A 66-year-old man presented with a 14-cm pancreatic mass and multiple metastases involving the liver, omentum and duodenum. Biopsies of the duodenal and omental nodules showed trabeculae of relatively uniform polygonal cells with delicate fibrovascular stroma (Figure 1A, left upper corner, 50×). The tumour cells had moderate eosinophilic cytoplasm, round to oval nuclei with finely granular ‘salt-and-pepper’ chromatin and inconspicuous nucleoli. Despite the bland appearance, mitotic figures were readily identified (Figure 1A). Immunohistochemistry demonstrated diffuse chromogranin expression and a Ki-67 proliferative index of 50%–80%. Based on the histomorphology and neuroendocrine marker expression, a diagnosis of well-differentiated neuroendocrine tumour, grade 3 (WD-NET, G3) was rendered, and the patient was treated with octreotide. Upon review at a second institute, the unusually high Ki-67 index prompted additional immunohistochemical evaluation. Wild-type p53 expression with retained RB1 and ATRX raised concern for acinar cell carcinoma (ACC). Positive trypsin immunostaining supported a revised diagnosis of ACC. Next-generation sequencing identified alterations in CDKN2A, CDKN2B and NRAS, while TP53 and RB1 were intact. Due to the discrepancy in diagnosis between institutes, the case was referred to our institution for consultation. A comprehensive immunohistochemical panel including markers of neuroendocrine and acinar differentiation, demonstrated diffuse chromogranin positivity and strong cytoplasmic BCL10 expression, with negative synaptophysin expression. Importantly, dual neuroendocrine and acinar marker expression was present within the same tumour cells, and the Ki-67 remained high (60%) (Figure 1B). While the overall composition and architectural features fall within the spectrum described in the literature as ‘amphicrine carcinoma’ (a descriptive, non-WHO term), the co-expression of acinar and neuroendocrine markers within the same cells, rather than in morphologically distinct components, supports classification of this tumour within the acinar cell carcinoma family as a mixed acinar carcinoma, rather than as a mixed neuroendocrine–non-neuroendocrine neoplasms (MiNEN), in which the two components are distinct, with each comprising ≥30% of the tumour. This distinction is clinically relevant, as mixed acinar carcinomas are epigenetically and biologically related to pure acinar cell carcinomas.1, 2 This case underscores a diagnostic pitfall stemming from the coexistence of well-differentiated neuroendocrine morphology and unexpectedly high proliferative activity. While cellular monotony, organoid architecture and delicate vasculature favour a well-differentiated neuroendocrine neoplasia, the markedly elevated proliferation is more characteristic of poorly differentiated carcinoma. Mixed acinar carcinomas exemplify this diagnostic challenge, combining deceptively bland cytomorphology with aggressive biological potential. Grade 3 well-differentiated neuroendocrine tumour are characterized by well-differentiated cytology (uniform cells with organoid or trabecular architecture and round- to- oval nuclei) combined with a Ki-67 index exceeding 20% or >20 mitoses per 10 high power fields.3 Ki-67 indices typically range from 20% to 50%; indices >50% are uncommon and raise consideration of poorly differentiated neuroendocrine carcinoma (NEC).4 Unlike NECs, WD-NETs retain well-differentiated morphology despite increased proliferative activity. The key message of this case is that acinar cell carcinoma or the mixed acinar carcinomas must always be considered in the differential diagnosis of highly proliferative pancreatic tumours with neuroendocrine-like morphology, even when neuroendocrine markers are diffusely expressed. The unusually high Ki-67 index (>50%) should have prompted diagnostic reconsideration, as WD-NET G3 typically show Ki-67 indices between 20% and 50%, with values approaching 50% being rare. A comprehensive immunohistochemical workup is essential in such cases, including acinar markers (e.g. trypsin and BCL10) as well as markers useful in the differential diagnosis of pancreatic neuroendocrine neoplasms, such as SSTR2 and ISL1,5, 6 which are typically negative in mixed acinar carcinomas. Misclassifying a tumour as NET G3 can have potentially life-threatening clinical consequences, since these tumours necessitate distinct therapeutic strategies. S.S. contributed to data collection. Q.L. drafted the manuscript, literature review and critical revision of the manuscript. All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work. No funding sources to report. The authors have no conflicts of interest to disclose. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
Sham et al. (Mon,) studied this question.