Syntaxin-1 and Insulinoma-Associated Protein 1 Expression in Breast Neoplasms with Neuroendocrine Features

Abstract

Introduction: A subset of breast neoplasia is characterized by features of neuroendocrine differentiation. Positivity for Neuroendocrine markers by immunohistochemistry is required for the diagnosis. Sensitivity and specificity of currently used markers are limited; based on the definitions of WHO Classification of Tumours, 5th edition, about 50% of breast tumors with features of neuroendocrine differentiation express chromogranin-A and 16% express synaptophysin. We assessed the applicability of two novel markers, syntaxin-1 and insulinoma-associated protein 1 (INSM1) in breast carcinomas.Methods: Hypercellular (Type B) mucinous carcinomas, solid papillary carcinomas, invasive carcinomas of no special type with neuroendocrine features and ductal carcinomas in situ of neuroendocrine subtype were included in our study. The immunohistochemical panel included chromogranin A, synaptophysin, CD56, syntaxin-1 and INSM1. The specificity of syntaxin-1 and INSM1 was determined using samples negative for chromogranin A, synaptophysin and CD56.Results: The sensitivity of syntaxin-1 was 84.7% (50/59), with diffuse positivity in more than 60% of the cases. Syntaxin-1 also had an excellent specificity (98.1%). Depending on the definition for positivity, the sensitivity of INSM1 was 89.8% (53/59) or 86.4% (51/59), its specificity being 57.4% or 88.9%. The sensitivities of chromogranin A, synaptophysin and CD56 were 98.3, 74.6 and 22.4%, respectively.Discussion: Syntaxin-1 and INSM1 are sensitive and specific markers of breast tumors with neuroendocrine features, outperforming chromogranin A and CD56. We recommend syntaxin-1 and INSM1 to be included in the routine neuroendocrine immunohistochemical panel.

Reply to Kawasaki et al Regarding “Nuclear Insulinoma-Associated Protein 1 Expression as a Marker of Neuroendocrine Differentiation in Neoplasms of the Breast”

“…Others adopted a 1% cut-point. 6 Additional studies are required to explore which cut-point is clinically and biologically meaningful, especially since Razvi et al suggested that INSM1 expression in breast tumors is associated with a more favorable outcome. 7 We agree with Kawasaki et al that any breast lesion harboring the aforementioned "classic" morphological features suggestive of neuroendocrine differentiation should provoke a more detailed work-up by means of immunohistochemistry for synaptophysin, chromogranin A and INSM1, as these stains might aid to establish a final diagnosis.…”

“…Others adopted a 1% cut-point. 6 Additional studies are required to explore which cut-point is clinically and biologically meaningful, especially since Razvi et al suggested that INSM1 expression in breast tumors is associated with a more favorable outcome. 7…”