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Year : 2020  |  Volume : 16  |  Issue : 6  |  Page : 1528-1531

Updates in primary neuroendocrine breast carcinoma – A case report and review of literature

Department of Surgical Oncology, Bombay Hospital and Medical Research Centre, Mumbai, Maharashtra, India

Date of Submission14-Mar-2019
Date of Decision30-Jun-2020
Date of Acceptance16-Jul-2020
Date of Web Publication18-Dec-2020

Correspondence Address:
Gaurav Patel
Department of Surgical Oncology, Bombay Hospital and Medical Research Centre, Mumbai - 400 020, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_176_19

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 > Abstract 

We present here a case of a 35-year-old woman diagnosed with primary neuroendocrine carcinoma of the breast (NECB) – small cell type. We discuss the importance of histological and molecular criteria for primary neuroendocrine mammary neoplasm, established by the World Health Organization in 2003 and 2012. We present information about differential diagnosis, prognostic factors, surgical treatment, adjuvant treatment, and novel therapies for primary NECB. Although this disease is not so uncommon but it is highly underreported and with consistent diagnostic criteria, surgeons should be able to keep this entity as differential diagnosis to enable them a timely treatment.

Keywords: Breast, carcinoma, neuroendocrine

How to cite this article:
Patel G, Bipte S. Updates in primary neuroendocrine breast carcinoma – A case report and review of literature. J Can Res Ther 2020;16:1528-31

How to cite this URL:
Patel G, Bipte S. Updates in primary neuroendocrine breast carcinoma – A case report and review of literature. J Can Res Ther [serial online] 2020 [cited 2021 Nov 27];16:1528-31. Available from: https://www.cancerjournal.net/text.asp?2020/16/6/1528/303910

 > Introduction Top

Neuroendocrine tumors (NETs), sometimes referred to as carcinoids, are abnormal growths that begin in the neuroendocrine cells, which are distributed widely throughout the body. While some features of NETs are unique to the site of origin, other characteristics are shared, regardless of site. Primary NETs of the breast are a group of NETs that morphologically show similar features of other NETs, such as that of the lung and gastrointestinal tract. Their incidence has reported to range from <1% to 5% of breast cancers, according to the different series and the different diagnostic criteria.[1] In fact, the true incidence of the disease is difficult to assess because immunohistochemistry neuroendocrine markers are not routinely used in breast tumors in India. Because of its low incidence, there is also scarcity of evidence regarding the optimal management and prognostic relevance of NETs of breast, with the only available data resulting from case reports and series.

 > Case Report Top

A 35-year-old female presented with lump in the left breast noticed 2 months back and pain for the past 1 month with no other complaint. On examination, a hard, irregular, ill-defined lump was palpable in 4 o'clock position of the left breast, and a left axillary node was noticed. Contralateral breast and axilla were normal. On mammography, a hypoechoic lesion measuring 4.5 cm × 4.5 cm × 3.1 cm in the lower lateral quadrant of the left breast with left axillary node measuring 1.6 cm × 0.8 cm × 0.5 cm was seen and suggestive of BIRADS IV C [Figure 1]. Ultrasonography (USG)-guided core biopsy of the breast lump done showed high-grade neuroendocrine carcinoma (NEC) expressing synaptophysin and chromogranin A (strongly and diffusely) and is immunonegative for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (Her 2)/neu, cytokeratin (CK), and transcription factor-1 (TTF-1). The MIB-1 labeling index was approximately 95%. To rule out any other possible extramammary location of NEC, positron emission tomography (PET) scan was performed, but no other lesion was detected. The patient underwent an upfront left sided modified radical mastectomy. Final histopathology report stated Neuroendocrine Carcinoma of Breast (NECB) of small cell type with extensive lymphovascular invasion. Three out of 18 nodes were metastatic with no extranodal extension. Immunostaining showed positivity for CK and diffuse and strong positivity for CD56, synaptophysin, and chromogranin A, i.e., more than 90% tumor cells are positive for these stains. Tumor cells were negative for ER, PR, Her 2/neu, mammaglobin, GATA3, E-cadherin, TTF-1, CK7, p63, CDX2, and S100 [Figure 2]. MIB-1 index was more than 95%. The patient was given adjuvant chemotherapy in form of doxorubicin, docetaxel, and cyclophosphamide. However, she progressed on chemotherapy with later developing brain metastasis. Unfortunately, she succumbed to her disease within 5 months of her diagnosis.
Figure 1: Mammography showing high-density mass with ill-defined margin in the left breast. Enlarged axillary lymph node is noted in the left mediolateral oblique view suggestive of BIRADS IV C

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Figure 2: Neuroendocrine tumor of the breast with a trabecular growth pattern, demonstrating strong expression of chromogranin A and synaptophysin

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 > Discussion Top

NECB was endorsed as a distinct entity in the 2003 World Health Organization (WHO).[1] The term NECB was revised to carcinomas with neuroendocrine features in the 2012 WHO Classification of Tumors of the Breast.[2] In addition, it was acknowledged that the 50% threshold for neuroendocrine marker positivity, which was defined in 2003, was arbitrary, and therefore, invasive carcinomas with neuroendocrine differentiation were included in the NEBC group, regardless of the percentage of tumor cells expressing neuroendocrine markers of immunohistochemistry after excluding other primary sites. Carcinomas with neuroendocrine features are subclassified into three groups: well-differentiated NET, which are low-grade tumors that architecturally resemble carcinoid tumors of other sites; poorly differentiated NEC or small cell carcinoma, which is identical to its pulmonary counterpart; and invasive breast carcinoma (BC) with neuroendocrine differentiation (IBC-NED), which is a BC of special or no special type that demonstrates neuroendocrine differentiation by immunohistochemistry.[2] In 2019, there was a radical change in the WHO classification of NETs/carcinomas, depending on the differentiation to create a common way of classification across sites to reduce inconsistencies and contradictions among the various systems currently in use.

This NET arises from divergent differentiation of neoplastic stem cells into epithelial and endocrine cell lines during early carcinogenesis. This theory is supported by the lack of benign NETs of the breast and evidence that the neuroendocrine cells are clonally related to malignant epithelial cells.[3]

NEBC possesses clinical features indistinguishable from other carcinomas. Indeed, NEBC is found as a palpable or nonpalpable mammary nodule, identifiable by USG, mammography, or magnetic resonance imaging. It has no unique radiological features, and the diagnosis is made on histology, which, in turn, is based on obtaining adequate tissues suitable for histological analysis. Tissues that show histological aspects, suggestive of neuroendocrine differentiation, should therefore undergo immunohistochemical staining for neuroendocrine markers to endorse the diagnosis. The possibility of breast metastases from other primitive neuroendocrine cancers should be denied performing a computed tomography (CT) scan. Somatostatin receptor (SSTR) scintigraphy or PET-CT with gallium-labeled somatostatin analogs 68 may also be indicated for differentiation from a diverse primitive site in the case of well-differentiated NECs, whereas PET-CT with 18-fluorodeoxyglucose could be performed with similar intention in the event of scarcely differentiated NEC with a high proliferation rate.[4]

Although morphologic features may suggest neuroendocrine differentiation, the diagnosis of NET requires expression of neuroendocrine markers. The most sensitive and specific immunohistochemical markers are synaptophysin and chromogranin A. Neuron-specific enolase and CD56 may show positivity but are less sensitive and specific.[1] NEBCs are typically positive for ER and PR and negative for ERBB2 (Her-2/neu). Despite its luminal (A or B) phenotype, most studies have reported an aggressive clinical course and poor outcome for patients with NEBC.[5]

The mutational profile and molecular characteristics of NECB have been the focus of several recent studies. The literature reports PIK3CA mutations in 7%–33% of cases. NEBCs differ from the common forms of BC ER +/HER2, not only due to the low frequency of PIK3CA mutations (similar to mucinous carcinomas), but also due to the lack of TP53 mutations and the presence of FOXA1 mutations (similar to lobular carcinomas). Similar to the NETs of other sites, NEBCs also host mutations in chromatin remodeling genes, including ARID1A and ATRX. Some NEBCs also host FGRF and RAS mutations.[6] Xiang et al. identified clonal chromosomal aberrations in five out of seven NEBC cases, with four of them showing complex karyotypes. They also found that NEBC shared some cytogenetic abnormalities such as trisomy 7 and 12 with other NETs in the lung and GI tract.[7]

The prognostic relevance of neuroendocrine differentiation in BC is still debated because several studies have been published with mixed result.[8] Neuroendocrine differentiation itself is independent adverse prognostic factor. Proliferative index (Ki-67 > 14%) is significantly associated with worse disease-free survival and overall survival. Large tumor size (>20 mm), higher tumor stage, negative hormone receptor status, and a lack of surgical treatment were associated with shorter overall survival. When the specific histologic subgroup was taken into account, small cell carcinoma was significantly associated with worse prognosis, in comparison with all the other NETs of the breast.[9]

To date, no therapeutic significance is attributed to neuroendocrine differentiation in breast neoplasms. Currently, the same therapeutic approach applied in the treatment of different types of invasive breast cancer is used in neuroendocrine cases, and we do not have data from prospective clinical trials on their optimal management. Surgery is the cornerstone of the therapy of early NEBC, and the localization of the neoplasm and its clinical stage decide the surgical procedure, similar to the primitive BCs of nonspecial histology. Breast conserving surgery with or without adjuvant therapy is a more frequent choice, but mastectomy is the preferred surgical treatment in relation to the aggressive potential at early stage of NETs. Axillary dissection with the removal of at least 10 lymph nodes is indicated in the presence of clinically suspected lymph nodes for metastasis, sentinel lymph node positive for macrometastasis, in the case of failure to find the sentinel lymph node in T4 tumors and in inflammatory carcinoma. Although axillary dissection is complete (I–II–III level) and considered a standard, the extension to the III level must take place in the case of the presence of macroscopic level II disease.[10]

Adjuvant radiation and systemic therapy must be decided in a personalizing view, taking into account the age of the patient, her comorbidities, the stage, and the biological characteristics of the disease that identify the risk of relapse. We should prefer regimens including anthracyclines and/or taxanes when the indication for chemotherapy exists. We must consider an anti-HER2 targeting approach for HER2-positive NEBC. Patients diagnosed with NEBC with positive hormone receptors are candidates to receive adjuvant endocrine therapy.[10]

For NEBC, which expresses SSTRs, evidenced by the use of 68-gallium PET-CT, receptor radionuclide therapy (PPRT) using 90Y-DOTATOC can be used.[11] NETs of the lung, prostate, and GI system, as well as breast, express SSTRs that have potent inhibitory effects on hormonal secretion and antiproliferative effects. Type 2A somatostatin receptors (SSTR2A) are associated with the strongest antiproliferative effects in vitro. A recent study demonstrated that the majority of primary NEBC express SSTR2A and SSTR5, with SSTR2 being the most consistently expressed.[12] Hence, as in other NET sites, SSTRs could be a potential therapeutic target. The relative high proportion of tumors negative for SSTRs, which may justify the therapeutic failure, suggest that it could be better to measure immunohistochemical SSTR status before commencing SSTR analog treatment. Based on the emerging evidence showing that receptor-derived peptide fragments are involved in cancer development and progression, Del Rio-Moreno et al. demonstrated that the truncated variant of somatostatin receptor subtype 5 (SST5TMD4)-derived peptides could contribute to the strong oncogenic role of SST5TMD4 observed in multiple cancer pathologies and represent potential candidates to identify new diagnostic, prognostic, and therapeutic targets in oncology.[13] Activating mutations of vascular endothelial growth factor receptor (VEGFR)-2 and the high level of expression of VEGF-C have been found in NEBC. Bevacizumab, a monoclonal antibody directed against VEGF and the spectrum of tyrosine kinase inhibitors targeted to VEGFR, including sorafenib, sunitinib, and pazopanib were evaluated with no much success. Furthermore, the use of new combinations between anti-VEGF therapies and systemic agents such as chemotherapy and hormone therapy is very interesting, given the different mechanisms of action of these agents.[14] As mentioned before, the mammalian target of rapamycin (mTOR) protein, a downstream protein of PI3K pathway, has a leading role in cell growth, nutrient signaling, and inhibition of autophagy. Everolimus, a selective and potent inhibitor of mTOR, showed effectiveness across different types of NETs. Its effectiveness could also be hypothesized in NEBC with a role added to existing regimens.[14]

Results of a study conducted by Vranic et al. for novel therapies for NEBC showed predictive expression of TROP-2, FOLR1, and H3K36Me3 in different subsets of tumors, and this may pave a way for the development of novel targeted therapies in some patients with NEBCs. Further, there was no evidence of DLL3 expression, NTRK gene fusions, or MGMT hypermethylation. No biomarkers predictive of immune checkpoint inhibitor efficacy (programmed death-ligand 1 [PD-L1] expression, tumor mutational burden (TMB), microsatellite instability [MSI]) were identified. Fibroblast growth factor receptor (FGFR) and CCND1 gene amplifications were detected in isolated cases. Their study identified several potential targets for novel therapies in NEBC, including farletuzumab and mirvetuximab soravtansine (FOLR1), sacituzumab govitecan (TROP-2), and HDAC inhibitors (H3K36Me3). In some cases, CCND1 gene amplification may indicate the usefulness of investigational therapies. FGFR inhibitors have been recently considered as a promising therapeutic option in breast cancer; the preliminary clinical data with FGFR inhibitors have yielded disappointing results. NEBC patients are unlikely to benefit from immune checkpoint inhibitors, as all current biomarkers (PD-L1, TMB, and MSI) are uniformly negative in this rare histotype.[6]

NEBCs are not so uncommon but are highly under-reported breast cancers. Advanced genetic and pathology studies are indispensable for better characterizing these neoplasms and establish the clinical fallout from these aspects. We do not have available literature data that direct us toward unambiguous therapeutic management, and it is difficult to reach adequate conclusions on their best treatment strategy. Currently, this group of tumors remains an intriguing area of research, and an increasing understanding of the biology of these rare tumors is necessary to develop the most appropriate therapeutic strategy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 > References Top

Hanby AM, Walker C, Tavassoli FA, Devilee P: Pathology and genetics: Tumours of the Breast and Female Genital Organs. WHO Classification of Tumours series. Vol 4. Lyon, France: IARC Press. Breast Cancer Res; 2004;6133.  Back to cited text no. 1
Pittella JE, Barbosa AJ. The new WHO classification of breast tumors. J Bras Patol E Med Lab 2012;48:406-7.  Back to cited text no. 2
Wachter DL, Hartmann A, Beckmann MW, Fasching PA, Hein A, Bayer CM, et al. Expression of neuroendocrine markers in different molecular subtypes of breast carcinoma. BioMed Res Int 2014;2014:408459.  Back to cited text no. 3
Arslan E, Fikret Çermik T, Didem Can Trabulus F, Canan Kelten Talu E, Başaran Ş. Diagnostic impact of 18F-FDG PET/CT on the management of rare breast carcinomas: Apocrine and neuroendocrine carcinomas. Rev Esp Med Nucl Imagen Mol 2019;38:147-53.  Back to cited text no. 4
Lavigne M, Menet E, Tille JC, Lae M, Fuhrmann L, Bonneau C, et al. Comprehensive clinical and molecular analyses of neuroendocrine carcinomas of the breast. Mod Pathol 2018;31:68-82.  Back to cited text no. 5
Vranic S, Palazzo J, Sanati S, Florento E, Contreras E, Xiu J, et al. Potential novel therapy targets in neuroendocrine carcinomas of the breast. Clin Breast Cancer 2019;19:131-6.  Back to cited text no. 6
Xiang DB, Wei B, Abraham SC, Huo L, Albarracin CT, Zhang H, et al. Molecular cytogenetic characterization of mammary neuroendocrine carcinoma. Hum Pathol 2014;45:1951-6.  Back to cited text no. 7
Wang J, Wei B, Albarracin CT, Hu J, Abraham SC, Wu Y. Invasive neuroendocrine carcinoma of the breast: A population-based study from the surveillance, epidemiology and end results (SEER) database. BMC Cancer 2014;14:147.  Back to cited text no. 8
Tian Z, Wei B, Tang F, Wei W, Gilcrease MZ, Huo L, et al. Prognostic significance of tumor grading and staging in mammary carcinomas with neuroendocrine differentiation. Hum Pathol 2011;42:1169-77.  Back to cited text no. 9
Wei B, Ding T, Xing Y, Wei W, Tian Z, Tang F, et al. Invasive neuroendocrine carcinoma of the breast: A distinctive subtype of aggressive mammary carcinoma. Cancer 2010;116:4463-73.  Back to cited text no. 10
Scaramuzzi G, Murgo RM, Cuttitta A, Ciuffreda L. Neuroendocrine carcinoma of the breast. Our experience and a proposal of a therapeutic algorithm for a rare tumor. G Chir 2008;29:203-6.  Back to cited text no. 11
Terlević R, Perić Balja M, Tomas D, Skenderi F, Krušlin B, Vranic S, et al. Somatostatin receptor SSTR2A and SSTR5 expression in neuroendocrine breast cancer. Ann Diagn Pathol 2019;38:62-6.  Back to cited text no. 12
Del Rio-Moreno M, Alors-Perez E, Borges de Souza P, Prados-Gonzalez ME, CastaÑo JP, Luque RM, et al. Peptides derived from the extracellular domain of the somatostatin receptor splicing variant SST5TMD4 increase malignancy in multiple cancer cell types. Transl Res 2019;211:147-60.  Back to cited text no. 13
Cella CA, Minucci S, Spada F, Galdy S, Elgendy M, Ravenda PS, et al. Dual inhibition of mTOR pathway and VEGF signalling in neuroendocrine neoplasms: From bench to bedside. Cancer Treat Rev 2015;41:754-60.  Back to cited text no. 14


  [Figure 1], [Figure 2]


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