Medullary carcinoma is a rare and distinct subgroup of breast carcinomas accounting for less than 5% of all invasive breast cancers.
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.
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.
Medullary carcinoma has a favorable prognosis in spite of its poorly differentiated histologic features and basal-like phenotype.
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.
Medullary carcinoma has been shown to display the basal-like molecular subtype by gene expression profiling, which correlates with its immunophenotypic profile. A high incidence of TP53 gene mutation also presents in these tumors.
Most cases are aneuploid with a high S-phase fraction. 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.
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.
Medullary carcinoma is unicentric in most of the patients, and bilateral carcinomas have presented in an incidence ranging from 3% to 18% of patients.
Bilateral tumors are common when family history is present.
Typical medullary breast carcinoma occurs more frequently in patients with mutations of the suppressor gene BRCA-1 present.
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.
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.
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:
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.
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.
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.
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.
Similar findings appear on ultrasound examination, where examples show as a well-circumscribed hypoechoic mass.
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. 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.
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.
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.
Histological differential diagnosis:
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).
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. The overall 10-year survival rate is 74% and over 90% in patients with negative lymph nodes. 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.
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%). 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%).
Patients must be instructed to perform breast self-examination regularly and consult their doctors if they detect any abnormality.
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 approach involving a team that consists of 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 and nurse practitioner 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, all 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 educate patients about compliance and side effects. [Level 5]
|||Foulkes WD,Smith IE,Reis-Filho JS, Triple-negative breast cancer. The New England journal of medicine. 2010 Nov 11; [PubMed PMID: 21067385]|
|||Chu Z,Lin H,Liang X,Huang R,Zhan Q,Jiang J,Zhou X, Clinicopathologic characteristics of typical medullary breast carcinoma: a retrospective study of 117 cases. PloS one. 2014; [PubMed PMID: 25375803]|
|||Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium. Lancet (London, England). 1997 May 24; [PubMed PMID: 9167459]|
|||Weigelt B,Horlings HM,Kreike B,Hayes MM,Hauptmann M,Wessels LF,de Jong D,Van de Vijver MJ,Van't Veer LJ,Peterse JL, Refinement of breast cancer classification by molecular characterization of histological special types. The Journal of pathology. 2008 Oct; [PubMed PMID: 18720457]|
|||Pedersen L,Larsen JK,Christensen IJ,Lykkesfeldt A,Holck S,Schiødt T, DNA ploidy and S-phase fraction in medullary carcinoma of the breast--a flow cytometric analysis using archival material. Breast cancer research and treatment. 1994; [PubMed PMID: 8049463]|
|||Vincent-Salomon A,Gruel N,Lucchesi C,MacGrogan G,Dendale R,Sigal-Zafrani B,Longy M,Raynal V,Pierron G,de Mascarel I,Taris C,Stoppa-Lyonnet D,Pierga JY,Salmon R,Sastre-Garau X,Fourquet A,Delattre O,de Cremoux P,Aurias A, Identification of typical medullary breast carcinoma as a genomic sub-group of basal-like carcinomas, a heterogeneous new molecular entity. Breast cancer research : BCR. 2007; [PubMed PMID: 17417968]|
|||Foschini MP,Eusebi V, Rare (new) entities of the breast and medullary carcinoma. Pathology. 2009 Jan; [PubMed PMID: 19089740]|
|||Ridolfi RL,Rosen PP,Port A,Kinne D,Miké V, Medullary carcinoma of the breast: a clinicopathologic study with 10 year follow-up. Cancer. 1977 Oct; [PubMed PMID: 907958]|
|||Jacquemier J,Padovani L,Rabayrol L,Lakhani SR,Penault-Llorca F,Denoux Y,Fiche M,Figueiro P,Maisongrosse V,Ledoussal V,Martinez Penuela J,Udvarhely N,El Makdissi G,Ginestier C,Geneix J,Charafe-Jauffret E,Xerri L,Eisinger F,Birnbaum D,Sobol H, Typical medullary breast carcinomas have a basal/myoepithelial phenotype. The Journal of pathology. 2005 Nov; [PubMed PMID: 16167361]|
|||Vu-Nishino H,Tavassoli FA,Ahrens WA,Haffty BG, Clinicopathologic features and long-term outcome of patients with medullary breast carcinoma managed with breast-conserving therapy (BCT). International journal of radiation oncology, biology, physics. 2005 Jul 15; [PubMed PMID: 15990007]|
|||Pedersen L,Holck S,Mouridsen HT,Schødt T,Zedeler K, Prognostic comparison of three classifications for medullary carcinoma of the breast. Histopathology. 1999 Feb; [PubMed PMID: 10064398]|
|||Kleer CG, Carcinoma of the breast with medullary-like features: diagnostic challenges and relationship with BRCA1 and EZH2 functions. Archives of pathology [PubMed PMID: 19886718]|
|||Matkovic B,Juretic A,Separovic V,Novosel I,Separovic R,Gamulin M,Kruslin B, Immunohistochemical analysis of ER, PR, HER-2, CK 5/6, p63 and EGFR antigen expression in medullary breast cancer. Tumori. 2008 Nov-Dec; [PubMed PMID: 19267102]|
|||Bandyopadhyay S,Bluth MH,Ali-Fehmi R, Breast Carcinoma: Updates in Molecular Profiling 2018. Clinics in laboratory medicine. 2018 Jun; [PubMed PMID: 29776638]|
|||Khomsi F,Ben Bachouche W,Bouzaiene H,Chargui R,Ben Hassouna J,Mtaalah MH,Dhiab T,Hechiche M,Benna F,Boussen H,Gamoudi A,Rahal K, [Typical medullary carcinoma of the breast: a retrospective study about 33 cases]. Gynecologie, obstetrique [PubMed PMID: 17977045]|
|||Meyer JE,Amin E,Lindfors KK,Lipman JC,Stomper PC,Genest D, Medullary carcinoma of the breast: mammographic and US appearance. Radiology. 1989 Jan; [PubMed PMID: 2642350]|
|||Yoo JL,Woo OH,Kim YK,Cho KR,Yong HS,Seo BK,Kim A,Kang EY, Can MR Imaging contribute in characterizing well-circumscribed breast carcinomas? Radiographics : a review publication of the Radiological Society of North America, Inc. 2010 Oct; [PubMed PMID: 21071383]|
|||Tominaga J,Hama H,Kimura N,Takahashi S, MR imaging of medullary carcinoma of the breast. European journal of radiology. 2009 Jun; [PubMed PMID: 18353587]|
|||Jeong SJ,Lim HS,Lee JS,Park MH,Yoon JH,Park JG,Kang HK, Medullary carcinoma of the breast: MRI findings. AJR. American journal of roentgenology. 2012 May; [PubMed PMID: 22528930]|
|||Eichhorn JH, Medullary carcinoma, provocative now as then. Seminars in diagnostic pathology. 2004 Feb; [PubMed PMID: 15074561]|
|||Kuroda H,Tamaru J,Sakamoto G,Ohnisi K,Itoyama S, Immunophenotype of lymphocytic infiltration in medullary carcinoma of the breast. Virchows Archiv : an international journal of pathology. 2005 Jan; [PubMed PMID: 15660281]|
|||Martinez SR,Beal SH,Canter RJ,Chen SL,Khatri VP,Bold RJ, Medullary carcinoma of the breast: a population-based perspective. Medical oncology (Northwood, London, England). 2011 Sep; [PubMed PMID: 20390465]|
|||Reinfuss M,Stelmach A,Mitus J,Rys J,Duda K, Typical medullary carcinoma of the breast: a clinical and pathological analysis of 52 cases. Journal of surgical oncology. 1995 Oct; [PubMed PMID: 7564387]|
|||Wargotz ES,Silverberg SG, Medullary carcinoma of the breast: a clinicopathologic study with appraisal of current diagnostic criteria. Human pathology. 1988 Nov; [PubMed PMID: 2846422]|
|||Rapin V,Contesso G,Mouriesse H,Bertin F,Lacombe MJ,Piekarski JD,Travagli JP,Gadenne C,Friedman S, Medullary breast carcinoma. A reevaluation of 95 cases of breast cancer with inflammatory stroma. Cancer. 1988 Jun 15; [PubMed PMID: 2835145]|
|||Pedersen L,Zedeler K,Holck S,Schiødt T,Mouridsen HT, Medullary carcinoma of the breast. Prevalence and prognostic importance of classical risk factors in breast cancer. European journal of cancer (Oxford, England : 1990). 1995 Dec; [PubMed PMID: 8652258]|