Metaplastic breast carcinomas are basal-like tumours

AIMS: Recently, an immunohistochemical panel comprising antibodies against HER2, oestrogen receptor (ER), epidermal growth factor receptor (EGFR) and cytokeratin (CK) 5/6 was reported to identify basal-like breast carcinomas, as defined by cDNA microarrays. Our aim was to analyse a series of metaplastic breast carcinomas (MBCs) using this panel plus two other basal markers (CK14 and p63) and progesterone receptor (PR), to define how frequently MBCs show a basal-like immunophenotype. METHODS AND RESULTS: Sixty-five cases were retrieved from the pathology archives of the authors' institutions and reviewed by three of the authors. Immunohistochemistry with antibodies for HER2, ER, EGFR, CK5/6, CK14 and p63 was performed according to standard methods. All but six cases (91%) showed the typical immunoprofile of basal-like tumours (ER- and HER2-, EGFR+ and/or CK5/6+). When CK14 and p63 were added to the panel, two additional cases could be classified as basal-like. The majority of MBCs lacked PR, except 4/19 (21%) carcinomas with squamous metaplasia. CONCLUSIONS: Our results demonstrate that MBCs show a basal-like phenotype, regardless of the type of metaplastic elements. Moreover, as these neoplasms frequently overexpress EGFR (57%), patients with MBC may benefit from treatment with anti-EGFR drugs.     

Metaplastic carcinomas of the breast. I. Matrix-producing carcinoma

The clinical and pathologic features of 26 examples of a histopathologically distinct form of metaplastic carcinoma of the breast are reported. All neoplasms had overt carcinoma with direct transition to a cartilaginous and/or osseous stromal matrix without an intervening spindle cell zone or osteoclastic giant cells. Therefore, we designate this distinctive form of metaplastic carcinoma as "matrix-producing carcinoma" (MPC). All patients were women, the average age was 58 years, and all patients were eligible for a minimum of 5 years follow-up (mean follow-up period, 8.6 years). Twenty-three patients were treated by a form of mastectomy and three were treated by local excision. The 5-year survival rate for patients following mastectomy or partial mastectomy was 70%, contrasted with 50% for patients treated by local excision. The cumulative 5-year survival rate for MPC was 68%. All of the nine lesions that recurred did so within 2.5 years of initial therapy. Eight of these patients (89%) died from tumor within 4 years of initial therapy. The ninth was alive at last contract. Radiation and chemotherapy were of limited effectiveness. Significant features of the neoplasm associated with progression were large size, diffuse cellularity of the stromal matrix, and atypical cartilaginous metaplasia. Ultrastructural examination of one case and immunohistochemical evaluation of 12 cases revealed MPC to have myoepithelial characteristics.     

Mucinous breast lesions: diagnostic challenges

Breast lesions with mucin represent a broad spectrum of entities, ranging from benign fibrocystic changes with luminal mucin to mucocele-like lesions (MLL), which can be associated with banal epithelial alterations, atypical ductal hyperplasia or ductal carcinoma in situ. Occasionally invasive mucinous carcinoma can be identified in contiguity with MLL. Diagnostic challenges are enumerated, histological differentials are discussed, and a practical approach towards resolving some of these issues is provided. In addition to these lesions with abundant extracellular mucin, there are also conditions that feature stromal mucinous or myxoid material, as well as rare entities that demonstrate both epithelial extracellular and stromal mucin.     

Liposarcomas: diagnostic pitfalls and new insights

Liposarcomas represent the most common histotype among soft tissue sarcomas. However, liposarcomas in fact constitute a heterogeneous group of distinctive lesions that pose several diagnostic difficulties. The current World Health Organization classification of soft tissue and bone tumours recognizes four major liposarcoma subtypes: (i) atypical lipomatous tumour/well‐differentiated liposarcoma; (ii) de‐differentiated liposarcoma; (iii) myxoid liposarcoma; and (iv) pleomorphic liposarcoma. These four main subgroups are characterized by distinctive morphologies, unique genetic findings as well as distinct clinical behaviour. Accurate classification requires the integration of morphological, immunohistochemical and (in selected situations) genetic findings, and is essential for providing patients with the best available treatments. This review will focus upon the main diagnostic pitfalls encountered in the routine diagnosis of liposarcoma, underlining the diagnostic value of combining morphology with cytogenetics and molecular genetics.     

Metaplastic carcinoma of the breast

Metaplastic carcinomas of the breast are a rare but morphologically heterogeneous group of tumours with a distinct immunoprofile. We describe a case of metaplastic carcinoma with mesenchymal differentiation in a patient who presented with a left breast lump. These tumours are typically composed of metaplastic cartilaginous, osseous or rhabdomyoid elements, usually with a malignant epithelial component. Here we outline the current WHO classification of metaplastic carcinomas of the breast, key clinical features and some diagnostic challenges.     

Borderline breast lesions: diagnostic challenges and clinical implications

Breast cancer remains a global public health problem and is currently the most polarized cancer in the world. Attention to this disease, public awareness, and advances in breast imaging have made a positive impact on breast cancer screening and detection. The growing use of image-detected biopsies has led to increased diagnosis of ductal carcinoma in situ and high-risk proliferative breast lesions. This progress, however, has created a challenge for pathologists. In lieu of the fact that these entities are difficult to diagnose even in tissue sections taken from surgically excised lesions, pathologist are now expected to diagnose them in small and often fragmented tissue/cellular samples obtained from image-guided biopsies. In addition, some proliferative lesions are associated with an increased risk of finding neighboring malignancy when diagnosed on minimally invasive procedures. Therefore, classifying these lesions in small biopsies is difficult and risky. Some of the most challenging areas in diagnostic pathology includes the differentiation between atypical ductal hyperplasia and low-grade ductal carcinoma in situ, lobular neoplasia versus solid low-grade ductal carcinoma in situ, the correct interpretation of papillary lesions with atypia, and classifying the spectrum of columnar cell changes. Although these issues have been recognized for years, consensus criteria and uniform terminology for the diagnosis of these problematic lesions are far from being achieved. The purpose of this study is to review these "borderline" proliferative lesions in an effort to clarify some criteria and prompt the most needed discussion for consensus.     

Metaplastic lipid-rich carcinoma of the breast

A case of lipld-rich mammary carcinoma identified in a lumpectomy specimen from a 56year-old female is presented. The tumor showed features of poorly differentiated invasive ductal carcinoma of clearcell phenotype. Cytoplasmic lucency was mainly accounted for by the accumulation of neutral fat and, to a lesser degree, glyco-gen. Tlnctorial properties Included positivity of tumor cells with Sudan iii dye and diastasesensitive periodic acid-Schiff staining. Ultrastructural examination confirmed the presence of abundant cytoplasmic lipid droplets and some glycogen rosettes. On immunohistochemistty, most tumor cells reacted for cytokeratin, vimentin and S-100 protein, and there was focal expression of carclnoembryogenic antigen. A minority of tumor cell nuclei expressed progesterone receptors. As an additional feature, part of the leslon exhibited chondroid metaplasia. Lipid-rich carcinoma of the breast is exceedlngly rare and, to our knowledge, no such example harboring metaplastic elements has been described previously.     

Metaplastic breast carcinomas are enriched in markers of tumor-initiating cells and epithelial to mesenchymal transition

Metaplastic breast carcinomas constitute a distinct aggressive form of invasive breast cancer with histological evidence of epithelial to mesenchymal transition toward spindle, chondroid, or osseous cell types. During tumorigenesis, epithelial to mesenchymal transition promotes invasion and metastasis and has been linked to the presence of stem cells. We hypothesized that metaplastic carcinomas may express epithelial to mesenchymal transition markers and may be enriched in tumor-initiating cells specifically in the non-glandular metaplastic elements. In 27 primary metaplastic carcinomas of the breast we tested the expression of epithelial to mesenchymal transition inducers ZEB1 and E-cadherin and the presence of tumor-initiating cells by using aldehyde dehydrogenase-1 (ALDH-1) and CD44(+)/CD24(-/low) immunohistochemistry. Of the 27 metaplastic carcinomas, 20 (74%) had squamous and/or spindle areas and 7 (26%) had heterologous elements (6 chondroid and 1 osseous). ALDH-1-positive and CD44(+)/CD24(-/low)-expressing cells were detected in the non-glandular metaplastic components (Fisher's exact, P=0.0017). E-cadherin expression was reduced or absent (aberrant) in all metaplastic components whereas it was normal in the glandular areas. On the contrary, overexpression of ZEB1 was detected in 41% (11 of 27) of the non-glandular, metaplastic components, and in none of the glandular areas. The presence of tumor-initiating cells, aberrant E-cadherin, and ZEB1 upregulation was associated in over 90% of the spindle areas and heterologous elements (χ(2) test, P<0.05). We provide first in situ evidence that epithelial to mesenchymal transition inducers and tumor-initiating cells are present specifically in the non-glandular components of metaplastic carcinomas.     

Metaplastic carcinoma of the breast: a clinicopathological review

BACKGROUND: Mammary metaplastic carcinoma encompasses epithelial-only carcinoma (high-grade adenosquamous carcinoma or pure squamous cell carcinoma), biphasic epithelial and sarcomatoid carcinoma and monophasic spindle cell carcinoma. AIM: To evaluate the clinicopathological features of a large series of 34 metaplastic carcinomas. METHODS: 10 epithelial-only, 14 biphasic and 10 monophasic metaplastic carcinomas were assessed for nuclear grade, hormone receptor status, HER2/neu (cerbB2) oncogene expression, Ki-67 and p53, lymph node status and recurrence on follow-up. RESULTS: Intermediate to high nuclear grade were assessed in most (33/34) tumours. Oestrogen and progesterone receptors were negative in 8 of 10 epithelial-only, all 14 biphasic, and 9 of 10 monophasic tumours, cerbB2 was negative in 7 of 10 epithelial-only, all 14 biphasic and 8 of 10 monophasic tumours. Ki-67 was found to be positive in 6 of 10 epithelial-only, 6 of 14 biphasic, and 7 of 10 monophasic tumours, whereas p53 was positive in 6 of 10 epithelial-only, 7 of 14 biphasic, and 8 of 10 monophasic tumours. Lymph node metastases were seen in 7 of 7 epithelial-only, 7 of 11 biphasic, and 3 of 7 monophasic tumours. Recurrences were seen in 4 of 7 epithelial-only, 8 of 9 biphasic, and 4 of 9 monophasic tumours. CONCLUSIONS: All three subtypes of metaplastic carcinoma are known to behave aggressively, and should be differentiated from the low-grade fibromatosis-like metaplastic carcinoma, which does not metastasize. Oncological treatment options may be limited by the frequently negative status of hormonal receptor and cerbB2.     

Metaplastic and medullary mammary carcinomas do not express mammaglobin

Mammaglobin A (MG-A) is purportedly useful for detecting metastatic carcinomas suspected to be of breast origin and has been advocated as a useful marker of micrometastasis in sentinel lymph nodes and minimal residual tumor in bone marrow. Little is known about its expression frequency in histologic subtypes of breast cancer. Excisional biopsy specimens from 1,079 untreated invasive mammary carcinomas were evaluated for immunohistochemical expression of MG-A. In addition to estrogen (ER) and progesterone receptors (PR) and HER2, staining for p63 and HLA-DR was used to further characterize histologic subtypes. Of the carcinomas, 36 were classified as metaplastic (based on morphologic features, ER-/PR-/HER2-, p63+), 38 as medullary (ER-/PR-/HER2-, HLA-DR+), and 1,005 as ductal, no special type (NST). All metaplastic and medullary carcinomas were negative for MG-A. Of 1,005 ductal carcinomas, NST, 492 (49.0%) were MG-A+, 62.0% with a reaction in fewer than 25% of the cells. MG-A immunohistochemical studies failed to detect all medullary and metaplastic cancers and more than 50% of ductal carcinomas, NST. In two thirds of MG-A+ ductal carcinomas, the reaction was only focal and usually in a minority of cells. These findings suggest that MG-A has limited value in identifying the mammary origin of carcinomas, particularly in small biopsy specimens used to detect metastasis or minimal residual disease.     

Opportunities and challenges of disease biomarkers: a new section in the journal of translational medicine

A new section of the Journal of Translational Medicine is being introduced to encourage rapid communication of methods and results that utilize computational modeling and epidemiologic approaches in translational medicine. The focus will be on population-based studies that extend towards more molecular level analysis. Submission of studies involving methods development is encouraged where actual application and results can be shown in the healthcare and life sciences domains.     

Metaplastic carcinoma of the breast--a rare breast tumour

Malignant breast neoplasms consisting of mixtures of epithelial and mesenchymal elements, are a rarity. Pathogenesis of such diverse elements within obviously infiltrating carcinomas has been the subject of much controversy. After the advent of immunohistochemistry, it is now generally accepted that metaplasia of the epithelial elements of a carcinoma gives these lesions their pseudosarcomatous appearance. Hence the name metaplastic carcinoma is given to malignant breast neoplasms which show Cytokeratin positivity in both epithelial and mesenchymal elements. We recently encountered such a case, which is being presented here along with relevant review of literature.     

Metaplastic breast carcinoma: a case report and systematic review of the literature

A 78‐year‐old retired woman was diagnosed with metaplastic breast carcinoma (MBC), a rare tumor, in our hospital. We reviewed 15 articles with a total of 1328 patients to determine the epidemiology, clinical features, biomarkers, histology, management and outcome of patients with this tumor. The mean age at presentation is 58.5 years (range 32–83). Eighty‐one percent of patients presented either with a breast mass or abnormal mammographic finding. Twenty‐three percent of patients had a family history of breast cancer. Estrogen receptors were only found in 12%, progesterone receptors in 10% and HER2 in 6% of patients. The main method of treatment was mastectomy (66.9%) in combination with chemotherapy (57%) and radiotherapy (47%). Five‐year disease‐free survival ranged between 40% and 84% and 5‐year overall survival ranged between 64 and 83%. We have further reviewed the nature of this disease in the light of advancement in genetics, such as microarray gene expression profiling. The relationship of MBC with triple‐negative tumor and basal‐like tumor is discussed. It is hoped that advances in genetics and biomarkers will bring forward the era of personalized medicine in the treatment of breast carcinoma.