Pure primary signet ring cell carcinoma breast: A rare cytological diagnosis.

Signet ring cell carcinoma (SRCC) of the breast is a rare tumor and it is classified by World Health Organization in 2003 classification under 'mucin producing carcinomas'. Pure form of SRCC breast is an extremely rare entity and very few cases have been reported in literature so far. We present a case of pure primary SRCC of the breast in a 70-year-old female, which was diagnosed on fine needle aspiration cytology. Cytological features generally show cellular smears with tumor cells showing eccentrically placed large, irregular nuclei showing indentations at places with cytoplasmic vacuoles. This case is being presented in view of its characteristic cytological features and its rarity.

Introduction

Signet ring cell carcinoma (SRCC) breast was first described by Saphir in 1941 as a type of mucinous carcinoma and since then only few cases have been reported in the literature.[12345]

SRCC is a mucin producing carcinoma with a very low incidence. It was classified by World Health Organization in 2003 as a separate entity and placed under ‘mucin producing carcinomas’.[6]

Some signet ring cells may be seen often in association with infiltrating lobular carcinoma and sometimes with ductal carcinoma, but pure primary SRCC is an extremely rare entity.[5]

Hence, we are presenting a case of pure primary SRCC breast in a 70-year-old female.

Case Report

A 70-year-old female noticed a palpable mass in her left breast in the lower outer quadrant for 2 months with bloody discharge from the left nipple for a week. Physical examination revealed a mass measuring approximately 3 cm × 2 cm. It was firm, hard and non-mobile. Another mass was palpable in the left axillary region measuring about 4 cm × 3 cm. There was no evidence of supraclavicular lymphadenopathy. The examination of the contralateral breast and axilla was normal.

On mammography, the lesion appeared as a radiodense mass measuring 2.5 cm × 2 cm in the inferolateral quadrant with axillary lymphadenopathy (4.8 cm × 2.9 cm) and was categorized as breast imaging reporting and data system (BIRADS) IV-C-highly suspicious. Patient was advised to undergo fine needle aspiration cytology (FNAC).

On aspiration of mass in the left breast the smears prepared were stained with May-Grünwald-Giemsa (MGG) stain. Smears were cellular showing epithelial cells in small clusters and few that were individually scattered. These cells showed eccentrically placed nuclei and abundant cytoplasm. Nuclei were large, irregular and showed indentations by cytoplasmic vacuoles at places. Nuclei showed coarse chromatin with indistinct nucleoli [Figure 1]. Background comprised of dirty necrotic material with occasional cystic macrophages.

Figure 1

Photomicrograph showing cellular smears with tumor cells having abundant cytoplasm, eccentrically placed irregular nuclei with coarse chromatin and indistinct nucleoli. Inset shows a magnified image of a typical signet ring cell (MGG, ×400)

FNAC of nodule in the left axilla yielded just adequate cellularity with cells showing similar cytological features and more cystic macrophages. No indigenous lymph node population was present.

Nipple discharge showed many cystic and hemosiderin laden macrophages and few dysplastic cells and degenerated cells in a hemorrhagic background. These dysplastic cells also had eccentric placed nuclei with abundant vacuolated cytoplasm [Figure 2].

Figure 2

Photomicrograph showing a collection of dysplastic cells with abundant vacuolated cytoplasm along with cystic macrophages and hemosiderin laden macrophages in the nipple discharge (MGG, ×100)

Periodic acid Schiff (PAS) staining and diastase-PAS (d-PAS) staining was carried out and the cytoplasm showed both PAS and d-PAS positivity suggestive of mucin [Figure 3]. The diagnosis of SRCC was made and was confirmed by histopathological examination of a trucut biopsy from the lesion. Patient was advised to undergo excision and chemotherapy, but she refused any further treatment.

Figure 3

Photomicrograph showing tumor cells with periodic acid Schiff (PAS) positivity (PAS, ×400)

Discussion

SRCC is a mucin producing carcinoma, which shows aggressive lesions with a high risk of metastatic spread.[7] It can originate from both invasive lobular carcinoma and infiltrating ductal carcinoma, but more often from invasive lobular carcinomas.[268] The prevalence of SRCC features varies from 2% to 4.5% of the total breast carcinomas, but a pure form of SRCC is an extremely rare entity.[2345]

Different authors differ on the number of signet cells that must be seen to label a carcinoma as SRCC, but >20% signet ring cells is considered to be a minimum requirement.[29]

Cytological smears are usually abundantly cellular and epithelial cells are generally seen in loose or dyscohesive clusters. Tumor cells may be of a variable size-small to intermediate, with large eccentrically placed nuclei, which are displaced to the edge by cytoplasmic mucin. There is moderate anisonucleosis with moderate to marked hyperchromasia. Cytoplasm is abundant and may also be vacuolated.[7] Similar cytological features were present in our case as well.

Histological features of SRCC may vary depending on the cell of origin. When it is related to lobular carcinoma, it comprises of relatively uniform cells, which are small to intermediate in size. The targetoid pattern of classical invasive lobular carcinoma and Indian file pattern may also be seen here. A large cell variant called pleomorphic variant of invasive lobular carcinoma is also seen. Another type of signet ring cell is similar to diffuse gastric carcinoma and can be seen in association with the signet ring cell variant of ductal carcinoma in situ.[26810]

These tumor cells assume a signet ring appearance because of a large mucin filled vacuole which displaces the nucleus to the periphery. This occurs probably due to blockage in secretions due to deficiency of catenin, which probably occurs due to mutations.[911]

In our case, MGG stained smears showed cells that were remarkably plasmacytoid in appearance with some cells showing eccentric nuclei and slightly basophilic cytoplasm and a perinuclear halo. Hence, PAS and d-PAS staining were done to confirm for the presence of mucin in this case.

Number and percentage of cells assuming signet ring appearance is also important in prognostication. Studies show that >10% signet ring cells seen in stage I of infiltrating lobular carcinoma is a poor prognostic marker.[9]

To differentiate between SRCC of the breast from metastatic SRCCs from other sites, gross cystic disease fluid protein-15 (GCPFP-15) can be used as it is a sensitive marker of signet ring breast carcinoma and is useful even as an adjunct tool to diagnose metastatic signet ring carcinoma of mammary origin.[12]

Studies show that SRCC needs to be separated from other forms of breast cancer as it shows a much poorer prognosis.[10] Patients with SRCC are generally more elderly and they present with a more advanced stage of disease. They have some unusual sites of metastasis such as serosa, gastrointestinal tract, urinary tract and spleen, besides the more usual sites such as stomach, endometrium and cervix.[13]

The differential diagnosis includes mucinous carcinomas and clear cell carcinomas and metastasis from other sites. It is important to differentiate from these carcinomas as the treatment options and the outcome varies considerably.[4]

Conclusions

Pure primary SRCC breast is a very rare tumor and a cytological diagnosis is still rarer. It is an aggressive tumor with a high risk of metastatic spread and a poor prognosis.