Clinicopathological Study of Medullary Breast Carcinoma: An Instututional Study

occurs under age of 50 years, often mistaken clinically for fibroadenoma.3 MBC are divided into typical and atypical medullary carcinomas , with a prerequisite of syncytial growth pattern in >75% of the tumor cells in both. Syncytial growth pattern is characterized by tumor cells arranged in sheets, usually more than four or five cells thick, separated by small amounts of loose connective tissue.4 Typical MBC is characterised by a constellation of five histological features, as defined first by Ridolfi et al in 1977.2 These carcinomas are often hormone (ER, PR, Her2/neu) negative with grade 3 Nottinghams criteria ,basal phenotype; but have a better prognosis.2 Strong association of marked inflammation with better prognosis is seen in triple negative carcinomas.5 Presence of lymphocytes and plasma cells keeps check on MBC and prevents its growth and spread.1Overall five year survival rate is 95% in typical, 80% in atypical medullary carcinoma and 70% in invasive breast carcinoma6.. With this background, the current study was undertaken to evaluate the prevalence of MBC and to study the clinicopathological and immunohistochemical profile in typical and atypical MBC.


Introduction
Medullary breast carcinoma (MBC) is a rare, distinct type of invasive breast carcinoma 1 with incidence of less occurs under age of 50 years, often mistaken clinically for fibroadenoma. 3 MBC are divided into typical and atypical medullary carcinomas , with a prerequisite of syncytial growth pattern in >75% of the tumor cells in both. Syncytial growth pattern is characterized by tumor cells arranged in sheets, usually more than four or five cells thick, separated by small amounts of loose connective tissue. 4 Typical MBC is characterised by a constellation of five histological features, as defined first by Ridolfi et al in 1977. 2 These carcinomas are often hormone (ER, PR, Her2/neu) negative with grade 3 Nottinghams criteria ,basal phenotype; but have a better prognosis. 2 Strong association of marked inflammation with better prognosis is seen in triple negative carcinomas. 5 Presence of lymphocytes and plasma cells keeps check on MBC and prevents its growth and spread. 1 Overall five year survival rate is 95% in typical, 80% in atypical medullary carcinoma and 70% in invasive breast carcinoma 6. . With this background, the current study was undertaken to evaluate the prevalence of MBC and to study the clinicopathological and immunohistochemical profile in typical and atypical MBC.

Materials and Methods
Retrospective study of invasive carcinoma of the breast was undertaken in the department of Pathology from 2009-2016. Total number of invasive breast carcinomas were 388, of which 12 cases were MBC on histomorphology. All the 12 cases of MBCs were taken up for the study. The clinical data such as age of patient and type of surgery were collected from the medical records. Gross features of specimen and appearance on cut surface were noted. Histopathology and IHC (ER, PR, Her2/neu) slides were retrieved. Blocks were collected when slides were not available, subsequently sections were made and histopathology slides evaluated. Primary histologic feature defining both typical and atypical MBC, was presence of more than 75% syncytial tumour growth pattern and lymphoplasmacytic infiltrate in varying proportions.
Histological features characterising typical medullary carcinoma was the constellation of five histolological features such as more than 75% syncytial growth pattern, complete lesional circumscription, moderate to marked diffuse lymphoplasmacytic infiltrate, moderate to severe nuclear pleomorphism, and lack of intraductal component and tubular differentiation. 4 Atypical medullary carcinoma was defined histologically by not more than two of the following four atypical features such as margins with focal or prominent infiltrative pattern, mononuclear infiltrate mild or at the tumor margins only, benign appearing nuclei and presence of microglandular features. 4 Immunohistochemical stained slides of ER, PR, Her2/ neu were reviewed and analysed. Interpretation of ER, PR was done depending on the extent and intensity of nuclear staining as per Allred score. Interpretation of Her2/neu was done based on intensity of membrane staining pattern.
Data was analysed and evaluated using descriptive statistics such as median, range standard deviation.

Result
During the study period a total of 388 cases of invasive breast carcinoma were diagnosed out of which 12 (3.1%) were MBC. Age range was 35-64 years(mean 49.08). All cases clinically presented as solitary lump in breast. There was no side predilection however the most common quadrant affected was upper inner quadrant consitituing around 50% (6 of 12) of cases. Modified radical mastectomy (MRM) was performed in all cases since FNA was reported as carcinoma breast.
Clinical features of typical and atypical medullary carcinomas are summarized in table 1. Overall tumour size ranged from 2.5 to 6 cm (mean 3.70 cm). Average size in typical MBC was 3.6 cms (range 2.5 to 6 cms ) and atypical MBC was 4.25 cms (range 3.5-5.0 cms). One of the twelve cases clinically presented with involvement of nipple areola region.
Grossly majority of the tumors were soft to firm in consistency. Fine needle aspiration cytology showed large, pleomorphic, singly scattered and disintegrated tumor cells with dense lymphoplasmacytic infiltrate in the background.
Histologically 10 out of 12 cases (83.3%) were diagnosed as typical MBC and 2 cases were atypical MBC (16.7%). Histological features of typical and atypical MBCs are summarised in table 2 and3. Axillary lymph node dissection was done and lymph nodes were isolated. Overall 40% of typical MBC and 50% of atypical MBC showed metastatic deposits. (Table 2 & 3) IHC showed triple negativity in 75% cases of MBC comprising of 80 % in typical and 50% in atypical MBC Discussion MBC was first described by Moore and Foote in 1949. 7 These are well circumscribed lesions, often soft, fleshy and tend to bulge above the surrounding parenchyma, hence the term encephaloid. 8     an uncommon tumor accounting for less than 5% of all invasive breast carcinomas. Prevalence of MBC in our study was 3.1% which is in concordance with various studies available in literature. 1,2 Radiologically and clinically MBC mimics fibroadenoma due to its smaller size. Median size of the tumor ranged from 2-3 cms. 3 Clinically they present as circumscribed tumor with tendency for cystic degeneration and ulceration of the skin in few. In present study 1 out of 12 cases showed ulceration of the skin involving the nipple areola region. According to the study conducted by Ridolfi et al 9 , age of presentation ranged from 47-52 years. Our study showed similar age range. 60% of typical MBC occurred in age group of 40-49 years, while 50 % of atypical MBC occurred in age group of 50-59 and 60-69 years (Table 1).
Grossly, medullary carcinomas are circumscribed, nodular, fleshy with grey pink appearance on cut surface (Fig 1A). Cystic degeneration, hemorrhage and necrosis are seen.
Histologically, MBC is characterized by syncytial growth pattern (Fig 1B), complete circumscription (Fig1C), moderate to marked diffuse lymphoplasmacytic infiltrate (Fig 1C), moderate to severe nuclear pleomorphism ( Fig 1D) and  10 .The average number of lymph nodes found grossly in axillary dissection specimen from a patient with MBC is greater than for the other types of carcinoma. This difference is due to the greater ease of finding enlarged hyperplastic reactive lymph nodes in MBC. 11 Most studies indicate that the incidence of axillary lymph node metastases is lower in patients with medullary carcinomas (19%- invasive carcinoma with medullary like features. 10 16.7%, similar to study conducted by Jagtap 46%) than in those with atypical medullary carcinomas (30%-52%) or invasive ductal carcinomas (29%-65%). 12 In our study, the number of positive metastatic lymph node involvement were more in atypical MBC (50%) compared to typical MBC. Typically MBCs are almost invariably triple hormone receptor negative, although some typical and atypical MBCs are ER, PR and/or HER-2 positive, indicating the heterogeneity of this type of breast carcinomas. 13 In our study IHC showed triple negativity in 75% cases of MBC (Fig 3) with majority of in typical MBC (80%) similar to study conducted by Jagtap et al 1 .Of the two cases of atypical MBC, one case was ER, PR positive, while Her 2/neu negativity was noted in both.
Typical MBC and atypical MBC are similar in presentation, treatment and prognosis. 14,15 Few cases of atypical MBCs were treated with adjuvant chemotherapy based on Her2 status and lymph node status along with Modified radical al. 1,10 . However the division into typical and atypical MBC has prognostic significance 1,16

Conclusion
MBC is a unique type of breast carcinoma with good prognosis. Larger studies are essential to understand the tumour biology in MBC. Atypical MBC have histological features of IDC as well. Histopathology plays an important role in diagnosing variants of MBC since the prognosis varies.