Re: INSM1 is a novel prognostic neuroendocrine marker for luminal B breast cancer

Abstract

We read with great interest the article by Razvi et al. published in Pathology.1Razvi H. Tsang J.Y. Poon I.K. et al.INSM1 is a novel prognostic neuroendocrine marker for luminal B breast cancer.Pathology. 2021; 53: 170-178Abstract Full Text Full Text PDF Scopus (12) Google Scholar The authors evaluated insulinoma-associated protein 1 (INSM1), a crucial transcription factor with a zinc-finger motif initially isolated from a human insulinoma phagemid cDNA library,2Goto Y. De Silva M.G. Toscani A. et al.A novel human insulinoma-associated cDNA, IA-1, encodes a protein with "zinc-finger" DNA-binding motifs.J Biol Chem. 1992; 267: 15252-15257Abstract Full Text PDF PubMed Google Scholar as a marker for neuroendocrine (NE) differentiation in infiltrating breast cancers (IBCs) in females. They demonstrated the usefulness of INSM1 expression, suggesting a favourable prognostic impact, with better disease-free survival, particularly for the luminal B phenotype, as well as having potential for stratifying NE neoplasms with different outcomes.1Razvi H. Tsang J.Y. Poon I.K. et al.INSM1 is a novel prognostic neuroendocrine marker for luminal B breast cancer.Pathology. 2021; 53: 170-178Abstract Full Text Full Text PDF Scopus (12) Google Scholar On the other hand, recently, we specifically described unusual cases with various NE phenotype mammary carcinomas in which the NE nature of the tumours was confirmed solely by INSM1, without expressions of traditional ‘gold-standard’ NE indicators, chromogranin (CG) A and synaptophysin (SYN).3Kawasaki T. Kaira K. Insulinoma-associated protein 1 (INSM1) expression in breast carcinomas with neuroendocrine morphologies: application and future prospective.Virchows Arch. 2020; Oct 6; https://doi.org/10.1007/s00428-020-02935-0Crossref Scopus (9) Google Scholar We also emphasised that the frequency of detecting NE differentiation in systemic neoplasms is anticipated to increase and that our observations might ultimately contribute to the development of novel treatments including molecular-targeted therapies for these frequently aggressive tumour entities.3Kawasaki T. Kaira K. Insulinoma-associated protein 1 (INSM1) expression in breast carcinomas with neuroendocrine morphologies: application and future prospective.Virchows Arch. 2020; Oct 6; https://doi.org/10.1007/s00428-020-02935-0Crossref Scopus (9) Google Scholar Herein, we ask, in the academic research conducted by Razvi et al., what were the actual number and proportion of IBCs showing INSM1+/CG–/SYN– and whether cases with these immuno-profiles consistently had NE morphologies, i.e., solid and/or trabecular growth pattern, a peripheral palisading arrangement, polygonal, spindle or plasmacytoid cell appearance, finely granular, eosinophilic cytoplasm, ‘salt-and-pepper’ nuclear chromatins, and a highly vascular stroma, as in our reported cases.3Kawasaki T. Kaira K. Insulinoma-associated protein 1 (INSM1) expression in breast carcinomas with neuroendocrine morphologies: application and future prospective.Virchows Arch. 2020; Oct 6; https://doi.org/10.1007/s00428-020-02935-0Crossref Scopus (9) Google Scholar,4Kawasaki T. Inoue A. Mochizuki K. et al.Neuroendocrine ductal carcinoma in situ, comedo type, of the breast detected by screening mammography: a potentially pre-invasive counterpart of high grade neuroendocrine tumours.Pathology. 2012; 44: 273-275Abstract Full Text PDF PubMed Scopus (3) Google Scholar In fact, in the histological figure presented by the authors, an IBC with distinct INSM1 expression characteristically shows a nested formation of polygonal or focally fusiform cancer cells, with relatively abundant, eosinophilic to clear, fine-granular cytoplasm and a finely granular chromatin pattern, although the expression status of CG and SYN in this case is not shown.1Razvi H. Tsang J.Y. Poon I.K. et al.INSM1 is a novel prognostic neuroendocrine marker for luminal B breast cancer.Pathology. 2021; 53: 170-178Abstract Full Text Full Text PDF Scopus (12) Google Scholar Accordingly, the nature and significance of INSM1 as a representative diagnostic marker as well as an innovative research tool warrant greater emphasis. In addition, Razvi et al. clarified INSM1+, CG+ and/or SYN+ IBCs to be relevant to luminal subtypes, showing both ER (p<0.001 for all) and PR (p≤0.015) positive status, while being negative for HER2 (p≤0.044) and high molecular weight cytokeratins (CKs) (p≤0.047), whereas CD56 (neural cell adhesion molecule, NCAM) reactive cases showed contrasting clinicopathological features.1Razvi H. Tsang J.Y. Poon I.K. et al.INSM1 is a novel prognostic neuroendocrine marker for luminal B breast cancer.Pathology. 2021; 53: 170-178Abstract Full Text Full Text PDF Scopus (12) Google Scholar The only positive correlation was actually with CK14 (p<0.001), and there were no relationships with ER, PR, HER2, CK5/6, or survival in luminal cancers.1Razvi H. Tsang J.Y. Poon I.K. et al.INSM1 is a novel prognostic neuroendocrine marker for luminal B breast cancer.Pathology. 2021; 53: 170-178Abstract Full Text Full Text PDF Scopus (12) Google Scholar It is well known that NCAM is generally used as an additional or supplementary NE indicator, except in specific circumstances such as the diagnosis of small cell pulmonary carcinoma.5Kawasaki T. Bussolati G. Castellano I. et al.Small-cell carcinoma of the breast with squamous differentiation.Histopathology. 2013; 63: 739-741PubMed Google Scholar We recently demonstrated that in the breast oncology field, NCAM is a considerably less sensitive and less specific NE marker than previously assumed, because its expression is commonly found in the epithelial cells comprising normal mammary ducts and lobules which are essentially devoid of NE cells.6Kawasaki T. Kondo T. Nakazawa T. et al.Is CD56 a specific and reliable neuroendocrine marker for discriminating between endocrine/neuroendocrine ductal carcinoma in situ and intraductal papilloma of the breast?.Pathol Int. 2011; 61: 49-51Crossref PubMed Scopus (10) Google Scholar We would also like to know the morphological findings of IBCs showing CD56 (NCAM) reactivity, especially those expressing this antibody exclusively, if possible, along with discussion of the implications and the potential utility.