Primary small-cell carcinoma of the breast

Abstract

Early diagnosis of rare breast cancers is expected to occur more frequently as screening compliance improves and diagnostic modalities become more sensitive. Well-defined treatment algorithms exist for the management of ductal and lobular carcinomas; however, less information is available to guide the treatment of atypical breast cancers. This case report describes a 38-year-old African American woman with primary small cell carcinoma of the breast and her treatment.

Extrapulmonary small cell cancer comprises only 5% of all small cell carcinomas (1), and small cell carcinoma of the breast comprises <1% of all breast cancers (2). For the minority of small cell cancers that are extrapulmonary, treatment guidelines and prognostic risk factors are not well defined. Here we report a case of primary small cell carcinoma of the breast; treatment involved multidisciplinary application of principles learned in the treatment of small cell lung cancer (SCLC) as well as other extrapulmonary small cell carcinomas.

CASE STUDY

A 38-year-old African American woman with no significant past medical history presented to her gynecologist complaining of a new-onset palpable mass in her left breast. An ultrasound demonstrated a 2 × 1.2 × 1.7 cm hypoechoic oval mass with irregular microlobulated margins (Figure 1). Ultrasound-guided core needle biopsy was performed. In the biopsy specimen, normal breast lobular architecture was visible just adjacent to the tumor, which demonstrated a high-grade malignant neoplasm with lymphovascular invasion. The tumor displayed some of the classic features of small cell carcinoma. The immunostains for pancytokeratin, chromogranin, and synaptophysin were positive, consistent with the neuroendocrine nature of small cell carcinoma (Figure 2). Pathologic interpretation supported the diagnosis of an epithelial lesion with at least some neuroendocrine differentiation consistent with small cell carcinoma of the breast.

Figure 1.

Sonographic image of the palpable area of concern in the 1 o'clock position of the left breast shows the dominant 2 cm hypoechoic mass with two smaller adjacent masses.

Figure 2.

Core needle biopsy with positive chromogranin staining.

The patient was referred to breast surgical oncology. On exam, the known breast mass was palpated, as well as a few abnormally large left axillary lymph nodes, concerning for nodal spread. Before definitive operative intervention, given the patient's young age of diagnosis and aggressive histology of the tumor, genetic testing and a staging positron emission tomography (PET) scan were performed. Genetic testing was negative for BRCA, and no additional cancer gene mutations were tested. PET scan demonstrated 3 hypermetabolic masses in the upper outer quadrant of the left breast, consistent with multifocal malignancy. Additionally, there was hypermetabolic left axillary lymphadenopathy, suggestive of axillary nodal metastatic disease. She was also found to be negative for systemic metastatic disease, excluding the existence of a lung primary.

Medical oncology recommended neoadjuvant carboplatin and etoposide, a standard double-agent regimen used in neuroendocrine tumors, including SCLC. Neuroendocrine tumors are highly replicative, as seen in this patient's proliferative index of 100%. Etoposide inhibits topoisomerase, which prevents DNA replication, therefore halting tumor growth (3). Carboplatin induces cross-linking of DNA strands to further prevent DNA replication and leads to cell death (4). The decision to undergo neoadjuvant, rather than adjuvant, therapy in our patient was twofold. Neoadjuvant therapy can be clinically monitored for effectiveness by examining the size of the mass during treatment. If the tumor demonstrates progression during neoadjuvant therapy, the clinician can change regimens or proceed directly to surgery. Additionally, after resection, the tumor can be evaluated microscopically for the exact degree of response to treatment.

After completing her course of chemotherapy, the patient had almost complete resolution of her palpable breast and axillary masses. She then underwent left skin and nipple-sparing modified radical mastectomy, which included a left axillary lymph node dissection. No sentinel lymph node biopsy was performed, as the patient's axillary nodes were already known to be involved. Per the patient's wishes, this surgery was immediately followed by breast reconstruction with a tissue expander.

Since the landmark NSABP B-06 study, published in 1985, treatment of breast cancer with lumpectomy and adjuvant radiation has been known to be oncologically safe, providing the same long-term survival as a mastectomy (5). Therefore, aside for a few contraindications, patients are given the option to undergo either mastectomy or lumpectomy with adjuvant radiation. Reasons for deciding between the two are multiple and diverse. This patient elected to undergo mastectomy.

Final pathology demonstrated a 0.1 mm microscopic focus suspicious for residual tumor, and an additional 1.2 cm area of high-grade ductal carcinoma in situ, negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor. The 7 axillary lymph nodes examined histologically were found to be negative for active invasive disease. Given that the patient had clinically palpable axillary lymph nodes, which were active on PET scan, we believe that her neoadjuvant therapy completely cured her nodal disease. On follow-up CT scans of the chest, abdomen, and pelvis, the patient had no evidence of residual disease. She is now undergoing postoperative care with routine screening right breast mammogram and bilateral breast exam.

DISCUSSION

The early diagnosis of rare breast cancers will continue to increase along with that of typical breast cancers as screening and diagnostic modalities continue to improve. Given the paucity of atypical diagnoses, the treating physician is left with limited consensus data to guide his or her management. Treatment of our patient's primary breast small cell carcinoma involved multidisciplinary application of principles learned in the treatment of SCLC as well as other extrapulmonary small cell carcinomas.

Pulmonary SCLC constitutes 95% of all small cell cancers (1). Standard management of pulmonary SCLC is complex; however, it essentially entails 4 cycles of cisplatin and etoposide along with thoracic radiotherapy with or without lobectomy. Prophylactic cranial irradiation is also given to patients who have proven response to chemotherapy and radiation (6). The delivery of this multimodal treatment has a proven survival benefit for patients with SCLC. Standard staging for SCLC consists of tumor, node, and metastasis evaluation. For practical treatment, however, a unique staging system, the Veterans Administration Lung Study Group, was developed. Under this system, SCLC patients are categorized as either limited disease or extensive disease (7). Under contemporary multimodal treatment, SCLC patients with limited disease have a 13.3% 5-year survival rate. SCLC patients with extensive disease have a 1.2% 5-year survival rate (8). Although this is a bleak outcome, survival without treatment rarely exceeds more than a few months.

For the remaining 4% to 6% of small cell cancers that are extrapulmonary, treatment algorithms and prognostic risk factors are less defined (1). The question at hand is whether or not the treatment of SCLC can be applied to extrapulmonary small cell cancer with similar results. A study published in 2010 from Peter MacCallum Cancer Centre in East Melbourne, Australia, attempted to answer this question. This retrospective review determined the recurrence rate, 5-year survival rate, and prognostic risk factors of 120 cases of extrapulmonary small cell cancer treated with the same algorithm as SCLC. Patients were staged according to the aforementioned Veterans Administration Lung Study Group staging system. The treatment, in general, consisted of 4 cycles of cisplatin/carboplatin and etoposide, radiation therapy to the primary site and involved lymph nodes to a dose equivalent of at least 50 G in 2 G fractions, and surgical resection if feasible. Prophylactic cranial irradiation was administered to 7 of the 120 patients. Recurrence-free survival at 1 year ranged from 13% (genitourinary) to 64% (head and neck). The overall 5-year survival rate was 25.4% for patients with limited disease and 0% for patients with extensive disease. Improved overall survival was seen in patients with associated weight loss, the use of definitive radiation therapy, higher-dose radiation therapy, higher number of chemotherapy cycles, and the combination of chemotherapy and radiation (8). Interestingly, surgical resection was not associated with an improved outcome. The use of prophylactic cranial irradiation was determined to be a positive prognostic factor for survival; however, given the low incidence of brain metastasis in the nonprophylactic cranial irradiation group, the study concluded that prophylactic cranial irradiation should not be a part of extrapulmonary small cell cancer treatment.

Prior case reports of primary small cell carcinoma of the breast suggest that a breast primary may carry a higher survival rate than other primary sites. A report of 9 cases from 1996 to 1999 at New York Presbyterian Hospital found all 9 patients alive at follow-up 3 to 35 months after treatment. All 9 patients presented with disease limited to either the breast or the axilla. Three underwent mastectomy, and 6 underwent lumpectomy. Eight of the 9 underwent axillary dissection, and 7 underwent adjuvant chemotherapy. Metastases to the liver and bone developed in 11 and 32 months in 2 patients (9).

Although possibly less fatal than SCLC, extrapulmonary small cell cancer remains a very aggressive cancer. Despite the lack of formal randomized controlled trials, the application of SCLC treatment to primary small cell carcinoma of the breast appears to carry the best chance of survival. Our patient underwent neoadjuvant treatment with the recommended platinum-based carboplatin and etoposide, followed by mastectomy and axillary dissection. At the time of writing, she was 15 months out from her diagnosis and was disease free.