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  Anatomic Abstracts





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March 2005

Michael Cibull, MD, Professor of Pathology and Laboratory Medicine and Director of Surgical Pathology, University of Kentucky Medical Center, Lexington
Subodh Lele, MD Assistant Professor of Pathology and Laboratory Medicine, University of Kentucky Medical Center
Melissa Kesler, MD, Hematopathology Fellow, University of Texas Southwestern Medical Center at Dallas

Nonalcoholic steatohepatitis: histologic features and clinical correlations
Accuracy of diagnostic testing read with and without clinical information
Rapid immunostaining using intermittent microwave irradiation
Bronchial margins in lung cancer specimens: utility of frozen sections
Bone marrow histological patterns and survival with follicular lymphoma

Nonalcoholic steatohepatitis: histologic features and clinical correlations

Thirty overweight patients with clinically characterized and biopsy-proven nonalcoholic steatohepatitis were enrolled in a 48-week treatment trial with rosiglitazone, a peroxisome proliferator-activator receptor-γ agonist that enhances insulin sensitivity. Improvement in laboratory liver tests, insulin resistance, and liver fat content were documented. Blinded biopsy review demonstrated decreases in necroinflammatory activity or grade and in individual components of grade, and changes in the relationship of lobular and portal inflammation, as well as in the nature of perisinusoidal fibrosis. This study identified correlations of histological features of the protocol entry biopsy specimens with contemporaneous laboratory and imaging tests. Significant correlations were found between histologically assessed steatosis and liver fat, evaluated by computed tomography (P=0.001); mean HbA 1C , a measure of glycemic control (P=0.004); and QUICKI, a measure of insulin sensitivity (P=0.05). Histologically determined grades of steatohepatitis correlated with HbA 1C (P=0.01), and a trend toward elevated fasting glucose levels was seen. No subject in the study was cirrhotic at entry. Fibrosis scores for the 30 subjects did not significantly correlate with age, gender, body mass index, or clinical tests. All subjects underwent three biopsies (prior, entry, and post-treatment), and all had undergone a prior biopsy with diagnostic steatohepatitis. By blinded analysis, seven study entry biopsy specimens did not fulfill published strict criteria for steatohepatitis. Laboratory results from these subjects included normal fasting glucose level and, compared with the 23 subjects with criteria for steatohepatitis, lower mean alanine aminotransferase and aspartate aminotransferase levels (P=0.02 for both), less insulin resistance (P=0.03), and lower mean HbA 1C (P=0.001). The authors concluded that biopsy findings determined by blinded analysis correlated with image-detected steatosis, laboratory markers of hepatic inflammation, insulin resistance, and long-term glycemia. The findings confirm the usefulness of strict histological criteria in evaluating nonalcoholic steatohepatitis.

Brunt EM, Neuschwander-T BA, Oliver D, et al. Nonalcoholic steatohepatitis: histologic features and clinical correlations with 30 blinded biopsy specimens. Hum Pathol. 2004;35:1070-1082.

Reprints: Dr. Elizabeth M. Brunt, Dept. of Pathology, Saint Louis University School of Medicine, 3635 Vista Ave., St. Louis, MO 63110

Accuracy of diagnostic testing read with and without clinical information

Although it is common practice to read tests with clinical information, whether this improves or decreases the accuracy of test reading is uncertain. To determine whether diagnostic tests are more accurate when read with or without clinical information, the authors performed a Medline search (1966 through 2003) extended by a search of reference lists and articles citing the articles retrieved (Web of Science, 1985 through 2003). All articles compared the accuracy of tests read twice by the same readers and once without and once with clinical information, but otherwise under identical conditions. Only articles that reported sensitivity and specificity or receiver operating characteristic (ROC) curves were included. Data were extracted by one author and reviewed independently by another. When the data were difficult to interpret, differences were resolved by discussion. Sixteen articles met the inclusion criteria. Eleven articles compared areas under ROC curves for tests read with and without clinical information, and five compared only sensitivity and specificity. Ten articles used clinical information, and six used constructed clinical information that was plausible. Overall, clinical information improved test-reading accuracy, although the effect was smaller in the articles using actual clinical information than in those using constructed clinical information. In no instances did clinical information result in a significant reduction in test-reading accuracy. In some instances, improved test-reading accuracy came from improved sensitivity without loss of specificity. The authors concluded that, at least for the tests examined, the common practice of reading diagnostic tests with clinical information seems justified. Future studies should be designed to investigate the best way of providing clinical information. These studies should also give an estimate of the accuracy of clinical information used, display ROC curves with identified data points, and include a wider range of diagnostic tests.

Loy CT, Irwig L. Accuracy of diagnostic testing read with and without clinical information: a systematic review. JAMA. 2004;292:1602-1609.

Reprints: Dr. Les Irwig, Screening and Test Evaluation Program, School of Public Health, Room 301, A27, Edward Ford Bldg., University of Sydney, NSW 2006, Sydney, Australia;

Rapid immunostaining using intermittent microwave irradiation

Immunostaining depending on antigen-antibody specificity is the most common approach for determining the localization of specific antigens in tissue sections. This procedure is applicable not only with frozen or specially fixed samples, but also has proven reliable with formalin-fixed, paraffin-embedded tissue sections by improving antigen retrieval. Immunostaining is, therefore, firmly established as a tool for diagnostic pathology. In the authors' institute, multiple antibodies are applied for 13 to 15 percent of the cases examined, as is hematoxylin-and-eosin staining. With the standard approach, approximately three hours is necessary from the beginning of deparaffinization until covering sections with the Envision system. The authors used intermittent microwave irradiation for 10 minutes during hybridization with primary and secondary antibodies in a special moist chamber to achieve all immunostaining steps within one hour in 178 primary antibodies frequently used for diagnostic pathology. According to the authors, such microwave irradiation not only led to significant specific staining for enhancing the specificity of antigen-antibody reactions, but also inhibited nonspecific binding. The authors presented the details of the methodology and recommendations for its application with particular primary antibodies. They concluded that this method can save time and energy, allowing pathologists to rapidly obtain diagnostic information.

Kumada T, Tsuneyama K, Hatta H, et al. Improved 1-h rapid immunostaining method using intermittent microwave irradiation: practicability based on 5 years application in Toyama Medical and Pharmaceutical University Hospital. Mod Pathol. 2004;17:1141-1149.

Reprints: Dr. K. Tsuneyama, Dept. of Pathology, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan;

Bronchial margins in lung cancer specimens: utility of frozen sections

Pathology reports for all lobectomy and pneumonectomy specimens at University of North Carolina Hospitals between 1991 and 2000 (n=405) were reviewed for correlation between frozen section and final bronchial margin, gross distance between tumor and margin, and tumor type. Frozen section was performed in 268 cases (66 percent)—a total of 243 were true negatives (90.6 percent), 16 (six percent) were true positives, four (1.5 percent) were false positives, and five (1.9 percent) were false negatives. The site of tumor in true-positive cases was mucosal (11), submucosal (three), lymphatics (one), and peribronchial (one). The site of tumor in false-negative cases was submucosal (two), lymphatics (one), and peribronchial (two). In 137 cases, no bronchial frozen sections were performed; there was one case (0.7 percent) with positive margin. No correlation was noted between final margin positivity and distance between gross tumor and margin. Tumor distance to margin in positive margin cases varied from grossly involved to 3 cm away. There were 72 cases in which wedge resection was performed before lobectomy in which no gross tumor remained in the lobectomy, and in all cases, final bronchial margins were negative. In all, 373 cases (92 percent) were nonsmall cell carcinomas. Of these, 10 (2.7 percent) had positive margins. Tumors other than nonsmall cell carcinoma accounted for a disproportionate number of positive margins. In all, three of six adenoid cystic/mucoepidermoid carcinomas, one of seven small cell carcinomas, and one of one lymphomas had positive margins. In conclusion, frozen section evaluation of bronchial margins is helpful in central lung tumors. Mucosal tumor is preferentially identified in frozen section. Gross evaluation of margins is problematic, as intramucosal carcinoma or tumor in lymphatics may not be detected, but 3 cm was a safe distance for gross tumor from margin. In lobectomies following wedge resection in which no gross tumor remained, all had negative margins. Salivary gland-type tumors have a high incidence of positive margins, and frozen section is particularly indicated in these tumors.

Maygarden SJ, Detterbeck FC, Funkhouser WK. Bronchial margins in lung cancer resection specimens: utility of frozen section and gross evaluation. Mod Pathol. 2004;17:1080-1086.

Reprints: Dr. S.J. Maygarden, Dept. of Pathology and Laboratory Medicine, CB 7525, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7525;

Bone marrow histological patterns and survival with follicular lymphoma

Bone marrow involvement is relatively frequent in follicular lymphoma and occurs in several patterns—focal paratrabecular, nodular nonparatrabecular, interstitial, and diffuse. Bone marrow involvement is considered by some authors to be a poor prognostic sign. The authors of this study correlated pattern and extent of marrow disease with event-free and overall survival. They included in the study 390 patients with grade 1 or 2 follicular lymphoma, and they assessed 267 positive marrows for lymphomatous growth pattern, number of lymphomatous foci within each intramedullary space, ratio of lymphoma to total marrow area, cytologic grade of lymphoma cells, and presence of myelofibrosis, as well as other histologic features. Inter- and intra-observer reproducibility for this classification were 91 percent and 96 percent, respectively. Uni- and multivariate analysis demonstrated that event-free survival was significantly adversely affected by the presence of two or more different histologic patterns in the same biopsy and by a ratio of lymphomatous foci to total marrow area of 0.1 or greater (further defined semiquantitatively as three or four nodules per intramedullary space or at least one nodule with foci of diffuse or interstitial involvement). The presence of two or more histologic patterns also adversely affected overall survival, but only in patients with high tumor burden. The authors concluded that theirs is a relatively simple and reproducible classification system for evaluating bone marrow histology in follicular lymphoma that can be used to predict survival for patients with follicular lymphoma.

Canioni D, Brice P, Lepage E, et al. Bone marrow histological patterns can predict survival of patients with grade 1 or 2 follicular lymphoma: a study from the Groupe d'Etude des Lymphomes Folliculaires. Br J Haematol. 2004;126:364-371.

Reprints: N. Brousse, Hopital Necker-Enfants Malades 149 rue e Sevres, 75743 Paris Cedex 15, France;