Coexistence of an Endocrine Tumour in a Serous Cystadenoma (Microcystic Adenoma) of the Pancreas, an Unusual Association

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800 J Clin Pathol 2000;53:800–802 Coexistence of an endocrine tumour in a serous cystadenoma (microcystic adenoma) of the pancreas, an unusual association

M Ö Üstün, N Tug˘yan, M Tunakan

Abstract within the head and the body of the pancreas. A pancreatic endocrine tumour arising Invasion to adjacent structures was not seen. within a serous cystadenoma is reported. There was central scarring with calcifications A 49 year old woman was admitted with a in the central region of the mass. Biochemical history of epigastric pain, nausea, vomit- analyses including amylase and bilirubin were ing, and weight loss of two months within the normal ranges except for raised duration. She had been diabetic for 12 alkaline phosphatase (1786 U/litre; normal years. An epigastric mass was palpated in range, 64–306) and alanine aminotransferase the physical examination, and computed (190 U/litre; normal range, 4–37). In addition, tomography revealed a multiloculated the patient was hyperglycaemic (fasting plasma cystic lesion in the pancreas. Pathological glucose concentration, 2770 mg/litre; normal examination of the pancreatic tumour range, 75–115). The clinical diagnosis was a revealed the coexistence of a serous cysta- cystic pancreatic neoplasm. A modified Whip- denoma and an endocrine tumour. The ple resection was performed and portions of endocrine tumour, which was located the small bowel (20 cm) and the proximal pan- inside the serous cystadenoma, was 1 cm creas (13 × 10 × 7 cm) were resected. Nearly in diameter. The first case of a serous cys- all of the resected pancreatic tissue was tadenoma of the pancreas containing a composed of a tan pink, multilocular cystic pancreatic endocrine tumour was re- neoplasm. A central stellate scar was present. ported in the literature recently. This The cystic spaces were filled with a clear fluid paper reports another incidentally found and ranged from 0.2 to 2.5 cm in diameter. pancreatic endocrine tumour arising The surgical specimen was fixed in 10% for- within a serous cystadenoma. malin and sections were stained with haema- ( 2000;53:800–802) J Clin Pathol toxylin and eosin, periodic acid SchiV (PAS), Keywords: pancreatic endocrine tumour; serous PAS with diastase, Alcian blue (pH 2.5), and cystadenoma; cystic neoplasms of the pancreas mucicarmine. Immunohistochemical studies were performed on paraYn wax embedded sections using a standard avidin–biotin– Serous cystadenomas, also known as micro- complex method with diaminobenzidine as the cystic adenomas or glycogen rich adenomas, chromogen. Commercially available mono- are benign tumours of the pancreas, which clonal antibodies against neuron specific eno- occur in elderly patients and have a slight lase (NSE; 1/50), chromogranin (1/100), female preponderance.12 These tumours are synaptophysin (1/10), epithelial membrane either discovered incidentally or present as an antigen (EMA; prediluted; Dako A/S, Den- abdominal mass with or without local pain. If mark), LEU 7 (1/25), gastrin (1/50), insulin the mass occurs in the pancreatic head, it can (1/500), glucagon (1/100), and somatostatin result in gastrointestinal or biliary tract ob- (1/50) were used. struction, and when suYcient islet cell tissue is Microscopic examination revealed multiple destroyed by the tumour, diabetes mellitus may cysts separated by fibrous connective septa. 1 also occur. Although these tumours usually Single layer cuboidal epithelial cells with bland arise in normal pancreas, rarely they are nucleus and clear or eosinophilic cytoplasm associated with other pancreatic neoplasms, 3 lined the cysts. PAS positive intracytoplasmic such as pancreatic ductal adenocarcinoma. material digested with diastase was consistent There is only one report in the literature on the Department of with glycogen (fig 1). Stains for mucin were coexistence of a pancreatic endocrine tumour negative in tumour cells. Although there were Pathology, Atatürk (PET) and a serous cystadenoma.4 In this arti- Teaching Hospital, micropapillary structures in some areas, necro- 35310 Izmir, Turkey cle, we report another patient presenting with a sis, nuclear atypia, and mitoses were absent. M Ö Üstün PET and a serous cystadenoma. Enlarged islets were seen under the cyst NTug˘yan, epithelium. The non-neoplastic pancreas was M Tunakan Case report normal in appearance; because serous cystad- Correspondence to: A 49 year old woman was admitted to hospital enomas usually grow slowly, the presence of Dr Üstün, Yahya Kaptan because of epigastric pain, nausea, vomiting, pancreatic islets within the tumours was an Postanesi, Posta Kutusu 2 1026, Kocaeli, Turkey and weight loss. She had a history of diabetes expected finding. In addition, enlargement of hasanustun@ mellitus for 12 years. Physical examination islets may accompany pancreatic endocrine netscape.net revealed a palpable epigastric mass. Computed neoplasms.5 Inside the central satellite scar, a Accepted for publication tomography scan showed a multiloculated microscopic focus of uniform cells in solid and 17 March 2000 cystic mass measuring 12 cm in diameter gyriform pattern was seen. At the periphery of

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Discussion To our knowledge, a PET arising in association with a serous cystadenoma was described first by Keel et al in 1996. The patient was a 47 year old woman with a history of systemic lupus erythematosus who had been using steroids chronically for seven years.4 Our case presented here is a 49 year old woman with a history of diabetes mellitus for 12 years. From the embryological and histogenetic point of view, the potential of pancreatic ductal stem cells for biphasic diVerentiation along either glandular epithelial or neuroendocrine Figure 1 A single layer of cuboidal epithelium lines the pathways would not be unexpected. The pres- cysts. The periodic acid SchiV (PAS) reaction has ence of endocrine cells within exocrine carci- disappeared after diastase in the cyst epithelium (PAS with nomas has been reported previously in pancre- diastase). atic tumours.6 Pour et al evaluated the pancreatic carcinomas of Syrian golden ham- sters and reported a close relation between endocrine and ductal cells, pointing towards a common origin from a totipotent cell. Accord- ing to this study, pancreatic carcinogenesis was accompanied by the proliferation of ductular formations between islets (intrainsular ductules). First an adenomatous and cystadenomatous pattern and then adenocarcinoma developed within pre-existing ductules, and within the newly formed intrainsular ductules. Simultaneously, during the process islets had gradually atrophied, but their remnants could be detected within the thin connective tissue septa of the cystadenomatous pattern. These findings suggest that both exocrine and endocrine components of the pancreas might have the same origin—the multipotential stem cell of the ductal epithelium, which originates from the endodermal epithelium.7 Biphasic diVerentiation is seen in some pancreatic disorders, either benign or malignant.8–10 Nesidioblastosis is another ex- ample of the close histogenetic relation between the exocrine and endocrine pancreas. An unusual case of pancreatic carcinoma with both adenocarcinomatous and islet cell diVer- entiation, along with ultrastructural evidence Figure 2 The periphery of the pancreatic endocrine tumour is surrounded by cyst epithelium (haematoxylin and of focal acinar diVerentiation, has also been eosin stained section). described.9 Pancreatoblastoma appears to be the coun- the tumour, these uniform cells were embed- terpart of childhood tumours that arise from ded in stroma as single cell lines. Cells were stem cells in other organs. Both endocrine and small with scant eosinophilic cytoplasm and exocrine diVerentiation have been identified in stippled nuclei, consistent with endocrine cells. component cells such that ductal, acinar, and The solid endocrine tumour focus was sur- islet cells may be seen at the histological, rounded completely by the serous cystad- immunohistochemical, and ultrastructural enoma (fig 2). Immunohistochemical examina- level.11 The acinar–endocrine cell tumour of tion revealed strong positive staining for EMA the pancreas is a rare mixed tumour reported within the serous cystadenoma component, only in one paediatric and one adult patient. It although no such staining was seen in the is sometimes impossible to diVerentiate acinar endocrine tumour component. In contrast, cell carcinomas from endocrine tumours by immunohistochemical staining for NSE, light microscopy because of the histological chromogranin, synaptophysin, LEU 7, insulin, similarities. The detection of both zymogen and glucagon was positive in the endocrine and neuroendocrine granules within the same tumour, whereas all were negative in the cyst cell by ultrastructural and enzymatic analyses epithelium. Focal and weak staining was seen in acinar–endocrine cell tumours suggests a for glucagon, whereas insulin staining was focal neoplastic proliferation of intermediate cells.810 but strong in intensity. Gastrin and somatosta- Similarly, simultaneous neuroendocrine gran- tin staining was not detected. ule formation concentrated in the basal pole or Although the diabetic status of the patient in the cytoplasmic processes with mucin did not change after the removal of the tumour, production have been described in amphicrine she was well one year after surgery. carcinomas (mucinous islet cell carcinomas).

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These are rare neoplasms composed of both from unsuspected endocrine tumours that exocrine and endocrine diVerentiated cells.12 were missed. Although both of the reported In the French literature, a patient with an cases are well on short term follow up, the endocrine tumour associated with a serous clinical relevance of this rare association is still cystadenoma and cystadenocarcinoma was unclear. reported, but all three tumours were located separately in the pancreas.3 Our case is The authors thank Dr Paul van Diest for providing and evaluat- ing the insulin, glucagon, gastrin, somatostatin, and LEU 7 composed of benign serous epithelial and neu- immunohistochemical stains. roendocrine components. Immunohisto- chemical studies in our case show the evidence 1 Alpert LC, Truong LD, Bossart MI, et al. Microcystic adenoma (serous cystadenoma) of the pancreas. A study of of divergent diVerentiation. The serous cystad- 14 cases with immunohistochemical and electron micro- enoma component of the tumour was strongly scopic correlation. Am J Surg Pathol 1988;12:251–63. immunoreactive for EMA only, the endocrine 2 Compagno J, Oertel JE. Microcystic adenomas of the pancreas (glycogen-rich cystadenomas). Am J Clin Pathol tumour component was immunoreactive for 1978;69:289–98. NSE, chromogranin, synaptophysin, LEU 7, 3 Heresbach D, Robert 1, Le Berre N, et al. Tumeurs kystiques et tumeur endocrine du pancreas [abstract]. Gas- insulin, and glucagon. In functional endocrine troenterol Clin Biol 1993;17:968–71. 4 Keel SB, Zukerberg L, Graeme-Cook F, et al. A pancreatic neoplasms, a minor population of hormone endocrine tumor arising within a serous cystadenoma of producing cells is often present in addition to the pancreas. Am J Surg Pathol 1996;20:471–5. 5 Klöppel G, Willemer S, Stamm B, et al. Pancreatic lesions the principal cellular type, as in our case. In the and hormonal proﬁle of pancreatic tumors in multiple current case, weak glucagon staining was seen endocrine neoplasia type 1. An immunohistochemical study of nine patients. Cancer 1986;57:1824–32. in addition to strong insulin staining. The dia- 6 Pour P. Islet cells as a component of pancreatic ductal neo- betic status of the patient despite insulin secre- plasms. Experimental study: ductular cells, including islet tion by the endocrine neoplasm might be the cell precursors, as primary progenitor cells of tumors. Am J Pathol 1978;90:295–316. result of excessive glucagon secretion and islet 7 Pour P, AlthoV J, Takahashi M. Early lesions of pancreatic ductal carcinoma in the hamster model. Am J Pathol 1977; cell tissue destruction by serous cystadenoma. 88:291–308. In summary, this is the second case of PET 8 Ichijima K, Akaishi K, Toyoda N, et al. Carcinoma of the arising within a serous cystadenoma in the lit- pancreas with endocrine component in childhood. A case report. Am J Clin Pathol 1985;83:95–100. erature. Incidentally found PETs were 1 and 9 Schron DS, Mendelsohn G. Pancreatic carcinoma with 1.5 cm in diameter in our case and in Keel and duct, endocrine, and acinar diVerentiation. A histologic, immunocytochemical and ultrastructural study. Cancer co-workers’ case, respectively. Serous neo- 1984;54:1766–70. plasms are almost always benign tumours, 10 Ulich T, Cheng L, Lewin K. Acinar–endocrine cell tumor of the pancreas. Cancer 1982;50:2099–105. although rare malignant examples have been 11 Morohoshi T, Kanda M, Horie A, et al. Immunocytochemi- 13 cal markers of uncommon pancreatic tumors. Acinar cell reported. The correlation between the mor- carcinoma, pancreatoblastoma, and solid cystic (papillary– phological features and the clinical behaviour cystic) tumor. Cancer 1987;59:739–47. 12 Ordonez NG, Balsaver AM, Mackay B. Mucinous islet cell of PET is poor. Only the existence of (amphicrine) carcinoma of the pancreas associated with metastatic disease indicates malignancy in watery diarrhea and hypokalemia syndrome. Hum Pathol PET. There are no reports of patients with 1988;12:1458–61. 13 Yoshimi N, Sugie S, Tanaka T, et al. A rare case of serous resected cystadenomas developing metastases cystadenoma of the pancreas. Cancer 1992;69:2449–53.