A rare case of apocrine carcinoma of the breast: Cytopathological and immunohistopathological study

Abstract

Invasive apocrine carcinomas of the breast are rare. Fine needle aspiration cytology (FNAC) has been increasingly used as a primary screening tool for breast lumps, with high level of sensitivity and specificity. Preoperatively, apocrine carcinoma needs to be distinguished from benign apocrine lesions and other eosinophilic and granular cell tumors. We report a rare case of invasive apocrine carcinoma in a 70-year-old female presenting with a breast lump and no axillary lymphadenopathy. FNAC was advised which yielded moderately cellular smears composed of loosely cohesive clusters of large, polygonal cells with centrally located pleomorphic, vesicular nucleus with prominent nucleoli and abundant, basophilic and granular cytoplasm. Based on above cytomorphological findings, diagnosis of apocrine carcinoma was offered. The patient then underwent right modified radical mastectomy with axillary clearance. Based on histomorphology and panel of immunohistochemical (IHC) markers the diagnosis was confirmed. Although apocrine/oncocytic cytomorphology is seen in few types of breast neoplasms, high index of suspicion and subsequent IHC study clinches the diagnosis.

Introduction

Apocrine carcinoma of the breast is rarely encountered.[1] The diagnosis of apocrine carcinoma on fine needle aspiration cytology (FNAC) at times poses problems on account of its cytomorphological mimicker's i.e., apocrine cyst, apocrine metaplasia, apocrine adenosis, atypical apocrine adenosis (borderline, malignant or atypical ductal hyperplasia of apocrine type), apocrine adenoma, apocrine carcinoma in situ and oncocytic carcinoma.[2] Hence experience of preoperative diagnosis on FNAC, which is substantiated by subsequent histopathological and immunohistochemical (IHC) marker study gives a better insight to the cytopathologist. We encountered a case of apocrine carcinoma of breast in a 70-year-old female, which was diagnosed on FNAC and confirmed on histopathology as well as IHC studies. This has prompted us to report this case.

Case Report

A 70-year-old female presented to the surgery outpatient department with a mass in the right breast for six months. It was small initially and gradually increased to its present size. Local examination revealed 3 × 3 cm mobile, firm to hard mass in the middle and outer quadrant of the right breast. There was no skin involvement or palpable axillary lymphadenopathy. Systemic examination findings were non-contributory. In view of elderly age, firm to hard slowly enlarging tumor and clinically suspicion of breast carcinoma, FNAC was advised.

FNAC from the breast mass yielded moderately cellular smears composed of loosely cohesive clusters of large, polygonal cells with abundant, basophilic and granular cytoplasm on Papanicolaou (Pap) and Leishman stain. The nucleus was centrally placed (eccentric at few places), vesicular, moderately pleomorphic and showed prominent nucleoli with irregular nuclear borders. The cells in clusters showed distinct cell margins with nuclear overlapping. Few binucleate forms were noted. All the cells were of apocrine type with no admixture of non-apocrine ductal cells. Background showed necrotic debris [Figure 1a]. Cytological report of apocrine carcinoma was offered and patient underwent right modified radical mastectomy (MRM) with axillary clearance.

Figure 1.

(a) FNAC photomicrograph showing moderately cellular aspirate, malignant epithelial cells with abundant cytoplasm in a granular background (Pap, ×100). Inset: Higher magnificati on with cells showing pleomorphic, vesicular, eccentric nucleus and prominent macronucleoli (Pap, ×1000) (b) Histopathology sections showing nests, sheets and cords of tumor cells with abundant granular eosinophilic cytoplasm and round to oval central and eccentric nuclei (H and E, ×400)

MRM specimen received was inked and serially sectioned. On gross examination, a solid growth measuring 4 × 3.8 × 2.8 cm was identified in the middle and outer quadrant. It was greyish white with tan brown, glistening areas having pushing borders.

Microscopic examination showed ill circumscribed tumor mass composed of cells arranged in nests, sheets and individually [Figure 1b]. They were round to oval polygonal cells, with abundant granular eosinophilic cytoplasm and round to oval nucleus with variably prominent nucleoli [Figure 1b]. The tumor cells were seen infiltrating the surrounding fibrofatty tissue. The cells showed moderate pleomorphism with few abnormal mitotic figures. Apocrine carcinoma in situ was identified in the surrounding ducts. Nine lymph nodes isolated were free of tumor. Based on these findings, differential diagnosis (d/d) of apocrine carcinoma, oncocytic carcinoma and neuroendocrine carcinoma was considered, and representative sections were subjected to immunohistochemical studies.

Immunohistochemical findings

Immunohistochemistry was performed with the following panel of antibodies utilized for the d/d of apocrine, oncocytic and neuroendocrine carcinoma. Hormonal status markers like ER (clone 6F11, Novacastra), PR (clone PGR312, Novacastra), HER-2 (clone CB11, Novacastra), neuroendocrine markers like non-specific enolase (NSE) (Dako), chromogranin-A (clone 5H7, Leica), synaptophysin (clone 27G12, Leica), myoepithelial marker like S-100 (Leica), collagen IV (clone PHM-12, Leica), SMA (clone1A4, Dako) and cell proliferative markers like P53 (cloneDO-7, Dako), Ki-67 (clone MIB-1, Dako). Considering the morphological features, GCDFP-15 and anti-mitochondrial antibody (AMA) was done (outsourced from Golwilkar Metropolis Laboratory). The tumor cells showed GCDFP-15 immunoreactivity and were AMA negative The tumor cells showed strong nuclear immunoreactivity for ER [Figure 2a] and strong membrane immunoreactivity for HER-2. [Figure 2b] PR, S-100, NSE, chromogranin and synaptophysin were non-immunoreactive. Ki67 labeling index was found to be 30% [Figure 2c]. P53 stained positive in about 25% of tumor nuclei [Figure 2d]. The final diagnosis was apocrine carcinoma of right breast with modified Bloom Richardson's grade 2 (score: 3 + 2 + 2 = 7).

Figure 2.

(a) ER showing strong nuclear immunoreactivity. (b) HER2 neu showing strong membrane immunoreactivity. (c) Ki67 labelling index was found to be 30% (d) P53 showing positivity in about 25% of tumor nuclei

Discussion

Apocrine carcinoma is a very rare morphologic entity of female invasive breast carcinoma.[1,2] Its incidence varies from 0.5 to 4%.[2,3] FNAC has been increasingly used as a primary screening tool for breast lumps with high level of sensitivity and specificity.[4] But atypical apocrine cells can pose diagnostic difficulties. Apocrine changes of lesions of the breast can be seen in a spectrum from microscopic cysts to invasive carcinomas.[2,5] Preoperatively, apocrine carcinoma needs to be distinguished from benign apocrine lesions and granular cell tumor.[6] FNAC smears in benign apocrine lesions, such as atypical apocrine adenosis, apocrine adenoma, granular apocrine metaplasia and degenerative cysts are of low cellularity and are composed of cells arranged in flat more regular sheets. Their nucleus is round to oval, bland and monotonous with centrally located nucleoli. Their cytoplasm is abundant and granular.[3,7] FNAC smears in invasive apocrine carcinoma are moderate to highly cellular and show predominantly dispersed or loosely cohesive tumor cells in a granular background. The carcinoma cells contain abundant, dense to granular cytoplasm, round to oval and sometimes eccentrically placed nuclei, a smooth nuclear outline, evenly dispersed chromatin and prominent eosinophilic macronucleoli. The cell borders are discrete.[3,7] In contrast to benign apocrine cells, the malignant cells show nuclear overlapping, more frequent nuclear pleomorphism, raised nucleo-cytoplasmic ratio and occasional mitotic figures.[3,7] Thus recognition of subtle cytologic differences renders a definite preoperative diagnosis possible. Tru-Cut biopsy helps in diagnosing lesions given as suspicious of malignancy. Subsequently on histopathological examination, using morphological criteria proposed by Japaze, helps confirming apocrine carcinoma.[1,8] It is interesting to note that the criteria are solely based on morphology.

In our case, differential diagnosis of oncocytic carcinoma was considered. Apocrine cells and oncocytes share similar morphological features on hematoxylin and eosin stain level. However there are subtle morphological, ultrastructural and immunohistochemical differences between the two cell types. Oncocytic carcinoma is composed of cells with low grade nuclei and abundant granular cytoplasm. Ultrastructurally, they are composed of abundant and dispersed mitochondria as against perinuclear distribution in apocrine carcinoma. IHC studies show that oncocytic carcinomas show diffuse strong staining with antimitochondrial antibody and are GCDFP-15 protein negative. Apocrine carcinomas are however GCDFP-15 positive and show focal weak staining with anti-mitochondrial stain.[9,10]

Most studies have shown no clear differences in behavior of apocrine carcinoma from invasive ductal carcinoma not otherwise specified.[8] Some studies have shown significantly better prognosis for apocrine carcinoma with overall six year survival of 72% as against 52% for IDC NOS.[8] In our case, in spite of having tumor of large size, we did not observe lymphovascular invasion and lymph node metastasis indicating better prognosis. This observation needs to be substantiated by cumulative data in future.

Apocrine lesions have long been reported to have altered expression profile for hormone receptors. Benign apocrine cells are androgen receptor positive, estrogen and progesterone receptor negative. This unique profile is largely retained in apocrine ductal carcinoma in situ but is more variable in apocrine carcinoma.[2] IHC studies done in this case showed strong ER and HER2 neu immunoreactivity and PR was found to be negative. Use of different antibody clones and different cut-off level to dichotomize results would account for some variability.[2]

Ki 67 positivity is significantly higher in malignant than benign apocrine breast lesions. None of the benign and borderline cases demonstrate P53 positivity but many malignant cases demonstrate p5 positivity. Ki67 and p5 are good markers for differentiating between benign and malignant breast apocrine lesions.[10] This finding was similar to our case.

Recognition of apocrine morphologic type may add to the understanding of disease pathogenesis and predict a better prognosis of breast cancer. It needs to be distinguished from benign apocrine metaplastic lesion preoperatively, so that appropriate treatment can be given to the patient.