ISL1 expression is not restricted to pancreatic well-differentiated neuroendocrine neoplasms, but is also commonly found in well and poorly differentiated neuroendocrine neoplasms of extrapancreatic origin

Abstract

The human insulin gene enhancer-binding protein islet-1 (ISL1) is a transcription factor involved in the differentiation of the neuroendocrine pancreatic cells. Recent studies identified ISL1 as a marker for pancreatic well-differentiated neuroendocrine neoplasms. However, little is known about ISL1 expression in pancreatic poorly differentiated and in extrapancreatic well and poorly differentiated neuroendocrine neoplasms. We studied the immunohistochemical expression of ISL1 in 124 neuroendocrine neoplasms. Among pancreatic neuroendocrine neoplasms, 12/13 with poor differentiation were negative, whereas 5/7 with good differentiation but a Ki67 420% were positive. In extrapancreatic neuroendocrine neoplasms, strong positivity was found in Merkel cell carcinomas (25/25), pulmonary small cell neuroendocrine carcinomas (21/23), medullary thyroid carcinomas (9/9), paragangliomas/pheochromocytomas (6/6), adrenal neuroblastomas (8/8) and head and neck neuroendocrine carcinomas (4/5), whereas no or only weak staining was recorded in pulmonary carcinoids (3/15), olfactory neuroblastomas (1/4) and basaloid head and neck squamous cell carcinomas (0/15). ISL1 stained the neuroendocrine carcinoma component of 5/8 composite carcinomas and also normal neuroendocrine cells in the thyroid, adrenal medulla, stomach and colorectum. Poorly differentiated neuroendocrine neoplasms, regardless of their ISL1 expression, were usually TP53 positive. Our results show the almost ubiquitous expression of ISL1 in extrapancreatic poorly differentiated neuroendocrine neoplasms and neuroblastic malignancies and its common loss in pancreatic poorly differentiated neuroendocrine neoplasms. These findings modify the role of ISL1 as a marker for pancreatic neuroendocrine neoplasms and suggest that ISL1 has a broader involvement in differentiation and growth of neuroendocrine neoplasms than has so far been assumed. 995 www.modernpathology.org differentiation in mouse experiments. 8 Apart from its role in the cell line development of the endocrine pancreas, ISL1 was found to have a major role as a marker of cardiac progenitor cell lineage. 9 Recently, ISL1 expression was studied in welldifferentiated pancreatic neuroendocrine neoplasms that are labeled by the WHO as neuroendocrine tumors (NETs). 10,11 In these neoplasms, ISL1 proved to be a good marker for pancreatic NETs and their metastases, with a specificity of 78.4-100% and a sensitivity of 74.3-77.8%. [10][11][12] Neuroendocrine carcinomas of pancreatic and extrapancreatic origin so far have not or only occasionally been tested for ISL1 expression. 12-15 Following our own observation of a strong ISL1 reactivity in a case of a widely metastatic small cell neuroendocrine carcinoma of unknown origin, we launched this study with the aim to test the reliability of ISL1 as a marker for distinguishing pancreatic neuroendocrine carcinomas from their extrapancreatic counterparts and mimics. In addition, we also studied some well-differentiated extrapancreatic neuroendocrine neoplasms such as thyroid ...

Embryonic maturation of epidermal Merkel cells is controlled by a redundant transcription factor network

“…Further understanding of the transcriptional regulators of Merkel cell development will be important not only for general understanding of Merkel cell biology, but also for uncovering processes leading to human pathologies, such as reduced tactile sensitivity in patients with diabetes and inflammation or with Merkel cell carcinoma, a highly aggressive form of cancer with no current treatment. Importantly, as both Sox2 and Isl1 have been shown to be upregulated in Merkel cell carcinoma cells, it will be important in the future to explore the contribution of these transcription factors to tumorigenesis (Agaimy et al, 2013;Tilling and Moll, 2012).…”

Expression pattern of ISL-1, TTF-1 and PAX5 in olfactory neuroblastoma

“…In a report regarding ISL-1 expression in a small group of 4 cases of ONB, only 1 case was positive [6]. In our cohort of ONB patients expression of ISL-1 was present in the majority of cases (63.63%).…”

“…Initially expression of ISL-1 was believed to be restricted to neuroendocrine tumors of pancreatic origin. However, recent data show that it can be expressed in the majority of neuroendocrine tumors of extrapancreatic origin, including Merkel cell carcinomas, pulmonary small cell neuroendocrine carcinoma, medullary thyroid carcinomas, paragangliomas/pheochromocytomas, and adrenal neuroblastomas [6].…”

“…Therefore, a continuous search for new markers that broaden differentiation with other neuroendocrine tumors is ongoing. Recent evidence shows that ISL-1, TTF-1 and PAX5 occur in a large percentage of neuroendocrine tumors [5,6,7,8,9]. However, the frequency of their expression and their expression pattern have not been studied in ONB.…”

Pathology: Classification and Immunoprofile

“…While all the above markers are of use in well-differentiated NETs, this is not the case for poorly differentiated NECs [27] . Immunohistochemistry here can be of help in the differential diagnosis between Merkel cell carcinomas and cutaneous metastases of pulmonary NECs: while Merkel cell carcinomas are usually positive for CK20, typically with a dot-like staining pattern, they are normally negative for TTF-1.…”