College of American Pathologists
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  Anatomic Abstracts





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February 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

Urinary bladder paraganglioma
Influence of breast cancer histology on ultrasound and tumor size measurements
Which breast carcinomas need HER2/neu gene study after immunohistochemical analysis?
HER2/neu oncogene amplification by FISH
Osteonecrosis of the jaw associated with use of bisphosphonates

Urinary bladder paraganglioma

Paraganglioma of the urinary bladder may be mistaken for a urothelial neoplasm, especially on transurethral resection specimens. The authors conducted a study in which they described the morphology of 15 such cases that may help the surgical pathologist in recognizing this rare tumor. Features that may hinder one's ability to recognize these tumors include a diffuse growth pattern (three of 15 cases), focal clear cells (three of 15), tumor necrosis (one of 15), and muscularis propria invasion (10 of 15). The latter feature was present as normal-looking muscle bundles entrapped by tumor cells without a desmoplastic reaction. Although random nuclear atypia of a degenerative type was common, extensive bizarre cytologic atypia was rare. In such cases, the authors suggested that the lack of appreciable mitotic activity in the background of such tumors is a clue that it is not urothelial carcinoma. Immunohistochemical positivity for neuroendocrine markers and negativity for cytokeratin and markers of melanoma are also useful in problematic cases. The authors did not detail the followup of the cases described, but they did note that one of the cases was clinically malignant. The authors concluded that paraganglioma of the urinary bladder is a rare neoplasm that may be mistaken for the more common urothelial carcinoma. A careful search of the morphologic features detailed in the study and, if necessary, supportive immunohistochemical studies, should lead to an accurate diagnosis.

Zhou M, Epstein JI, Young RH. Paraganglioma of the urinary bladder: a lesion that may be misdiagnosed as urothelial carcinoma in transurethral resection specimens. Am J Surg Pathol. 2004;28:94-100.

Reprints: Dr. Robert H. Young, James Homer Wright Pathology Laboratories, Massachusetts General Hospital, 55 Fruit St., WRN 215, Boston, MA 02114

Influence of breast cancer histology on ultrasound and tumor size measurements

Establishing the size of primary invasive breast cancer is crucial for patient management. Although ultrasonographic measurement is reported to correlate reliably with the gold standard of pathology measurement, few authors have examined the influence of histologic subtype on ultrasound measurement. The common subtypes of invasive breast carcinoma, ductal and lobular, have different growth patterns, which may influence the ability of ultrasound to predict pathologic size. The authors conducted a study in which ultrasound and pathology reports were retrospectively reviewed for 204 women with 210 invasive breast cancers, including 129 ductal, 41 lobular, and 40 mixed pattern ductal and lobular carcinomas. For each tumor, the largest pathology and ultrasound dimensions were compared using Pearson’s correlations, linear regression, paired t tests, and Wilcoxon signed ranks tests, stratified by histologic subtype. The Hodges-Lehmann approach was used to obtain 95 percent confidence intervals for the median difference of the sizes. Ultrasonography consistently underestimated pathologic tumor size; the overall median difference was 3.5 mm (CI, 2.5-4.0 mm), and for subtypes it was: 2.5 mm (CI, 1.5-3.5 mm) for ductal pattern; 3.0 mm (CI, 1.5-4.5 mm) for mixed pattern; and, in contrast, 7.5 mm (CI, 5.0-13.5 mm) for lobular pattern tumors. Significant correlations of similar magnitude were observed between size measurements for ductal, lobular, and mixed subtypes (r=0.816, 0.811, and 0.672, respectively; all P<0.001); however, linear regression models differed between subtypes. Although practical and widely available, ultrasonography tends to underestimate pathologic tumor size. The size difference may be large for lobular carcinomas, potentially influencing stage. Differences are less pronounced for ductal and mixed subtypes. Pathologic tumor size can be estimated from ultrasonographic measurement, particularly if the histologic tumor subtype is known. The results of this study underscore the continued benefit of pretreatment tumor histology.

Pritt B, Ashikaga T, Oppenheimer RG, et al. Influence of breast cancer histology on the relationship between ultrasound and pathology tumor size measurements. Mod Pathol. 2004;17:905-910.

Reprints: Dr. D.L. Weaver, Dept. of Pathology, Given E-203, Health Science Complex, University of Vermont College of Medicine, Burlington, VT 05405-0068;

Which breast carcinomas need HER2/neu gene study after immunohistochemical analysis?

Editor’s note: The following two abstracts highlight a potential problem with the correlation between immunohistochemistry and fluorescence in situ hybridization, which may signify a need to reassess the testing paradigm used for HER2 in breast cancer specimens.

Evaluating HER2 gene amplification in breast cancers is a compelling, routine procedure. The authors conducted a study to evaluate which breast carcinomas would benefit from HER2/neu gene analysis. They studied 130 invasive breast carcinomas by immunohistochemistry using CB11 and TAB250 MAbs directed against different domains of the c-erbB2 molecule. From this series, the authors selected 106 cases (32 G1, 36 G2, and 38 G3) in which HER2/neu gene analysis using chromogenic in situ hybridization (CISH) was successful. Immunohistochemistry results were scored using the FDA-approved system with three score values: 0/1+ (negative), 2+, 3+ (positive). The authors also developed a double scoring system with six score values (0/1+, 2+ negative, 3+, 4+, 5+, 6+ positive) obtained by summating the individual scoring values obtained with each MAb. All double scoring negative cases were nonamplified (100 percent sensitivity), whereas all cases scored 6+ were amplified. Double scoring values and CISH results were then correlated with grade and histological type. G1 ductal carcinomas and carcinomas of lobular and special histological type did not show HER2/neu amplification, even in the presence of protein overexpression. The authors found that the combined results of immunohistochemical analysis (double scoring values) obtained using MAbs directed against different c-erbB2 domains correctly indicated HER2/neu gene status in 57.5 percent of cases. They concluded that simple morphological features such as low grade and special histological type are good predictors of nonamplification of the HER2/neu gene in breast carcinoma.

Sapino A, Coccorullo Z, Cassoni P, et al. Which breast carcinomas need HER-2/neu gene study after immunohistochemical analysis? Results of combined use of antibodies against different c-erbB2 protein domains. Histopathology. 2003;43:354-362.

Reprints: Dr. Anna Sapino, Dip. Scienze Biomediche e Oncologia Umana, Università di Torino, Via Santena 7, 10126 Torino, Italy;

HER2/neu oncogene amplification by FISH

Breast cancer patients with HER2/neu oncogene amplification by fluorescence in situ hybridization (FISH) have been shown to have a better response to trastuzumab (Herceptin) therapy than those showing only HER2/neu protein overexpression. Many centers perform FISH only on tumors showing 2+ HER2/neu positivity by immunohistochemistry, assuming that 3+ positivity equates with amplification. Results of FISH performed on 102 breast cancer cases during a 12-month period were correlated with HER2/neu immunohistochemistry results. FISH was performed using a ratio of HER2/neu and chromosome 17 centromere signal counts (PathVysion; Vysis, Downers Grove, Ill.). Immunohistochemical expression of HER2/neu was evaluated according to the published scoring guidelines of the HercepTest (Dako, Carpinteria, Calif.). Only 22 of 45 tumors with 3+ positivity (49 percent) showed amplification by FISH. Only two of 25 cases with 2+ staining by immunohistochemistry (six percent) showed gene amplification, and one of 25 cases with negative im mu no histo chem ical staining (four percent) showed weak amplification. Of the 25 cases showing oncogene amplification, 22 (88 percent) showed 3+ immunohistochemistry positivity, two (eight percent) showed 2+ positivity, and one (four percent) was negative by immunohistochemistry. More than 50 percent of breast tumors showing strong 3+ HER2/neu staining do not show oncogene amplification by FISH. Most tumors with 2+ and negative immunohistochemistry also fail to amplify. In the authors' experience, FISH studies should be performed on all 3+ and 2+ staining tumors to avoid inappropriate and toxic treatment. The decision to perform FISH on immunohistochemical-negative tumors should be guided by additional parameters, including tumor grade and estrogen receptor status.

Hammock L, Lewis M, Phillips C, et al. Strong HER-2/neu protein overexpression by immunohistochemistry often does not predict oncogene amplification by fluorescence in situ hybridization. Hum Pathol. 2003;34:1043-1047.

Reprints: Dr. Lauren Hammock, 3206 Kensington Rd., Avondale Estates, GA 30002

Osteonecrosis of the jaw associated with use of bisphosphonates

Bisphosphonates are widely used in managing metastatic disease to the bone and in treating osteoporosis. The authors encountered in the past three years a cluster of patients with necrotic lesions in the jaw who shared one common clinical feature—all had received chronic bisphosphonate therapy. The necrosis that was detected was otherwise typical of osteorad ionecrosis, an entity the authors rarely encountered at their center, with less than two patients per year presenting with a similar manifestation. The authors performed a retrospective chart review of patients who presented to their oral surgery service between February 2001 and November 2003 with the diagnosis of refractory osteomyelitis and a history of chronic bisphosphonate therapy. Sixty-three patients were identified with such a diagnosis. Fifty-six patients had received intravenous bisphosphonates for at least one year, and seven patients were receiving chronic oral bisphosphonate therapy. The typical presenting lesions were a nonhealing extraction socket or an exposed jaw bone; both were refractory to conservative debridement and antibiotic therapy. Biopsy of these lesions showed no evidence of metastatic disease. The majority of these patients required surgical procedures to remove the involved bone. In view of the current trend of increasing and widespread use of chronic bisphosphonate therapy, an associated risk of osteonecrosis of the jaw should alert practitioners to the need to monitor for this previously unrecognized potential complication. An early diagnosis might prevent or reduce the morbidity resulting from advanced destructive lesions of the jawbone.

Ruggiero SL, Mehrotra B, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. 2004; 62:527-534

Reprints: Dr. S.L. Ruggiero, Division of Oral and Maxillofacial Surgery, Long Island Jewish Medical Center, New Hyde Park, NY 11040;