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  Anatomic Abstracts





September 2011

Michael Cibull, MD
Melissa Kesler, MD
Rouzan Karabakhtsian, MD
Megan Zhang, MD

Beta-catenin/Wnt signaling pathway in fibromatosis and other tumors of breast Beta-catenin/Wnt signaling pathway in fibromatosis and other tumors of breast

The Wnt signaling pathway plays a critical role in carcinogenesis and in epithelial-to-mesenchymal transition. Upon Wnt activation, β-catenin is translocated from the membrane to the cytoplasm and nucleus, where it interacts with transcriptional activators. It has been suggested that various spindle cell lesions of the breast may harbor Wnt pathway activation. Given that β-catenin nuclear localization constitutes a good surrogate marker of Wnt canonical pathway activation, the authors have investigated the distribution of β-catenin in spindle cell lesions of the breast and whether it could be employed in the differential diagnosis of these lesions. A total of 52 metaplastic breast carcinomas, eight fibromatoses, and 23 phyllodes tumors were retrieved from the archives of the authors’ institutions. The authors performed immunohistochemistry using two anti-β-catenin antibodies. In all, three fibromatoses and 21 metaplastic breast carcinomas were subjected to CTNNB1 (β-catenin encoding gene) mutation analysis by direct gene sequencing. The authors observed a good correlation between the two antibodies (Spearman rank correlation coefficient, r>0.82; P<0.001). All fibromatoses and 23 percent of metaplastic breast carcinomas expressed nuclear β-catenin. In fibromatosis, β-catenin was more often diffusely expressed, whereas in metaplastic breast carcinomas, expression was more often focal. Membranous β-catenin expression was significantly lower in spindle cell carcinomas than in other subtypes of metaplastic breast carcinomas. In phyllodes tumors, stromal cells of benign and malignant subtypes displayed nuclear β-catenin expression in 94 percent and 57 percent of cases, respectively. No CTNNB1 mutation was identified in any of the 21 metaplastic carcinomas analyzed, whereas the mutations 45S>S/P and 41T>T/A were found in samples of fibromatosis. The authors concluded that β-catenin nuclear expression is a common feature in fibromatoses and in the stromal component of phyllodes tumors, but it also may be observed in metaplastic breast carcinomas. β-catenin nuclear expression should not be used as a single marker to differentiate fibromatosis from other spindle cell tumors of the breast.

Lacroix-Triki M, Geyer FC, Lambros MB, et al. β-catenin/Wnt signalling pathway in fibromatosis, metaplastic carcinomas and phyllodes tumours of the breast. Mod Pathol. 2010;23:1438–1448.

Correspondence: J. S. Reis-Filho at or Dr. A. H. S. Lee at
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Tumor-infiltrating lymphocytes in stage II colon cancer Tumor-infiltrating lymphocytes in stage II colon cancer

The most reliable prognostic factor in colon cancer is the tumor-node-metastasis classification. The authors conducted a study to assess and compare the prognostic role of tumor-infiltrating lymphocytes (TILs) in stage II colon cancer. They used immunohistochemistry to assess the density of TILs that were positive for cluster of differentiation three (CD3; T-cell coreceptor), CD45 isoform RO (CD45RO; protein tyrosine phosphatase), nuclear transcription factor forkhead box P3 (FOXP3), and CD25 (a type 1 transmembrane protein) according to tumor site (intraepithelial and stromal) in samples from 87 patients who had stage II colon cancer. These variables were evaluated for their association with histopathological features and with overall survival and disease-free survival. The authors found that intraepithelial CD3-positive (CD3+), CD45RO+, CD25+, and FOXP3+ TILs were associated significantly with better disease-free survival (P=0.049, P=0.009, P=0.013, and P=0.001, respectively). The estimated five-year overall survival rate for patients who had high-density CD45RO+ and FOXP3+ expression was 100 percent for both, compared with 79.2 percent and 78.8 percent for patients who had low-density CD45RO+ and FOXP3+ expression (P=0.017 and P=0.040, respectively). A significant prognostic factor for overall survival and disease-free survival was high-density stromal CD45RO+ lymphocytic infiltration (overall survival: P=0.031; relative risk, 0.134; 95 percent confidence interval [CI], 0.015–1.164/disease-free survival: P=0.013; relative risk, 0.198; 95 percent CI, 0.055–0.710), whereas intraepithelial FOXP3+ expression was an independent prognostic factor for disease-free survival (P=0.032; relative risk, 0.108; 95 percent CI, 0.014–0.821). The authors concluded that FOXP3+ and CD45RO+ TILs demonstrated independent prognostic significance for survival. These results may help improve the prognostication of early stage colon cancer.

Lee WS, Park S, Lee WY, et al. Clinical impact of tumor-infiltrating lymphocytes for survival in stage II colon cancer. Cancer. 2010;116(22):5188–5199.

Correspondence information not available.
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Analysis of epidermal growth factor receptor in adrenocortical tumors Analysis of epidermal growth factor receptor in adrenocortical tumors

Adrenocortical carcinoma is a rare but highly malignant neoplasm with limited treatment options. Epidermal growth factor receptor (EGFR) has been shown to be overexpressed in many solid tumors, but its expression in adrenocortical carcinoma has been studied in a limited number of cases. Therefore, the authors analyzed the expression of EGFR in 169 adrenocortical carcinoma samples and compared it with 31 adrenocortical adenomas. And in 30 cases of adrenocortical carcinoma they cloned and sequenced exons 18 to 21 of the EGFR gene. EGFR expression was found in 128 of 169 adrenocortical carcinoma samples (76 percent), and strong membrane staining was detected in 60 of these samples (36 percent). However, no significant correlation with clinical outcome was noted. Furthermore, all 30 sequenced cases revealed unmutated EGFR genes. In contrast, only one of 31 adrenocortical adenomas weakly expressed EGFR (three percent). Because EGFR is weakly expressed in adrenocortical adenomas, these results suggest that its expression in adrenocortical tumors indicates a malignant phenotype, which may be used in the differential diagnosis of adrenocortical adenomas and carcinomas.

Adam P, Hahner S, Hartmann M, et al. Epidermal growth factor receptor in adrenocortical tumors: analysis of gene sequence, protein expression and correlation with clinical outcome. Mod Pathol. 2010;23:1596–1604.

Correspondence: Dr. M. Fassnacht at
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Histologic artifacts in hysterectomy specimens Histologic artifacts in hysterectomy specimens

Total laparoscopic hysterectomy is a minimally invasive technique that results in comparable morbidity and better cosmesis than total abdominal hysterectomy. The literature is discrepant as to whether it is associated with a higher incidence of positive peritoneal cytology compared with total abdominal hysterectomy. Associated artifacts, including vascular pseudoinvasion (VPI), recently have been described. The authors reported on a retrospective histopathologic review of 266 hysterectomy specimens from two centers. The observers, blinded to surgical technique, assessed for the presence of artifactual changes, including disruption of the endometrial lining, nuclear crush artifact, VPI, endomyometrial cleft artifact with or without epithelial displacement, inflammatory debris within vessels, serosal carryover, and intratubal contaminants. Rates of positive peritoneal washings over a five-year period, and use of immunohistochemistry to aid in cell typing over a three-year period, were compared between hysterectomies in which a uterine manipulator device had and had not been used. The hysterectomies were performed for malignant (n=160) and benign (n=102) uterine disease or for ovarian or cervical disease (n=4) and included total abdominal (n=108), vaginal (n=17), laparoscopy-assisted vaginal (n=24), laparoscopy converted to laparotomy (n=10), nonrobotic laparoscopic (n=51), and robot-assisted laparoscopic (n=56) hysterectomies. One hundred and two (38 percent) of these hysterectomies involved the use of a uterine manipulator. Artifactual changes of disruption of the endometrial lining, endomyometrial clefts, intratubal contaminants, nuclear crush artifact, intravascular inflammatory debris, and VPI were significantly more common with laparoscopic hysterectomy and with the use of a uterine manipulator, independent of whether the endometrial pathology was benign or malignant. Immunohistochemistry to aid in endometrial cancer subtyping was more likely to be used in manipulated hysterectomies (P=0.0166). Furthermore, peritoneal washings were significantly more likely to be positive in hysterectomies in which a uterine manipulator had been used (P=0.0061). The authors concluded that histologic artifacts are significantly more common in laparoscopic hysterectomy and specifically in hysterectomies in which a uterine manipulator is used. Such artifacts impair the pathologist’s interpretation of cell type requiring an increased use of immunohistochemistry, and displaced epithelial fragments within vessels or artifactual clefts may result in misinterpretation of prognostic and staging parameters. Furthermore, cases that are subjected to uterine manipulation have a significantly higher rate of positive peritoneal cytology, suggesting dissemination of malignant cells into the abdominal cavity. The clinical significance of this finding needs to be determined.

Krizova A, Clarke BA, Bernardini MQ, et al. Histologic artifacts in abdominal, vaginal, laparoscopic, and robotic hysterectomy specimens: a blinded, retrospective review. Am J Surg Pathol. 2011;35(1):115–126.

Correspondence: Dr. Blaise A. Clarke at
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Model for predicting microsatellite instability in colorectal cancers Model for predicting microsatellite instability in colorectal cancers

Identifying colorectal cancers with high levels of microsatellite instability is clinically important. Microsatellite instability (MSI-H) is a positive prognostic marker for colorectal cancers, a predictive marker for resistance to standard 5-fluorouracil-based adjuvant chemotherapy, and an important feature for identifying individuals and families with Lynch syndrome. The authors conducted a study to compare the existing predictive pathology models for MSI-H colorectal cancers and improve on them. They tested two models used to predict MSI-H tumors—revised Bethesda guidelines and MsPath—in a population-based cohort of colorectal cancers diagnosed in subjects younger than 75 years who were from Newfoundland (n=710). They also scored additional histologic features not described in the other models. From this analysis, the authors developed a model for predicting MSI-H colorectal carcinomas, called Pathologic Role in Determination of Instability in Colorectal Tumors (PREDICT). An independent pathologist validated this model in a second cohort of all colorectal carcinomas (n=276). It was determined that tumor histology was a better predictor of MSI status than was personal and family history of cancer. MsPath identified MSI-H colorectal carcinomas with a sensitivity of 92.1 percent and specificity of 37.8 percent, whereas the revised Bethesda guidelines had a sensitivity of 81.3 percent and specificity of 39.5 percent. PREDICT included some new histology features, including peritumoral lymphocytic reaction and increased proportion of plasma cells in the tumor stroma. PREDICT was superior to the aforementioned models in the development cohort, with a sensitivity of 97.4 percent and specificity of 53.9 percent. In the validation cohort, sensitivity was 96.9 percent and specificity was 76.6 percent. The authors concluded that PREDICT is a good predictor of MSI-H colorectal carcinoma.

Hyde A, Fontaine D, Stuckless S, et al. A histology-based model for predicting microsatellite instability in colorectal cancers. Am J Surg Pathol. 2010;34(12):1820–1829.

Correspondence: Dr. Banfield Younghusband at
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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.