Primary neuroendocrine carcinoma of male breast: A cytologically diagnosed rare entity.

Primary neuroendocrine (NE) carcinoma of the male breast is very rare. NE breast cancers encompass a heterogeneous group of tumors exhibiting morphological features similar to those of NE tumors of the gut and lung. They express one or more NE markers in at least 50% of the tumor cells. They are rare lesions representing about 2-3% of all breast cancers and more frequently affecting elderly patients. The present case report deals with a NE breast carcinoma in an 80-year-old male who presented with a right breast mass and axillary lymphadenopathy. The cytological features were suggestive of NE carcinoma. A thorough clinical evaluation helped confirm the primary nature of the tumor. The histopathology and immunohistochemistry helped confirm the cytological diagnosis. The histogenesis and prognostic implications of this rare breast tumor with predominant NE differentiation, unusually occurring in a male, is discussed here.

Introduction

Neuroendocrine (NE) carcinoma of the breast was first described by Cubilla and Woodruff in 1977.[1] Primary NE carcinomas of the breast are rare and represent about 2-3% of breast carcinomas.[2] They are much rarer in the male breast occurring in less than 1% of the cases.

NE breast cancers encompass a heterogeneous group of tumors exhibiting morphological features similar to those of NE neoplasms of the gut and lung. They invariably express one or more NE markers (neuron specific enolase, chromogranin, synaptophysin) in at least 50% of the tumor cells.[2] We report one such rare case in male breast diagnosed by fine needle aspiration cytology (FNAC).

Case Report

An 80-year-old male presented with a mass in the right breast of 10 years’ duration with rapid progression in growth since the previous 3 months.

Mammography showed a well-defined mass in the right breast with ipsilateral axillary lymphadenopathy.

Ultrasonography of the abdomen and computerized tomography of thorax showed no abnormalities.

Fine-needle aspiration cytology showed cellular smears with dispersed single cells and loose sheets. Tumor cells showed moderate cytoplasm and indistinct cell borders. Many nuclei showed moderate anisocytosis, irregular nuclear contours, prominent nucleoli and sprinkled chromatin [Figure 1a and 1b].

Figure 1

(a) Highly cellular smear, dispersed cells and loose sheets (Pap, ×100). (b) Tumor cells with anisocytosis, irregular nuclear borders, prominent nucleoli and sprinkled chromatin (Pap, ×400)

Considering these features, a cytological diagnosis of NE carcinoma of the breast was arrived at. Confirmation of diagnosis by histopathological examination and immunohistochemical study was suggested.

The patient underwent right radical mastectomy with axillary lymph node dissection. Gross examination revealed a tumor measuring 10 cm × 8 cm × 8 cm, with a solid, grey-white appearance and a focal cystic area [Figure 2a]. Six lymph nodes were identified. Extensive tissue sampling was done from the breast tumor and the lymph nodes. Histopathological sections studied showed a malignant tumor with cells in solid nests, trabecular and organoid patterns, separated by delicate fibro-vascular connective tissue stroma. The tumor cells contained moderate amounts of eosinophilic cytoplasm and showed nuclear pleomorphism. The nuclei were round to oval with occasional grooving and irregular outlines. Many nuclei contained large prominent nucleoli and sprinkled chromatin [Figure 2b]. Atypical mitoses ranging from 6 to 10/10 hpf were seen. A tiny focus showed a mucin pool with floating small nests of tumor cells. A focal area in the tumor also showed features of invasive papillary carcinoma [Figure 2c]. Four out of the six resected lymph nodes showed metastatic deposits from the primary breast tumor.

Figure 2

(a) Gross specimen showing solid, grey-white tumor with a cystic area. (b) Tumor cells in organoid patterns. Nuclei with prominent nucleoli and sprinkled chromatin (H and E, ×100). (c) Focal area in the tumor with features of papillary carcinoma (H and E, ×400). (d) Tumor cells with cytoplasmic chromogranin positivity (IHC, ×400)

Immunohistochemical staining revealed cytoplasmic positivity for chromogranin which confirmed the NE nature of the tumor [Figure 2d]. To exclude a non-mammary primary site, the chest, abdomen and pelvis were thoroughly examined for abnormalities, but none was detected.

Final diagnosis of primary pure solid NE carcinoma of the breast with a minor component of papillary carcinoma and metastasis to ipsilateral axillary lymph node was arrived at, following which the patient received adjuvant chemotherapy.

Discussion

Features of primary pure neuroendocrine breast carcinomas (NEBC) were considered to be special features within conventional breast carcinomas until recently.[3]

In 2003, the World Health Organization classification of breast tumors definitely established that, the immunohistochemical expression of NE markers in more than 50% of the tumor cell population is the unique requisite for NEBC diagnosis.[3] The tumor in the present case was diagnosed as NEBC based on these criteria.

Invasive papillary carcinoma is frequently associated with male breast carcinoma.[4] But, invasive papillary carcinoma associated with NE carcinoma in the male breast as seen in the present case is an unusual occurrence.[5]

Endocrine hormone related syndromes are rare in primary NEBC despite the presence of widespread disease.

The tumor cells in NE carcinomas of the breast are argyrophilic in contrast to the gut and lung carcinomas which may be of either argyrophil or argentaffin types and are hence called “argyrophilic carcinomas.”[6] Argyrophilic carcinomas of the male breast are NE tumors containing predominantly chromogranin B.[78] Most argyrophilic tumors show uniform cellularity and expansive growth as in the present case.[7] Despite being a distinct morphological and immunohistochemical entity, no statistically significant differences are seen between argyrophilic and the other commoner types of male breast carcinomas.[4]

Stage on an average is higher than for the other breast carcinomas, as in the present case, since more than 50% of the patients show lymph node metastasis at the time of presentation.

NE carcinoma may co-exist with invasive ductal carcinoma as a composite tumor.[6] However, in the present case, the predominant component was NE carcinoma which was associated with a minor component of papillary carcinoma. No mention of this kind of association is seen in the earlier studies.

About 50% of well-differentiated and moderately differentiated NE carcinomas express chromogranin A and B. Only 16% express synaptophysin. Chromogranin A may also be expressed by poorly differentiated NE carcinomas.

Mucin as seen in the present case, as also observed by Stita et al., in 26%[9] of cases and was considered to be a favorable prognostic factor by them.

NE breast carcinomas are observed not to exhibit aggressive behavior despite the presence of adverse prognostic factors.[3] Good prognosis in these tumors relates to their intrinsic nature and high rate of treatment responses.

Conclusion

NE carcinoma in male breast is a rare entity but does occur and can be diagnosed on FNAC. However, it is important to distinguish the primary NEBC from metastatic carcinoma because the management and prognosis differ.

Primary NE carcinoma of the breast may pose a cyto-histologic diagnostic challenge due to the rarity of its occurrence and paucity of literature. Nevertheless, it is an entity which no pathologist can afford to miss since it is less aggressive and shows a high rate of treatment response.