Primary Small Cell Neuroendocrine Carcinoma of the Breast: A Case Report With Literature Review

According to 2019 WHO classification, tumors with ≥ 10% neuroendocrine morphology are considered neuroendocrine neoplasms. They can be divided into 1) neuroendocrine tumors with grade 1 or 2 nuclei, and 2) neuroendocrine carcinomas with grade 3 nuclei including small cell and large cell carcinomas. Small cell neuroendocrine carcinoma is a high-grade and poorly differentiated tumor typically presenting as primary pulmonary neoplasm [1]. Extrapulmonary small cell carcinoma is rare, accounting for 2.5%–5.0% of all small cell carcinomas [2]. The pathogenesis of extrapulmonary small cell carcinoma is not well understood. It is thought to arise either from a multipotent stem cell developing neuroendocrine features or a more organ-typical carcinoma with a late-stage phenomenon in genetic progression. The most common locations of extrapulmonary small cell carcinomas are gastrointestinal and genitourinary systems. However, primary small cell neuroendocrine carcinoma of the breast (SCNCB) is extremely rare, with an incidence of less than 0.1% of all breast cancers [3].

Owing to its rarity, imaging features of SCNCB are not well documented in the literature. Herein, we report a case of SCNCB diagnosed in a 58-year-old woman with descriptions of mammography, ultrasound, and MRI findings.

A 58-year-old woman presented with abnormal findings on postoperative screening mammography. She showed no symptoms of palpable lumps or nipple discharge. Two and a half years ago, she had been diagnosed with invasive ductal carcinoma (IDC) in her left breast, which was a 20-mm intermediate-grade tumor with positive estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) receptor status. She had undergone breast-conserving surgery with axillary lymph node dissection, in which resection margins were negative for the tumor. One metastatic lymph node was detected. Following the operation, adjuvant chemotherapy including four cycles of docetaxel and cyclophosphamide, adjuvant radiotherapy of 5440 cGy in 30 daily fractions for 9 weeks, and hormone therapy with letrozole and anti-HER2 agent with trastuzumab were administered.

On postoperative screening mammography (Fig. 1), a 15-mm irregular hyperdense mass with an indistinct margin, which was not seen on the previous mammography performed 6 months ago, was observed in the mid-central portion of the right breast, 17 mm from the nipple. Microcalcifications were not observed in or around the mass (Fig. 1A). Further ultrasound revealed a 12-mm round mass with partially microlobulated margins. Complex cystic and solid echogenicity with a predominantly solid component was observed in the corresponding location in the right breast (Fig. 1B). Color Doppler imaging showed that the tumor was poorly vascularized. Strain elastography revealed softness of the tumor (Fig. 1C and D). Based on mammography and ultrasound features, the tumor was assessed as Breast Imaging Reporting and Data System category 4C. Ultrasound-guided core-needle biopsy was performed with a 14-gauge spring-loaded needle. The pathologic examination was suggestive of IDC.

Fig. 1
A 58-year-old woman with abnormal findings in the right breast on postoperative surveillance mammography. A: A right mediolateral oblique mammogram showing a 15-mm irregular hyperdense mass with indistinct margin in the mid-portion of right breast (arrow). B: Ultrasonography showing a 12-mm round mass with partially microlobulated margins and complex cystic and solid echogenicity with predominantly solid component in the corresponding location of the right breast (arrow). C: Color Doppler imaging revealing poor vascularization of the tumor. D: Strain elastography showing softness of the tumor. E: Axial fat-suppressed T1-weighted early-phase dynamic contrast-enhanced magnetic resonance images showing an 18-mm round mass with rim and heterogeneous intratumoral enhancement in the right breast, with two small nodular portions in the tumor showing mild enhancement (arrowheads). F and G: Diffusion weighted image (DWI) at b-value of 1000 s/mm² and an apparent diffusion coefficient (ADC) map revealing high signal intensity on DWI and a low ADC value of 0.6 × 10^-3 mm²/s in these nodular portions, representing restricted diffusion (arrowheads). H: The tumor showing a relatively homogeneous intermediate signal intensity on axial T2-weighted images surrounded by a dark rim. Furthermore, there is moderate to marked peritumoral edema surrounding the tumor. I: Microphotographs (hematoxylin & eosin stain, × 400) showing densely packed, fairly uniform, small and dark hyperchromatic cells with a high nuclear to cytoplasm ratio, scant cytoplasm, and inconspicuous nucleoli. J-L: Positive immunohistochemical staining results of Bcl-2, CD56, and synaptophysin collectively supporting the pathological diagnosis of small cell neuroendocrine carcinoma (× 400).

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For preoperative evaluation of disease extent, breast MRI was performed using a 3-T MR scanner (Ingenia, Philips Healthcare, Amsterdam, the Netherlands). On MRI, an 18 × 15 × 12-mm circumscribed round mass with rim and heterogeneous intratumoral enhancement was observed on fat-suppressed T1-weighted contrast-enhanced images. Two small nodular portions in the mass showed mild enhancement, while the remaining portion showed poor enhancement. The tumor showed rapid enhancement in the early phase with washout-enhancing kinetic features in the delayed phase of the dynamic enhancement study (Fig. 1E). On diffusion-weighted images with b-values of 0 and 1000 s/mm², a circular ROI that best fit in the lesion was drawn to measure signal intensities according to an equation “S₁₀₀₀ = S₀ × exp(-b × ADC),” where ADC was an apparent coefficient value, and S₀ and S₁₀₀₀ were signal intensities measured on b = 0 and b = 1000 s/mm² images, respectively. As such, two small nodular portions in the mass revealed restricted diffusion with an apparent diffusion coefficient value of 0.6 × 10^-3 mm²/s (Fig. 1F and G). The tumor showed a relatively homogeneous intermediate signal intensity on T2-weighted images surrounded by a dark rim. In addition, moderate to marked peritumoral edema was observed surrounding the tumor (Fig. 1H).

The patient underwent breast-conserving surgery with sentinel lymph node biopsy. On gross examination of the surgical specimen, a 1.7 × 1.5-cm well-defined white mass was identified. The tumor showed high nuclear and histologic grade on microscopic examination (Fig. 1I). Immunohistochemical staining revealed ER negativity, PR negativity, HER2 negativity, and a Ki-67 proliferation index of 60%–70%. Notably, immunochemical staining for Bcl-2, CD56, and synaptophysin revealed positive results (Fig. 1J-L), which collectively supported the pathological diagnosis of small cell neuroendocrine carcinoma. There was no evidence of tumor in resection margins. Sentinel lymph node biopsy revealed no evidence of metastasis. Chest CT and whole-body positron emission tomography–CT (PET-CT) revealed no evidence of primary small cell neuroendocrine carcinoma elsewhere in the body, which confirmed a primary disease of the breast. The patient received adjuvant chemotherapy using doxoruicin (Adriamycin) and cyclophosphamide 4 times for 12 weeks and adjuvant radiation therapy of 5040 cGy in 28 daily fractions for 8 weeks. No tumor recurrence was observed during the 2-year follow-up visits after surgery.

SCNCB is a rare type of breast cancer. It is commonly diagnosed in postmenopausal women over the age of 60 [4, 5]. It has been reported to occur at a significantly older age than conventional invasive breast cancer [4, 6]. The most common manifestation is a palpable lump in the breast. Bloody nipple discharge, nipple retraction, and skin changes have also been reported [3, 4, 5]. The present case was incidentally diagnosed in an asymptomatic woman during postoperative surveillance mammography following treatment of IDC in the contralateral breast. Although it is well documented that a personal history of breast cancer increases the risk of breast cancer in the contralateral breast whether such a history also increases the risk of this rare type of breast cancer is unknown.

Histologically, SCNCB resembles small-cell neuroendocrine carcinoma of the lung. It is characterized by positive staining for Bcl-2, CD56, and synaptophysin, with densely packed hyperchromatic cells and scant cytoplasm [2]. Therefore, it is important to exclude the possibility of metastatic disease from other primary sites using CT scans and PET-CT before establishing a diagnosis of SCNCB as in our case. Specifically, such differentiation is critical in terms of treatment because surgical treatment would be a primary treatment for SCNCB while detection and local control of the primary site as well as performing a systemic therapy would be more emphasized for metastatic neuroendocrine tumors. Immunohistochemical markers such as GATA3, GCDFP15, and mammaglobin can provide information regarding such differentiation as these markers are stained negative in metastatic tumors [4].

SCNCB has been reported to have an aggressive behavior similar to small cell neuroendocrine carcinomas in other organs [3]. SCNCB often presents at a higher clinical stage and higher histologic grade than other types of breast cancer. Recent studies have reported significantly worse prognosis in terms of local and distant recurrence and overall survival in patients with SCNCB than in those with IDC [6]. Axillary metastases are detected in 50%–67% of SCNCBs at the time of presentation [3]. The patient in the present case was diagnosed during postoperative surveillance. She had a relatively small tumor size without evidence of regional or distant metastasis. However, metastases from SCNCB are known to occur years after initial treatment. Thus, long-term follow-up is mandatory. Common sites of metastasis include bones, liver, lungs, pleura, brain, adrenal glands, pancreas, and ovaries [6]. Old age, PR negativity, positive lymph node status, and lack of surgical treatment have been suggested as poor prognostic factors for SCNCB [6].

Several case reports and case series have described radiological findings of SCNCB. However, none of these findings has been clearly defined owing to its rarity. According to the literature, SCNCB is often detected as a high-density, oval or round mass with circumscribed margins on mammography, thus mimicking benign entities such as fibroadenomas, intramammary lymph nodes, and cysts [7]. Microcalcifications were found in 26.4% of cases. Associated architectural distortion was rare [4, 5]. On ultrasound, SCNCB most commonly appears as an irregular hypoechoic mass with indistinct margins. It frequently shows increased vascularity on color Doppler imaging [5, 7]. MRI features included a mass with irregular shape, non-circumscribed margins, and heterogeneous enhancement with rapid early enhancement and delayed washout kinetics [4, 5]. Multicentric or multifocal disease is occasionally observed on MRI. It can be found in up to 43% of cases [4].

In the present case, imaging findings did not agree well with those reported in previous studies. The mass had an irregular shape and indistinct margin on mammography. On the contrary, it appeared as round mass with partially microlobulated margin on ultrasound and MRI. The mass was surrounded by moderate to marked peritumoral edema on ultrasonography and MRI, which might have contributed to the indistinct margin of the mass on mammography. On ultrasound, the mass resembled papillary neoplasm with a complex cystic and solid appearance. The solid component revealed minimal enhancement and obvious diffusion restriction on MRI. Such imaging features of SCNCB have not been demonstrated in the literature. A possible explanation for this discrepancy could be related to the triple-negative subtype of the tumor because a round shape, circumscribed margin, rim enhancement with internal cystic or necrotic components, and pronounced peritumoral edema are not unusual MRI features of the triple-negative subtype of conventional breast cancers [8]. SCNCBs with triple-negative subtypes are uncommon. Previous studies have reported that tumors are most likely to be of the luminal subtype, with ER and PR positivity in 92% and 69% of cases, respectively, and HER2 negativity in almost all cases [4, 5]. Another explanation is that features of round shape or rim enhancement detected in the present case of SCNCB are not unusual for small cell neuroendocrine cancers occurring in other organs such as the lung or pancreas [9, 10].

SCNCB can be diagnosed by core needle biopsy. However, a precise diagnosis is not made until surgical removal in up to 40% of cases as estimating the proportion of cells exhibiting neuroendocrine differentiation would be limited with a biopsy specimen [7]. However, the therapeutic approach of SCNCB is similar to that of other types of breast cancer because no treatment protocol has been established specifically for SCNCB. Surgical treatment with lumpectomy or mastectomy is the mainstay. Chemotherapy can be performed either as neoadjuvant or adjuvant treatment in accordance with the stage and molecular characteristics of the disease. Chemotherapy is often performed using regimens used to treat conventional breast cancer and pulmonary small-cell carcinoma. Hormonal treatment is administered in cases with positive hormone receptor status. Radiation therapy may be performed, but one study has suggested that it does not prolong the survival of patients with SCNCB [6]. Efforts to develop novel targeted therapies for SCNCB are also under investigation [4].

In conclusion, we present a case of SCNCB with mammography, ultrasonography, and MRI features. Due to its low incidence, imaging features of SCNCB are not well documented yet. Thus, preoperative differential diagnosis from other types of breast cancer is challenging. Further studies are required to better understand this disease entity.