Cytodiagnosis of secretory carcinoma of the breast.

Secretory carcinoma is a rare form of breast carcinoma which has a predilection for juveniles and young adults (usually less than 30 years of age), becoming progressively less common with advancing age. It is a low grade breast carcinoma which shows distinct features at histology. Diagnosis of this carcinoma on fine needle aspiration cytology (FNAC) is difficult. We report a case of a 62-year-old woman diagnosed to have secretory carcinoma of breast on FNAC. Histopathological examination confirmed the diagnosis. The recognition of secretory carcinoma is important because the cytological findings can be confused with those of lactating breast. Preoperative diagnosis is essential for appropriate surgical therapy. Secretory carcinoma is reported to have good prognosis, but surgical therapy with an axillary node dissection is recommended, since axillary metastases have been found in approximately 30% of the recorded cases.

Introduction

Secretory carcinoma is a rare histologic type of breast carcinoma. The characteristic features are pronounced intracellular and intramicrocystic periodic acid Schiff (PAS) positive secretions. The presence of vacuolated cytoplasm is also characteristic of this tumor. As this carcinoma usually occurs in children and young adults, it was originally referred to as a type of juvenile carcinoma. Recently, however, this tumor has been shown to occur at any age.[1] The secretory carcinoma in adults is potentially more aggressive than childhood. Nodal metastasis is more frequent and extensive. Slow growth and delayed recurrence are characteristic of many of these tumors. Prolonged follow-up is needed to assess accurately the biological behavior of this tumor.[2]

Case Report

A female aged 62 years presented with painful swelling in the right breast since two years, which was gradually increasing in size since six months. Clinical examination revealed a hard mobile lump measuring about 5 × 4 cm2 in the upper outer quadrant of the right breast. There was no ulceration of overlying skin and no nipple discharge.

Fine needle aspiration smears revealed loose clusters and isolated population of tumor cells showing abundant finely granular and vacuolated cytoplasm [Figure 1]. The tumor cells had eccentrically placed nuclei with mild pleomorphism and inconspicuous nucleoli [Figure 1]. There was no colloid material in the background and no evidence of mitotic activity in the tumor cells. A possibility of secretory carcinoma of the breast was suggested.

Figure 1

Tumor cells showing vacuolated and abundant granular eosinophilic cytoplasm (H and E). Left upper: Tumor cells showing eccentrically placed nuclei (H and E)

The patient underwent modified radical mastectomy and the specimen was sent to pathology department for histopathological examination. Cut section of the specimen revealed circumscribed firm grey-white lesion with tiny cystic areas measuring 5 × 3 × 2.5 cm3 in size [Figure 2]. Axillary pad of fat showed twelve lymphnodes.

Figure 2

Gray white tumor with pushing borders and with tiny cystic spaces filled with gray brown material

On microscopic examination, the sections revealed tumor cells arranged in solid sheets, ducts, tubular and microcystic pattern [Figure 3]. The cystic spaces showed eosinophilic secretions. The tumor cells were round to polygonal exhibiting mild atypia. Some of the cells showed intracytoplasmic vacuolation. The secretions in the lumen of microcysts were PAS positive. The tumor cells showed carcinoembryonic antigen (CEA) positivity on immunohistochemistry [Figure 3]. The sections from the lymph nodes showed reactive hyperplasia without tumor deposits.

Figure 3

Microcystic pattern of arrangement of tumor cells (H and E). Right lower: Tumor cells showing CEA positivity (IHC, ×400)

Discussion

Secretory carcinoma is a rare form of breast carcinoma seen primarily in children, but it can also occur in adults.[2] These lesions appear to have an excellent prognosis in women under the age of 20 years. The behavior in older women is less favorable with late recurrence.

Fine needle aspiration smears tend to be poorly cellular, but show abundant material in the background resembling thyroid colloid. This material does not show streaming around embedded epithelial cells as does mucin in a colloid carcinoma.[3] The tumor cells may be dispersed or in small sheets showing prominent cytoplasmic vacuolation. Some cells have granular cytoplasm. Most of the cells have bland appearance and some of them show malignant appearance. Fine needle aspiration cytology (FNAC) smears stained with May-Grünwald-Giemsa (MGG) were highly cellular with a monotonous population of dissociated and clustered tumor cells that show a bland cytological appearance with cytoplasmic vacuolation.

The cytological features of secretory carcinoma of the breast resembles that of benign epithelial proliferating lesions, particularly lactational changes or lactating adenoma,[4] which may lead to the misdiagnosis of the lesion on FNAC. Important diagnostic clues suggesting malignancy are high cellularity of the FNA cytologic material and absence of bipolar naked nuclei, which are present in the lactating adenoma.[5]

Grossly, it is usually well circumscribed, less than 6 cm in diameter. The microscopic appearance is distinctive. The margins are “pushing type” and prominent hyalinization is often present in the central portion. Tubuloalveolar and focally papillary formations lined by cells with a vacuolated cytoplasm are seen forming lumina filled by eosinophilic PAS positive secretions. Ultrastructurally, the tumor cells contain numerous membrane bound intracytoplasmic secretory vacuoles.[6]

Immunohistochemically, there is strong positivity for α – lactalbumin, S-100, CEA, lysozyme salivary type amylase and variable positivity for GCDFP 15.[6]

The differential diagnosis of secretory carcinoma of the breast are histiocytoid carcinoma, mucinous carcinoma, signet ring cell carcinoma, lipid-rich carcinoma, apocrine carcinoma, glycogen-rich, clear cell carcinoma.

In histiocytoid carcinoma, the tumor cells are strongly GCDFP 15 positive and have scant or granular mucin. Mucinous carcinoma is characterized by pools of extracellular mucin with tumor cells floating in mucin. The secretory carcinoma can be distinguished from mucinous carcinoma because of the granular background metachromasia that differs markedly from the ‘sea of mucin’ appearance seen in mucinous carcinoma. The background mucus will be less in secretory carcinoma than in mucinous carcinoma, attributing this to the fact that secretory carcinoma retains some intracellular mucins where as the mucinous carcinoma shows predominantly extracellular mucin.[7] Signet ring cell carcinoma is often associated with classic lobular carcinoma pattern and has no predilection for young patients. Smears in signet ring cell carcinoma are cellular containing poorly cohesive large malignant cells with marked anisonucleosis and hyperchromatism. The tumor cells in lipid-rich carcinoma show scant PAS positivity and stain positive for fat stains. However, secretory carcinoma is negative for fat stains. The tumor cells in apocrine carcinoma have large vesicular nuclei with prominent nucleoli and show granular cytoplasmic staining for PAS. In glycogen-rich, clear cell carcinoma the mucin is PAS positive and diastase sensitive. The diagnosis can be made definitely only on histopathological examination and with special stains.

Secretory carcinomas are distinguished from infiltrating ductal carcinomas not otherwise specified (IDC NOS) of the breast by the characteristic cytomorphology of the tumor cells which show more pleomorphism, hyperchromatic nuclei and a high nucleocytoplasmic (N:C) ratio. The presence of ETV6-NTRK3 fusion gene seems to make these particular neoplasms behave more indolent than their aggressive ductal carcinoma counterparts, which do not harbor the ETV6-NTRK3 gene fusion.[8]

Tavassoli and Norris[9] suggested three features of secretory carcinoma that indicate a favorable prognosis, namely, tumor size less than 2cm, age of less than 20 years at diagnosis and tumor with circumscribed margin.

Case reports of local recurrence following local excision suggest that local excision alone may not be adequate and have advocated mastectomy. Lymph nodal metastasis develops late in the course of disease and is observed in approximately 20-30 % of the cases.[10]

Conclusion

Secretory carcinoma is a rare breast tumor which can be diagnosed by FNAC. It is very important to differentiate this lesion cytologically from other benign lesions particularly lactating adenoma. The correct cytodiagnosis helps in appropriate surgical management.