Intratumoral heterogeneity of HER2 protein and amplification of HER2 gene in salivary duct carcinoma

Abstract

Salivary duct carcinoma (SDC) is an aggressive adenocarcinoma of the salivary glands, and accounts for 1-3% of all malignant salivary gland tumors, resembling morphologically invasive ductal carcinoma (IDC) of the breast. In contrast to IDC of the breast and gastric carcinoma (GC), the study of human epidermal growth factor receptor 2 (HER2) in SDC has not progressed. Therefore, we investigated the relationship between HER2 protein expression and amplification of the HER2 gene, and compared them in terms of intratumoral heterogeneity (ITH) in 13 cases of SDC using immunohistochemistry and dual color in situ hybridization. We found seven cases with protein overexpression (53.8%) and five cases with gene amplification (38.5%) in accordance with ASCO/CAP guidelines. ITH of HER2 protein expression was seen in seven cases (53.8%). Interestingly, the ratio of the HER2 gene showed homogenous distribution with or without the presence of ITH of HER2 protein expression. SDC tends to have more ITH of HER2 protein similarly to GC, in contrast to IDC of the breast. ITH of HER2 protein in SDC has no heterogeneity of the HER2 gene amplification. The mechanism of HER2 protein expression in SDC might proceed through a more complex pathway relative to that of IDC of the breast.

Discordant human epidermal growth factor receptor 2 overexpression in primary and metastatic upper gastrointestinal adenocarcinoma signifies poor prognosis

“…For oesophageal and gastric cancer there is an ongoing quest to understand not only the effect of HER2 overexpression on prognosis and the best method to evaluate overexpression, but also how this is affected by tumour heterogeneity. The results of this quest are, so far, ambiguous …”

Salivary duct carcinoma: An aggressive salivary gland malignancy with opportunities for targeted therapy

“…ErbB2 overexpression is also noted in a large proportion of ductal breast carcinoma and associated with a negative prognosis [28]. ErbB2 expression has been evaluated in dozens of SDC studies by immunohistochemistry and fluorescence in situ hybridization (FISH) (Table 3).…”

“…ErbB2 expression has been evaluated in dozens of SDC studies by immunohistochemistry and fluorescence in situ hybridization (FISH) (Table 3). The percentage of SDC tumors positive for ErbB2 varies widely across studies due to different evaluation and scoring methods, with only a subset of studies using ASCO guidelines for ErbB2 scoring [28]. While proportions of SDC that are positive for ErbB2 by IHC are often quite high, those showing increased expression by FISH or chromogenic in situ hybridization are much lower [23].…”

“…Percentages for each alteration were obtained by totaling the number of positive cases (by IHC or sequencing for ErbB2, EGFR, AR) divided by total cases found in the literature [3, 4, 6, 7, 15, 18, 22, 28, 33, 39, 40, 44, 49–53, 55, 57–64, 67, 86–91]. Percentages representing expression are best estimates, as positivity was defined heterogeneously among studies.…”

“…Interestingly, a high proportion of SDC tumors are found within a benign pleomorphic adenoma; SDC tumors that are also classified as carcinoma ex pleomorphic adenoma may be frequent, with studies reporting evidence of prior pleomorphic adenoma in 20–70% of SDCs [7, 11, 27, 28]. An encapsulated, in situ form of SDC has also been described, characterized by lack of capsular invasion.…”