Defining triple-negative breast cancer with neuroendocrine differentiation (TNBC-NED)

Q: What defines TNBC-NED in this study?

TNBC-NED refers to triple-negative breast cancers showing neuroendocrine differentiation with positivity for one or more NE markers, including synaptophysin, chromogranin, and INSM1.

Q: How were p53 and Rb status assessed?

p53 aberrant staining was evaluated by immunohistochemistry and is described as correlating with TP53 gene mutation, while Rb protein loss was also determined by immunohistochemistry.

Q: What molecular relationship did transcriptomic analysis reveal?

In TCGA PanCancer Atlas data for basal/TNBC patients, transcriptomic analysis showed RB1 mRNA expression correlated negatively with SYN1 mRNA and INSM1 mRNA in the cohort.

Sep 24, 2026

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Primary breast neuroendocrine (NE) neoplasms are rare, and diagnostic definitions remain controversial. This retrospective study evaluated 73 triple-negative breast cancers (TNBC) for NE biomarker expression and for p53 aberrant staining (linked to TP53 mutation) plus Rb protein loss by immunohistochemistry. Eleven cases (15%) showed neuroendocrine differentiation (TNBC-NED) with NE marker positivity (synaptophysin/chromogranin/INSM1), and a separate small cell NE carcinoma was identified.

LanguageEnglish

CategoryHealthcare

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Pages9

Reading Time23 min

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Abstract

Introduction

The Journal of Pathology: Clinical Research J Pathol Clin Res July 2023; 9: 313–321 Published online 20 April 2023 in Wiley Online Library (wi[leyonlinelibrary.com](leyonlinelibrary.com). DOI: 10.1002/cjp2.318)[).](leyonlinelibrary.com). DOI: 10.1002/cjp2.318)[ DOI: 10.1002/cjp2.318](leyonlinelibrary.com). DOI: 10.1002/cjp2.318) ORIGINAL ARTICLE Deﬁning triple-negative breast cancer with neuroendocrine differentiation (TNBC-NED) Sean M Hacking 1,2,3, Evgeny Yakirevich2,3 and Yihong Wang2,3* 1 Laboratory Medicine Program, University Health Network, Toronto General Hospital, Toronto, Canada 2Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Providence, RI, USA 3Department of Pathology and Laboratory Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA *Correspondence to: Yihong Wang, Department of Pathology, Rhode Island Hospital and Lifespan Medical Center, 593 Eddy Street, Providence, RI 02903, USA. E-mail: [yihong_wang@brown.edu](yihong_wang@brown.edu) Abstract Primary breast neuroendocrine (NE) neoplasms are uncommon, and deﬁnitions harbor controversy. We retrospectively collected 73 triple-negative breast cancers (TNBC) and evaluated NE biomarker expression along with p53 aberrant staining (which correlates with TP53 gene mutation) and Rb protein loss by immunohistochemistry. In the study cohort, we found 11 (15%) cases of TNBC with neuroendocrine differentiation (TNBC-NED) showing positivity for one or more NE markers (synaptophysin/chromogranin/insulinoma-associated protein 1 [INSM1]). We also identiﬁed one separate small cell neuroendocrine carcinoma. Histologic types for these 11 TNBC-NED cases were as follows: 8 invasive ductal carcinoma (IDC) not otherwise speciﬁed (NOS), 2 IDC with apocrine features, 1 IDC with solid papillary features. INSM1 had the highest positivity and was seen in all 11 carcinomas. Seven (64%) cases showed p53 aberrant staining, 6 (55%) had Rb protein loss, while 6 (55%) had p53/Rb co-aberrant staining/protein loss. TNBC-NED was associated with Rb protein loss (p < 0.001), as well as p53/Rb co-aberrant staining/protein loss (p < 0.001). In 61 cases negative for NE markers, 37 (61%) showed p53 aberrant staining, while 5 (8%) had Rb protein loss. We also analyzed genomic and transcriptomic data from The Cancer Genome Atlas (TCGA) PanCancer Atlas of 171 basal/TNBC patients. Transcriptomic analysis revealed mRNA expression of RB1 to be correlated negatively with SYN1 mRNA expression (p = 0.0400) and INSM1 mRNA expression (p = 0.0106) in this cohort. We would like to highlight the importance of these ﬁndings. TNBC-NED is currently diagnosed as TNBC, and although it overlaps morphologically with TNBC without NED, the unique p53/Rb signature highlights a genetic overlap with NE carcinomas of the breast. Keywords: breast; neuroendocrine; carcinoma; RB1 ; TP53; TNBC-NED Received 2 January 2023; Revised 3 March 2023; Accepted 7 March 2023 No conﬂicts of interest were declared. Introduction Primary breast carcinoma with neuroendocrine (NE) features is an uncommon tumor that was ﬁrst recognized in the 1960s; argyrophilic tumor cells were ﬁrst recognized in breast mucinous carcinomas from ultrastructural studies by Feyrter and Hartmann [1]. In the decades since, immunohistochemical markers such as chromogranin (CHGA) and synaptophysin (SYN), insulinoma-associated protein 1 (INSM1), neuron-speciﬁc enolase, and CD56 (N-cellular adhesion molecule) have become widely used forthe identiﬁcation of the NE phenotype. An oft-deliberated topic in breast pathology is the identiﬁcation and signiﬁcance of NE differentiation (NED) in primary breast cancer. Compared with other sites such as the lung and gastrointestinal (GI)-pancreatic systems, a cogent taxonomy remains largely elusive. The recently updated World Health Organization classiﬁcation, ﬁfth edition classiﬁes invasive breast carcinomas (IBCs) with NED

FAQs

What defines TNBC-NED in this study?

TNBC-NED refers to triple-negative breast cancers showing neuroendocrine differentiation with positivity for one or more NE markers, including synaptophysin, chromogranin, and INSM1.

How were p53 and Rb status assessed?

p53 aberrant staining was evaluated by immunohistochemistry and is described as correlating with TP53 gene mutation, while Rb protein loss was also determined by immunohistochemistry.

What molecular relationship did transcriptomic analysis reveal?

In TCGA PanCancer Atlas data for basal/TNBC patients, transcriptomic analysis showed RB1 mRNA expression correlated negatively with SYN1 mRNA and INSM1 mRNA in the cohort.

Sep 24, 2026

Uploaded by Ophelia