Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases

Abstract

Background: In the pancreas, poorly differentiated neuroendocrine carcinomas include small cell carcinoma and large cell neuroendocrine carcinoma and are rare; data regarding their pathologic and clinical features are very limited.

Design: A total of 107 pancreatic resections originally diagnosed as poorly differentiated neuroendocrine carcinomas were reassessed using the classification and grading (mitotic rate/Ki67 index) criteria put forth by the World Health Organization in 2010 for the gastroenteropancreatic system. Immunohistochemical labeling for neuroendocrine and acinar differentiation markers was performed. Sixty-three cases were reclassified, mostly as well-differentiated neuroendocrine tumor (NET) or acinar cell carcinoma, and eliminated. The clinicopathologic features and survival of the remaining 44 poorly differentiated neuroendocrine carcinomas were further assessed.

Results: The mean patient age was 59 years (range, 21 to 82 y), and the male/female ratio was 1.4. Twenty-seven tumors were located in the head of the pancreas, 3 in the body, and 11 in the tail. The median tumor size was 4 cm (range, 2 to 18 cm). Twenty-seven tumors were large cell neuroendocrine carcinomas, and 17 were small cell carcinomas (mean mitotic rate, 37/10 and 51/10 HPF; mean Ki67 index, 66% and 75%, respectively). Eight tumors had combined components, mostly adenocarcinomas. In addition, 2 tumors had components of well-differentiated NET. Eighty-eight percent of the patients had nodal or distant metastatic disease at presentation, and an additional 7% developed metastases subsequently. Follow-up information was available for 43 patients; 33 died of disease, with a median survival of 11 months (range, 0 to 104 mo); 8 were alive with disease, with a median follow-up of 19.5 months (range, 0 to 71 mo). The 2- and 5-year survival rates were 22.5% and 16.1%, respectively.

Conclusions: Poorly differentiated neuroendocrine carcinoma of the pancreas is a highly aggressive neoplasm, with frequent metastases and poor survival. Most patients die within less than a year. Most (61%) are large cell neuroendocrine carcinomas. Well-differentiated NET and acinar cell carcinoma are often misdiagnosed as poorly differentiated neuroendocrine carcinoma, emphasizing that diagnostic criteria need to be clearly followed to ensure accurate diagnosis.

Figure 1

This large, tan-yellow, vaguely nodular, fleshy mass with areas of necrosis suggests that the lesion is not a ductal adenocarcinoma, and the differential diagnoses include poorly differentiated neuroendocrine carcinoma as well as acinar cell carcinoma.

Figure 2

Large cell neuroendocrine carcinomas reveal various growth patterns (trabecular-A- and glandular-B- patterns are depicted here). The cells are often round to polygonal and the nuclei have either vesicular chromatin or prominent nucleoli. Note multiple mitotic figures.

Figure 3

Small cell carcinoma. The majority of the tumor cells are relatively small with a high nucleus-to-cytoplasm ratio, hyperchromatic nuclei, and nuclear molding. However, scattered giant tumor cells with bizarre, large nuclei are also common.

Figure 4

Combined neuroendocrine carcinomas: In 4 cases, individual ductal adenocarcinoma glands are intimately admixed with nests of neuroendocrine tumor cells (A). The ductal adenocarcinoma glands express glycoprotein markers (CEA is shown here, B). Conventional ductal adenocarcinoma and neuroendocrine carcinoma components are sharply segregated in 2 cases (C). One small cell carcinoma exhibits widespread squamous differentiation (D).

Figure 5

Sharply segregated well differentiated neuroendocrine tumor regions, composed of cells with clear cytoplasm and monotonous, round nuclei, exhibit a nested growth pattern (A). A Ki67 stain shows a labeling index of 1% in this component (as opposed to 50% in the poorly differentiated neuroendocrine carcinoma component, B).

Figure 6

The Kaplan-Meier analysis of the overall disease-specific survival of all poorly differentiated neuroendocrine carcinomas.