Final Diagnosis
High-grade neuroendocrine carcinoma, compatible with small cell neuroendocrine carcinoma of the breast.
Discussion
Neuroendocrine neoplasms of the breast (NENB) are a rare and heterogeneous category of breast neoplasms. Due to low incidence and shifting diagnostic criteria and characterizations, there is a lack of large-sample and prospective clinical research, leading to a limited understanding of the disease and a lack of standardized therapeutic guidelines1.
The histogenesis of NENB is currently unclear. Some researchers propose that NENB does not originate from pre-existing neuroendocrine cells but rather from differentiation events in breast cancer, as neuroendocrine cells have not been detected in normal breast tissues by some studies2. Conversely, other studies have shown benign neuroendocrine cells in the background of breast parenchyma with NENB, suggesting that neuroendocrine cell proliferation might be linked to a precancerous state3. For small cell neuroendocrine carcinomas of the breast (SCNECs) specifically, findings suggest they may result from a specific line of differentiation of mammary cancer stem cells towards neuroendocrine/small cell-type differentiation, which can occur at either the in situ or invasive stage, rather than from malignant transformation of normal breast neuroendocrine cells4.
NENB are extremely rare, although the reported incidence is highly variable due to changes in classification and differing diagnostic criteria. SCNECs account for approximately 0.1% of all breast cancers 5 and 3–10% of extrapulmonary small cell carcinomas 6. Large cell NECs (LCNECs) are even more rare. NENBs mainly affect postmenopausal women, with patient age at diagnosis typically between 50 and 70 years (majority aged >60 years)7. While rare, cases have been reported in younger patients and men8,9. Approximately 40% of small cell carcinomas have nodal metastasis at diagnosis. In population-based studies, 70–81% of SCNECs had localized disease, while 19–30% presented with distant metastasis5.
NENB can present as infiltrative mass lesions or well-circumscribed nodules. Histologically, low- or intermediate-grade invasive primary breast neuroendocrine tumors (NETs) are morphologically similar to their pulmonary and gastrointestinal counterparts. They consist of dense, cellular solid nests and/or trabeculae of tumor cells with eosinophilic or clear cytoplasm, separated by delicate fibrovascular stroma, sometimes with rosettes and peripheral palisading10.
High Nottingham grade NENB includes SCNEC and LCNEC. SCNEC shows an infiltrative growth pattern and is composed of densely packed, small, dark and hyperchromatic nuclei with a high nuclear:cytoplasmic ratio, nuclear molding, scant cytoplasm, inconspicuous nucleoli, and poorly defined cytoplasmic boundaries. Similar to breast NETs, its histological features are challenging to distinguish from lung and gastrointestinal counterparts. An in-situ component with the same cytological features may be present, and lymphatic tumor emboli are frequently seen. LCNEC shows highly pleomorphic nuclei with coarse chromatin and moderate cytoplasm. Both SCNEC and LCNEC commonly show high numbers of mitotic figures and focal areas of necrosis10.
NENB is supported by morphologic appearance and diffuse (more than 50%), uniform immunoreactivity for neuroendocrine markers by immunohistochemistry. The most sensitive neuroendocrine markers are chromogranin A and synaptophysin. Neuron-specific enolase (NSE) and CD56 (NCAM) are also positive in the majority of cases but have lower sensitivity and specificity. SCNEC consistently stains for cytokeratin markers. Estrogen receptor (ER) positivity has been reported in 30–50% of SCNEC cases, with progesterone receptor (PR) positivity in a smaller proportion. HER2 is negative4,11. Most NENB are generally hormone receptor-positive and HER2-negative, presenting a luminal-like phenotype. The presence of an associated ductal carcinoma component, especially ductal carcinoma in situ (DCIS) with the same cytological features, is strong evidence of primary breast origin. Staining for site-specific lineage markers can also help in diagnosis. GATA3 expression has been reported in breast NEC but not in metastatic NECs from the lung12. Although TTF1 expression has been observed in SCNEC of the breast, it typically does not show the diffuse and intense nuclear staining characteristic of pulmonary small cell carcinoma13. Similar to their pulmonary counterparts, SCNEC of the breast shows TP53 and RB1 somatic genetic alterations in as many as 75% and 19% of cases, respectively11. Clinical history is crucial for a definitive diagnosis.
The findings regarding the prognosis of NENB are controversial. Most studies suggest a poor prognosis for breast NETs. Compared to invasive ductal carcinoma of no special type (IDC-NST), NETs are more likely to present with systematic metastasis at diagnosis and have shorter disease-free survival (DFS). Some studies also show worse overall survival (OS) and disease-specific survival (DSS)7,14. However, one study reported better survival for NETs than invasive ductal and lobular carcinoma15. As expected, SCNEC portends a significantly worse prognosis than other NETs of the breast. Despite this, outcomes for patients with breast SCNEC are superior to those with stage-matched small cell carcinoma of the lung, except in cases with distant disease5.
There are currently no standardized therapeutic guidelines for NENB due to its rarity and lack of randomized controlled trials. Treatment often relies on guidelines for invasive ductal carcinoma, with adjustments based on histopathological characteristics and receptor status. Surgery remains the primary treatment for early-stage NENB, similar to other forms of breast cancer. Options include breast-conserving surgery, modified radical mastectomy, breast reconstruction, and total mastectomy, considering factors like age, physical condition, tumor size, and location1. For poorly differentiated NECs, including SCNEC and LCNEC, platinum/etoposide-containing regimens are typically used, akin to small cell lung carcinoma regimens16,17.
References
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