The correct answer is the 3^rd option (C). This is a mixed adenoneuroendocrine neoplasm, also known as mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN).  MiNENs are heterogeneous groups of epithelial tumors with variable morphologic features and prognosis. Although, some of these neoplasms may behave more indolently, depending on their composition, many subtypes are aggressive (the 1^st option is incorrect). To quality as MiNEN, discrete neuroendocrine and non-neuroendocrine components should be recognizable (by morphology and immunostaining), with an arbitrary cut-off of each component equal or greater than 30% of total tumor.

As reflected in the most recent WHO of digestive system tumors (5^th Edition), MiNEN is a current term for what was previously classified under MANEC (mixed adenoneuroendocrine carcinoma). MiNEN is a conceptual category and more precise diagnoses should be based on site-specific terminologies.  In this regard, examples include: Mixed adenocarcinoma-Neuroendocrine tumor (NET) or Mixed adenocarcinoma-NEC (in stomach or colorectum), Mixed ductal adenocarcinoma-NET or Mixed ductal adenocarcinoma-NEC (in pancreas), Mixed HCC-NEC or Mixed cholangiocarcinoma-NEC (in liver), and Mixed Squamous cell carcinoma-NEC (in anal canal).  The generic term “non-neuroendocrine” has been used in place of “adeno” (in MANEC) to encompass other histological variants such as squamous or sarcomatoid elements (the 5^th option is incorrect).

While neuroendocrine markers would differentially stain the different components of these tumors, pancytokeratin immunostains are not discriminatory in many instances (the 2^nd option is incorrect). Adenomatous components, such as in the present case, can be also positive with mucin stain, Alcian Blue or PASD. Although each tumoral component plays a role, the overall prognosis of MiNENs is mostly derived by the higher-grade component.

The pathogenesis of MiNEN remains controversial. While some investigators theorize that different components of tumor arise from distinct precursor cells, many postulate a common pluripotent progenitor that acquires biphenotypic differentiation during carcinogenesis. Collision tumors, featuring independent neuroendocrine and non-neuroendocrine neoplasms with distinct spatial territories, should not be classified as MiNENs (the 4^th option is incorrect). In contrast, MiNENs are typically characterized by discrete neuroendocrine and epithelial tumor nests that are interspersed amongst each other. Scenarios when only isolated cells have neuroendocrine differentiation do not reach the diagnostic criteria for MiNEN.

References:

De Luca-Johnson J, Zenali M. A Previously Undescribed Presentation of Mixed Adenoneuroendocrine Carcinoma. Case Rep Pathol. 2016;2016:9063634.

Frizziero M, Chakrabarty B, Nagy B, et al. Mixed Neuroendocrine Non-Neuroendocrine Neoplasms: A Systematic Review of a Controversial and Underestimated Diagnosis. J Clin Med. 2020;9(1):273. Published 2020 Jan 19.

WHO Classification of Tumours Editorial Board. WHO Classification of Tumours. 5^th Edition. International Agency for Research on Cancer. Lyon: International Agency for Research on Cancer. 2018; 18-19.

Wu C, Bao W, Rao Q, et al. Clinicopathological features and prognosis of gastric mixed adenoneuroendocrine carcinoma. Int J Clin Exp Pathol. 2018;11(3):1499-1509. Published 2018 Mar 1.