High-grade carcinomas of the breast showing patterns of mixed ductal and myoepithelial differentiation (including myoepithelial cell-rich carcinoma of the breast)

AIMS: To assess the clinical, morphological and immunophenotypic characteristics of breast carcinomas showing patterns of mixed epithelial and myoepithelial differentiation. METHODS AND RESULTS: Included in the study were four carcinomas containing a mixed population of epithelial and myoepithelial cells identified using morphological features at the light microscopic level which were found amongst a review of 500 archival cases and two recently accessioned cases. The carcinomas varied in size from 20 to 38 mm and all were grade 3 ductal carcinomas. Most showed nodular and sheet-like cellular aggregates, although one case showed small solid cell aggregates with duct formation. The cells were large, round, polygonal or spindle-shaped and had areas of clear or eosinophilic cytoplasm in variable proportions. Foci of metaplasic carcinoma were present in three cases. All cases showed strong, patchy positivity for cytokeratin (CK)14, calponin, smooth actin and muscle specific actin. Epithelial membrane antigen and CK8 were positive in a similar proportion of cells. One patient died 23 months following diagnosis with metastatic carcinoma, another patient died of unrelated disease and four patients are alive with follow-up ranging from 18 months to 25 years. CONCLUSIONS: High-grade carcinomas of the breast showing patterns of mixed ductal and myoepithelial differentiation may show additional morphological features such as foci of metaplasia and appear to have a good prognosis similar to myoepithelial cell-rich carcinomas. However, young age and lymph node metastasis may portend a worse prognosis.     

乳腺肌上皮癌3例临床病理特征分析

目的探讨乳腺肌上皮癌的临床表现、组织形态学改变和免疫表型特征。方法采用HE及免疫组化Leica BOND-MAX全自动染色仪Bond Polymer Refine Detection法,对3例乳腺肌上皮癌进行染色,并复习相关文献。结果乳腺肌上皮癌的癌组织多由梭形细胞组成,部分病例可见上皮样细胞、浆样细胞和透明细胞,呈实性片状、肺泡样、条索状排列;核分裂象易见;无坏死;可发生腋窝淋巴结转移。免疫表型:3例均表达CK、EMA、CD10、p40、actin、Calponin、p63;2例表达CK5/6、CK14、SMA;1例表达S-100蛋白、D2-40、CAM5.2;CD117、CD34、ER、PR、C-erb B-2/HER-2和desmin均不表达;Ki-67增殖指数为10%~20%。结论肌上皮癌细胞形态多样,结合免疫组化组合标记可做出明确诊断,治疗方式以乳腺癌根治术为主。     

Esophageal basaloid carcinoma with marked myoepithelial differentiation

A case of esophageal basaloid carcinoma with marked myoepithelial differentiation in a 60-year-old man is reported. The tumor arose as an exophytic mass, measuring 65 x 60 mm, in the middle thoracic esophagus. Approximately two-thirds of the tumor surface was covered with non-cancerous esophageal epithelium. The depth of tumor invasion was limited to the submucosal layer. Histologically, about 70% of the tumor contained a typical basaloid carcinoma component and about 30% contained glandular and intercalated duct-like components with distinct epithelial and myoepithelial differentiation. The tumor presented no component of distinct squamous cell carcinoma, but a small portion of cribriform-like structure, which is typical of adenoid cystic carcinoma, was visible. The inner epithelium composing the intercalated duct-like structure showed immunohistochemical positivity for cytokeratin 14, and the outer epithelium lining adjacent to the stroma showed positivity for alpha-smooth muscle actin. These findings supported epithelial/myoepithelial differentiation. To our knowledge, our case is the first patient with an esophageal basaloid carcinoma showing marked myoepithelial differentiation.     

Angiogenesis in salivary carcinomas with and without myoepithelial differentiation

To investigate whether salivary carcinomas with and without myoepithelial differentiation could present differences regarding degree of angiogenesis, we compared tumor vascularization between adenoid cystic (31 cases) and epithelial-myoepithelial carcinomas (14) versus mucoepidermoid (37) carcinoma. The expression of peroxiredoxin I was also studied to verify the potential relationship between cellular metabolism and microvascular density. Microvascular density for CD34 and CD105 were significantly lower in carcinomas with myoepithelial differentiation. However, no correlation was found between degree of angiogenesis and amounts of myoepithelial cells. High-grade peroxiredoxin I expression was found in 73.7% of mucoepidermoid carcinomas, whereas 85.1% of carcinomas with myoepithelial differentiation presented low-grade expression. In conclusion, carcinomas with myoepithelial differentiation, regardless of the amounts of myoepithelial cells, are associated to a significantly lower vascular density. The reasons for this lower angiogenic activity remain to be determined but could be related to metabolic characteristics of the cancer cells.     

Small cell undifferentiated carcinoma of the submandibular gland: immunohistochemical evidence of myoepithelial, basal and luminal cell features

A primary small cell undifferentiated carcinoma of the submandibular gland is reported. Histological studies revealed that the major part of this tumor was composed of cells slightly larger (10-14 microm) than lymphocytes. These tumor cells showed myoepithelial-cell differentiation, which was confirmed by the immunohistochemical and ultrastructural findings. Furthermore, some of them showed luminal-cell and basal-cell differentiation immunohistochemically. However, there was no evidence of neuroendocrine differentiation. These findings demonstrated that the tumor had the features of all the salivary ductal components (myoepithelial, basal, and luminal cells) and supported that the tumor might arise from the salivary duct. Furthermore, it supports the hypothesis of multipotential stem cells as the origin for small cell undifferentiated carcinomas in salivary glands.     

Breast carcinoma with basal differentiation: a proposal for pathology definition based on basal cytokeratin expression

AIM: To assess the expression and coexpression of a range of different biomarkers that have been used to define breast carcinomas with a basal phenotype (BP) and their relationship with prognosis in an attempt to refine the definition of BP and to evaluate the reliability of using a single biomarker to identify these tumours. METHODS AND RESULTS: The expression pattern of basal cytokeratins (CK5/6 and CK14), oestrogen, progesterone and androgen receptors, epidermal growth factor receptor, HER2, BRCA1, P-cadherin and myoepithelial markers (smooth muscle actin and p63) were studied in a well-characterized series of invasive breast carcinoma (1872 cases) with long-term follow-up using immunohistochemistry and tissue microarray. Although the additional markers were associated with basal CK expression, they did not serve to improve recognition of cases with differing outcome when compared with basal CKs alone and, if used to define cases, reduced considerably the proportion of cases allocated to this poor prognostic type of breast cancer. CONCLUSION: BP can be defined based on the expression of basal CKs regardless of the expression of other markers.     

Cytological criteria to predict basal phenotype of breast carcinomas

Breast carcinoma is a heterogeneous disease. It can be classified into phenotypes based on the expression of certain proteins, with distinct differences in prognosis. The basal phenotype is associated with worse prognosis and it still remains without specific treatment. However, there is currently no international consensus on the cytological criteria that could predict this phenotype. The purpose of the study was to evaluate the cytological criteria in fine‐needle aspiration biopsy and to identify their association with the basal phenotype of breast carcinoma. Fine‐needle aspiration biopsy specimens and tissue sections (mastectomy specimen) from 74 cases of high‐grade invasive ductal breast carcinomas were consecutively retrieved from the files of three institutions. Breast carcinomas were studied using the tissue microarray technique, being classified into phenotypes: luminal A, luminal B, HER2 overexpression, and basal. The cytological criteria for all cases were reviewed blindly by two pathologists according to five cytological criteria: cellularity, cell pattern, presence of necrosis, nucleoli, and nuclear atypia. Exact Fisher test was used to test the association between cytological criteria and the phenotypes of breast carcinoma. Necrosis was present in 64.7% of basal breast carcinomas, and 31.1% of nonbasal breast carcinomas, and that result was statistically significant, showing an odds ratio (OR) of 3.80. The basal phenotype, compared with the luminal A, showed more necrosis (OR = 6.97), present/prominent nucleoli (OR = 8.18), and cellularity more frequently (OR = 18.03). Necrosis, as well as present/prominent nucleoli and abundant cellularity are criteria more frequently associated to the basal phenotype of breast carcinoma. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Extensive extranodal metastases of basal-like breast cancer with predominant myoepithelial spindle cell differentiation

A differentiation towards myoepithelial cells has been demonstrated in several types of lesions in the breast. These include multifocal myoepitheliomatosis, the rare mixed tumor or pleomorphic adenoma, adenoid cystic carcinoma, adenomyoepithelioma and myoepithelial carcinoma (malignant myoepithelioma). Myoepithelial carcinoma is the only lesion purely composed of myoepithelial cells. All these tumors are benign and/or of low-grade malignancy, with the exception of malignant myoepithelioma. In contrast to the statement of the current World Health Organization (WHO), recent studies have reported that regional and distant metastases may occur in about 50% of pure myoepithelial carcinomas. The presented case of a breast carcinoma with dominant myoepithelial/spindle cell differentiation in a 58-year-old woman is an excellent example to document the highly aggressive biological behavior of this tumor phenotype. Despite an extensive chemotherapy and radiotherapy, the tumor was rapidly progressive, forming a finally exulcerating local tumor relapse and widespread metastases to the myocardium, lungs, liver, kidneys and skin. Similarities in morphology and biological behavior compared to patients with “triple-negative” (hormone receptor and Her2) monophasic sarcomatoid carcinomas and pure spindle cell sarcomas are discussed.     

The histological and immunohistochemical evidence of squamous metaplasia from the myoepithelial cells in the breast

Squamous metaplasia in the breast is well documented. However, the putative cell of origin for the squamous epithelium is not clear. This paper describes a case of fibroadenoma of the breast with myoepithelial hyperplasia and squamous metaplasia. The histological finding of transition between myoepithelial cells and squamous cells and the immunohistochemical expressions of actin and S-100 in the metaplastic squamous cells support the myoepithelial origin of squamous epithelium in the breast.     

Pulmonary myoepithelial carcinoma resembling matrix‐producing carcinoma of the breast: case report and review of the literature

Tanahashi J, Kashima K, Daa T, Yada N, Tanaka K‐I, Kawano Y, Yokoyama S. Pulmonary myoepithelial carcinoma resembling matrix‐producing carcinoma of the breast: case report and review of the literature. APMIS 2010; 118: 401–6. We report a case of pulmonary myoepithelial carcinoma with extensive myxohyaline stroma, resembling matrix‐producing carcinoma of the breast. A 76‐year‐old Japanese man presented with a nodular lesion in the left lung (S8), and underwent partial resection of the left lower lobe. Microscopically, the resected tumor was relatively well circumscribed with central hypocellular myxohyaline and peripheral hypercellular area. In the central area, eosinophilic and clear polygonal cells proliferated in a cord‐like or reticulated pattern with extensive myxohyaline stroma, while the peripheral area was composed of solid lobules of different shapes and sizes with occasional comedonecrosis. The tumor cells were markedly atypical with frequent mitotic figures. Vascular and lymphatic invasion was evident with regional lymph node metastasis. No squamous or glandular differentiation was evident in the tumor. Immunohistochemical staining implied myoepithelial differentiation. The patient developed multiple brain metastases, and died of the disease 11 months after the surgery. In this report, we discuss the histopathologic uniqueness of the present case together with a review of the literature.     

Features of basal cell carcinomas in basal cell nevus syndrome

Basal cell nevus syndrome (BCNS) is an autosomal dominant genodermatosis that is characterized by early onset basal cell carcinomas (BCCs) that define the disease and often lead to diagnosis of the underlying syndrome. The objective of this study was to investigate the anatomic location, subtypes, and impact of BCCs on a group of 61 individuals affected with BCNS attending a research colloquium. Fifty individuals had at least one prior BCC with 22 participants having over 100 lesions. The median age of syndrome diagnosis was 11 years and median age of first BCC was 16 years. Males had more lesions on the upper back, upper extremities, and M-zone of the face, while females had more lesions on the scalp, back, and lower extremities. Pigmented BCCs were concentrated on the neck, upper trunk, and extremities. Subjects with >100 lesions showed wider anatomic distribution. The number of BCCs did not correlate with any of the other major features of the syndrome. Eighty percent of affected individuals reported great concern related to BCCs, citing the limitations and morbidity of available treatments. Vigilant surveillance, which was found to be inconsistent for participants in this study, is warranted. Future work should include development of a consensus guideline on skin examinations and strategies to optimize therapy of BCCs in this syndrome.     

Morphometric analysis and p63 improve the identification of myoepithelial cells in breast lesion cytology

Nuclear findings, including size, shape, chromatin, or nucleoli, affect the cytological diagnosis and were found to have prognostic significance in several studies based on morphometric analysis. In this study, we investigated whether the nucleus area relates to the appearance of p63-positive myoepithelial cells. The nucleus area was analyzed in 101 breast cancers and 14 benign breast lesions using morphometric analysis and immunohistochemistry for p63. Breast cancer patients were classified into two groups; small nucleus group (n = 19) and large nucleus group (n = 82) based on the average nucleus area of ductal cells. The nucleus area was significantly negative correlating with p63-positive myoepithelial cells (P = 0.031), and there was a significant positive correlation with small cells with hyperchromatic nuclei (P = 0.002). Although small cells with hyperchromatic nuclei were similar to myoepithelial cells, there was no significant correlation with the appearance of small cells with hyperchromatic nuclei and p63-positive myoepithelial cells in breast cancer patients (P = 0.189). Although the identification of normal myoepithelial cells is mainly performed by immunostaining for p63, morphometric analysis of the nucleus area also suggests the existence of p63-positive myoepithelial cells.     

Nuclear DNA content in breast carcinomas with neuroendocrine differentiation

Sixty-one breast carcinomas (54 infiltrating ductal carcinomas and seven infiltrating lobular carcinomas) were immunostained with anti-NSE and analysed with respect to nuclear DNA content. Nine of the 23 NSE-positive breast carcinomas were diploid, five were triploid, six tetraploid and three pentaploid. Twenty-one of the 38 NSE-negative tumours were diploid, 10 were triploid, seven tetraploid, and none were pentaploid. Three of the eight histologically grade I tumours in the NSE-positive group were aneuploid, whereas all the six grade I tumours in the NSE-negative group were diploid. The results show that a proportion of breast carcinomas with neuroendocrine differentiation are aneuploid and that aneuploid tumours that are grade I histologically are found in the NSE-positive group and not in the NSE-negative group.     

Relative paucity of gross genetic alterations in myoepitheliomas and myoepithelial carcinomas of salivary glands

The diagnosis of salivary gland myoepithelioma, an entity with heterogeneous cytomorphology and inconsistent immunophenotype, rests on conventional histology. However, the clinical course cannot be predicted reliably from cytomorphological and immunophenotypic analysis. The present study determined the immunophenotype of a representative series of 12 myoepitheliomas and 21 malignant myoepitheliomas. Among the seven markers tested, antibodies against cytokeratins 5/6, S-100 protein, and vimentin produced the most consistent reactivity profile. Comparative genomic hybridization (CGH) profiles of 12 myoepitheliomas showed chromosomal losses in three of 12 cases. In myoepithelial carcinomas, however, ten of 19 tissues investigated by CGH lacked detectable cytogenetic aberrations. In five cases, aberrations involved chromosome 8, in line with observations in salivary gland carcinomas of other differentiation. One case that was represented in three separately localized manifestations of the disease proved informative as to the relevance of gross aberration for tumour development, as these tumours differed in their CGH profiles. Staining for cytokeratins 5/6 is a useful addition to the established immunohistological marker panel in the work-up of myoepitheliomas, because of its reliable expression in most cases and because it may underline the epithelial nature of the lesion. CGH proved to be of limited value as a diagnostic adjunct; the presence of numerous gross cytogenetic aberrations should raise the suspicion of malignancy. The low frequency of aberrations detectable by CGH in overtly malignant myoepithelial neoplasms suggests that gross cytogenetic alterations were acquired in the course of tumour progression and points to the relevance of genetic changes not resolved by CGH.     

Distribution and significance of 14-3-3sigma, a novel myoepithelial marker, in normal, benign, and malignant breast tissue

14-3-3sigma is a candidate tumour suppressor gene transactivated by p53 in response to DNA damage. In gene expression analysis of normal luminal and myoepithelial cells, 14-3-3sigma was preferentially expressed by myoepithelial cells. This study has analysed the immunohistochemical distribution and subcellular localization of 14-3-3sigma in normal breast tissue and in a large series of benign and malignant breast lesions on whole tissue sections and by tissue microarray. Immunohistochemistry demonstrated that 14-3-3sigma was consistently expressed in the cytoplasmic compartment and occasionally in the nuclei of myoepithelial cells arranged as a continuous layer around normal ducts and lobular units, whereas luminal epithelial, stromal, endothelial, pericytic, lipomatous, and neural cells showed no staining. Myoepithelial cells of benign proliferations and pre-invasive lesions were consistently positive for 14-3-3sigma. Strong expression of 14-3-3sigma was evident in one case of ductal carcinoma in situ (5.5%) and in 105/554 invasive cancers (18.9%). Survival data were available for 452 patients with invasive breast carcinoma. 14-3-3sigma cytoplasmic subcellular localization was a statistically significant prognostic factor for the whole series of invasive carcinomas, as well as for those positive for oestrogen (ER) or progesterone receptors (PR). This analysis demonstrates the utility of 14-3-3sigma as a new adjunct antibody for characterization of myoepithelial cells and myoepithelial lesions and it may be a novel prognostic factor for breast cancer patients.     

Myoepithelial carcinoma arising in an adenomyoepithelioma of the breast: case report with immunohistochemical and mutational analysis

Adenomyoepithelioma (AME) of the breast is an uncommon tumor characterized by biphasic proliferation of both epithelial and myoepithelial cells. In rare instances, the epithelial, the myoepithelial or both components of an AME may become malignant. Described herein is the case of a 69-year-old woman who presented with myoepithelial carcinoma of the breast in an AME. Malignancy of myoepithelial component (MEC) was evidenced by the presence of cytological atypia, high mitotic rate, necrosis and local invasion. Immunohistochemical study demonstrated strong expression of P53 and phosphorylated extracellular signal-regulated kinase 1/2 in MEC. Laser capture microdissection technique and mutational analysis further revealed point mutation of the p53 gene (T-->G transversion at codon 270) in this population, but not in glandular epithelial cells or adjacent normal ductal epithelium. No mutations in exons 1 and 2 of the K-, H-, and N-ras genes were identified in any of the neoplastic component. To the authors' knowledge this is the first report of a mutation in the p53 gene in a malignant AME of the breast.     

Why classify basal cell carcinomas?

Basal cell carcinoma of the skin is the commonest form of cancer in the white population. A simple pathological classification is presented and recommended for general use to aid clinicians in their management of cases. Basal cell carcinoma can be classified as nodular, infiltrative, superficial apparently multifocal and mixed in terms of the histological growth pattern. These patterns can be related to the likelihood of complete excision and, if excision is incomplete, to the frequency of recurrence.     

p63 correlates with both BRCA1 and cytokeratin 5 in invasive breast carcinomas: further evidence for the pathogenesis of the basal phenotype of breast cancer

AIMS: To study the expression of p63, cytokeratin (CK) 5 and CK8/18 in invasive ductal carcinomas and their relationship with BRCA1 and other pathological and immunohistochemical features of clinical significance. METHODS AND RESULTS: Immunohistochemistry with the antibodies p63, CK5, CK8/18, BRCA1, oestrogen receptor, progesterone receptor, p53, c-erbB-2 and Ki67 was performed in 102 formalin-fixed paraffin-embedded samples of invasive ductal carcinomas. The CK5+ cases were submitted to a double-immunolabelling study with p63. There was a strong relationship between CK5 and p63 expression and both markers were associated with hormonal receptor-negative high-grade carcinomas with high proliferative rate. Furthermore, there was coexpression of CK5 and p63 in neoplastic cells, indicating that p63, like CK5, is a marker of the basal phenotype of breast cancer. There was a strong relationship between reduced expression of BRCA1 with both p63 and CK5 expression as well as an inverse correlation between p63 and CK8/18 expression, suggesting that loss of p63 expression is required for the transition between a basal to a luminal phenotype of breast carcinoma. CONCLUSIONS: Since p63 is thought to be a marker of stem cells and may act as an oncogene, our data support the idea that BRCA1 acts as stem cell regulator.