Mixed Adenoneuroendocrine Carcinomas (MANECs) of the Gastrointestinal Tract: An Update

Abstract

The systematic application of immunohistochemical techniques to the study of tumors has led to the recognition that neuroendocrine cells occur rather frequently in exocrine neoplasms of the gut. It is now well known that there is a wide spectrum of combinations of exocrine and neuroendocrine components, ranging from adenomas or carcinomas with interspersed neuroendocrine cells at one extreme to classical neuroendocrine tumors with a focal exocrine component at the other. In addition, both exocrine and neuroendocrine components can have different morphological features ranging, for the former, from adenomas to adenocarcinomas with different degrees of differentiation and, for the latter, from well differentiated to poorly differentiated neuroendocrine tumors. However, although this range of combinations of neuroendocrine and exocrine components is frequently observed in routine practice, mixed exocrine-neuroendocrine carcinomas, now renamed as mixed adenoneuroendocrine carcinomas (MANECs), are rare; these are, by definition, neoplasms in which each component represents at least 30% of the lesion. Gastrointestinal MANECs can be stratified in different prognostic categories according to the grade of malignancy of each component. The present paper is an overview of the main clinicopathological, morphological, immunohistochemical and molecular features of this specific rare tumor type.

Figure 1

Schematic representation showing the wide spectrum of combinations of exocrine and neuroendocrine components in human tumors, ranging from neuroendocrine neoplasms with a focal exocrine component at one extreme (left) to exocrine carcinomas with interspersed neuroendocrine cells at the other (right). However, mixed exocrine-neuroendocrine tumors (middle) are only those neoplasms in which each component represents at least 30% of the lesion. NE: neuroendocrine; tum.: tumor; ca.: carcinoma (modified from Volante et al. [6]).

Figure 2

Ano-rectal NEC showing a focal squamous differentiation characterized by groups of squamous cells with eosinophilic cytoplasm.

Figure 3

An adenocarcinoma showing scattered neuroendocrine cells, demonstrated using anti-chromogranin A antibody, cannot be classified as a MANEC.

Figure 4

(A) is an example of a colonic high grade MANEC composed of an adenoma (right) and of a small-intermediate cell NEC invading the bowel wall (left). The small-intermediate cell NEC is composed of atypical small cells with scarce cytoplasm and hyperchromic nuclei lacking nucleoli. High mitotic index is observed (B).

Figure 5

The exocrine component of high grade MANECs can be represented by tubular adenocarcinoma (A) or adenocarcinoma with obvious mucin secretion (C). The neuroendocrine component can be represented by a large cell NEC showing large cells with abundant eosinophilic cytoplasm and nuclei with dispersed chromatin showing evident nucleoli (B). Adenocarcinomas with obvious mucin secretion showing abundant mucinous deposits stained with the alcian blue-PAS staining (D).

Figure 6

The neuroendocrine component of high grade MANECs generally shows p53 nuclear immunoreactivity (A). In addition, CDX2 (B) and TTF1 (C) nuclear positivity can be also demonstrated in neoplastic cells. CD117 immunoreactivity can be observed in some cases and its expression has been recently demonstrated to be associated with worse patient outcome in colorectal MANECs (D).

Figure 7

Patients with gastric MANECs show a better survival than patients with gastric NECs in our series.

Figure 8

The intermediate grade MANEC category includes mixed adenocarcinomas-NETs which are formed by areas of adenocarcinoma and areas of grade 1 or 2 NET. In (A) the tubular adenocarcinoma component is evident on the left, while the NET showing a trabecular pattern of growth is observed on the right. The neuroendocrine component is immunoreactive for synaptophysin (B) and is characterized by well differentiated neuroendocrine cells without significant atypia growing in trabecular structures (C) negative for Ki67, which is conversely well expressed in the adenocarcinomatous areas (D).

Figure 9

On the left, there is a slide with lymph nodes isolated in the perirectal fat tissues of the tumor shown in Figure 7. In one lymph node there was a metastasis from the NET component (A) which shows very low Ki67 index (B). In another lymph node the metastasis was from the adenocarcinoma (C) which shows a high Ki67 proliferative index (D).

Figure 10

Mixed poorly cohesive carcinoma-NET is a combined neoplasm composed of noncohesive signet ring cells diffusely admixed with neuroendocrine cells (A), which are easily detectable using chromogranin A antibody (B).

Figure 11

Adenoma-neuroendocrine tumor is a very rare neoplastic lesion containing both an adenomatous (top) and a NET (central portion) component (A and B, lower and higher magnification, respectively). The NET component is positive for Grimelius’s silver stain (C) and Chromogranin A (D).