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  Anatomic Abstracts






September 2007

Michael Cibull, MD
Melissa Kesler, MD

Measurement of invasion depth of extrahepatic bile duct carcinoma
Stromal CD10 expression in invasive breast carcinoma
Ovarian metastases of intestinal-type gastric adenocarcinomas
Differentiating Ewing’s sarcoma from other round blue cell tumors
HER-2 amplification and overexpression in tumors of non-breast origin
Verruca vulgaris of the vulva in children and adults

bullet Measurement of invasion depth of extrahepatic bile duct carcinoma

Tumor staging of extrahepatic bile duct carcinoma is problematic for a number of reasons, including definitional problems with the T classification of the American Joint Committee on Cancer staging system and the common occurrence of severe desmoplastic stromal reaction around the advancing edges of these tumors. To address these problems, the authors evaluated the depth of invasion in 222 cases of extrahepatic bile duct (EBD) carcinoma by measuring the distance from the basal lamina of the adjacent normal epithelium to the most deeply infiltrating tumor cells. They compared this evaluation to time of survival and other clinical and pathologic parameters. The authors observed a complex pattern of survival time versus the depth of invasion by censored local regression. The recursive-partitioning technique was coupled with the log-rank test to identify two significant cutoff points for the depth of invasion—5 and 12 mm. These cutoffs segregated patients into three groups with statistically significant decreasing lengths of median survival—less than 5 mm, 61 months; 5 to 12 mm, 23 months; and more than 12 mm, 17 months (P<0.001). On the basis of this data, the authors proposed that depth of invasion should be measured in cases of EBD carcinoma and that the T classification of EBD carcinoma should be changed to incorporate this measurement: T1, less than 5 mm; T2, 5 to 12 mm; and T3, more than 12 mm.

Hong SM, Cho H, Moskaluk CA, et al. Measurement of the invasion depth of extrahepatic bile duct carcinoma: an alternative method overcoming the current T classification problems of the AJCC staging system. Am J Surg Pathol.2007;31:199–206.

Reprints: Dr. Seung-Mo Hong, Dept. of Pathology, University of Virginia Health System, P.O. Box 800214, Charlottesville, VA 22908;

bullet Stromal CD10 expression in invasive breast carcinoma

CD10 is a zinc-dependent peptidase (metalloproteinase) that degrades a variety of bioactive peptides. Earlier studies suggested that CD10 expression in tumor stroma is associated with the biological aggressiveness of the tumor. The authors conducted a study to evaluate stromal CD10 expression in breast carcinoma and to examine associations between CD10, clinicopathological variables, and patient outcome. They assembled tissue microarrays containing 438 cases of invasive breast carcinoma and 15 cases of ductal carcinoma in situ with 15 years’ median followup. The authors assessed CD10 expression by immunohistochemistry and scored it as negative, weak, and strong. They performed nonparametric correlational tests and univariate and multivariate survival analyses. The authors found that stromal CD10 was preferentially expressed in invasive compared to noninvasive breast cancers (P=0.003). Correlations were found between stromal CD10 expression and higher tumor grade (P=0.01) and estrogen receptor-negative status (P=0.002). No correlation was found between CD10 and lymph node status, tumor size, histological subtype, progesterone receptors, and HER2 status. Stromal CD10 expression was associated with decreased long-term disease-specific and overall survival in the entire cohort (P<0.01) and in a lymph node-negative (P<0.05) subset of patients. It approached prognostic significance in multivariate analysis (P=0.06) when lymph node status, tumor size, estrogen receptor, and HER2 were considered in the same model. And it was associated with a relative risk of death of 2.8, compared to a relative risk of 2.4 for lymph node-positive status. The authors concluded that stromal CD10 expression in invasive carcinoma of the breast is associated with estrogen receptor negativity, higher tumor grade, and decreased survival. It constitutes a potential prognostic marker and a target for developing novel therapies.

Makretsov NA, Hayes M, Carter BA, et al. Stromal CD10 expression in invasive breast carcinoma correlates with poor prognosis, estrogen receptor negativity, and high grade. Mod Pathol. 2007;20:84–89.

Reprints: Dr. N.A. Makretsov, Dept. of Pathology and Laboratory Medicine, Health Care Corporation of St. John’s, 300 Prince Philip Drive, St. John’s, NL, Canada A1B3V8;

bullet Ovarian metastases of intestinal-type gastric adenocarcinomas

Ovarian metastases of intestinal-type gastric adenocarcinomas are rare, and information about them is very limited compared with that on signet-ring cell carcinomas that result in Krukenberg tumors. The authors reported on four cases of the former. The patients were an average of 55 years of age. In three patients, ovarian metastases were identified several to 21 months after the diagnosis of the gastric primary, and the tumors were synchronous in the fourth. Two tumors were bilateral and one unilateral. It was not known if the tumors were unilateral or bilateral in the remaining patient. The ovarian tumors were characteristically solid and cystic, with multinodular growth in two. In two cases, the ovarian tumors had pseudoendometrioid morphology with tubulo-glandular, cribriform, and papillary patterns; they also had focal trabecular and insular patterns. Prominent necrosis was present, including segmental and intraluminal “dirty” necrosis. In the other two cases, the ovarian tumors had a mucinous appearance, one being dominantly cystic with occasional goblet cells and the other with prominent foveolar-type cells. Nuclei ranged from deceptively bland to highly atypical. Surface implants were identified in two cases. Two of the ovarian tumors examined expressed cytokeratin 7 and 20 but not estrogen receptor. Three patients with followup information died within one year of the ovarian metastases. Although the information is limited, the authors’ results suggest that metastatic spread to the ovary by intestinal-type gastric adenocarcinoma is usually seen in patients older than those with Krukenberg tumors, with a known history of gastric carcinoma, and with concomitant widespread disease. Involvement of the ovary by intestinal-type gastric carcinoma produces a microscopic picture distinctly different from that of a Krukenberg tumor. These metastatic intestinal-type tumors may be confused with metastases from other gastrointestinal sites that are more frequently the cause of pseudoendometrioid or mucinous metastases, and like such tumors may be confused with primary ovarian endometrioid and mucinous neoplasms.

Lerwill MF, Young RH. Ovarian metastases of intestinal-type gastric carcinoma: a clinicopathologic study of 4 cases with contrasting features to those of the Krukenberg tumor. Am J Surg Pathol. 2006;30:1382–1388.

Reprint: Dr. Melinda F. Lerwill, Dept. of Pathology, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114;

bullet Differentiating Ewing’s sarcoma from other round blue cell tumors

Ewing’s sarcoma is a common malignancy of bone and soft tissue that occurs most often in children and young adults. Differentiating Ewing’s sarcoma from other round blue cell tumors can be a diagnostic challenge because they are similar in histology and clinical presentation. Therefore, ancillary molecular tests for detecting disease-defining translocations are important for confirming the diagnosis. The authors analyzed 65 round blue cell tumors, including 53 Ewing’s sarcoma samples from 50 unique cases. Samples were processed for RNA from archived formalin-fixed paraffin-embedded tissue blocks. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assays specific for Ewing’s sarcoma (EWS-FLI1, EWS-ERG, EWS-ETV1, EWS-ETV4, and EWS-FEV), synovial sarcoma (SYT-SSX1 and SYT-SSX2), and rhabdomyosarcoma (PAX3-FKHR and PAX7-FKHR) were tested across the samples. The translocation panel had a sensitivity of 81 percent (43 of 53 samples) for diagnosing Ewing’s sarcoma when using the histological criteria as the gold standard. None of the Ewing’s-specific translocations were found in the non-Ewing’s samples (100% specificity). Of the 43 samples with translocations detected, 26 (60%) had an EWS-FLI1 type 1 translocation, 13 (30%) an EWS-FLI1 type 2 translocation, three (7%) an EWS-ERG translocation, one an EWS-ETV1 translocation, and one both an EWS-FLI1 type 1 and type 2 translocation. The authors concluded that the real-time RT-PCR assay for detecting sarcoma translocations used in this study has high sensitivity and specificity for Ewing’s sarcoma. It also has clinical utility in differentiating Ewing’s sarcoma from other small round blue cell tumors in the clinical lab.

Lewis, TB, Coffin CM, Bernard PS. Differentiating Ewing’s sarcoma from other round blue cell tumors using a RT-PCR translocation panel on formalin-fixed paraffin-embedded tissues. Mod Pathol. 2007;20:397–404.

Reprints: Dr. P.S. Bernard, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Suite 3345, Salt Lake City, UT 84105-5550;

bullet HER-2 amplification and overexpression in tumors of non-breast origin

The relationship between HER-2 overexpression and gene amplification is well evaluated for breast cancers but remains unclear or controversial for many other tumors. Therefore, the authors tested HER-2 status for more than 120 different tumors. They analyzed 5,751 tumor samples on TMAs by immunohistochemistry (Hercept-Test, Dako) and fluorescence in situ hybridization (PathVysion, Abbott-Vysis) under highly standardized conditions. HER-2 overexpression (score, 2/3+) and amplification occurred most often in breast cancers but was also noted in 18 other tumors, including cancers of the urinary bladder (amplification in 14.3%, overexpression in 6.7%), stomach (8.3/ 4.9%), endometrium (6.6/6.8%), lung (2.8/3.1%), and ovary (2.3/1.2%). A strong association between overexpression and amplification was found in all of the cancers. Trastuzumab therapy is highly efficient in HER-2 amplified breast cancer, in metastatic disease and as an adjuvant therapy. A variety of other tumors, including frequent neoplasms and cancers with often limited therapeutic options, have similar patterns of HER-2 alterations as observed in breast cancer—that is, high overexpression due to high-level gene amplification. Such tumors should be carefully evaluated for possible utility of trastuzumab treatment.

Tapia C, Glatz K, Novotny H, et al. Close association between HER-2 amplification and overexpression in human tumors of non-breast origin. Mod Pathol. 2007;20:192–198.

Reprints: Dr. G. Sauter, Dept. of Pathology, Center of Clinical Pathology University Medical Center, Martinistrasse 52, Hamburg-Eppendorf 20246, Germany;

bullet Verruca vulgaris of the vulva in children and adults

Condyloma acuminata, common lesions of the vulva in adults, are associated with infection by human papillomavirus types 6 and 11, which are acquired through sexual contact. Therefore, detection of a human papillomavirus (HPV) 6/11 condyloma in the genital tract of a child raises the question of sexual abuse. In this study, 29 genital warts in girls less than five years of age were examined for nongenital and genital tract HPVs by in situ hybridization. These results were compared with 275 vulvar lesions clinically suspicious for condyloma from adults. Of the 27 HVP-related lesions in young girls, 11 (41%) were due to HPV 2 and the other 16 (59%) were associated with HPV 6/11 infections. Of the 214 of 275 (78%) HPV-positive vulvar lesions in adults, six (3%) were due to HPV 2, and 202 of 214 (94%) contained HPV 6/11; one lesion contained HPV 16 and the five others contained HPV 42, 43, or 44. Histologic correlation documented that the vulvar lesions positive for HPV 2 commonly showed the marked hyperkeratosis typical of verruca vulgaris. However, the verrucous pattern was also present in lesions positive for HPV 6/11. The authors concluded that verruca vulgaris of the vulva, which is likely not transmitted sexually, can occur, albeit rarely, in the genital tract of women and is common in the genital tract of young girls. This highlights the value of HPV testing in such cases, especially if the histologic changes are consistent with verruca vulgaris. Aguilera-Barrantes I, Magro C, Nuovo GJ. Verruca vulgaris of the vulva in children and adults: a nonvenereal type of vulvar wart. Am J Surg Pathol. 2007;31(4):529–535.

Aguilera-Barrantes I, Magro C, Nuovo GJ. Verruca vulgaris of the vulva in children and adults: a nonvenereal type of vulvar wart. Am J Surg Pathol. 2007;31(4):529–535.

Reprints: Dr. Gerard J. Nuovo, Dept. of Pathology, Ohio State University Medical Center, S. 305 Rhodes Hall, 450 W. 10th Ave., Columbus, OH;

Dr. Cibull is professor of pathology and laboratory medicine and direct of surgical pathology, University of Kentucky Medical Center, Lexington. Dr. Kesler is hematopathology fellow, University of Texas Southwestern Medical Center at Dallas.