Primary Neuroendocrine Carcinoma of Breast: Changing Paradigm

Abstract  

Neuroendocrine carcinomas are one of the most rare malignancies of the breast. Theoretically they can arise from any organ of the body, but incidence in breast is very rare. Due to the ever-changing definition of the disease, no specific therapeutic guideline is available in current literature. Currently WHO defines neuroendocrine carcinoma of breast as malignant lesions that expresses > 90% of neuroendocrine markers like synaptophysin, chromogranin A with characteristic histopathology features with exclusion of solid papillary carcinoma, and hypercellular-type mucinous carcinoma.

Introduction

In 2003, the World Health Organization (WHO) officially defined neuroendocrine carcinoma of breast (NECB) as malignancies expressing neuroendocrine markers in more than 50% of tumor cells. The WHO Classification of tumors of the breast in 2012 removed this 50% expression criteria and suggested that the diagnosis could be confirmed regardless of the percentage of tumor cells expressing neuroendocrine biomarkers [1].

The latest WHO Classification 2019 unified neuroendocrine neoplasm (NEN) of the breast with that of other organ systems based on histological features and defined NEN into well-differentiated neuroendocrine tumors (NETs), highly aggressive neuroendocrine carcinomas (NECs), and invasive breast cancers of no special type (IBCs-NST) with neuroendocrine differentiation [2].

At present there is no conclusive evidence of the origin of the disease. NEN may be seen theoretically arising from anywhere in the body as neuroendocrine cells are present, albeit in small percentage in each organ.

NEC breast are presentation wise identical to invasive breast carcinomas. The only crux is that NECB is more likely to present with systemic metastasis at diagnosis. Most NECB patients show positive estrogen receptor (ER) and/or progesterone receptor (PR) expression, implying that NECB is part of the luminal-like subtype [3].

Histogenesis and prognosis of NECB are still ill defined. In addition, there are no standardized therapeutic guidelines or norms for these invasive tumors, and treatment often refers to nonspecific breast cancer reported in case reports and retrospective studies. Surgery remains the primary treatment for IDC-NST followed by taxane-based or anthracycline chemotherapy, endocrine therapy, and targeted therapy according to the receptor status. Given the low prevalence of NECB, knowledge is limited to case reports and small retrospective studies, and the understanding of the clinical features and management of this disease is limited.

WHO Classification

Neuroendocrine differentiation in breast cancer was first described in 1963 [4].

In 1977, Cubilla and Woodruff presented a few breast cancer cases with a carcinoid growth pattern and produced the term breast primary carcinoid tumor [5].

In 1985, Bussolati et al. demonstrated positive chromogranin A (CgA) expression in the normal mammary parenchyma, offering definitive proof of neuroendocrine (NE) differentiation [6].

In 2000, Sapino et al. first proposed the diagnostic criteria for NECB, and they considered breast carcinomas resembling neuroendocrine tumors of the gastrointestinal tract and lungs in morphological features, demonstrating significant expression of neuroendocrine markers [greater than 50%, particularly CgA and synaptophysin (Syn)] [7].

Since then the WHO definition and classification of NECB have changed multiple times in last 20 years (Tables 1 and 2).

Table 1.

Evolution of definition of neuroendocrine carcinoma breast in last two decades [8]

WHO	Terminology	Diagnosis	Subgroups
2003	Neuroendocrine tumor	• Morphological feature similar to those of neuroendocrine tumors of both GI tract and lung • Tumors of epithelial origin • Expression of neuroendocrine markers in > 50% of tumor cells	• Large-cell carcinoma • Small-cell/oat cell carcinoma • Solid neuroendocrine carcinoma
2012	Carcinomas with neuroendocrine features	• Morphological feature similar to those of neuroendocrine tumors of both GI tract and lung • Express neuroendocrine markers regardless of the percentage of tumor cells • Include IBC-NST and special subtype with neuroendocrine differentiation	• NET well differentiated • NET poorly differentiated/small-cell carcinoma • IBC with neuroendocrine differentiation
2019	Neuroendocrine neoplasm IBC-NST with neuroendocrine features	• > 90% neuroendocrine histological features/marker expression • Exclude solid papillary carcinoma/hypercellular subtype of mucinous carcinoma 90% or less histological features/marker expression 10–90%: mixed invasive NST (or other special type) and NEC  < 10%: invasive NST with a comment on focal neuroendocrine pattern	• NET well differentiated • NET poorly differentiated (small cell NEC, large-cell NEC)

IBC, invasive breast cancer; NST, no specific type; NEC, neuroendocrine carcinoma)

Table 2.

Highlighted changes in WHO definitions in last two decades

2003: Based on NE markers expression > 50%: SCNEC*/LCNEC**/solid NECs

2012: Scraped the marker expression criteria (any percentage): WDNET***/PD NEC**** or SCNEC/IBC with NE differentiation

2019: > 90% NE histological features or NE marker expression: WDNET***/PDNEC (SCNEC/LCNEC)

^*SCNEC, small-cell neuroendocrine carcinoma; **LCNEC, large-cell neuroendocrine carcinoma; ***WDNET, well-differentiated neuroendocrine tumor; ****PDNEC, poorly differentiated neuroendocrine carcinoma

Evolution of WHO Classification

In addition, if neuroendocrine biomarker expression or histological features make up ≤ 90% of the tumor area, it is defined as an IBC-NST with neuroendocrine features. When cancers have a 10–90% NEN pattern, the terminology of mixed invasive (NST or other special type) or NEC may be used, and the NEC percentage should be reported. Cancers with < 10% NEN pattern should be classified as NST or other special types with an option to describe the focal specialized neuroendocrine pattern in the report comment.

Epidemiology

True incidence of NECB is an enigma. According to the WHO diagnostic criteria of 2003, only 0.1% of breast cancer is NECB, which is lower than the 2–5% reported by the WHO in 2012, suggesting that NECB may be underestimated because immunohistochemical (IHC) examination for neuroendocrine biomarkers is not routinely performed and cytomorphologic evaluation underestimates neuroendocrine differentiation. Therefore, it is difficult to confirm the true incidence of NECB [9].

The clinical feature of NEC breast is typically that of an aggressive carcinomatous lump of breast. Most of the time they present in advanced stage. The primary is usually solitary lump in breast with advanced features present in most of the cases. Symptoms pertaining to metastases were seen in majority of the patients reported [10].

Patient age at diagnosis is mainly between the fifth and seventh decades of life (majority aged > 60 years), ranging from 26 to 99 years, and most patients are postmenopausal women. However the youngest person affected was reported be a 13-year-young girl [11].

Approximately 40% of NECB has axillary lymph nodal metastasis at diagnosis [12].

Compared to IDC-NST, NECB patients are more likely to present systematic metastasis at initial diagnosis, and the most common metastatic sites are bone, liver, lungs, brain, bone marrow, and pleura, and several cases involve skin [13].

Kawasaki et al. reported peculiar endovascular spread [14].

FNAC alone may not suffice for the diagnosis, as in most of the cases FNAC findings may point out as adenocarcinoma. Furthermore, neuroendocrine marker study may not be adequate in a FNAC sample. Hence, image-guided core biopsy is essential in pre-op setting. However the authors believe that the diagnosis of neuroendocrine carcinoma of breast depends on the final surgical histopathology specimen. This is important because according to the new WHO guidelines, excluding the breast tumor as a metastatic component from any other primary site (mostly gastrointestinal tract/lung) is mandatory to fulfill the criteria as primary neuroendocrine tumor of breast. Further IHC expression of GATA3, mammaglobin, and GCDFP-15 may also be helpful in this regard (Fig. 1A–D).

Fig. 1.

A Synaptophysin expression; B chromogranin expression; C GATA 3 expression in Immunohistochemistry; D, histopathology picture showing small dark hyperchromatic cells with a high N:C ratio and scant cytoplasm with necrosis (suggestive of small-cell carcinoma). The features are indistinguishable from the lung counterpart

Regarding the molecular subtype, most NECBs are hormone receptor positive and human epidermal growth factor receptor 2 (HER-2) negative, presenting a luminal-like phenotype, and ER may help distinguish the two entities [15].

Prognosis

There has been mixed data regarding survival status. Most of the studies have shown decreased OS [16] and DFS [12].

In addition, cancer antigen 15–3 has been shown to be remarkably elevated in a patient at baseline and to significantly decrease after treatment, indicating that CA15-3 may be a prognostic factor [17].

Treatment

Surgery remains an essential method of treatment for early-stage NECB. The selection of surgery method for NECB resembles that for general breast cancer. To date, there is still a lack of evidence for selecting the most effective chemotherapy protocols. Chemotherapy agents can be selected based on the histopathological characteristics of NECB. In general, poorly differentiated, small-cell NEC or large-cell NEC are treated with platinum/etoposide-containing regimens [18].

There is little evidence regarding NACT in NEC breast. One study showed a stable disease after using carboplatin, etoposide as neoadjuvant therapy [19].

In another study, 4# TEC (docetaxel, epirubicin, and cyclophosphamide) was used in neoadjuvant setting, resulting in a significant decrease in the Ki-67 proliferation rate from 40 to 10% [20].

The author’s opinion is that each case should be treated on individualized basis, where desire to preserve breast, biology of the tumor has to be given importance. According to these factors, neoadjuvant and adjuvant therapies should be planned. This may be followed by adjuvant endocrine therapy effectively in patients whose tumor expresses appropriate receptors, as was seen in some studies [21].

In sporadic cases anti Her2 agents have also been used successfully. There is an ongoing research trend to look for efficacy of PRRT in metastatic NEC breast. But the results are yet to be disclosed.

The future perspective depends on the PI3K inhibitors (alpelisib), TROP 2 inhibitors, and molecular research.

Declarations

Conflict of Interest

The author declares no competing interests.