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December 2011

Editors:
Michael Cibull, MD
Melissa Kesler, MD
Rouzan Karabakhtsian, MD
Megan Zhang, MD

Association between SerpinA5 protein expression and serous ovarian tumors Association between SerpinA5 protein expression and serous ovarian tumors

Epithelial ovarian cancer, the most lethal neoplasm of the female genital tract, is usually diagnosed at an advanced stage as obvious symptoms are absent at early stages. The disease is believed to originate from malignant transformation of the ovarian surface epithelium or fallopian tube. Histologically, several subtypes have been recognized, with serous histology accounting for the majority of cases. Serous tumors include serous borderline tumors and serous carcinomas. A better understanding of the tumor biology and molecular mechanisms involved in these tumors is needed as both patient management and prognosis differ substantially. Previous microarray analyses identified SerpinA5, a uPA inhibitor, as a key regulator for indolent borderline behavior. Because carcinomas are characterized by loss of SerpinA5 mRNA expression, the authors hypothesized that SerpinA5 protein expression is reduced or lost in carcinomas when compared with borderline tumors. The authors conducted a study in which they performed SerpinA5 immunohistochemical staining on 32 serous borderline tumors, 187 primary serous carcinomas, and 62 serous omental metastases. Reduced SerpinA5 protein staining or a complete lack of such staining was observed in carcinomas when compared with borderline tumors (P<0.001). SerpinA5 protein expression was significantly lowered in the omental metastases (P<0.001) when compared with the matching primary carcinoma. Interestingly, SerpinA5 protein expression was reduced in advanced-stage borderline tumors, which often are characterized by micropapillary growth or microinvasion, or both, when compared with early-stage borderline tumors (P=0.015). The authors concluded that SerpinA5 expression is significantly reduced in advanced-stage serous borderline tumors and serous carcinomas when compared with their early-stage counterparts. Reduced SerpinA5 protein expression is also linked to the more aggressive features of borderline tumors.

Bijsmans IT, Smits KM, de Graeff P, et al. Loss of SerpinA5 protein expression is associated with advanced-stage serous ovarian tumors. Mod Pathol. 2011;24:463–470.

Correspondence: Dr. K. K. Van de Vijver at koen.vande.vijver@mumc.nl
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Semiquantitative hormone receptor level and response to neoadjuvant chemotherapy with trastuzumab Semiquantitative hormone receptor level and response to neoadjuvant chemotherapy with trastuzumab

Pathologic complete response to neoadjuvant chemotherapy without trastuzumab in hormone receptor-negative/HER2+ tumors is seen in 27 percent to 45 percent of cases. In contrast, estrogen receptor (ER)+/HER2+ tumors demonstrate pathologic complete response in approximately eight percent of cases. Some medical professionals have speculated that adding trastuzumab to a neoadjuvant chemotherapy regimen will increase pathologic complete response rates in all HER2+ tumors. The authors conducted a study in which they obtained from their hospital database a list of HER2+ patients who received neoadjuvant chemotherapy with trastuzumab between 2007 and 2010. The 104 HER2+ tumors were classified into three groups based on semiquantitative hormone receptor and HER2 results: ERBB2 (ER–/PR–[H-score, <10]/HER2+), luminal B-HER2 hybrid (LBHH; weak-to-moderate ER+[H-score, 11 to 199]/HER2+), and luminal A-HER2 hybrid (LAHH; strong ER+[H-score, >200]/HER2+). Pathologic complete response was defined as absence of invasive carcinoma in the resection specimen and lymph nodes. Percentage tumor volume reduction was also calculated based on pre-therapy size and detailed evaluation of the resection specimen. Fifty-two percent (25 of 48 cases) of ERBB2 tumors showed pathologic complete response, which was significantly higher than the pathologic complete response rate in LBHH (33 percent; 10 of 30) and LAHH (eight percent; two of 26) tumors. Average percentage tumor volume reduction was also highest in ERBB2 tumors (86 percent), followed by LBHH (74 percent) and LAHH (64 percent) tumors. The authors concluded that adding trastuzumab to a neoadjuvant chemotherapy regimen significantly increases the pathologic complete response rates in all HER2+ tumors. However, the benefit of trastuzumab is highest in ER-negative tumors and progressively decreases with increase in tumor ER expression. This information can be used to counsel patients being considered for neoadjuvant chemotherapy, and the same principle could be applied in the adjuvant setting.

Bhargava R, Dabbs DJ, Beriwal S, et al. Semiquantitative hormone receptor level influences response to trastuzumab-containing neoadjuvant chemotherapy in HER2-positive breast cancer. Mod Pathol. 2011;24:367–374.

Correspondence: Dr. R. Bhargava at rbhargava@mail.magee.edu
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Prognostic model for soft tissue sarcoma of the extremities and trunk wall Prognostic model for soft tissue sarcoma of the extremities and trunk wall

In soft tissue sarcoma, better distinction of high-risk and low-risk patients is needed to individualize treatment and improve survival. Prognostic systems used in clinical practice identify high-risk patients based on various factors, including age, tumor size and depth, histological type, necrosis, and grade. The authors reviewed whole-tumor sections from 239 soft tissue sarcomas of the extremities for the following prognostic factors: size, vascular invasion, necrosis, and growth pattern. A new prognostic model, referred to as SING (size, invasion, necrosis, growth) was established and compared with other systems applied clinically. The authors found, in multivariate analysis, that size, vascular invasion, necrosis, and peripheral tumor growth pattern provided independent prognostic information with hazard ratios of 2.2 to 2.6 for developing metastases. When these factors were combined into the prognostic model SING, high risk of metastasis was predicted with a sensitivity of 74 percent and specificity of 85 percent. Moreover, the prognostic performance of SING compared favorably with that of other widely used systems. The authors concluded that SING represents a promising prognostic model and that vascular invasion and tumor growth pattern should be considered in soft tissue sarcoma prognostication.

Carneiro A, Bendahl PO, Engellau J, et al. A prognostic model for soft tissue sarcoma of the extremities and trunk wall based on size, vascular invasion, necrosis, and growth pattern. Cancer. 2011;117(6):1279–1287.

Correspondence: A. Carneiro at ana.carneiro@med.lu.se
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A calculator for predicting ovarian carcinoma subtype A calculator for predicting ovarian carcinoma subtype

With emerging evidence that the five major ovarian carcinoma subtypes—high-grade serous, clear cell, endometrioid, mucinous, and low-grade serous—are distinct disease entities, management of ovarian carcinoma will become subtype-specific in the future. To improve diagnostic accuracy, the authors set out to determine if an immunohistochemical panel of molecular markers could reproduce consensus subtype assignment. They examined immunohistochemical expression of 22 biomarkers on tissue microarrays constructed from 322 archival ovarian carcinoma samples from the British Columbia Cancer Agency archives for the period between 1984 and 2000. They also examined an independent set of 242 cases of ovarian carcinoma from the Gynaecologic Tissue Bank at Vancouver General Hospital from 2001 to 2008. The authors used nominal logistic regression to produce a subtype prediction model for each of these sets of cases. They then cross-validated these models against the other cohort. Both models were further validated in an independent cohort of 81 ovarian carcinoma samples from five centers. Starting with data for 22 markers, full model fit, backwards, nominal logistic regression identified the same nine markers—CDKN2A, DKK1, HNF1B, MDM2, PGR, TFF3, TP53, VIM, WT1—as being most predictive of ovarian carcinoma subtype in the archival and tumor bank cohorts. These models were able to predict subtype in the respective cohort in which they were developed with a high degree of sensitivity and specificity (k statistics, 0.88±0.02 and 0.86±0.04, respectively). When the models were cross-validated—that is, using the model developed in one case series to predict subtype in the other series—the prediction equation’s performances were reduced (k statistics, 0.70±0.04 and 0.61±0.04, respectively) due to differences in frequency of expression of some biomarkers in the two case series. Both models were then validated on the independent series of 81 cases, with very good to excellent ability to predict subtype (k=0.85±0.06 and 0.78±0.07, respectively). The authors concluded that a nine-marker immunohistochemical marker panel can be used to objectively support classification into one of the five major subtypes of ovarian carcinoma.

Kalloger SE, Köbel M, Leung S, et al. Calculator for ovarian carcinoma subtype prediction. Mod Pathol. 2011;24:512–521.

Correspondence: Dr. C. B. Gilks at blake.gilks@vch.ca
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The significance of a grade of indefinite for dysplasia in Barrett metaplasia The significance of a grade of indefinite for dysplasia in Barrett metaplasia

For a confident diagnosis of dysplasia in Barrett metaplasia, the epithelial atypia should also involve the surface epithelium. However, pathologists are often faced with biopsies in which the crypts show dysplasia but the surface epithelium is uninvolved or unevaluable. The authors previously grouped these cases in the grade of indefinite for dysplasia (IND). The authors conducted a study to determine the clinical significance of IND grading in Barrett metaplasia. For the study, all biopsies from 276 prospectively followed patients with Barrett metaplasia who did not have high-grade dysplasia or esophageal adenocarcinoma (EAC) on initial biopsy were graded as negative for dysplasia, IND, low-grade dysplasia, high-grade dysplasia, and EAC. Biopsies with multifocal IND or low-grade dysplasia were graded as INDM or LGDM, respectively. Only three of 193 patients (two percent) with an initial diagnosis of negative for dysplasia and only one of 48 patients (two percent) diagnosed with IND progressed to high-grade dysplasia or EAC. By contrast, one of seven patients (14 percent) with INDM, two of 21 (10 percent) with low-grade dysplasia and one of seven (14 percent) with LGDM progressed to high-grade dysplasia or EAC. There was no significant difference in progression rate between patients with an initial diagnosis of negative for dysplasia and those diagnosed as IND, nor were there significant differences among patients with initial diagnoses of INDM, low-grade dysplasia, or LGDM. Kaplan-Meier analysis showed that patients with INDM, low-grade dysplasia, or LGDM on initial biopsy (group one) were more likely to progress to high-grade dysplasia or EAC than were those patients diagnosed as negative for dysplasia or IND (group two; log-rank test, P<0.001). The authors concluded that multifocal IND in an esophageal biopsy from a patient with Barrett metaplasia has the same clinical implication as low-grade dysplasia.

Younes M, Lauwers GY, Ertan A, et al. The significance of “indefinite for dysplasia” grading in Barrett metaplasia. Arch Pathol Lab Med. 2011;135(4):430–432.

Correspondence: Dr. Mamoun Younes at myounes@bcm.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; Melissa Kesler, MD, and Rouzan Karabakhtsian, MD, assistant professors of pathology and laboratory medicine, University of Kentucky College of Medicine; and Megan Zhang, MD, visiting fellow, Division of Dermatopathology, University of California, San Francisco.