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Medullary Breast Carcinoma
Introduction
Medullary carcinoma is a rare and distinct subgroup of breast carcinomas accounting for less than 5% of all invasive breast cancers.[1] This unique histologic subtype has very strict criteria for diagnosis, including complete circumscription, the syncytial growth pattern of at least 75% of the tumor, intermediate to high nuclear grade, an associated diffuse lymphocytic infiltrate, and a lack of intraductal components or glandular differentiation.[2] The 2012 World Health Organization (WHO) updated the classification of medullary carcinoma under the umbrella term “carcinomas with medullary features,” including atypical medullary carcinoma and invasive carcinoma of no special type with medullary features.[2] Medullary carcinoma has a favorable prognosis despite its poorly differentiated histologic features and basal-like phenotype.
Etiology
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Etiology
It has been well established that both medullary and invasive ductal carcinoma with medullary features are associated with germline mutations in the BRCA1 gene. Among BRCA1-associated breast cancers, 7.8% to 19% are medullary carcinomas, and 35% to 60% show the presence of medullary features. This rate contrasts with only 2% of medullary carcinomas among sporadic, non-BRCA-associated tumors.[3] Medullary carcinoma has been shown to display the basal-like molecular subtype by gene expression profiling, which correlates with its immunophenotypic profile.[4] A high incidence of TP53 gene mutation also presents in these tumors. Most cases are aneuploid with a high S-phase fraction.[5] Array-based comparative genomic hybridization analysis has demonstrated a recurrent pattern of chromosomal alterations in medullary carcinoma, including 1q, 8q, 9p, 10p, and 16q gains; 4p and X losses; and 1q, 8p, 10p, and 12p amplicons.[6]
Epidemiology
The patient’s age at presentation is younger than that for invasive ductal carcinoma NOS, with a mean age ranging from 45 to 54 years.[7] Medullary carcinoma is unicentric in most of the patients, and bilateral carcinomas have presented in an incidence ranging from 3% to 18% of patients.[7] Bilateral tumors are common when a family history is present.[8] Typical medullary breast carcinoma occurs more frequently in patients with mutations of the suppressor gene BRCA-1 present.[9]
Pathophysiology
Medullary carcinoma has been shown to contain an increased number of activated cytotoxic lymphocytes, and most of the lymphoid infiltrate consists of T cells. This feature reflects an active host response to the tumor and may account for its favorable prognosis.[9]
Histopathology
Macroscopy:
Medullary carcinoma is well-circumscribed and moderately firm. The cut surface is fleshy and gray-tan and may appear lobular or nodular. Foci of hemorrhage, necrosis, and even cystic degeneration are not unusual. These tumors tend to be smaller than 3 cm, with a median size of 2 to 3 cm.
Histopathology:
The histologic criteria for medullary carcinoma were first clearly defined by Ridolfi and associates in 1977 [10], and since then, several proposed modified classification schemes have been proposed.[11] The diagnosis of medullary carcinoma is established based on H&E sections using histologic criteria in the majority of cases without the need for ancillary studies. Medullary carcinoma should meet all of the following 5 morphologic criteria as defined by the WHO[12]:
- Syncytial growth pattern in more than 75% of the tumor
- No glandular or tubular structures, even as a minor component
- Moderate to marked diffuse lymphoplasmacytic infiltrate in the stroma
- Moderate to marked nuclear pleomorphism
- Complete histologic circumscription
Mitoses are numerous, and atypical giant cells may be present. The terms ''atypical medullary carcinoma'' and ''carcinoma with medullary features'' have been proposed for tumors that do not fulfill all these criteria. 2012 WHO recommends grouping classic medullary carcinoma, atypical medullary carcinoma, and invasive carcinoma of no special type with medullary features within the category of carcinomas with medullary features.
Immunoprofile:
Medullary carcinomas are most often negative for estrogen and progesterone receptors and HER2 and variably express keratins 5/6 and 14, smooth muscle actin, EGFR, P-cadherin, p53, and caveolin-1. They have a high Ki-67 proliferation index.[9][4][13] P53 mutation occurs at an increased level in medullary carcinoma and is considered a biological marker for this tumor type.[14] The lymphoid infiltrate shows a predominance of CD3+ T-lymphocytes.[4]
History and Physical
Most patients with medullary carcinoma present with a palpable mass, usually in the upper outer quadrant. The tumor is often well-defined clinically and in imaging studies. Some patients with this tumor type exhibit axillary lymphadenopathy at the time of presentation, suggesting the presence of metastatic disease.[15]
Evaluation
By mammography, medullary carcinoma manifests as a mass with rounded, oval, or lobulated contours. The mass is noncalcified and has a well-defined tumor border.[16] Similar findings appear on ultrasound examination, where examples show a well-circumscribed hypoechoic mass.[16] MRI studies show round, oval, or lobular mass with a smooth margin. Internal enhancement can be homogeneous or heterogeneous with delayed peripheral enhancement by contrast-enhanced MRI.[17][18][19] Although these MRI features present consistently, they are not specific for medullary carcinoma and can be found in other histologic types of breast cancers as well as in benign lesions.[17][18]
Treatment / Management
The treatment for medullary carcinoma, either typical or atypical, is similar to invasive ductal carcinoma. The division into typical and atypical subtypes does not modify treatment options and has only prognostic significance. The treatment of medullary breast carcinoma includes modified or radical mastectomy along with radiation or chemotherapy, depending on the stage.[20] Medullary carcinomas are sensitive to radiation and chemotherapy. Breast-conserving surgery followed by adjuvant radiation may be appropriate for tumors that are 3 cm or smaller. Indications for chemotherapy include larger tumor size, nodal metastasis, and lymphovascular invasion.
Differential Diagnosis
The differential diagnosis for medullary breast carcinoma is as follows:
- Invasive carcinoma of no special type
- Chronic inflammation
- Lymphoma
- Lymphoepithelioma-like carcinoma
- Melanoma
Staging
The most widely used clinical staging system for medullary breast carcinoma is the 1 adopted by the International Union for Cancer Control and the American Joint Commission on Cancer. It is based on the TNM system (T, tumor; N, nodes; M, metastases).
Prognosis
Despite its histopathologically highly malignant characteristics, medullary breast carcinoma carries a favorable prognosis compared with the more common infiltrating ductal breast carcinoma. Medullary carcinoma is a biologically distinct cancer in which prognostic factors valid for other types of breast cancer appear to have less impact. Nodal status and tumor size remain the 2 most important prognostic factors in medullary carcinoma. There is a postulate that the extensive presence of plasma cells and lymphocytes prevents it from growing and spreading quickly.[21] The overall 10-year survival rate is 74% and over 90% in patients with negative lymph nodes.[15] Pure medullary carcinoma has a better prognosis than atypical features. Hence, strict adherence to diagnostic criteria is critical to provide a more accurate prognosis. Several studies have documented lymph nodal involvement to decrease overall survival significantly.[22] Also, the size of the tumor and distant metastasis affect overall survival.[23]
Complications
Axillary lymph node metastases:
Most published studies have reported a lower incidence of axillary lymph node involvement in patients with medullary carcinoma (19% to 46%) than those with atypical medullary carcinomas (30% to 52%) or invasive ductal carcinomas (29% to 65%).[24][25][8][26] Some authors have shown that patients with medullary carcinoma of the breast with positive lymph nodes have a 10-year overall survival lower than those with N0 nodal disease (58.8% versus 97.1%).[23]
Consultations
Consultations that are typically requested for patients with medullary breast carcinoma include the following:
- Surgical oncologist
- Oncologist
Deterrence and Patient Education
Patients must be instructed to perform breast self-examination regularly and consult their doctors if they detect any abnormality.
Enhancing Healthcare Team Outcomes
Medullary breast carcinoma is a rare subtype of triple-negative breast cancer that has distinctive clinical, morphological, and molecular features. Management of medullary breast carcinoma needs an interprofessional team involving a surgical oncologist, an oncologist, a pathologist, and a radiologist. After the treatment of medullary breast carcinoma, long-term follow-up is necessary to detect local and distant relapse. The primary care provider must refer patients with suspected breast masses to a radiologist for further workup. Medullary breast carcinoma requires an interprofessional team approach, including primary care providers, specialists, specialty-trained nurses, and pharmacists, collaborating across disciplines to achieve optimal patient results. Breast care nurses assist in evaluation, patient education, and documentation for the team. Oncology nurses administer treatments, monitor patients, and report changes to the team. Oncologic pharmacists collaborate with oncologists, reviewing the dose and drug interactions and educating patients about compliance and side effects.
References
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