Medullary Breast Carcinoma


Article Author:
Faten Limaiem


Article Editor:
Mouna Mlika


Editors In Chief:
Charles St Hill
Richard Orr
Lisa Bellin


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
5/22/2019 8:59:18 AM

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 updated the classification of medullary carcinoma under an umbrella term of “carcinomas with medullary features,” which also includes atypical medullary carcinoma and invasive carcinoma of no special type with medullary features.[2]

Medullary carcinoma has a favorable prognosis in spite of its poorly differentiated histologic features and basal-like phenotype.

Etiology

It has been well established that both medullary carcinoma 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 the presence of only 2% 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 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, there have been several proposed modified classification schemes.[11]

The diagnosis of medullary carcinoma in the majority of cases is established based on H&E sections using histologic criteria without the need for ancillary studies.

Medullary carcinoma should meet all of the following five morphologic criteria as defined by the WHO[12]:

  1. Syncytial growth pattern in more than 75% of the tumor
  2. No glandular or tubular structures, even as a minor component
  3. Moderate to marked diffuse lymphoplasmacytic infiltrate in the stroma
  4. Moderate to marked nuclear pleomorphism
  5. 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 show a predominance of CD3+ T-lymphocytes.[4]

History and Physical

Most of the patients with medullary carcinoma present with a palpable mass, usually in the upper outer quadrant. The tumor is often well-defined clinically and on 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 as 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

Histological differential diagnosis:

  • 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 one adopted by both the International Union for Cancer Control (UICC) and the American Joint Commission on Cancer (AJCC). Its basis is in 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 two 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 as compared to the one with 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

  • 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 a multidisciplinary approach involving a team that consists of a surgical oncologist, an oncologist, a pathologist, and a radiologist. After treatment of medullary breast carcinoma, long-term follow up is necessary to detect local and distant relapse. The primary care provider and nurse practitioner must refer patients with suspected breast masses to an oncologist for further work up.

 

Medullary breast carcinoma requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]


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Medullary Breast Carcinoma - Questions

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A 51-year-old woman with a personal history of clear cell carcinoma of the ovary 8 years earlier underwent radical mastectomy for a breast mass initially diagnosed as invasive carcinoma of no special type on core biopsy. On histologic examination of the surgical specimen, the breast tumor was well circumscribed with a pushing border. The neoplasm was composed of malignant cells that are not forming glands but, instead, large sheets with no architectural pattern. In addition, there is a rim of lymphocytes and mononuclear cells. At high magnification, highly atypical cells with vesicular nuclei and prominent single or multiple nucleoli are apparent. There are nuclear pleomorphism and numerous mitotic figures. Lymphocytes are very prominent and are mixed in with the tumor cells. What is the most likely immunohistochemical profile of this tumor?



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Which type of breast cancer has a lymphocytic infiltrate?



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A 65-year-old female patient with no past family history of breast carcinoma, presented with a lump in the left breast for three months. Physical examination showed a well-circumscribed, ulcerative mass, in the right upper outer quadrant of the left breast measuring 5×5 cm and was associated with foul smelling bloody discharge. A left axillary lymph node was palpable measuring 3×2 cm. Imaging studies did not disclose distant metastases. What is the most accurate TNM stage of this patient?



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A 49-year-old female presents to the clinic with complaints of a right breast lump with unilateral bloody nipple discharge for seven months. On examination, a well-delineated mass is present in the upper and outer quadrant of the right breast measuring 6x5 cm. An anterior axillary lymph node is palpable measuring 2x2 cm. The patient undergoes radical mastectomy with axillary lymphadenectomy. Histopathological analysis of the mass disclosed a well-circumscribed lesion showing pleomorphic cells arranged in sheets and cords. The tumor cells were round or oval with hyperchromasia and prominent nucleoli. The sheets of cells exhibited pushing borders without evidence of any infiltration. There was a prominent and diffuse lymphoplasmacytic infiltrate in the stroma with no evidence of vascular invasion. All the margins and base of the specimen were free of malignant cell infiltration. On immunohistochemistry, the tumor was triple negative. Which of the following is the most likely diagnosis?



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A 53-year-old woman presents to the clinic with a left-breast lump. On physical examination, the patient has a well-demarcated mass located in the upper outer quadrant of her left breast with a palpable unilateral axillary lymph node. Mammography and ultrasonography depict a well-defined heterogeneous lesion measuring 6-cm in diameter without calcifications. Fine-needle aspiration cytology of the lesion reveals highly cellular smears containing large atypical cells arranged in syncytial sheets and intimately admixed with lymphocytes and neutrophils. The nuclear to cytoplasmic ratio was high in tumor cells whose nucleus exhibited coarse chromatin with one or more conspicuous nucleoli. Which of the following histological criteria can be appreciated on the macroscopic and histological examination of the surgical specimen and not on smears to establish the diagnosis of medullary carcinoma?



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A 60-year-old female underwent a modified radical mastectomy. On serial sectioning, 5.5 cm × 5 cm × 2.5 cm well-circumscribed tumor in the upper outer quadrant is found. Microscopic examination establishes the diagnosis of medullary breast carcinoma. Four lymph nodes dissected out of the specimen were metastatic. Immunohistochemically, the tumor is estrogen receptor/progesterone receptor (ER/PR) and CerbB2 negative. The work-up for the spread of breast carcinoma did not show metastases. Which of the following is the most appropriate pTNM classification of this tumor?



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A 55-year-old female undergoes a modified radical mastectomy for a breast carcinoma lesion. Histopathological examination shows a lesion showing pleomorphic cells arranged in sheets in greater than 75% of the tumor mass. The tumor cells are round or oval with hyperchromasia and prominent nucleoli. There is a prominent and diffuse lymphoplasmacytic infiltrate in the stroma. The pathologist hesitates between the diagnosis of poorly differentiated invasive carcinoma of no special type and medullary breast carcinoma. Which of the following statements favors the diagnosis of poorly differentiated invasive carcinoma of no special type?



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Medullary Breast Carcinoma - References

References

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