CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation
Undifferentiated endometrial carcinomas are very aggressive high-grade endometrial carcinomas that are frequently underrecognized. The authors conducted a study to analyze the molecular alterations underlying the development of these endometrial carcinomas, focusing on those related to dedifferentiation. They assessed a series of 120 tumors: 57 grade 1 and 2 endometrioid endometrial carcinomas, 15 grade 3 endometrioid endometrial carcinomas, 27 endometrial serous carcinomas, and 21 undifferentiated endometrial carcinomas. The authors found a high frequency of DNA mismatch repair deficiency (38 percent) and moderate rate of p53 overexpression (approximately 33 percent) in undifferentiated carcinomas. In contrast to the characteristic endometrioid phenotype, a dramatic downregulation of E-cadherin expression was noted in the undifferentiated subtype. Quantitative methylation studies dismissed CDH1 promoter hypermethylation as the mechanism responsible for this change in gene expression, while immunohistochemistry revealed that the E-cadherin repressor ZEB1 was frequently overexpressed (62 percent) in undifferentiated endometrial carcinomas. This finding was accompanied by a sharp downregulation in the expression of the miR-200 family of microRNAs, well-known targets of ZEB1. Furthermore, there was enhanced expression of epithelial-to-mesenchymal transition markers in undifferentiated endometrial carcinomas, such as N-cadherin, cytoplasmic p120, and osteonectin. In addition, HMGA2, a regulator of epithelial-to-mesenchymal transition that is expressed in aggressive endometrial tumors, such as endometrial serous carcinomas and carcinosarcomas, was expressed in more than 20 percent of undifferentiated carcinomas. These results suggest that ZEB1 overexpression, associated with E-cadherin and miR-200s downregulation, and the expression of mesenchymal markers might enhance the metastatic potential of undifferentiated endometrial carcinomas, leading to a poor prognosis. Furthermore, these observations suggest that immunohistochemical analysis of E-cadherin and ZEB1 can aid in the differential diagnosis of the more aggressive undifferentiated endometrial carcinomas from grade 3 endometrioid carcinomas.
Romero-Pérez L, López-Garcia MA, Díaz-Martin J, et al. ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation is characteristic of undifferentiated endometrial carcinoma. Mod Pathol. 2013;26:1514–1524.
Correspondence: Dr. R. A. Soslow at soslowr@mskcc.org or Dr. Jose Palacios at jose.palacios@salud.madrid.org
Human papillomavirus-associated oral intraepithelial neoplasia
The authors evaluated an unusual subset of oral epithelial dysplasia for the presence of transcriptionally active high-risk human papillomavirus subtypes and to further characterize the histological criteria for this condition. Clinical and followup data were collected and histopathological features documented. Twenty cases were diagnosed as epithelial dysplasia with marked apoptosis of the anterior oral cavity. Immunoperoxidase studies were performed for p16, and in situ hybridization studies were performed for low- and high-risk HPV subtypes. Gender- and site-matched controls of conventional moderate to severe oral epithelial dysplasia were similarly evaluated using immunoperoxidase studies for p16 and in situ hybridization. The number of apoptotic cells for study and control cases was counted at two tissue sites. The evaluation focused on 17 men and three women who were a median age of 56 years. Seventeen lesions were described as white and five as rough or papillary. Thirteen were located on the lateral or ventral tongue, some extending onto the floor of the mouth. Epithelial hyperplasia with marked karyorrhexis and apoptosis were present in all the cases, along with features of conventional oral epithelial dysplasia. A statistically significant number of apoptotic cells were identified in the study cases when compared with controls (P>0.0001). Twenty cases were positive for high-risk HPV by in situ hybridization, and all 19 cases evaluated for p16 demonstrated overexpression. Two patients were diagnosed with squamous cell carcinomas and one patient developed recurrent disease. For consistency in nomenclature with HPV-associated lesions of the lower anogenital tract, the authors propose using the term HPV-associated oral intraepithelial neoplasia to characterize a subset of oral intraepithelial dysplasia that occurs mostly on the ventral or lateral tongue of adult males and is positive for high-risk HPV and p16.
Woo SB, Cashman EC, Lerman MA. Human papillomavirus-associated oral intraepithelial neoplasia. Mod Pathol. 2013;26:1288–1297.
Correspondence: Dr. M. A. Lerman at mark_lerman@hsdm.harvard.edu
Association between tumor-infiltrating lymphocyte grade in
primary melanomas and melanoma-specific survival
Although most hospital-based studies suggest more favorable survival outcomes with tumor-infiltrating lymphocytes present in primary melanomas, it is uncertain whether TILs provide prognostic information beyond melanoma-staging definitions. The authors addressed this issue in an international population-based study of patients with single and multiple primary melanomas. On the basis of the Genes, Environment and Melanoma (GEM) Study, they conducted followup of 2,845 patients diagnosed from 1998 to 2003 with 3,330 invasive primary melanomas centrally reviewed for TIL grade (absent, nonbrisk, or brisk). They examined the odds of TIL grades associated with clinicopathologic features and survival by TIL grade. The authors found that the independent predictors (P<0.05) for nonbrisk TIL grade were site, histologic subtype, and Breslow thickness, and for brisk TIL grade were age, site, Breslow thickness, and radial growth phase. Both nonbrisk and brisk TIL grades were associated with lower American Joint Committee on Cancer (AJCC) tumor stage compared with TIL absence (P [trend] <0.001). Death rate as a result of melanoma was 30 percent less with nonbrisk TIL grade (hazard ratio [HR], 0.7; 95 percent confidence interval [CI], 0.5–1.0) and 50 percent less with brisk TIL grade (HR, 0.5; 95 percent CI, 0.3–0.9) relative to TIL absence, adjusted for age, gender, site, and AJCC tumor stage. The authors concluded that at the population level, higher TIL grade of primary melanoma is associated with a lower risk of death as a result of melanoma independent of tumor characteristics used for AJCC tumor stage. TIL grade deserves further prospective investigation to determine whether it should be included in future AJCC staging revisions.
Thomas NE, Busam KJ, From L, et al. Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based Genes, Environment and Melanoma Study. J Clin Oncol. 2013;31:4252–4259.
Correspondence information not provided.
Study of PEComas of the gastrointestinal tract with evaluation of prognostic parameters
Perivascular epithelioid cell tumors (PEComas) are distinctive mesenchymal neoplasms that typically arise in the retroperitoneum, visceral organs, and abdominopelvic sites and usually show reactivity for melanocytic and smooth muscle markers. Fewer than 20 PEComas of the gastrointestinal tract have been reported, and behavior and criteria for malignancy are incompletely defined. The authors conducted a study to examine the clinicopathologic features of a series of GI PEComas and to evaluate prognostic parameters. Thirty-five PEComas of the GI tract were retrieved from consult and surgical files. Clinical and pathologic features were evaluated, and immunohistochemical analysis was performed. Clinical followup information was obtained from medical records and referring physicians. Nineteen patients were female and 16 male (median age, 45 years; range, 7–70 years). One patient had tuberous sclerosis. Nineteen tumors arose in the colon, 12 in the small bowel, two in the stomach, and one each in the gallbladder and omentum. Median tumor size was 6.2 cm (range, 0.8–22 cm). Three tumors were limited to the mucosa and submucosa, while eight extended to the muscularis propria, 15 to the subserosa/serosa, and eight into the mesentery. The tumors were composed of nests and sheets of usually epithelioid cells with abundant granular eosinophilic to clear cytoplasm surrounded by a delicate capillary vasculature. Thirteen tumors had mixed epithelioid and spindle cell components and two were purely spindled. Sixteen tumors showed marked nuclear atypia. Seventeen tumors contained occasional pleomorphic cells and 12 showed diffuse cellular pleomorphism. The median mitotic rate was 2/10 high-power field (HPF; range, 0–36). Vascular invasion was present in five cases, and 16 tumors showed necrosis. By immunohistochemistry, 23 of 35 tumors were positive for HMB45, 23 of 34 for melan-A, 15 of 25 for MiTF, 20 of 35 for smooth muscle actin, 26 of 35 for desmin, and three of 20 for TFE3. Focal cytoplasmic S100 protein was present in five of 27 cases, while two of 25 cases were positive for KIT, and one case each was positive for epithelial membrane antigen and keratin. Followup information was available for 31 patients (median, 36 months; range, 2–176 months). Thirteen patients had developed metastases (10 liver, three peritoneum, four lymph node, three lung, one bone, one brain, and one adrenal). The authors reported that five patients had died of disease. Metastases were significantly associated with marked atypia, diffuse pleomorphism, and mitoses ≥ 2/10 HPF. The authors concluded that PEComas of the GI tract occur at similar frequency in female and male patients, most commonly involve the colon, and exhibit variable clinical behavior that ranges from benign lesions to aggressive, high-grade sarcomas. The presence of marked nuclear atypia, diffuse pleomorphism, and mitotic activity are the strongest predictors of malignant behavior.
Doyle LA, Hornick JL, Fletcher CD. PEComa of the gastrointestinal tract: clinicopathologic study of 35 cases with evaluation of prognostic parameters. Am J Surg Pathol. 2013;37 (12):1769–1782.
Correspondence: Dr. C. D. M. Fletcher at cfletcher@partners.org