Anatomic Abstracts
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August 2009 Editors:
Endometrial changes from short-term therapy with CDB-4124
Selective progesterone receptor modulators are a class of drugs with progesterone antagonist activity that may confer therapeutic benefit for reproductive disorders in premenopausal women. Endometrial structure, which is dynamically controlled by circulating sex hormones, is likely to be perturbed by progesterone receptor modulators through their progesterone antagonist properties. The authors examined endometrial histology in 58 premenopausal women treated with the progesterone receptor modulator CDB-4124, also known as Proellex (Repros Therapeutics), for endometriosis or uterine leiomyomata in two clinical trials. Endometrial biopsies obtained after three or six months with doses of 12.5, 25, or 50 mg daily oral CDB-4124 were reviewed independently by three pathologists. Consensus diagnoses using the World Health Organization hyperplasia scoring system, comments on specific histologic features, and clinical annotation were collected and analyzed. The majority of the endometrial biopsies (103 of 174) contained histologic changes that are not seen during normal menstrual cycles. The histology of CDB-4124–treated patients was generally inactive or atrophic, and, less frequently, proliferative or secretory, superimposed upon which were novel changes, including formation of cystically dilated glands, and secretory changes coexisting with mitoses and apoptotic bodies. With increasing treatment dose and duration, the cysts became predominant and their lining inactive or atrophic. Cystic glands in the CDB-4124–treated subjects correlated with increased endo-metrial thickness by ultrasound. None of the CDB-4124–treated patients developed endometrial carcinoma or hyperplasia while receiving therapy. The authors concluded that CDB-4124 therapy for three to six months produces histologic changes that are sufficiently novel that they might easily be misinterpreted by pathologists, often as disordered proliferative or hyperplastic endometrium. Knowledge of the constellation of endometrial changes associated with this agent and other progesterone receptor modulators, including cystic architecture and mixed nonphysiologic epithelial changes, will prevent misdiagnosis. Ioffe OB, Zaino RJ, Mutter GL. Endometrial changes from short-term therapy with CDB-4124, a selective progesterone receptor modulator. Mod Pathol. 2009;22:450–459. Correspondence: Dr. G. L. Mutter at gmutter@rics.bwh.harvard.edu
Gastrointestinal stromal tumors are the most common mesenchymal tumors in the gastrointestinal tract. Mutations in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene are present in approximately 85 percent of such tumors. About 95 percent of gastrointestinal stromal tumors (GISTs) are positive for KIT (CD117) by immunohistochemistry, and approximately five percent lack KIT expression. DOG1.1 is a mouse monoclonal antibody reported to have greater sensitivity and specificity than KIT (CD117) and CD34. The authors evaluated this new antibody on 81 GISTs obtained from 74 patients with special re-gard to KIT-negative GISTs (n=28), pediatric GISTs (n=11), and GISTs associated with neurofibromatosis type 1 (NF1; n=16). Conventional GISTs (n=26) were also included. All conventional KIT-positive and NF1-associated GISTs and nine of 11 pediatric GISTs expressed DOG1.1. The mouse monoclonal antibody also was expressed in 10 of 28 (36 percent) KIT-negative tumors. The staining pattern was cytoplasmic or membranous, or both. The authors concluded that DOG1.1 has a higher sensitivity than KIT for the diagnosis of GISTs. It is a sensitive marker for unusual GIST subgroups lacking KIT or PDGFRA mutations. In tumors that are negative for KIT and DOG1.1, mutational screening may be required to confirm the diagnosis of GIST. Liegl B, Hornick JL, Corless CL, et al. Monoclonal antibody DOG1.1 shows higher sensitivity than KIT in the diagnosis of gastrointestinal stromal tumors, including unusual subtypes. Am J Surg Pathol. 2009;33:437–446. Correspondence: Dr. Christopher D. Fletcher at cfletcher@partners.org
Tumor stage and grade of gastrointestinal stromal tumors are poorly defined. To develop a better evaluation system, the authors assessed 12 clinical and pathological parameters in 613 patients with followup information. These parameters were classified into two gross spread parameters, including liver metastasis and peritoneal dissemination; five microscopic spread parameters, including lymph node metastasis and vascular, fat, nerve, and mucosal infiltration; and five histological parameters, including mitotic count ≥10 per 50 high-power fields, muscularis propria infiltration, coagulative necrosis, perivascular pattern, and severe nuclear atypia. The five-year disease-free and overall survival rates for 293 patients without any of these predictive parameters of malignancy were 99 and 100 percent, respectively. The tumors were regarded as nonmalignant, and further evaluations on stage and grade were not performed. Between one and seven pre-dictive parameters of malignancy were identified in 320 patients. For these patients, the five-year disease-free and overall survival rates were 44 percent (mean, 6.7 years) and 60 percent (mean, 9.3 years), respectively. The disease-free survival rate showed significant difference between patients with and without gross spread (P<.0001), with and without microscopic spread (P=.0009). Disease-free and overall survival rates were associated with the number of predictive parameters of malignancy in patients without gross spread (P<.0001 for disease-free survival and overall survival), but not in patients with gross spread (P=.882 and 0.441, respectively). Malignant gastrointestinal stromal tumors could be divided into clinical stage I and II based on the absence and presence of gross spread, respectively. The degree of malignancy for patients in clinical stage I could be graded according to the number of predictive parameters of malignancy. Patients in clinical stage II were of the highest degree of malignancy, regardless of the number of parameters. The authors concluded that clinical stage and grade were strongly associated with prognosis. Hou YY, Lu SH, Zhou Y, et al. Stage and histological grade of gastrointestinal stromal tumors based on a new approach are strongly associated with clinical behaviors. Mod Pathol. 2009;22:556–569. Correspondence: Dr. Y-Y Hou at houyingyong@hotmail.com
Most HER2 testing guidelines recommend that all cases scoring HER2 2+ by immunohistochemistry be analyzed by fluorescence in situ hybridization to determine HER2 status to confirm eligibility for trastuzumab therapy in breast cancer. The authors conducted a study in which they determined HER2 gene and chromosome 17 (CEN17) status in a series of 108 HER2 2+ consecutive cases to analyze the correlation between pathological characteristics of the tumors and HER2 amplification. Invasive breast cancers were tested by fluorescence in situ hybridization (FISH) using the Dako HER2 FISH pharmDx kit. The HER2 immunohistochemistry protocol was performed using the polyclonal AO485 antibody (Dako) diluted to 1:1,500. HER2 and CEN17 status were correlated to tumor Scarf-Bloom-Richardson (SBR) grade, mitotic count, estrogen receptor, progesterone receptor status, and percentage of HER2 immunohistochemistry-positive cells. Adhering to Food and Drug Administration guidelines—that is, HER2/CEN17 ratio of two or more and HER2 copy number greater than four—amplified cases were observed in 36 (33 percent) and 49 (45 percent) cases, respectively. Following the guidelines of the American Society of Clinical Oncology/College of American Pathologists—that is, HER2/CEN17 ratio greater than 2.2 and HER2 copy number greater than six—amplified cases represented 30 percent and 24 percent of the study population, respectively. Chromosome 17 polysomy (CEN17 greater than 2.25) was observed in 39 (36 percent) tumors. Significant positive correlations were found between FISH HER2-amplified cases and HER2 immunostaining greater than 60 percent (P=1.1.10-5), SBR grade 3 (P=.0001), nuclear atypia (P=.03), and mitotic count (P=.008). By multivariate analysis, HER2 immuno-staining greater than 60 percent (P<10-3) and SBR grade 3 (P<10--3) were independent factors predicting HER2 amplification status irrespective of cutoff guidelines. All SBR grade 3 cases with more than 60 percent HER2+ cells had a HER2/CEN17 ratio of 2.0 or more, and only one had a ratio of between 2.0 and 2.2. In this series of consecutive HER2 2+ cases, one-third demonstrated HER2 amplification and one-third had chromosome 17 polysomy. Pathological factors, in particular SBR grade 3 and more than 60 percent HER2+ cells, were significantly correlated with HER2 amplification. Chibon F, de Mascarel I, Sierankowski G, et al. Prediction of HER2 gene status in HER2 2+ invasive breast cancer: a study of 108 cases comparing ASCO/CAP and FDA recommendations. Mod Pathol. 2009;22:403–409. Correspondence: Dr. F. Chibon at chibon@bergonie.org 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. |
