Gelareh Farshid

The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1

Epithelial to mesenchymal transition (EMT) facilitates tissue remodelling during embryonic development and is viewed as an essential early step in tumour metastasis. We found that all five members of the microRNA-200 family (miR-200a, miR-200b, miR-200c, miR-141 and miR-429) and miR-205 were markedly downregulated in cells that had undergone EMT in response to transforming growth factor (TGF)-β or to ectopic expression of the protein tyrosine phosphatase Pez. Enforced expression of the miR-200 family alone was sufficient to prevent TGF-β-induced EMT. Together, these microRNAs cooperatively regulate expression of the E-cadherin transcriptional repressors ZEB1 (also known as δEF1) and SIP1 (also known as ZEB2), factors previously implicated in EMT and tumour metastasis. Inhibition of the microRNAs was sufficient to induce EMT in a process requiring upregulation of ZEB1 and/or SIP1. Conversely, ectopic expression of these microRNAs in mesenchymal cells initiated mesenchymal to epithelial transition (MET). Consistent with their role in regulating EMT, expression of these microRNAs was found to be lost in invasive breast cancer cell lines with mesenchymal phenotype. Expression of the miR-200 family was also lost in regions of metaplastic breast cancer specimens lacking E-cadherin. These data suggest that downregulation of the microRNAs may be an important step in tumour progression.

An autocrine TGF-β/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition

Epithelial-mesenchymal transition is a form of cellular plasticity that is critical for embryonic development and tumor metastasis. This study shows that a signaling network involving autocrine TGF-β signaling, ZEB transcription factors, and the miR-200 family regulates interconversion between epithelial and mesenchymal states.

Leiomyosarcoma of somatic soft tissues : a tumor of vascular origin with multivariate analysis of outcome in 42 cases

Leiomyosarcomas of the somatic soft tissues (SST) are rare compared with their retroperitoneal and cutaneous counterparts and, therefore, have not been extensively studied. We have analyzed the clinicopathologic features of 42 SST leiomyosarcomas referred in consultation to determine what factors affect outcome. Cutaneous, visceral, retroperitoneal, uterine, gastrointestinal, and major vessel leiomyosarcomas were excluded. By definition all lesions possessed at least focal cytologic atypia and mitotic activity, although the latter varied from <1/10 high power fields to 66/10 high power fields. The patients (21 females and 21 males) ranged in age from 26 to 86 years (mean 60 years); tumors developed in the lower (n = 28) or upper extremity (n = 11) and trunk (n = 3). Most arose in deep (n = 27) as opposed to superficial (n = 15) soft tissue; 39 arose from a small vein. During the follow-up period (mean 47 months, range 9–162 months), 3 of 38 (8%) patients developed local recurrence and 17 of 38 metastasized (45%) mostly to the lungs. In a univariate analysis age >62 years, size >4 cm, extensive necrosis, modified updated French Federation of Cancer Centers (FFCC) grade, and whether the tumor had been “disrupted” by a previous incisional biopsy or incomplete excision were significantly correlated with metastasis. AJCC stage also approached significance (p = 0.096) but could not be reliably tested because of the sparseness of the data. In multivariate analyses the logistic regression model that best predicted metastasis at 36 months incorporated the effects of age, FFCC grade, and disruption and had a sensitivity of 94.1% and a specificity of 95.2%. Disruption was the only significant risk factor for metastasis in a multivariate analysis (relative risk 2.70; p = 0.0001) but was strongly correlated with large size and deep location. Other parameters did not improve the predictive power of the model significantly. We concluded that the majority of SST leiomyosarcomas are actually of vascular origin, an observation that has clinical and possibly biologic ramifications. Our histologic definition of leiomyosarcoma to include atypia and any level of mitotic activity appears warranted by the biologic outcome in our cases. The risk of metastasis can be calculated from a model incorporating age, FFCC grade, and disruption. Because disruption correlates with size and depth, it could represent a surrogate as opposed to causal marker for metastasis. Nevertheless, in view of their vascular origin, the possibility that tumor disruption may facilitate or promote access to the bloodstream merits further study.

Massive Localized Lymphedema in the Morbidly Obese: A Histologically Distinct Reactive Lesion Simulating Liposarcoma

We report 14 cases of a soft tissue lesion in the limbs of morbidly obese adults that presents as a large mass and histologically simulates well-differentiated liposarcoma (WDL). Based on its distinctive clinical setting and morphologic identity to diffuse lymphedema we have termed this process massive localized lymphedema (MLL). All cases occurred in morbidly obese adults (mean weight 372 lbs; mean age 47 years). Women predominated (9 women; 5 men). The lesions affected the proximal medial aspect of the extremities (12 thigh; 2 arm) and were unilateral in all but two patients. Etiologically significant antecedent events include ipsilateral axillary lymphadenectomy in both patients with arm lesions, chronic lymphedema resulting from vein-stripping 10 years prior in one patient. inguinal lymphadenectomy for anal carcinoma in another patient, and significant blunt trauma to the inner thigh during a motor vehicle accident in a third patient. The tumors were long standing ( I-IO years) and extremely large (mean size 33.4 cm, 7408 g). Clinically, they were diffuse, ill-defined masses that histologically consisted of lobules of mature fat interrupted by expanded connective tissue septa. The constituents of the septa were fine, fibrillary collagen, edema fluid, and uniformly distributed fibroblasts. Clusters of capillaries were frequently found at the interface between fat and connective tissue. The widened septa simulated the fibrous bands of sclerosing WDL, but MLL lacks the degree of nuclear atypia seen in the former. The consistent clustering of reactive vessels at the interface between the fat and fibrous tissue also contrasted with WDL. Six patients experienced persistent or recurrent lesions within 10 months to 10 years. No aggressive growth or histologic progression was observed during this time, however. Awareness of the features of MLL is important to avoid misclassification of this reactive lesion with WDL.

Phyllodes tumours of the breast: a consensus review.

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.

Detection by screening mammography is a powerful independent predictor of survival in women diagnosed with breast cancer

Four hundred and sixteen invasive breast cancers, detected initially by mammography, were compared with 929 presenting symptomatically, all treated at a South Australian teaching hospital. Predictable differences included lower stages and grades, less vascular invasion and proliferative activity, and more hormone-receptor expression among the mammographically detected. Unpredicted differences included significantly higher survivals for mammographically detected cases throughout the 9 year follow-up period after adjusting for stage and the Nottingham Prognostic Index. In a multivariable analysis, differences in stage, grade, and hormone receptor expression accounted for only about half the survival advantage of mammographically detected tumours. Accounting for additional person and tumour characteristics had only a marginal effect on this result. This suggests that detection by mammography has independent favourable prognostic significance beyond that explained by conventional indicators. If confirmed, this finding would have important implications for the prognostic advice given to women and may merit further investigation into its underlying biological mechanisms.

Assessment of 142 stellate lesions with imaging features suggestive of radial scar discovered during population-based screening for breast cancer

Because some lesions diagnosed as radial scars (RS) on core biopsy have been found to be malignant on excision, core biopsy has not had an established role in the assessment of RS. In our breast cancer-screening program, we have avoided core biopsy if RS is suspected on imaging. Recently, two reports have expanded the experience with core biopsy of RS, prompting this review of our assessment protocols for lesions suspected as being RS. Between January 1996 and January 2003, stellate lesions with imaging features of RS in which core biopsy was omitted because of a presumptive radiologic diagnosis of RS are included. Demographic, radiologic, and cytologic data were correlated with the histologic findings in the excised specimen. On imaging, 9% (142) of all stellate lesions were suspected to be RS. Only 66.2% (94) were confirmed as RS on histology; 38 cases (28.6%) were carcinomas (36 invasive, 2 in situ) and 7% showed benign fibrocystic changes; 87.1% of the carcinomas required further surgery for positive margins. Axillary staging was also needed for the invasive cancers. Among the histologically proven RS, 28 of 94 (29.8%) showed areas of atypical ductal hyperplasia, lobular neoplasia, ductal carcinoma in situ, or invasive carcinoma. These proliferations were typically focal and unpredictable and were usually completely excised by the initial diagnostic biopsy. Core biopsy would be valuable in the assessment of lesions with imaging features suggestive of RS since 28.6% of such lesions are indeed carcinomas that mimic RS. Identification of these cancers would permit one stage breast and axillary surgery to be planned. The policy of mammographic surveillance for lesions with nonmalignant core biopsies remains controversial because of the paucity of data. Ongoing evaluation is needed as more experience is reported.

Morphology of breast cancer as a means of triage of patients for BRCA1 genetic testing

BackgroundWomen who have germline mutations in the BRCA1 gene are at substantially increased lifetime risk of developing breast and ovarian cancer but are otherwise normal. Currently, early age of onset of cancer and a strong family history are relied upon as the chief clues as to who should be offered genetic testing. Certain morphologic and immunohistochemical features are overrepresented in BRCA1-associated breast cancers but these differences have not been incorporated into the current selection criteria for genetic testing. DesignEach of the 4 pathologists studied 30 known cases of BRCA1- and BRCA2-associated breast cancer from kConFab families. After reviewing the literature, we agreed on a semiquantitative scoring system for estimating the chances of presence of an underlying BRCA1 mutation, based on the number of the reported prototypic features present. After a time lag of 12 months, we each examined a series of 62 deidentified cases of breast cancer, inclusive of cases of BRCA1-associated breast cancer and controls. The controls included cases of BRCA2-associated breast cancer and sporadic cases. ResultsOur predictions had a sensitivity of 92%, specificity of 86%, positive predictive value of 61%, and negative predictive value of 98%. For comparison the sensitivity of currently used selection criteria are in the range of 25% to 30%. ConclusionThe inclusion of morphologic and immunohistochemical features of breast cancers in algorithms to predict the likelihood of presence of germline mutations in the BRCA1 gene improves the accuracy of the selection process.

Computer simulations of lymph node metastasis for optimizing the pathologic examination of sentinel lymph nodes in patients with breast carcinoma

Many empiric protocols are used to detect metastases in sentinel lymph nodes (SLNs), but comparison of the efficacy of these methods is impractical because tissue is lost in processing, making reassessment with another policy difficult. Consequently, performance indicators of this test are largely unknown.

Gastric HER2 testing study (GaTHER): An evaluation of gastric/ gastroesophageal junction cancer testing accuracy in Australia

Trastuzumab provides a survival benefit in patients with human epidermal growth factor receptor 2 (HER2)-amplified/overexpressed advanced gastric and gastroesophageal junction cancers (GC/GJCs). However, the optimal method for testing is unclear. The aim of this study was to assess interlaboratory agreement on HER2 scoring in GC/GJC to aid the development of a robust testing algorithm for diagnostic practice in Australia. Nine laboratories assessed the HER2 status of 100 GC/GJC tissue samples by immunohistochemistry (IHC) and in situ hybridization (ISH) [chromogenic (CISH) or silver (SISH)] using both HER2 copy number and HER2:chr17 (chromosome 17) ratio. Results were compared with reference fluorescence ISH (FISH). Interlaboratory agreement on IHC3+ scoring was good (&kgr;=0.76), and there was good/very good agreement between IHC (positivity defined as IHC3+) and ISH when HER2 copy number was used (&kgr;=0.72 to 0.87). Agreement on CISH/SISH scoring was good/very good when HER2 copy number was used (&kgr;=0.68 to 0.86), and agreement between CISH/SISH and FISH using HER2 copy number was very good (&kgr;=0.88 to 0.91). Agreement was reduced when HER2:chr17 ratio was used. The good agreement for HER2 copy number determined by bright-field ISH suggests that this is the optimal method for testing in GC/GJC cases. An IHC3+ score was strongly predictive of a positive ISH result, although agreement for all IHC scores was only moderate, suggesting that IHC triage before ISH testing would be the most cost-effective strategy. However, because of the unique features of GC/GJC samples and the difficulty of ensuring consistent HER2 staining in the community setting, it is recommended that HER2 status in advanced GC/GJC be determined by both IHC and ISH in the same laboratory.