Primary pancreatic PD-NECs are extremely rare and must be distinguished from metastatic PD-NECs from another organ or direct invasion from a contiguous site, particularly the ampulla of Vater [21] or stomach. When there is a single mass in the pancreas and, after critical evaluation, no convincing clinical, radiographic, or pathologic evidence of a lung primary (or another site), then pancreatic origin is reasonable. It should be kept in mind that TTF1 immunohistochemical staining is not helpful, as small cell carcinomas from both pulmonary and a variety of extrapulmonary sites are TTF1 positive. Clinical information and a history of a previous carcinoma are especially important in the accurate diagnosis of such cases.

Pancreatic well-differentiated NETs can show significant nuclear pleomorphism or small cell change (high nuclear/cytoplasmic ratio resembling small cell carcinoma) [22], and features such as a markedly infiltrative growth pattern and necrosis can also be identified [6]. On casual examination, these findings falsely suggest a PD-NEC. If thorough mitotic counting as well as immunolabeling for Ki-67 are not performed, misclassification can occur, which can have therapeutic consequences [2, 23]. A recent landmark study has shown that not all patients with a grade 3 NEC defined based on WHO 2010 criteria benefit from the platinum-based chemotherapy typically used for PD-NECs. In this study, grade 3 tumors with a Ki-67 index <55 % were less responsive than grade 3 NECs with a Ki-67 index ≥55 %, although the latter group experienced early recurrence of shorter ultimate survival than the group with a Ki-67 in the 20–55 % range [2], supporting the concept that the 2010 WHO grade 3 category is heterogeneous, and the tumors at the lower end of the grade 3 range are in fact well-differentiated NETs with an elevated proliferation rate. These well-differentiated NETs typically have a Ki-67 index around 40 %, whereas PD-NECs’ Ki-67 index is about 70 % [3, 4]. Also, a recent study has shown that most pancreatic PD-NECs abnormally immunolabel for p53 (nuclear expression) and Rb (loss of expression) in 95 % and 74 % of cases, respectively. In that study, the abnormal expression of these proteins correlated with intragenic mutations in the TP53 and retinoblastoma genes coding for these proteins. By contrast, immunohistochemical studies only detect rare p53 abnormalities and Rb immunolabeling is intact in pancreatic well-differentiated NETs [5, 24]. In addition, approximately 45 % of sporadic pancreatic well-differentiated NETs show mutually exclusive loss of expression of DAXX (death-domain-associated protein) or ATRX (α-thalassemia/mental retardation syndrome X-linked) immunohistochemical stains, which correlates with mutations in the DAXX and ATRX genes [5, 25] (see Molecular Pathology section for more details).