Human epidermal growth factor receptor HER neu also known as
Human epidermal growth factor receptor 2 (HER2/neu, also known as CerbB-2, or ERBB-2) is a proto-oncogene located on chromosome 17q21, which encodes a transmembrane protein with tyrosine kinase activity, and belongs to the HER receptor family (EGFR, named also HER1, HER3, and HER4) . HER2 is involved in signal transduction pathways, leading to cell growth and differentiation, as well as anti-apoptotic activity. HER2 amplification/overexpression is a reliable tumor predictive marker in breast and gastroesophageal cancer (in the latter being much more common for the intestinal subtype) and HER2-targeted therapy has remarkably improved the overall survival of patients with HER2-positive tumors [7,8]. HER2 status has been found amplified with different frequency in adenocarcinomas of various sites . In colorectal cancer (CRC) HER2 overexpression has been reported with rates of positivity from 2% to 11% . In ITACs, the results are contradictory [, , , ], thus deserve further investigation. Indeed, the detection of HER2 amplification/overexpression in ITACs could disclose the possible use of anti-HER2 therapy.
Materials and methods
Discussion The present is one of the largest studies of sinonasal ITACs tested for HER2 status. The main result of the study is the absence of HER2 overexpression/amplification in all cases. Unlike other cancers, ITACs have few treatment options and evidence of specific targeted therapy in their management is scarce . These tumors are rare and only a few studies have investigated a relevant number of cases. Morphological and some genetic similarities between sinonasal ITAC and CRC suggested the lp-pla2 inhibitor that analogous oncogenes, such as HER2, could be involved in the pathogenesis of both malignancies [11,28]. Contrasting results are available from the literature, with occasional ITACs reported to harbor HER2 overexpression/amplification [, , ]. Several factors may account for these differences, including the small sample size of the available series, the potential effect of preanalytical variables (such as cold ischemia, fixation duration, or decalcification), differences of methods (immunohistochemistry or in situ hybridization), different clones of antibodies used for IHC, lack of tumor-specific criteria for IHC interpretation and diverse scoring system, and analysis of subgroup of patients with heterogeneous clinico-pathologic characteristics. Gallo and Vivanco-Allende immunohistochemically documented HER2 overexpression (along with some prognostic implications) respectively in 9 out of 28  and in 5 out of 66 ITAC  cases. However, the definition of the HER2 assessment method used was somewhat ambiguous and the results obtained at the protein level were not supported by an analysis at the genetic level, which is the gold standard in other better-defined settings, namely breast and gastroesophageal cancer. Thus, the HER2 positive cases reported by these authors could not be determined by a gene amplification. Moreover, these studies did not discuss the eventual decalcification of the specimens and their cold ischemic time, which could be source of variability. Bashir and colleagues, instead, reported a strong diffuse membrane HER2 immunoreaction (without stating if observed in more than 10% of cells) in 4 out of 11 cases of sinonasal primary non-salivary gland adenocarcinomas (2 intestinal type and 2 solid type cases). This finding was sustained by the detection of HER2 amplification using CISH only in one solid type tumor . Another solid type adenocarcinoma resulted HER2 amplified, but with a 0 immunohistochemical score . Of note, none of the amplified samples reported expressed CK20, more specific than CDX2 in the identification of ITAC , and CDX2 was not performed. These cases would be more appropriately classified as non-intestinal-type adenocarcinoma than ITAC [13,16]. Of the 2 intestinal type tumors with HER2 overexpression only one was CK20 positive. In the present series, 4 samples of solid type ITAC were tested and all were scored 0 with IHC and lacked HER2 amplification with CISH.