Medullary Carcinomas Of The Breast Research Articles

The Immunophenotype of Nodular Variant of Medullary Carcinoma of the Breast.

The histologic and immunohistochemical profile of typical medullary carcinomas (TMC) of the breast are well established. Among the strict histologic criteria for the diagnosis of TMC is complete circumscription of tumor with pushing borders. Those tumors that do not fulfill all morphologic requirements of TMC are designated as atypical medullary carcinomas (AMC). We herewith describe the histology and immunophenotype of a heretofore undescribed variant of TMC composed of multiple distinctly separate nodules that otherwise meet all other histologic and immunohistochemical phenotypes of TMC. Among 2952 cases of infiltrating mammary carcinomas, 111 (3.8%) met the strict criteria for TMC, including positivity for HLA-DR. Nine of these tumors were composed of multiple separate noncoalescing nodules. Immunohistochemical stains for ER, PR, HER2, and HLA-DR, as well as for p53 and Ki-67 were repeated on these nodular forms. Staining for p63 was used to identify possible intraductal components of these tumors. The age of patients ranged from 34 to 53 years. All 9 patients had negative sentinel lymph nodes. Tumors ranged in the overall size from 2.2 to 3.9 cm and were composed of 3 to 6 distinct nodules ranging in size from 0.2 to 1.1 cm surrounding a larger main tumor nodule. The nodules were composed of syncytial groups of large cells with atypical nuclei and prominent nucleoli. A lymphoplasmacytic infiltrate was present within and around each satellite nodule. Serial sections did not show coalescing of the nodules into a single tumor mass. Similarly, staining for p63 failed to support the possibility of nodules representing intraductal components of main tumor. All tumors were negative for ER, PR, and HER2, but positive for HLA-DR. Eight of 9 tumors were diffusely positive for p53 and all 9 showed a high proliferation index in >70% of tumor cells with Ki-67. We conclude that the nodular variants of medullary carcinomas (nTMC) of the breast are uncommon forms of TMC. They occur in relatively younger women and share the same immunophenotype with TMCs; they are triple negative, express HLA-DR and p53, and show a high proliferative index. As the diagnosis of TMC carries major clinical and prognostic implications, the recognition of its nodular variant becomes equally important.

CD8+ lymphocytes and apoptosis in typical and atypical medullary carcinomas of the breast

Medullary breast carcinoma (MBC) is a form of ductal invasive carcinoma (DIC) characterized by an abundant infiltration of the tumour by lymphocytes. MBC has been classified histologically into typical medullary carcinoma (TMC) and atypical medullary carcinoma (AMC), with TMC having a better prognosis than AMC and other DIC. The distribution of CD8+ lymphocytes within tumour nests and lymphocyte tracts, and apoptosis in lymphocytes and tumour cells within tumour nests, were studied in archived formalin fixed and paraffin embedded tissues of TMC and AMC. CD8+ lymphocytes tend to accumulate along the margins of lymphocyte tracts that adjoin tumour nests. There were significantly more CD8+ lymphocytes within tumour nests of TMC than AMC. TMC also tended to have more CD8+ lymphocytes within lymphocyte tracts than AMC. Apoptosis of lymphocytes in contact with tumour cells and of tumour cells in contact with lymphocytes was observed in both AMC and TMC within tumour nests but differences in the proportions of apoptotic tumour cells and lymphocytes between the two tumour types could not be established. The findings are consistent with CD8+ cytotoxic lymphocyte-mediated immunity contributing to the more favourable prognosis for TMC compared to AMC.

Medullary Carcinoma of the Breast: MRI Findings

The objective of our study was to describe the MRI findings of medullary carcinoma of the breast and to correlate those findings with the histopathologic findings. From January 2005 to June 2010, MR images of 15 patients (age range, 32-73 years; mean age, 50 years) with pathologically confirmed medullary carcinoma of the breast were retrospectively evaluated according to BI-RADS. MR images were reviewed for the following: enhancement type (mass vs nonmass), size, shape, margins, contrast enhancement, signal intensity, and time-intensity curve pattern on a dynamic study. These MR features were correlated with the histopathologic features. All 15 tumors were seen as a mass on MRI. The median size of the masses was 2.7 cm (range, 1.5-6.3 cm) and the most common features were an oval or lobular shape (13/15, 86.7%) and a circumscribed margin (13/15, 86.7%). Rim enhancement with enhancing internal septations was seen in seven masses (46.7%), and rim enhancement was seen in six masses (40%). A hypointense rim on T2-weighted images was seen in nine tumors (9/15, 60%). Last, the kinetics curve showed a rapid initial increase in enhancement and a washout or plateau pattern on delayed phase imaging in all 15 tumors. On MRI, medullary carcinomas of the breast appeared as masses with an oval or lobular shape and circumscribed margins. Rim enhancement with or without enhancing internal septations was frequently seen on contrast enhancement.

Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch-dependent mechanism

Wnt and Notch signaling have long been established as strongly oncogenic in the mouse mammary gland. Aberrant expression of several Wnts and other components of this pathway in human breast carcinomas has been reported, but evidence for a causative role in the human disease has been missing. Here we report that increased Wnt signaling, as achieved by ectopic expression of Wnt-1, triggers the DNA damage response (DDR) and an ensuing cascade of events resulting in tumorigenic conversion of primary human mammary epithelial cells. Wnt-1-transformed cells have high telomerase activity and compromised p53 and Rb function, grow as spheres in suspension, and in mice form tumors that closely resemble medullary carcinomas of the breast. Notch signaling is up-regulated through a mechanism involving increased expression of the Notch ligands Dll1, Dll3, and Dll4 and is required for expression of the tumorigenic phenotype. Increased Notch signaling in primary human mammary epithelial cells is sufficient to reproduce some aspects of Wnt-induced transformation. The relevance of these findings for human breast cancer is supported by the fact that expression of Wnt-1 and Wnt-4 and of established Wnt target genes, such as Axin-2 and Lef-1, as well as the Notch ligands, such as Dll3 and Dll4, is up-regulated in human breast carcinomas.

O-67. An audit of clinical and radiological characteristics of medullary carcinomas of the breast

O-67. An audit of clinical and radiological characteristics of medullary carcinomas of the breast

Comparison of Mammographic and Sonographic Findings in Typical and Atypical Medullary Carcinomas of the Breast

AIM: The aim of this study was to describe the contribution of mammographic and sonographic findings to the discrimination of typical and atypical histopathologic groups of medullary carcinomas of the breast. MATERIALS AND METHODS: Imaging findings were retrospectively assessed in 33 women with medullary carcinomas (15 typical medullary carcinomas and 18 atypical medullary carcinomas) identified during pre-operative mammography. Twenty-nine of these women also had ultrasound and these findings were reviewed. RESULTS: Mammography showed a well circumscribed mass in 10 of the 15 (67%) typical medullary carcinomas and in four of the 17 (24%) atypical medullary carcinomas (P<0.02). One small tumour in a woman with atypical medullary carcinoma was missed on mammography and was shown only on sonography. Sonographically, an irregular margin surrounding the whole mass or part of it was seen in three out of 14 (21%) patients with typical medullary carcinoma and in nine out of 15 (60%) patients with atypical medullary carcinomas (P<0.05). Posterior acoustic shadowing was more often observed in the typical medullary carcinoma group than in atypical medullary carcinoma and the difference was found to be statistically significant (P<0.05). None of the other mammographic and sonographic findings were sufficiently characteristic to allow for a differentiation between two groups. CONCLUSION: When typical medullary carcinomas were compared with atypical medullary carcinomas according to imaging features, they tended to be well circumscribed masses on both mammography and sonography, and a posterior acoustic shadow was not found on sonography. However, the imaging findings in these two subgroups often resembled each other and histopathology will always be required to confirm the diagnosis. Yilmaz, E. etal. (2002). Clinical Radiology57, 640–645.

Sonographic and pathologic findings in typical and atypical medullary carcinomas of the breast.

We investigated whether there was a relationship between the sonographic and histologic appearances of medullary carcinomas of the breast to determine whether sonography is helpful in the differentiation of typical and atypical medullary carcinomas. We retrospectively reviewed the histologic slides and sonograms of 20 patients who had been diagnosed with medullary carcinoma of the breast. We then classified the carcinomas as typical or atypical based on strict histologic criteria. We also evaluated the relationship between sonographic findings and the histologic reclassification. Eight (40%) of the 20 medullary carcinomas were classified as typical, and 12 (60%) were classified as atypical. On sonography, a smooth outline was visualized in 6 (75%) of the 8 typical medullary carcinomas but in none of the 12 atypical carcinomas. A jagged margin was sonographically visualized in 10 (83%) of the 12 atypical carcinomas, and a focal irregularity in the margin was visualized in 2 (17%) of the 12 atypical carcinomas. Four of the typical medullary carcinomas had posterior enhancement, and 9 of the atypical medullary carcinomas showed retrotumoral shadowing. The difference in tumor-margin regularity between typical and atypical medullary carcinomas was found to be statistically significant (p < 0.001) using the 2-tailed Fisher's exact test. To prevent overdiagnosis of medullary carcinoma, a thorough pathologic review of the entire tumor is recommended if sonography shows a jagged margin or a margin with focal irregularity.

Prognostic comparison of three classifications for medullary carcinomas of the breast.

The aim of this study was to make prognostic comparisons between the modified scheme of Pedersen et al. the definitions of Tavassoli and the Ridolfi criteria for medullary carcinomas. Sixty breast carcinomas primarily diagnosed as medullary carcinomas were reclassified into typical medullary carcinoma (TMC), atypical medullary carcinoma (AMC) and non-medullary carcinoma (NMC) according to the three classifications. The Ridolfi classification proved to be superior to the two other schemes in discriminating survival differences between the three groups TMC, AMC and NMC. All 13 patients with TMC are still alive indicating an excellent prognosis, while 29% and 39% of the 47 patients in the AMC and NMC category, respectively, have died of their disease. In the simplified system of Pedersen et al. the survival at 10 years for TMC patients decreased to 75% and no significant survival difference between the three groups could be demonstrated. As the prognosis for AMC proved to be worse compared to TMC and in fact was similar to NMC with values of 43% at 10 years in the Ridolfi classification, we find no reasons to maintain this category. We conclude that as long as no alternative and more easily applicable diagnostic method exists, pathologists should still apply the Ridolfi criteria on these tumours with medullary features leaving two diagnostic possibilities: TMC or NMC (i.e. poorly differentiated ductal carcinoma). Only lesions that fulfil all six criteria without any doubt should be diagnosed as TMC, thus avoiding overdiagnosis and a resulting risk of undertreatment.

Medullary Carcinoma of the Breast: An Ultrastructural Morphometric Study of Nine Cases

Ultrastructural and morphometric features of 10 medullary carcinomas of the breast (MC) were investigated. Cases with a long follow-up were selected by applying stringent histologic criteria. All tumors had a homogeneous appearance by light microscopy. Under transmission electron microscopy, they showed occasional intracellular lumen formation or keratinization. In one tumor squamous differentiation was prominent and diffuse. Tumors with lymph node metastases possessed over 40% more desmosomes than nonmetastatic tumors. The number of cells with three or more nucleoli per nuclear section was significantly higher in metastatic than in nonmetastatic tumors (p = .02). Classic cases of MC of the breast display a relatively uniform appearance. However, subtle differences can be identified between metastatic and nonmetastatic tumors by ultrastructural morphometry. Although these differences are not associated with changes in the outcome of patients in this study, they seem to bear some relationship to the peculiar behavior of MC.

Absence of Epstein-Barr virus in medullary carcinoma of the breast as demonstrated by immunophenotyping, in situ hybridization and polymerase chain reaction.

Medullary carcinoma of the breast is an epithelial malignant proliferation that shares many characteristics (macroscopic, microscopic, epidemiologic, and prognostic) with lymphoepithelioma-like carcinomas of various sites. The authors hypothesized that they could also share the same etiologic agent, the Epstein-Barr virus (EBV). Epstein-Barr virus, a virus of the herpesvirus family, is to be associated with lymphoepithelioma-like carcinomas of the nasopharynx, stomach, lung, thymus, and salivary gland. Therefore, the authors looked for the virus in a series of 10 medullary carcinomas of the breast. Using immunohistochemistry, in situ hybridization and polymerase chain reaction, this investigation failed to show evidence of EBV. Similar negative results have been reported in lymphoepithelioma-like carcinomas arising in the skin and in the uterine cervix, which like the breast do not originate in the foregut. These results suggest that the pathogenesis of these tumors is not unique, implicating probably different etiopathogenic entities.

Vimentin expression in 98 breast cancers with medullary features and its prognostic significance.

The expression of vimentin, as assessed by immunohistochemistry, has been evaluated in 69 medullary carcinomas of the breast: 28 typical medullary carcinomas (TMC), 41 atypical medullary carcinomas (AMC), and 29 invasive ductal carcinomas with subtle medullary features that, however, did not fulfill the strict criteria of TMC or AMC. Immunoreactivity of at least 10% of the component cells was found in 14 of the medullary carcinomas (5 out of 28 TMC, 9 out of 41 AMC whereas only 1 of the invasive ductal carcinomas was vimentin-positive. The patients were followed for 8-13 years. No difference in recurrence-free survival or overall survival could be documented between vimentin-positive and vimentin-negative carcinomas with medullary features. No biological significance could be established for vimentin labelling in these lesions.

Role of antibody to S100 protein in diagnostic pathology.

Normal tissues and various tumors were examined for S100 protein, using anti-S100 protein antiserum, in an immunoperoxidase reaction. Among normal tissues, in addition to the previously reported presence of S100 protein in some neurons, glial, and Schwann cells of the nervous system, melanocytes and Langerhans cells of the skin, interdigitating reticulum cells of lymph nodes, and chondrocytes, we demonstrated it in myoepithelial cells and ducts of sweat glands, salivary glands, and the breast, serous glands of the lung, fetal neuroblasts, and sustentacular cells of the adrenal medulla. Among neoplasms, S100 protein previously has been reported in neurogenic tumors, melanomas, and neuroblastomas; we have demonstrated it in mixed sweat gland tumors, histiocytosis X, pleomorphic adenomas of the salivary gland, medullary carcinomas of the breast, bronchioloalveolar carcinomas of the lung, sustentacular cells of pheochromocytomas, teratomas of the ovary, and tumors of cartilage (enchondromas, osteochondromas, and chondrosarcomas). With S100 protein producing tumors, a normal progenitor cell was identified, indicating that demonstration of S100 protein in tumors confirmed their origin.