Mixed Exocrine-Neuroendocrine Carcinoma of the Nasal Cavity: Clinico-Pathologic and Molecular Study of a Case and Review of the Literature

Abstract

Sinonasal intestinal-type adenocarcinomas (ITACs) are rare neoplasms histologically resembling intestinal adenocarcinomas. Although a neuroendocrine differentiation in ITACs has been described, true mixed exocrine-neuroendocrine carcinomas, neoplasms in which each component represents at least 30 % of the lesion, are extremely rare and their molecular alterations are largely unknown. We describe herein the clinico-pathologic features, the methylation profile, chromosomal gains and losses, and mutation analysis of KRAS, BRAF and p53 in a nasal mixed exocrine-neuroendocrine carcinoma resected in a 79-year-old man. The tumor was composed of an ITAC and a poorly differentiated neuroendocrine carcinoma. Both exocrine and neuroendocrine components were CK8, CK20, CDX2 and p53 positive, and CK7 and TTF1 negative. The neuroendocrine component also showed immunoreactivity for chromogranin A, synaptophysin, serotonin and glicentin. Gains and losses were found at following chromosome regions: 17p13 (TP53), 14q24 (MLH3), 19q13 (KLK3), 5q21 (APC), 7q21 (CDK6), 9q34 (DAPK1), 12p13 (TNFRSF 1A, CDKN1B), 13q12 (BRCA2), 17p13.3 (HIC1), 18q21 (BCL2), and 22q12 (TIMP3). Aberrant methylation was detected only in the neuroendocrine component and involved APC and DAPK1 genes. No mutation of KRAS (exons 2-4), BRAF (exon 15), and p53 (exons 4-10) was found in both components. The results suggest a monoclonal origin of the tumor from a pluripotent cell undergoing a biphenotypic differentiation and that the neuroendocrine differentiation may be from an exocrine to an endocrine pathway. We have also reviewed the literature on sinonasal mixed exocrine-neuroendocrine carcinomas to give to the reader a comprehensive overview of these very rare tumor types.

Lymphatic endothelial cancerization in papillary thyroid carcinoma: Hidden evidence of lymphatic invasion

“…In addition to lung and thyroid normal and neoplastic counterparts, TTF1 nuclear reactivity has been observed in various neuroendocrine neoplasms, and in low frequency in tumors from other sites such as GI tract, prostate and ovary. Reactivity to TTF1 in lymphatic and vascular endothelia has not been observed [27][28][29][30] In this study, the cystic spaces were round to flat or slit-like with branching and anastomosis with adjacent cysts. We demonstrate focal membranous reactivity for D2-40 in scattered cyst lining cells.…”

“…In addition to lung and thyroid normal and neoplastic counterparts, TTF1 nuclear reactivity has been observed in various neuroendocrine neoplasms, and in low frequency in tumors from other sites such as GI tract, prostate and ovary. Reactivity to TTF1 in lymphatic and vascular endothelia has not been observed…”

Primary Combined Neuroendocrine and Squamous Cell Carcinoma of the Maxillary Sinus: Report of a Case with Immunohistochemical and Molecular Characterization

“…Similarly, a prostatic combined small cell carcinoma and adenocarcinoma showed an identical mutation in the DNA binding domain of TP53 in both components, although the acinar component apparently retained a wild-type allele while the small cell component showed a homozygous mutant form, which could be interpreted as a stepwise progression to the neuroendocrine phenotype [17]. In a nasal mixed exocrine-neuroendocrine carcinoma with histological features of an intestinal type adenocarcinoma and a poorly differentiated neuroendocrine carcinoma, the two components showed strong genetic relationships, although TP53 mutation was not detected in either neoplastic component [4]. These findings supported the hypothesis of a monoclonal origin of the tumor, with biphenotypic differentiation likely occurring during tumor progression [4].…”

“…Here, they represented approximately 10 % of all neuroendocrine carcinomas and consisted of a combination of squamous cell and small cell carcinoma or atypical carcinoid [2,3]. In the few cases reported in the sinonasal tract, the neuroendocrine carcinoma was more frequently combined with an adenocarcinoma not otherwise specified or with intestinal type adenocarcinoma, while inverted papilloma was associated in one instance [4], and squamous cell carcinoma in two instances [5,6]. The present case consisted of a combination of well-differentiated squamous cell carcinoma and large cell neuroendocrine carcinoma.…”

“…In the head and neck region, these tumors occur more frequently in the larynx, where they represent approximately 10 % of all neuroendocrine carcinomas [2,3]. In the sinonasal tract only few examples have been reported, which consisted mostly of a combination of adenocarcinoma and neuroendocrine carcinoma [4], while cases of combined small cell and squamous cell carcinoma seem to be exceedingly rare [5,6].…”