No abstract

Breast cancer is a heterogeneous disease encompassing a variety of entities with distinct morphological features and clinical behaviors. Although morphology is often associated with the pattern of molecular aberrations in breast cancers, it is also clear that tumors of the same histological type show remarkably different clinical behavior. This is particularly true for 'basal-like cancer', which is an entity defined using gene expression analysis. The purpose of this article was to review the current state of knowledge of basal-like breast cancers, to discuss the relationship between basal-like and triple-negative breast cancers, and to clarify practical implications of these diagnoses for pathologists and oncologists.

Phyllodes tumours constitute an uncommon but complex group of mammary fibroepithelial lesions. Accurate and reproducible grading of these tumours has long been challenging, owing to the need to assess multiple stratified histological parameters, which may be weighted differently by individual pathologists. Distinction of benign phyllodes tumours from cellular fibroadenomas is fraught with difficulty, due to overlapping microscopic features. Similarly, separation of the malignant phyllodes tumour from spindle cell metaplastic carcinoma and primary breast sarcoma can be problematic. Phyllodes tumours are treated by surgical excision. However, there is no consensus on the definition of an appropriate surgical margin to ensure completeness of excision and reduction of recurrence risk. Interpretive subjectivity, overlapping histological diagnostic criteria, suboptimal correlation between histological classification and clinical behaviour and the lack of robust molecular predictors of outcome make further investigation of the pathogenesis of these fascinating tumours a matter of active research. This review consolidates the current understanding of their pathobiology and clinical behaviour, and includes proposals for a rational approach to the classification and management of phyllodes tumours.

The diagnostic yield of EBUS-TBNA for stage I and II sarcoidosis is higher than for TBLB.

EBUS-TBNA is less invasive and acceptably sensitive as a method for obtaining pathological confirmation of sarcoidosis.

Lobular neoplasia (LN) is a term that encompasses both lobular carcinoma in situ and atypical lobular hyperplasia. These lesions have been shown to constitute both risk indicators and nonobligate precursors of invasive breast cancer, they are relatively uncommon, and are most often identified in specimens taken for other reasons. Their incidence has increased in the last 2 decades, and novel variants, including a pleomorphic type, have been described. Loss of E-cadherin expression is recognized as a hallmark diagnostic feature of LN and invasive lobular carcinomas, and immunohistochemical (IHC) analysis using anti-E-cadherin antibodies has been proven to be a useful method to differentiate between lobular and ductal lesions. The frequent use of E-cadherin IHC analysis in routine diagnostic histopathology, however, has resulted in confusion with regard to the actual value of IHC with antibodies against E-cadherin and other proteins of the cadherin-catenin complex. This review provides an update on recent clinicopathologic and molecular data on LN and invasive lobular carcinoma and a discussion about the use and limitations of IHC with E-cadherin in diagnostic breast pathology.

PI3K-Akt signaling is critical for the development, progression, and metastasis of malignant tumors, but its role in the tumor microenvironment has been relatively little studied. Here, we report that the Akt substrate Girdin, an actin-binding protein that regulates cell migration, is expressed and activated by Akt phosphorylation in cancer-associated fibroblasts (CAF) and blood vessels within the tumor microenvironment. Lewis lung tumors grafted into mice defective in Akt-mediated Girdin phosphorylation (SA transgenic mice) exhibited a decrease in both CAF infiltration and tumor growth, compared with wild-type (WT) host control animals. Contrasting with the findings of other studies, we found that Akt-dependent phosphorylation of Girdin was not a rate-limiting step in the growth of endothelial cells. In addition, Lewis lung tumors displayed limited outgrowth when cotransplanted with CAF derived from tumor-bearing SA transgenic mice, compared with CAF derived from tumor-bearing WT mice. Collectively, our results revealed a role for Akt-mediated Girdin phosphorylation in CAF during tumor progression, highlighting the need to inhibit Akt function in both tumor cells and cells that comprise the tumor microenvironment. Cancer Res; 75(5); 813-23. Ó2015 AACR.

Microglandular adenosis (MGA) is a rare proliferative lesion of the breast composed of small glands lacking myoepithelial cells and lined by S100-positive, oestrogen receptor (ER)-negative, progesterone receptor (PR)-negative and HER2-negative epithelial cells. There is evidence to suggest that MGA may constitute a non-obligate precursor of triple-negative breast cancer (TNBC). We sought to define the genomic landscape of pure MGA and of MGA, atypical MGA (AMGA) and associated TNBCs, and to determine whether synchronous MGA, AMGA and TNBCs would be clonally related. Two pure MGAs and eight cases of MGA and/or AMGA associated with in situ or invasive TNBC were collected, microdissected and subjected to massively parallel sequencing targeting all coding regions of 236 genes recurrently mutated in breast cancer or related to DNA repair. Pure MGAs lacked clonal non-synonymous somatic mutations and displayed limited copy number alterations (CNAs); conversely, all MGAs (n=7) and AMGAs (n=3) associated with TNBC harboured at least one somatic non-synonymous mutation (range 3-14 and 1-10, respectively). In all cases where TNBCs were analyzed, identical TP53 mutations and similar patterns of gene CNAs were found in the MGA and/or AMGA and in the associated TNBC. In the MGA/AMGA associated with TNBC lacking TP53 mutations, somatic mutations affecting PI3K pathway-related genes (e.g. PTEN, PIK3CA and INPP4B) and tyrosine kinase receptor signalling-related genes (e.g. ERBB3 and FGFR2) were identified. At diagnosis, MGAs associated with TNBC were found to display subclonal populations and clonal shifts in the progression from MGA to AMGA and/or to TNBC were observed. Our results demonstrate the heterogeneity of MGAs, and that MGAs associated with TNBC, but not necessarily pure MGAs, are genetically advanced, clonal and neoplastic lesions, harbouring recurrent mutations in TP53 and/or other cancer genes, supporting the notion that a subset of MGAs and AMGAs may constitute non-obligate precursors of TNBCs.