A Clinicopathologic and Molecular Update of Pancreatic Neuroendocrine Neoplasms With a Focus on the New World Health Organization Classification

Abstract

Context.—: According to the 2017 World Health Organization classification, pancreatic neuroendocrine neoplasms (PanNENs) include a new category of pancreatic neuroendocrine tumor, grade 3, which is often difficult to differentiate from pancreatic neuroendocrine carcinoma. However, pancreatic neuroendocrine tumor grade 3 and pancreatic neuroendocrine carcinoma are distinct entities with very different clinical presentation, prognosis, and therapeutic strategies. Recent discoveries on the molecular characteristics of pancreatic neuroendocrine tumors also play an essential role in the pathologic differential diagnosis of PanNENs. In addition, the histopathologic varieties of PanNENs bring in many differential diagnoses with other pancreatic neoplasms, especially acinar cell carcinoma, solid pseudopapillary neoplasm, and ductal adenocarcinoma.

Objective.—: To provide a brief update of the World Health Organization classification; the clinical, histopathologic, immunohistochemical, and molecular characteristics; and the differential diagnoses and biological behavior of PanNENs.

Data sources.—: Analysis of the pertinent literature (PubMed) and authors' clinical practice experience based on institutional and consultation materials.

Conclusions.—: The evolving clinical, histopathologic, immunohistochemical, and molecular features of PanNENs are reviewed. Important differential diagnoses with other neoplasms of the pancreas are discussed.

Figure 1.

Well-differentiated low-grade pancreatic neuroendocrine tumors (PanNETs), macroscopic: solitary tumors that are well circumscribed and range in color from pink-red to tan-brown. A, Most tumors are solid. B, A small fraction can have cystic degeneration and hemorrhage. These 2 tumors were microscopically consistent with grade 2 PanNETs.

Figure 2.

Low-grade well-differentiated pancreatic neuroendocrine tumors (PanNETs). A, Grade 1 PanNET: small cells with finely granular cytoplasm and classic salt-and-pepper chromatin, arranged in a trabecular pattern. C, Grade 2 PanNET. B and D, Ki-67 less than 3% and 3% to 20% classifies these PanNETs into grades 1 and 2, respectively (hematoxylin-eosin, original magnification ×200 [A and C]; original magnification ×100 [B and D]).

Figure 3.

Clear cell variant of pancreatic neuroendocrine tumors (PanNETs). A, Small cells with clear, multivacuolated cytoplasm. Salt-and-pepper chromatin may be difficult to appreciate. B, Strong, diffuse synaptophysin staining supports neuroendocrine differentiation. C, Low Ki-67 less than 3% supports PanNET grade 1 (hematoxylin-eosin, original magnification ×200 [A]; original magnification ×200 [B and C]).

Figure 4.

Morphologic resemblance among high-grade pancreatic neuroendocrine neoplasms. A through C, Well-differentiated pancreatic neuroendocrine tumor (PanNET), grade 3. B, Ki-67 more than 20% classifies this PanNET into grade 3. D, Poorly differentiated pancreatic neuroendocrine carcinoma (PanNEC), large cell carcinoma. E, Poorly differentiated PanNEC, small cell carcinoma (hematoxylin-eosin, original magnification ×200 [A, C, D, and E]; original magnification ×100 [B]).

Figure 5.

Morphologic mimickers of pancreatic neuroendocrine neoplasms. A and B, Acinar cell carcinoma: relatively uniform cells forming acinar architecture with granular, eosinophilic cytoplasm. B, Trypsin immunohistochemical stain is strongly positive. C and D, Solid pseudopapillary neoplasm: sheets of polygonal cells with degenerative changes. D, The tumor cells are diffusely positive for nuclear β-catenin (hematoxylin-eosin, original magnification ×100 [A and C]; original magnification ×400 [B and D]).