A complete pathological response to preoperative chemotherapy in a male patient with primary neuroendocrine breast cancer: a case report.

Introduction
Globally, breast cancer is the second most commonly diagnosed cancer, while in Syria it represents the most prevalent cancer (21.5% of all cases in both sexes) [1, 2]. Less than 1% of all breast cancer cases occur in men [3]. Invasive ductal carcinoma is the most frequent histologic type of primary male breast cancer, representing about 85% of reported cases. Papillary carcinoma is the second most common subtype, accounting for approximately 2.6% of cases, and it occurs about twice as often in men compared with women. Lobular carcinoma is rare in male individuals, comprising only 1–1.5% of cases. Invasive mucinous carcinoma is also uncommon, representing just around 1% of male breast cancers [4, 5]. Neuroendocrine neoplasms arise from neuroendocrine cells distributed throughout the body, most commonly found in the gastrointestinal tract and respiratory system. Primary neuroendocrine breast carcinoma (NEBC) is exceedingly rare, constituting less than 0.1% of all breast cancers and less than 1% of all neuroendocrine tumors [6, 7].
According to the World Health Organization (WHO) Classification of Breast Tumors, neuroendocrine neoplasms of the breast are categorized as either neuroendocrine carcinomas, which include small-cell and large-cell carcinomas, or breast neuroendocrine tumors (NETs), which are defined as invasive carcinomas of histological grade 1 or 2 displaying neuroendocrine morphology and extensive expression of neuroendocrine markers [8]. NEBC exhibits similar morphological and phenotypic features to their counterparts arising in the gastrointestinal and respiratory tracts [9]. There are no specific clinical or radiological features of this subtype of breast cancer. Furthermore, their optimal treatment has not been clearly defined. In this report, we present a case of small-cell breast carcinoma in a male patient, notable for its rare clinical and imaging features as well as its treatment course.

Case presentation
A 47-year-old Syrian male, a nonsmoker and nondrinker with no medical or family history, presented to Albairouni University Hospital in January 2024 with a suspicious mass in the left breast, which he had first noticed 2 months earlier.
On physical examination, a solid, nontender, irregular mass measuring approximately 1 × 1.5 cm was found in the upper outer quadrant of the breast. No axillary lymphadenopathy or other abnormal findings were noted.
Breast ultrasound revealed a lobulated, partially circumscribed parenchymal lesion measuring 11 × 18 mm, highly suggestive of malignancy, along with a small (6 mm) axillary lymph node. Computed tomography (CT) showed no evidence of lung, pancreatic, adrenal, or pelvic masses except a transverse axial scan showed an 18 × 10 mm mass in the left breast with a small (6 mm) axillary lymph node, and no other abnormalities were noted (Fig. 1).
A core needle biopsy of the breast mass was performed, and histopathological examination indicated poorly differentiated NEBC (small-cell carcinoma) (Fig. 2A). This was confirmed through immunohistochemical staining, which showed positivity for synaptophysin and cytokeratin (CK; weakly positive), negativity for HER2, and a Ki-67 proliferation index exceeding 70% (Fig. 2B–D).
A multidisciplinary team discussed the case. The patient was classified as having a localized, potentially curable stage of disease. He subsequently received five cycles of preoperative chemotherapy consisting of cisplatin 75 mg/m2 in D1 and etoposide 100 mg/m2 for 3 days, administered every 21 days. Clinical evaluation after three cycles showed a significant response, with the tumor size reduced to approximately 0.5 cm. Mild alopecia, nausea, and bone marrow suppression (which resolved with granulocyte-colony stimulating factor) were observed during treatment. The treatment was well tolerated by the patient with no other side effects noted.
A modified radical mastectomy with axillary lymph node dissection was subsequently performed. A histological examination revealed a complete pathological response with 17 reactive axillary lymph nodes showing extensive fatty necrosis. In the multidisciplinary team’s assessment, neither postoperative breast irradiation nor prophylactic cranial irradiation was recommended. Therefore, the patient was placed under surveillance. A post-treatment CT scan demonstrated no evidence of recurrence, and the patient remains disease-free after 18 months of follow-up (Fig. 3). The timeline of the case is shown in Fig. 4.

Discussion
Breast neuroendocrine carcinoma (small-cell carcinoma) is a poorly differentiated neuroendocrine tumor, most commonly observed in women in their sixth to seventh decade. It is rare in men [10]. The majority of small-cell carcinomas arise in the lungs, with only 2–5% occurring at extrapulmonary sites [11]. It is rare in the breast, accounting for 0.4% of primary breast tumors in women according to the Surveillance, Epidemiology, and End Results (SEER) database in 2012, and less than 0.1% in men [12]. A few cases have reported NEBC in male patients, with ages ranging from 52 to 83 years. Expression of neuroendocrine markers was variable (chromogranin A, synaptophysin, CD56), while estrogen receptor/progesterone receptor (ER/PR) were often positive, and HER2 was mostly negative. Most cases were diagnosed at an early stage, though some presented with metastatic disease. Outcomes were diverse and closely related to tumor stage and treatment. The best results were generally observed with surgery combined with systemic therapy (commonly platinum/etoposide regimens). Radiotherapy and endocrine therapy were also employed in selected cases. An important difference in our case is that treatment was aimed at a cure despite a poor prognosis. Table 1 summarizes these reported cases [13–21].
It is widely believed that small-cell carcinoma arises from the divergent differentiation of a neoplastic stem cell in both epithelial and neuroendocrine cells. An alternative theory suggests these tumors originate either from neural crest cells that migrate to the mammary glands or from preexisting neuroendocrine cells within breast tissue [22].
WHO guidelines define NEBC on the basis of specific criteria. Firstly, neuroendocrine neoplasms are defined as tumor classes characterized by predominant neuroendocrine differentiation, including both well and scarcely differentiated tumors. Invasive neuroendocrine tumors demonstrate low/intermediate grade with a neuroendocrine morphology and immunoreactivity for neuroendocrine markers such as chromogranin A and synaptophysin. Due to their normal presence in breast tissue, neuron-specific enolase (NSE) and CD56 appear to result in lower sensitivity and specificity [14, 23]. Tumor stage and histological grade, including mitotic counts, are the main prognostic factors. The second basis of the criteria is exclusion of primary extra-mammary tumors, especially those in the lungs and gastrointestinal tract [22, 24]. In our case, immunohistochemistry demonstrated synaptophysin positivity, supporting a neuroendocrine origin consistent with neuroendocrine carcinoma (small-cell carcinoma). Further staining was not undertaken owing to financial limitations. According to Wang et al., estrogen receptor status in NEBC may not provide prognostic value, as these tumors frequently show hormone receptor positivity yet continue to demonstrate poorer survival outcomes despite systemic therapy. This observation suggests that NEBC could be less responsive to current endocrine treatments than invasive ductal carcinomas, underscoring the need for further investigation in this area.
Because small cell carcinoma in the breast is rare, it remains unclear whether it should be treated according to breast cancer protocols or neuroendocrine tumors guidelines. Clinical management of this rare tumor type is challenging due to a lack of clinical trials to guide treatment decisions [23]. As there is no treatment guideline, neoadjuvant chemotherapy is often administered to reduce tumor size. In most cases, radiotherapy or chemotherapy is used after radical modified mastectomy with axillary lymph node dissection [14, 25].
One study suggested that patients with a high Ki-67 index or small-cell carcinoma may benefit from the combination of etoposide and platinum, while anthracyclines or taxanes may be more appropriate for patients with a low Ki-67 index [25]. It is currently unknown how effective such an approach would be. There is no statistically significant difference in overall survival between patients receiving single-agent adjuvant therapy and those receiving combination regimens [26]. The role of radiotherapy remains controversial in the treatment of NEBC. While some studies have reported survival benefits in patients with extrapulmonary small-cell carcinoma, including small-cell breast carcinoma [27], other studies have found that adjuvant radiation did not significantly improve overall survival [11, 28]. As in our case, a complete response was achieved; therefore, radiotherapy was not administered.
This report has some limitations. In well-differentiated neuroendocrine carcinomas, scintigraphy or positron-emission tomography (PET)-CT with gallium-labeled somatostatin analogs 68 may also be used to differentiate the tumors from multiple primitive sites. PET-CT with 18-fluorodeoxyglucose could be used in the same manner in neuroendocrine carcinomas that are poorly differentiated and show high proliferation rates [29]. PET-CT scan was not performed in this case. Another limitation is the absence of genetic testing, as the genetic risk factors associated with NEBC remain poorly understood. Several genetic aberrations, such as TP53, BRCA1/2, and others, have been proposed as possible risk factors [30]. Genetic testing in the patient’s case was not conducted. PET-CT scan and genetic testing are not available in the public hospitals and are not covered by insurance in Syria.

Conclusion
Primary NEBC (especially small-cell carcinomas subtypes) is a rare and distinct entity that has a worse prognosis than other breast cancers. We present a rare case of small-cell neuroendocrine breast cancer in a male patient who was treated successfully with neoadjuvant chemotherapy similar to small-cell lung cancer protocols followed by surgery in accordance with breast cancer standards. However, optimal treatment strategies remain undefined and require a better understanding of the disease’s pathophysiology.

Supplementary Information