Original contributionAchaete-scute homolog 1 as a marker of poorly differentiated neuroendocrine carcinomas of different sites: a validation study using immunohistochemistry and quantitative real-time polymerase chain reaction on 335 cases☆
Introduction
High-grade poorly differentiated neuroendocrine carcinomas that, according to the 2010 World Health Organization (WHO) classification, are simply labeled neuroendocrine carcinomas (NECs) [1] and can arise at different sites including lung, gastrointestinal tract, urogenital system, and skin. They show typical histologic and immunohistochemical features and high proliferative activity. NECs can be composed of small to intermediate or large cells growing in poorly formed trabeculae, nests, or sheets but more commonly with diffuse patterns, with more or less extensive areas of necrosis. The small cell variant is characterized by small- to medium-sized cells with markedly hyperchromatic round to oval nuclei, inconspicuous nucleoli, a high nuclear/cytoplasmic ratio, and poorly defined cytoplasmic borders. The large cell subtype shows a proliferation of large cells with vesicular nuclei, prominent nucleoli, and abundant finely granular eosinophilic cytoplasm. In addition to these 2 main categories, neoplasms composed of cells showing intermediate features (intermediate cell type) can be observed. Tumor cells express general neuroendocrine markers, such as synaptophysin, neuron-specific enolase, CD56, and chromogranin A and, more rarely, hormone peptides [1], [2]. The above-described morphological and immunohistochemical features overlap among NECs irrespective of their site of origin, making impossible the identification of the primary site when they are first diagnosed as metastases of unknown origin. In recent years, several attempts have been made to solve this problem, but the identification of site-specific markers still remains a matter of study.
It is generally easy to distinguish between NECs and well- to moderately differentiated neuroendocrine tumors (NETs) in surgical material on morphological grounds, considering nuclear atypia, mitotic count, and Ki-67 proliferative index. Particularly, in NECs, mitotic count and Ki-67 proliferative index are by definition more than 20 per 10 high-power fields and 20%, respectively. However, when using small biopsy specimens, this distinction may be problematic due to frequent crush artifacts and the small number of neoplastic cells.
Achaete-scute homolog 1 (ASH1), termed mASH1 in rodents and hASH1 in humans, is a transcription factor belonging to the basic helix-loop-helix family. It plays a crucial role in neural/neuroendocrine determination and differentiation and is known to be involved in the development of neuroendocrine cells of the thyroid, adrenal medulla, and foregut [3], [4], [5], [6]. Expression of ASH1 has been demonstrated in NECs of the lung [7], [8], but its role as a site-specific diagnostic marker is not clear because ASH1 expression has been reported in NECs of other organs, including gastrointestinal tract and prostate [9], [10], [11]. By contrast, ASH1 expression in NETs is not fully understood, so its usefulness in the differential diagnosis between NECs and NETs needs to be verified. For these reasons, we have investigated the expression of ASH1 in a large series of neuroendocrine neoplasms of different sites, and we have reviewed the literature on this topic to provide an overview of the research on the distribution of ASH1 and its possible utility as a diagnostic marker. The 2 main aims of the present study were to evaluate the usefulness of ASH1 expression to differentiate NECs from NETs and to check its utility as a marker of lung origin.
Section snippets
Cases
Tumors of 335 patients (194 NECs and 141 NETs) were retrieved from the files of the Department of Pathology of the Ospedale di Circolo in Varese and of the San Luigi Hospital in Orbassano, Turin. The 194 NECs included 34 lung, 12 head and neck, 83 digestive (8 esophageal, 18 gastric, 12 pancreas/biliary tract, and 45 intestinal), 42 urogenital (15 prostatic, 19 of the urinary bladder, 2 renal, and 6 uterine), and 23 skin (Merkel cell carcinoma) cases. The 141 NETs comprised 107 lung (84 typical
Immunohistochemical findings
The main clinicopathologic data and the immunohistochemical results in NECs are summarized in Table 1. We observed some differences between the 2 anti-ASH1 antibodies used. Using the MAb-ASH1 antibody, 93 (48%) of 194 NECs were positive, whereas a higher percentage (51%) of cases resulted immunoreactive with the poly-ASH1. Most NECs positive for the MAb-ASH1 antibody (72%) showed a 2+ score, whereas only 10% of poly-ASH1–positive NECs presented a 2+ score. Interestingly, among lung NECs, 82%
Discussion
In the present article, we have investigated the expression of ASH1 in a large series of neuroendocrine neoplasms of different sites to check its usefulness as a diagnostic marker. In particular, one of the aims of the present study was to check whether ASH1 could be considered as a marker of NECs and, more specifically, whether it could be used as a marker of lung origin. The need to search for site-specific markers for NECs derives from the fact that these high-grade cancers show overlapping
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2020, Annals of Diagnostic PathologyCitation Excerpt :ASH1 is a useful marker for cancers with neuroendocrine features, as it has been documented as a key player in modulating neuroendocrine differentiation in tumor cells [34]. ASH1 expression levels are inversely associated with the degree of tumor differentiation (high-grade tumors show increased expression of protein), which correlates well with studies indicating that expression of ASH1 appears to be restricted to immature cells [32-34,37]. Prior work from our group [35] showed expression of MASH1 in high-grade neuroendocrine tumors (SmCNECs, LCNECs, and high-grade ONBs), with absent or modest levels in well-differentiated counterparts (low-grade olfactory neuroblastoma and carcinoids).
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Conflict of interest: The authors declare no conflict of interest.