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  Anatomic Abstracts





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October 2004

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

Isolated high-grade prostatic intraepithelial neoplasia on needle biopsy
Observations from the College of American Pathologists’ NGC program
MHC class II gene and protein expression in diffuse large B-cell lymphoma
Significance of morphologic features and biologic markers in DCIS of breast
Diagnosis of tularemia—a potential bioterrorism agent endemic to North America

Isolated high-grade prostatic intraepithelial neoplasia on needle biopsy

The risk of carcinoma following a diagnosis of high-grade prostatic intraepithelial neoplasia on biopsy was, in some recent studies, comparable to that noted with benign initial biopsies used as controls. The authors conducted a study to determine which factors may help identify patients likely to have synchronous invasive carcinoma after a diagnosis of isolated high-grade intraepithelial neoplasia (HGPIN) on needle biopsy (n=132). Overall, 28.8 percent of subjects had carcinoma on followup biopsies. However, if more than one core had HGPIN on initial biopsy, 35.9 percent had carcinoma on followup. Most (89.5 percent) of the cancers were identified on the first two followup biopsies. If the first repeat biopsy had more than one core with HGPIN, the risk of finding carcinoma was as high as 50 percent. The tufting or flat histologic types of HGPIN were associated with a higher cancer risk (31.9 percent) on followup than the cribriform or micropapillary patterns (22 percent). (Atypical cribriform lesions were excluded from the study.) In conclusion, the number of cores involved by HGPIN on initial and first repeat biopsy appears to be more informative than histologic subtype of HGPIN in predicting which patients have synchronous invasive carcinoma.

Bishara T, Ramnani DM, Epstein JI. High-grade prostatic intraepithelial neoplasia on needle biopsy: risk of cancer on repeat biopsy related to number of involved cores and morphologic pattern. Am J Surg Pathol. 2004;28:629-633.

Reprints: Dr. Jonathan I. Epstein, Johns Hopkins Hospital, Weinberg Building, 401 N. Broadway, Room 2242, Baltimore, MD 21231;

Observations from the College of American Pathologists’ NGC program

Body cavity fluid examination presents a common and sometimes difficult diagnostic challenge in daily cytology practice. Separating benign from malignant cellular changes may require meticulous screening, careful scrutiny of cellular features, and an understanding of the range of reactive changes. The authors used data from the CAP Interlaboratory Comparison Program in Nongynecologic Cytology (NGC) to identify characteristics of fluids that place them at opposite ends of the diagnostic spectrum. They assessed the features of individual body cavity fluid slides that correlate with good performance characteristics and compared them to slides that were poor performers. A data bank of 10,396 laboratory responses, including a variety of malignant and benign cases obtained from 1997 through 2001, was used to select cases. A cumulative slide history was used to identify slides that performed well or poorly in each reference diagnosis. Cases were confirmed by consensus of four CAP Cytopathology Resource Committee members. Observations and characterizations of good and bad performers in each category were recorded and summarized. Percentage of concordance of poor performers ranged from zero to 58 percent. Conversely, good performers were identified with high concordance of laboratory diagnosis in each reference category (greater than 80 percent). Several patterns emerged. Poorly performing cases of adenocarcinoma consisted of slides with rare tumor cells, hypercellular malignant cases without two cell populations, and cases with single cells. Poor performance in confirmed squamous cell carcinoma cases related to rare cells without keratinization. Small cell carcinoma and melanoma cases performed poorly when there were few malignant cells. Lymphoma cases demonstrated poor performance when there were abundant pleomorphic lymphoid cells or when rare Reed-Sternberg-like cells were present. Reactive or negative slides performed best with a polymorphous population; poor performers were those with a predominant lymphocyte population mistaken for a hematopoietic neoplasm. Close attention to classic cytologic criteria and careful examination of slides may enhance the educational experience of participants and the performance characteristics of body cavity fluid specimens in the CAP NGC program. Lessons from “bad actors” in the CAP NGC program may increase awareness of potential diagnostic problems in daily practice or help identify areas for laboratory quality improvement.

Moriarty AT, Stastny J, Volk EE, et al. Fluids—good and bad actors: observations from the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytology. Arch Pathol Lab Med. 2004;128:513-518.

Reprints: Dr. Ann T. Moriarty, AmeriPath Indiana, 2560 N. Shadeland Ave., Suite A, Indianapolis, IN 46219;

MHC class II gene and protein expression in diffuse large B-cell lymphoma

The Leukemia and Lymphoma Molecular Profiling Project recently published results from DNA microarray analyses of 240 diffuse large B-cell lymphomas in which four distinct gene expression signatures were identified as correlating with patient outcome. One signature involved expression of the major histocompatibility complex (MHC) class II genes—for example, HLA-DRA—which correlated with better survival. The authors conducted a study in which they further analyzed the effects of HLA-DRA on survival and correlated gene expression with protein status and number of tumor-infiltrating cytotoxic T-cells. They stratified cases into four groups based on their relative levels of HLA-DRA expression. Overall five-year survival was 24 percent in patients with the lowest 10 percent of HLA-DRA expression, 37 percent in the 10 to 25 percent group, 50 percent in the 20 to 50 percent group, and 55 percent for patients in the top 50 percent. The hazard ratio of death was nonlinear and inversely related to HLA-DRA expression. Adjusting for the International Prognostic Index did not alter the impact of HLA-DRA on survival, and other MHC class II genes were found to predict survival similarly. Microarray HLA-DRA expression correlated with the presence or absence of human leukocyte antigen-DR (HLA-DR) protein in 20 of 22 cases assessed. Furthermore, fewer tumor-infiltrating CD8(+) T-cells were detected in MHCclass II-negative cases compared with positive cases (median, 2.8 percent versus 11 percent). The findings support the authors’ hypothesis that loss of tumor immunosurveillance is an important and negative determinant of patient outcome in diffuse large B-cell lymphomas.

Rimsza LM, Roberts RA, Miller TP, et al. Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling Project. Blood. 2004;103:4251-4258.

Reprints: Lisa Rimsza, Dept. of Pathology, College of Medicine, University of Arizona, 1501 N. Campbell Ave., P.O. Box 245043, Tucson, AZ 85724-5043;

Significance of morphologic features and biologic markers in DCIS of breast

A number of conventional histopathologic features have been associated with recurrence of ductal carcinoma in situ after surgery alone and are included in the Van Nuys Pathologic Classification and Prognostic Index. To the authors' knowledge, very little is known about the prognostic significance of the many biologic markers that have been studied in ductal carcinoma in situ (DCIS) in the past decade. The authors conducted a study in which they analyzed the clinical and pathologic data from 151 patients who underwent wide local excision alone for DCIS that was diagnosed by mammography or as an incidental finding between 1982 and 2000. Using local disease recurrence as an endpoint, the authors studied the prognostic significance of a large number of histopathologic parameters as well as biologic markers—estrogen receptor, progesterone receptor, p53, Her2/neu, Ki-67, p21, and bcl-2—as determined by immunohistochemical staining on contemporary or archival tissue. With a median followup of 65 months, 42 recurrences were reported between 11 months and 97 months after definitive surgery. In a univariate analysis, tumor size, Van Nuys pathologic classification, and degree of necrosis demonstrated significant correlations with the rate of recurrence. Tumor size, necrosis, nuclear grade, and comedonecrosis were found to be significantly associated with time to disease recurrence. None of the biologic markers demonstrated a significant association with rate of recurrence or time to disease recurrence. In a multivariate analysis, only large tumor size (Van Nuys two or three) and higher degrees of necrosis (Van Nuys two or three) were found to be significantly associated with rate of recurrence and time to recurrence. No biologic marker showed a significant correlation with recurrence. Using classification and regression-tree analysis and tree-structured survival analysis, progesterone receptor greater than 3.5 percent and bcl-2 of less than 97.5 percent were associated with a higher recurrence rate in the subgroup of patients with small tumor size (Van Nuys one) and higher degrees of tumor necrosis (Van Nuys two or three). The authors concluded that the results of their study confirm the value of conventional histopathologic parameters, as outlined in the Van Nuys classification system, in predicting local recurrence of DCIS. Using traditional logistic analyses, no significant correlation was found between a variety of biologic markers and disease recurrence.

Cornfield DB, Palazzo JP, Schwartz GF, et al. The prognostic significance of multiple morphologic features and biologic markers in ductal carcinoma in situ of the breast: a study of a large cohort of patients treated with surgery alone. Cancer. 2004;100: 2317-2327.

Reprints: Dr. Dennis B. Cornfield, Dept. of Pathology, Lehigh Valley Hospital, I-78 and Cedar Crest Blvd., Allentown, PA 18103;

Diagnosis of tularemia—a potential bioterrorism agent endemic to North America

Francisella tularensis, a zoonotic bacterium that causes tularemia, has received attention as a possible bioterrorism threat. Consequently, the authors developed a polymerase chain-reaction assay for use in fixed, processed tissues, which are safer to handle and allow archival testing. PCR analysis for a 211-bp fragment of the Francisella tularensis (FT) lipoprotein gene was performed on tissue from 16 cases of tularemia. In all, 14 of 15 cases with intact DNA (93 percent) were positive for FT by PCR. Frequent histologic findings in PCR-positive tissues included irregular microabscesses and granulomas in liver, spleen, kidney, and lymph nodes, and necrotizing pneumonia. Unusual cases featuring suppurative leptomeningitis and gastrointestinal ulcers were also seen. Because this disease is endemic to North America and has been identified as a potential bioterrorist threat, it has become increasingly important that health care workers be aware of the clinicopathologic spectrum of disease and available detection methods. The authors concluded that this PCR assay, the first designed for use in processed tissues, is an excellent method for diagnosing tularemia.

Lamps LW, Havens JM, Sjostedt A, et al. Histologic and molecular diagnosis of tularemia: a potential bioterrorism agent endemic to North America. Mod Pathol. 2004;17:489-495.

Reprints: Dr. L.W. Lamps, Dept. of Pathology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Slot 517, Little Rock, AR 72205;