrounding rich vascular network. (H&E; 100x)
Figure 3: The cells lining the cysts were positive for CK7 (CK7, 40x)
Figure 4: The cyst lining is weakly and patchily positive for inhibin. ( Inhibibin, 100x)
Figure 5: PAS stain highlights the intracytoplasmic granules in the cyst lining (PAS; 400x)

A prior EUS-guided biopsy initially read as negative for malignancy or atypical cells was reviewed.  On low power, the cell block appeared paucicellular with blood clots, unremarkable pancreatic parenchyma and dense hyalinized connective tissue (Figure 6). Examination on higher magnification demonstrated focal areas of small glandular/cystic spaces lined by single layer of bland, cuboidal to flattened cells with uniform nuclei and clear cytoplasm similar to those present the resection specimen (Figure 7). The lining cells of the cysts  were positive for CK7 and inhibin with granular cytoplasmic labeling with PAS stain (Figures 8, 9, 10). 

Figure 6: Paucicellular-appearing cell block of prior FNA/Biopsy (H&E; 20x)
Figure 7: Higher magnification of FNA/biopsy shows focal areas of small glandular/cystic spaces lined by single layer of bland, cuboidal to flattened cells with uniform nuclei and clear cytoplasm (H&E; 200x)
Figure 8: The cells lining the glandular/cystic spaces is focally highlighted by CK7 immunostain (CK7; 200x)
Figure 9: The cells lining the glandular/cystic spaces are positive for inhibin (Inhibin; 200x)
Figure 10: PAS stain highlights intracytoplasmic granulesin the lining cells. (PAS; 400x)

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Answer: Serous cystadenoma of the pancreas.


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Final diagnosis:  

Serous cystadenoma of the pancreas


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.


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.


  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).
  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.
  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


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

Conflict of Interest: No

One thought on “Case 2: Quarter 2, 2023

  1. Very nice example with a nice discussion. Another helpful immunohistochemical stain we perform and find useful also in FNA specimens in the confirmation of SCA is CD31 (or other endothelial markers) because they highlight the capillary network that was mentioned in this nice discussion. CD31 demonstrates this network hugging the epithelium that is not as evident in H&E sections. The pattern of this capillary network is quite distinctive and different than those in other tumors. Considering the other stains are not very specific (like CK7) or can be weak (like inhibin), this stain becomes surprisingly helpful in some cases.

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