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  Anatomic Abstracts

 

 

 

 

May 2012

Editors:
Michael Cibull, MD
Thomas Cibull, MD
Rouzan Karabakhtsian, MD

Atypical ductal hyperplasia: interobserver and intraobserver variability Atypical ductal hyperplasia: interobserver and intraobserver variability

Interobserver reproducibility in the diagnosis of benign intraductal proliferative lesions has been poor. The authors conducted a study to investigate the inter- and intraobserver variability and the impact on variability of adding an immunostain for high- and low-molecular weight keratins. Nine pathologists reviewed 81 cases of breast proliferative lesions in three stages and assigned each lesion to one of the following diagnoses: usual ductal hyperplasia, atypical ductal hyperplasia, or ductal carcinoma in situ. The authors evaluated hematoxylin-and-eosin–stained slides and corresponding slides stained with ADH-5 cocktail (cytokeratins 5, 14, 7, 18, and p63) by immunohistochemistry, as well as concordance at each stage of the study. The interobserver agreement among the nine pathologists for diagnosing the 81 proliferative breast lesions was fair (K-value, 0.34). The intraobserver K-value ranged from 0.56 to 0.88 (moderate to strong). Complete agreement among the nine pathologists was achieved in only nine (11 percent) cases; at least eight agreed in 20 (25 percent) cases and seven or more agreed in 38 (47 percent) cases. Following immunohistochemical stain, the authors observed a significant improvement in interobserver concordance (overall K-value, 0.50; P=.015). After using the ADH-5 immunostain, there was a significant reduction in the total number of atypical ductal hyperplasia diagnoses made by the nine pathologists. Atypical ductal hyperplasia still remains a diagnostic dilemma, with wide variation in inter- and intraobserver reproducibility among pathologists. Adding an immunohistochemical stain improved the concordance rate significantly. More importantly, there was an eight percent decrease in the number of lesions classified as atypical ductal hyperplasia in favor of usual hyperplasia. In clinical practice, this could lead to a decrease in the number of surgeries for intraductal proliferative lesions.

Jain RK, Mehta R, Dimitrov R, et al. Atypical ductal hyperplasia: interobserver and intraobserver variability. Mod Pathol. 2011;24:917–923.

Correspondence: Dr. S. Badve at sbadve@iupui.edu
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Use of a specific molecular assay to determine tissue type of origin for malignancies Use of a specific molecular assay to determine tissue type of origin for malignancies

The FDA has cleared the Tissue of Origin Frozen (TOO-FRZ) assay from Pathwork Diagnostics as a diagnostic study for malignancies of unknown primary. The authors conducted a study to evaluate the performance of TOO-FRZ on a diverse collection of 49 malignancies. They classified each case into one of four groups: common morphology from a tissue type included in the TOO-FRZ assay (n=29), uncommon morphology from a tissue type included in the TOO-FRZ assay (n=10), tumor from a tissue type not included in the TOO-FRZ assay (n=3), and malignancies of unknown primary (n=7). The authors found strong diagnostic performance for common morphologies from tissue types on the TOO-FRZ (overall accuracy, 26 of 29 [90 percent; 95 percent confidence interval, 73–97 percent]), with perfect performance in all tissue types except gastric (zero of two) and pancreatic (one of two) tissues. There was a significant decline in performance for uncommon morphologies from tissue types included in the TOO-FRZ assay (six of 10 [60 percent] cases with an indeterminate result; one of 10 [10 percent] cases with an incorrect prediction; and three of 10 [30 percent] cases with a correct prediction) and for tumors from tissue types not included in the assay (incorrect prediction in two of three cases). For the seven malignancies of unknown primary in the study set, the TOO-FRZ provided a result that was likely clinically useful in only two of seven cases. These results provide insight into the strengths and limitations of this molecular assay for the surgical pathologist, and the findings suggest future directions for research in this area.

Beck AH, Rodriguez-Paris J, Zehnder J, et al. Evaluation of a gene expression microarray-based assay to determine tissue type of origin on a diverse set of 49 malignancies. Am J Surg Pathol. 2011;35(7):1030–1037.

Correspondence: Dr. Iris Schrijver at ischrijver@stanfordmed.org
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Classification of epithelial-mesenchymal transition phenotypes in esophageal squamous cell carcinoma Classification of epithelial-mesenchymal transition phenotypes in esophageal squamous cell carcinoma

Epithelial-mesenchymal transition is characterized by a loss of cell adhesion and increased cell mobility due to cells gaining a mesenchymal phenotype. During the epithelial-mesenchymal transition process, tumor cells are expected to lose their epithelial phenotype and gradually and sequentially acquire a mesenchymal phenotype. Epithelial-mesenchymal transition is a dynamic and reversible process that has displayed a wide spectrum of phenotypes in patient tissues. However, little is known about the clinical significance of the various phenotypes of the epithelial-mesenchymal transition. Based on the expression pattern of various epithelial-mesenchymal transition-related proteins, the authors divided 168 esophageal squamous cell carcinomas into different phenotypes, including complete type; incomplete type, including hybrid type and null type; and wild type. They investigated the clinical significance of each phenotype. Of the 168 cases, 31 were categorized as complete type, 53 as incomplete type (hybrid type, 26 cases; null type, 27 cases), and 84 as wild type. Epithelial-mesenchymal transition phenotype was significantly associated with tumor size (P=.021), differentiation (P=.001), and invasion depth (P&.001). Overall survival and disease-free survival rates were significantly worse for those with the complete type, better for the incomplete type, and best for the wild type. Within the incomplete type group, the survival curve for those patients with the hybrid type was similar to that for those with the complete type, whereas overall survival for those with the null type was similar to that for those with the wild type. The complete type had a noticeably poorer prognostic effect on survival for patients with early invasion (pT≤2) than on survival for patients with advanced invasion (pT≥3). The complete phenotype was an independent prognostic factor for overall (P=.009) and disease-free survival (P&.001). The authors concluded that classification of epithelial-mesenchymal transition phenotypes has novel clinical implications, and identification of a specific phenotype might provide a tool to better stratify and predict patient outcomes.

Sung CO, Park CK, Kim SH. Classification of epithelial-mesenchymal transition phenotypes in esophageal squamous cell carcinoma is strongly associated with patient prognosis. Mod Pathol. 2011;24(8):1060–1068.

Correspondence: Dr. C. K. Park at ckpark@skku.edu and platoshkim@daum.net
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Interobserver variability of laryngeal mucosal premalignant lesions Interobserver variability of laryngeal mucosal premalignant lesions

The authors conducted a study to measure interobserver variability in the classification of laryngeal mucosal premalignant lesions by reassessing the histopathology of previously diagnosed cases and to determine the possible therapeutic consequences of disagreement among observers. Three pathologists conducted a histopathological assessment of 110 laryngeal mucosal premalignant lesions. Each slide had to be classified according to the World Health Organization, Squamous Intraepithelial Neoplasia, and Ljubljana Squamous Intraepithelial Lesions systems. A joint meeting took place after the independent assessment. To analyze the relationship between histopathological grading and subsequent clinical management, the authors created a two- and three-grade system, as well as one comprising all options. They used SAS/STAT statistical software for all analyses. The highest unweighted K-values for the all-options system were observed for the Squamous Intraepithelial Neoplasia classification (0.28; 95 percent confidence interval [CI], 0.23–0.33), followed by the World Health Organization and Ljubljana classifications. For the two-grade system, the Ljubljana classification showed the highest unweighted K-values (0.50; 95 percent CI, 0.39–0.61), followed by the World Health Organization and Squamous Intraepithelial Neoplasia classifications. For the three-grade system, the unweighted K-values were similar. The implementation of weighted K-values led to higher scores within all three classification systems, although these did not exceed 0.55 (moderate agreement). Given the high level of consensus, simultaneous pathological assessment may provide added value in comparison with independent assessment. No clear tendency was observed in favor of any one classification system in this study. The authors concluded that the proposed three-grade system could be an improved histopathological tool because it is easier to correlate with clinical decisionmaking and because it yields better unweighted K-values and proportions of concordance than the all-options system. Furthermore, having more than one pathologist assess suspected cases of dysplasia or carcinoma could benefit clinical management.

Fleskens SA, Bergshoeff VE, Voogd AC, et al. Interobserver variability of laryngeal mucosal premalignant lesions: a histopathological evaluation. Mod Pathol. 2011;24(7):892–898.

Correspondence: Dr. Stijn A. Fleskens at a.fleskens@kno.umcn.nl
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Androgen receptor expression in breast cancer relative to molecular phenotype Androgen receptor expression in breast cancer relative to molecular phenotype

Previous studies have demonstrated that androgen receptor is expressed in many breast cancers, but its expression in relation to the various breast cancer subtypes, as defined by molecular profiling, has not been studied in detail. The authors constructed tissue microarrays from 3,093 breast cancers found in women enrolled in the Nurses’ Health Study. Tissue microarray sections were immunostained for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin 5/6, epidermal growth factor receptor (EGFR), and androgen receptor. Immunostain results were used to categorize each cancer as luminal A or B, HER2, or basal like. The authors analyzed the relationships between androgen receptor expression and molecular subtype. Overall, 77 percent of invasive breast carcinomas were androgen receptor positive. Among 2,171 invasive cancers, 64 percent were luminal A, 15 percent luminal B, six percent HER2, and 11 percent basal like. The frequency of androgen receptor expression varied significantly across molecular phenotypes (P<.0001). In particular, androgen receptor expression was commonly observed in luminal A (91 percent) and luminal B (68 percent) cancers but was less frequently seen in HER2 cancers (59 percent). Despite being defined by the absence of ER and PR expression and being considered hormonally unresponsive, 32 percent of basal-like cancers expressed androgen receptor. Among 246 cases of ductal carcinoma in situ, 86 percent were androgen receptor positive, but the frequency of androgen receptor expression differed significantly across molecular phenotypes (P=.001), and high nuclear grade lesions were less likely to be androgen receptor positive compared with lower-grade lesions. Androgen receptor is most commonly expressed in luminal A and luminal B invasive breast cancers. However, androgen receptor is also expressed in approximately one-third of basal-like cancers, providing further evidence that basal-like cancers represent a heterogeneous group. The authors concluded that their findings raise the possibility that targeting the androgen receptor pathway may represent a novel therapeutic approach to managing patients with basal-like cancers.

Collins LC, Cole KS, Marotti JD, et al. Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses’ Health Study. Mod Pathol. 2011;24:924–931.

Correspondence: L. C. Collins at lcollins@bidmc.harvard.edu
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Anatomic pathology abstracts editors: Michael Cibull, MD, professor and vice chair, Department of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington; Rouzan Karabakhtsian, MD, assistant professor of pathology and laboratory medicine, University of Kentucky College of Medicine; and Thomas Cibull, MD, dermatopathologist, Evanston Hospital, NorthShore University HealthSystem, Evanston, Ill.