Rajan Dewar

VEGF-A and Tenascin-C produced by S100A4+ stromal cells are important for metastatic colonization

Increased numbers of S100A4+ cells are associated with poor prognosis in patients who have cancer. Although the metastatic capabilities of S100A4+ cancer cells have been examined, the functional role of S100A4+ stromal cells in metastasis is largely unknown. To study the contribution of S100A4+ stromal cells in metastasis, we used transgenic mice that express viral thymidine kinase under control of the S100A4 promoter to specifically ablate S100A4+ stromal cells. Depletion of S100A4+ stromal cells significantly reduced metastatic colonization without affecting primary tumor growth. Multiple bone marrow transplantation studies demonstrated that these effects of S100A4+ stromal cells are attributable to local non–bone marrow-derived S100A4+ cells, which are likely fibroblasts in this setting. Reduction in metastasis due to the loss of S100A4+ fibroblasts correlated with a concomitant decrease in the expression of several ECM molecules and growth factors, particularly Tenascin-C and VEGF-A. The functional importance of stromal Tenascin-C and S100A4+ fibroblast-derived VEGF-A in metastasis was established by examining Tenascin-C null mice and transgenic mice expressing Cre recombinase under control of the S100A4 promoter crossed with mice carrying VEGF-A alleles flanked by loxP sites, which exhibited a significant decrease in metastatic colonization without effects on primary tumor growth. In particular, S100A4+ fibroblast-derived VEGF-A plays an important role in the establishment of an angiogenic microenvironment at the metastatic site to facilitate colonization, whereas stromal Tenascin-C may provide protection from apoptosis. Our study demonstrates a crucial role for local S100A4+ fibroblasts in providing the permissive “soil” for metastatic colonization, a challenging step in the metastatic cascade.

Best practices in diagnostic immunohistochemistry: Myoepithelial markers in breast pathology

CONTEXT Numerous immunohistochemical stains have been shown to exhibit exclusive or preferential positivity in breast myoepithelial cells relative to their luminal/epithelial counterparts. These myoepithelial markers provide invaluable assistance in accurately classifying breast proliferations, especially in core biopsies. Although numerous myoepithelial markers are available, they differ in their sensitivity, specificity, and ease of interpretation, which may be attributed, to a large extent, to the variable immunoreactivity of these markers in stromal cells including myofibroblasts, vessels, luminal/epithelial cells, and tumor cells. OBJECTIVE To review commonly used myoepithelial markers in breast pathology and a selection of diagnostic scenarios where they may be useful. DATA SOURCES The information outlined in this review article is based on our experiences with routine cases and a review of English-language articles published between 1987 and 2008. CONCLUSIONS To demonstrate the presence or absence of myoepithelial cells, a panel-based approach of 2 or more markers is recommended. Markers that most effectively combine sensitivity, specificity, and ease of interpretation include smooth muscle myosin heavy chains, calponin, p75, p63, P-cadherin, basal cytokeratins, maspin, and CD10. These markers, however, display varying cross-reactivity patterns and variably reduced expression in the myoepithelial cells bordering in situ carcinomas. The choice of a myoepithelial marker should be dependent on a combination of factors, including published evidence on its diagnostic utility, its availability, performance characteristics that have been achieved in a given laboratory, and the specific diagnostic scenario. When its use is deemed necessary, immunohistochemistry for myoepithelial cells in breast pathology is most effective when conceptualized as supplemental, rather than central to routine morphologic interpretation.

Best practices in diagnostic immunohistochemistry: Workup of cutaneous lymphoid lesions in the diagnosis of primary cutaneous lymphoma

CONTEXT Primary cutaneous lymphoma is a common extranodal non-Hodgkin lymphoma. These lesions share common features with their nodal counterparts, but also have differences in morphology, unique clinical presentations, and immunohistochemical features. OBJECTIVE To review the 2008 World Health Organization (WHO) and 2005 consensus WHO-EORTC (European Organisation for Research and Treatment of Cancer) classifications, and address the immunohistochemical findings in the most common primary cutaneous T- and B-cell lymphomas. Since clonality testing is commonly used as an ancillary test in the evaluation of cutaneous lymphoma, a brief section in the use and pitfalls of clonality testing is included. DATA SOURCES The WHO and EORTC classification publications and the relevant recent literature were used to compile appropriate and practical guidelines in this review. CONCLUSIONS The practice of dermatopathology and hematopathology varies widely. Thus, while this review provides an overview and guideline for the workup of lymphoid lesions of the skin, the practitioner should understand the importance of clinical correlation as well as appropriate utility of available resources (such as clonality testing) in arriving at a diagnosis in cutaneous lymphoid lesions.

Can the misinterpretation amendment rate be used as a measure of interpretive error in anatomic pathology?: Implications of a survey of the directors of anatomic and surgical pathology

A repeat survey of the Association of the Directors of Anatomic and Surgical Pathology, done 10 years after the original was used to assess trends and variability in classifying scenarios as errors, and the preferred post signout report modification for correcting error by the membership of the Association of the Directors of Anatomic and Surgical Pathology. The results were analyzed to inform on whether interpretive amendment rates might act as surrogate measures of interpretive error in pathology. An analyses of the responses indicated that primary level misinterpretations (benign to malignant and vice versa) were universally qualified as error; secondary-level misinterpretations or misclassifications were inconsistently labeled error. There was added variability in the preferred post signout report modification used to correct report alterations. The classification of a scenario as error appeared to correlate with severity of potential harm of the missed call, the perceived subjectivity of the diagnosis, and ambiguity of reporting terminology. Substantial differences in policies for error detection and optimal reporting format were documented between departments. In conclusion, the inconsistency in labeling scenarios as error, disagreement about the optimal post signout report modification for the correction of the error, and variability in error detection policies preclude the use of the misinterpretation amendment rate as a surrogate measure for error in anatomic pathology. There is little change in uniformity of definition, attitudes and perception of interpretive error in anatomic pathology in the last 10 years.

Informing and "consenting": ethical concerns regarding illiterate and vulnerable participants in clinical trials.

[ 1 ] We appreciate the article by Eric Suba (1), highlighting some inadequacies in trials comparing various methods of screening for cervical cancer. Our response pertains to his reference to the Office for Human Research Protections (OHRP) raising concerns about issues relating to informed consent. We wish to present our perspective on the process of “informing” and “consenting” vulnerable patients in lowand middle-income countries (LMICs).