The Clinical Significance of Neuroendocrine Features in Invasive Breast Carcinomas

Abstract

The latest World Health Organization (WHO) classification categorized invasive breast carcinomas (IBCs) with neuroendocrine (NE) differentiations into neuroendocrine neoplasms (including well‐differentiated neuroendocrine tumor [NET] and poorly differentiated neuroendocrine carcinoma [NEC]) and IBC no special type with NE features (IBC‐NST‐NE). However, little is documented of the clinical significance of this classification; also the precise thresholds and choices of NE markers were variable. In the current study, a large cohort of patients with IBC with NE differentiation were morphologically classified based on the WHO criteria and the clinical relevance of expression of different NE markers (synaptophysin [SYN], chromogranin [CG], and CD56) was evaluated. Among 1,372 IBCs, 52 NET (3.8%) and 172 IBC‐NST‐NE (12.5%) were identified. Compared with the IBC–no NE cases, NET and IBC‐NST‐NE were similarly associated with positive estrogen receptor (ER) expression and lower grade (p < .001). For patient outcome, IBC‐NST‐NE, but not NET, demonstrated significantly worse survival than the IBC–no NE cases. Based on high (≥50%) and low (<50%) expression for each NE marker, independent poor disease‐free survival for SYNloCGlo and SYNhiCGlo cancers (IBC–no NE cases as references, hazard ratio [HR], ≤1.429; p ≤ .026) was found. Interestingly, SYN and CG expression correlated with each other and they shared similar clinicopathologic characteristics; but not with with CD56. In addition, CD56‐only positive cases were associated with hormone receptors negativity and basal markers positivity (p ≤ .019), and patients’ outcome was similar to IBC–no NE cancers. Our findings suggested that NE markers expression may provide information to fine tune treatment strategy. The relevance of CD56 as NE marker requires further studies. Implications for Practice Invasive breast carcinomas (IBCs) with neuroendocrine (NE) differentiation are heterogeneous in clinicopathologic parameters, biomarker expression, and prognosis. However, there are no specific therapies targeting NE differentiation, and all carcinomas with any NE differentiation are treated similarly as other IBCs. The results of this study suggest that stratification based on NE marker expression levels may provide added prognostically pertinent information, aiding better treatment strategy. In addition, CD56‐only positive carcinomas showed a different clinicopathologic and biomarker expression profile compared with those with chromogranin and synaptophysin expression. Relevance of CD56 as an NE marker requires further studies.

Primary Neuroendocrine Neoplasms of the Breast: Still Open Issues

“…On the other side, a low level of expression of neuroendocrine markers was correlated with more aggressive clinical parameters, such as higher histological grade and pathological T and N stages. These results are suggestive of a better prognosis of invasive breast cancer with neuroendocrine features compared to their non-neuroendocrine counterparts ( 48 ). These data were confirmed in a prospective observational study performed on a cohort of 35 patients with BNEN reporting a lower recurrence rate in breast cancers with an expression of neuroendocrine markers >50% compared to those with focal expression ( 49 ).…”

“…Furthermore, the study from Lai et al. provides an interesting food for thought, demonstrating a different behavior of CD56-only positive carcinomas compared to those expressing chromogranin and synaptophysin ( 48 ). In 2017, Rosen et al.…”

“…These findings provide a stratification based on neuroendocrine markers expression and may be helpful for detecting better treatment strategies, since all invasive breast carcinomas are currently treated according to non-endocrine tumor components guidelines. Furthermore, the study from Lai et al provides an interesting food for thought, demonstrating a different behavior of CD56-only positive carcinomas compared to those expressing chromogranin and synaptophysin (48). In 2017, Rosen et al demonstrated a longer overall survival (OS) and disease-free survival (DFS) in patients with BNEN treated with endocrine therapy/radiation therapy rather than chemotherapy, compared to those who did not receive treatment (45).…”

Transcriptomics and Prognosis Analysis to Identify Critical Biomarkers in Invasive Breast Carcinoma

“…Invasive breast cancer is the most common malignancy in females and seriously threatens physical and mental health. [25][26][27] In recent years, bioinformatics analysis has been widely used in cancer research. [28][29][30] This kind of research using a public database containing many samples provides an excellent way to identify tumor biomarkers.…”

Neuroendocrine Neoplasms of the Breast: The Latest WHO Classification and Review of the Literature

“…However, there is no clear evidence to suggest that NETs of the breast carry a better prognosis than IBC-NST. A recent study of 1372 invasive breast cancers, which included 52 (3.8%) NETs, showed similar survival data between the NETs and invasive breast cancers without neuroendocrine features [ 82 ]. On the other hand, a recent SEER database analysis of 239 NETs and 491,908 of invasive ductal carcinomas of NST as defined according to the WHO 2019 classification revealed five-year disease-specific survival rates of 63.39% and 89.17%, respectively [ 80 ].…”