Combined Serous Microcystic Adenoma and Well-Differentiated Endocrine Pancreatic Neoplasm: A Case Report and Review of the Literature Open Access

Microcystic adenoma (MA) or serous cystadenoma of the pancreas is a rare benign neoplasm that occurs most commonly in elderly women.1 Most neoplasms are located in the body and tail of the pancreas.1 Occasionally, MA is associated with pancreatic adenocarcinoma.2–4 Recently, several cases of MA admixed with pancreatic endocrine tumor (PEN) have been reported5–8; all of these patients were women. In the present study we describe the first case of combined MA and well-differentiated PEN in a male patient. In addition, we summarize all available literature reports that describe serous cystadenomas in association with endocrine neoplasms. We argue that combined MA and PEN may be a distinct clinicopathologic entity rather than the incidental concurrence of 2 separate tumors.

A 53-year-old white man underwent a computed tomography (CT) scan of the chest for evaluation of chronic persistent cough with hoarseness, which developed after an acute respiratory infection. The CT scan showed a 4-mm nodule in the lung, thought to be a granuloma, and mediastinal lymphoadenopathy. A follow-up CT scan of the chest 6 months later included sectional views of the upper abdomen and showed an abnormality in the pancreas. Subsequently, an abdominal CT scan revealed a distinct mass in the head of the pancreas of heterogeneous intensity with associated calcifications. The patient was asymptomatic and without signs of pancreatic insufficiency. He worked vigorously and continued to feel well. His past medical history included cholecystectomy at age 51, and there was no previous history of malignancy. A pylorus-sparing pancreaticoduodenectomy was performed to remove the tumor.

The pancreaticoduodenectomy specimen included the head of the pancreas (8.0 × 4.5 × 4.0 cm) and a 15-cm-long segment of duodenum. The head of the pancreas contained a 4.0-cm (maximum dimension) well-circumscribed encapsulated neoplasm with an irregular central scar (Figure 1, A). The cut surface of the neoplasm was spongy yellow-white, with a 1.2-cm focus of solid yellow tumor adjacent to the central scar and surrounded by cystic areas. In addition, small 0.1- to 0.2-cm solid yellow areas were seen between cystic areas around the scar.

Microscopic examination showed a biphasic pattern with alternating cystic areas and solid areas (Figure 1, B). Cystic areas consisted predominantly of medium-sized cysts lined by a single layer of cuboidal or flat epithelial cells with clear or eosinophilic cytoplasm and uniform round nuclei with inconspicuous nucleoli (Figure 1, C). The solid areas consisted of nests of cells arranged in trabecular, lobular, or occasionally acinar patterns, with abundant eosinophilic or clear cytoplasm and a prominent vasculature (Figure 1, C). Also, there were areas with enlarged nuclei with moderate nuclear pleomorphism and nuclear-cytoplasmic pseudoinclusions. Four peripancreatic lymph nodes were negative for neoplasia.

The epithelial cells lining cysts contained abundant glycogen, as demonstrated by periodic acid–Schiff stain. Immunostaining demonstrated strong positivity for chromogranin A and synaptophysin in cells within the solid component (Figure 1, D). Occasionally, positive chromogranin staining was observed in cells lining cysts close to the neuroendocrine component (Figure 1, E). However, no chromogranin positivity was observed in larger cysts toward the periphery of the tumor, away from the endocrine component. None of the cells in cystic and solid areas were S100 positive. Somatostatin immunoreactivity was present in the majority of cells in solid areas. However, the endocrine component of the tumor was negative for insulin, glucagons, and pancreatic polypeptide.

Electron microscopic examination demonstrated that cyst-lining cells contained abundant ribosomes, lakes of granular glycogen, and fat globules. Solid areas were composed by cuboidal cells joined by desmosomes and contained extensive smooth endoplasmic reticulum, abundant mitochondria, and scattered 320-nm neuroendocrine granules (noninsulin, nonglucagon type) (Figure 1, F).

Here we describe the occurrence of combined microcystic cystadenoma and pancreatic endocrine tumor in a male patient. All 4 previously reported cases of a similar neoplasm occurred in women.5–8 These cases of combined MA and PEN are summarized in the Table. The most typical feature of this tumor is the presence in the head of the pancreas of an endocrine neoplasm that is surrounded by an MA. The combined MA and PEN, like MA, occurs more often in women (female-male ratio 4:1); however, the age of the patients at presentation was younger (mean age 49 years for combined MA and PEN) than for MA (mean age 66 years).1 Three reported cases occurred in Asian patients,5,7,8 the ethnic origin of one patient is unknown,6 and the patient reported here is white.

One additional patient with von Hippel-Lindau disease, coexistent pancreatic cyst, an islet cell tumor, and MA has been reported in the literature.9 However, no information regarding the gross and microscopic appearance of the tumor was provided, and it has not been determined whether these tumors were separate or admixed.

With regard of the histogenesis of combined MA and PEN neoplasms, two possibilities exist. Both components of the neoplasm arose closely but independently and are simply admixed (collision tumor). Alternatively, the tumor was derived from a neoplastic clone capable of exocrine and endocrine differentiation. Although we believe that the coincidental occurrence of both tumors (ie, collision tumor) is possible, in this event, separate tumor epicenters would be expected. Indeed, 3 separately located tumors, including MA, cystadenocarcinoma, and PEN, have been reported in the pancreas of a 70-year-old patient.10 In contrast, the endocrine component in a combined neoplasm is embedded within and intermixed with MA. Therefore, for the combined neoplasm with features summarized in this report, we favor concurrent development and differentiation of distinct epithelial and endocrine cells within the same tumor. In support of this mechanism, biphasic differentiation has been observed in the pancreas in patients with conditions such as nesidioblastosis,11,12 pancreatoblastoma,13 amphicrine neoplasms,14 and mixed acinar-endocrine carcinomas.15 Moreover, we observed rare chromogranin A–positive endocrine cells within the epithelial lining of cystic structures in the vicinity of PEN (Figure 1, E) in the present case, and this supports the development of a combined neoplasm from the same precursor clone. In addition, this finding indicates that, as in the case of nesidioblastosis, endocrine components of neoplasm can be formed by the neogenesis of endocrine cells from transformed duct cells. In the other reports of admixed PEN-MA neoplasms, chromogranin-positive cells were not demonstrated in cystic components of the neoplasms.5,7. However, both of these tumors5,7 were large and symptomatic, and the two dominant lineages, endocrine and exocrine, may have completely diverged. In a less advanced tumor, as in our case, scattered neuroendocrine cells could persist in the exocrine lining of the cystic component.

Since combined MA and PEN has distinct general and pathologic features, albeit in a small number of cases, we consider that this tumor may represent a separate clinicopathologic entity. Like nesidioblastosis, a combined MA-PEN tumor forms complexes of transformed ductal structures and endocrine cells. Therefore, the term microcystic nesidioblastoma is a suggested appellation for this type of complex neoplasm.

Combined MA and PEN may have a higher malignant potential when compared to MA. This appears to be related to the PEN component, since features suggestive of of the malignant potential of the PEN component, such as perineural and lymphatic invasion8 or duodenal invasion and lymphatic permeation,7 have been reported in 2 cases of combined neoplasm. However, no metastatic tumor was seen in both of these cases.7,8 

In summary, combined MA and PEN pancreatic neoplasms are rare, and based on all recorded cases, the tumors probably represent a distinct clinicopathologic entity. The malignant potential and prognostic features of this neoplasm await long-term follow-up and further examples. Careful gross examination and histologic sampling of MA-type neoplasms should be performed to exclude the presence of an endocrine component.