CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Anatomic pathology abstracts editors: Michael Cibull, MD, professor of pathology, University of Kentucky, Lexington; Rouzan Karabakhtsian, MD, attending pathologist, Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; Thomas Cibull, MD, dermatopathologist, Evanston Hospital, NorthShore University HealthSystem, Evanston, Ill.; and Rachel Stewart, DO, resident physician, Department of Pathology and Laboratory Medicine, University of Kentucky.
Cytokeratin 17: an adjunctive marker of invasion in anal squamous neoplastic lesions
Diagnosing anal squamous cell carcinoma, which is often preceded by anal intraepithelial neoplasia, may be challenging in small biopsies. Cytokeratin 17 (CK17) is a basal/myoepithelial cell keratin induced in activated keratinocytes and associated with disease progression in squamous cell carcinoma (SCC) of the uterine cervix, esophagus, and oral cavity. The authors investigated the utility of CK17 in diagnosing invasion in anal squamous neoplastic lesions. Immunohistochemical staining for CK17 was evaluated in 11 anal intraepithelial neoplasias (AINs), 12 invasive SCCs, eight invasive SCCs with basaloid features (BSCC), and two invasive pure basaloid carcinomas. The pattern of staining was scored as surface/central, peripheral/rim, diffuse, or absent. All cases of invasive SCC and BSCC stained positive for CK17. Eleven of 12 (92 percent) SCCs showed diffuse staining, and one of 12 (eight percent) showed peripheral staining. Six of eight (75 percent) BSCCs showed diffuse staining and two of eight (25 percent) showed peripheral staining. Both pure basaloid carcinomas were negative for CK17. One of 11 (nine percent) AINs was diffusely positive for CK17; all other AINs had surface or no CK17. Of the six patients with concurrent AIN and invasive carcinoma, superficial expression of CK17 was present in one AIN, whereas all invasive components showed diffuse staining. The sensitivity and specificity of CK17 for identifying invasion in SCC and BSCC were 100 percent and 91 percent, respectively. The authors concluded that peripheral or diffuse staining for CK17 is a useful marker of invasion in anal squamous neoplastic lesions. A potential drawback to the utility of CK17 is that the pure basaloid variant of anal carcinoma is negative for CK17.
Nazarian RM, Primiani A, Doyle LA, et al. Cytokeratin 17: an adjunctive marker of invasion in squamous neoplastic lesions of the anus. Am J Surg Pathol. 2014;38(1):78–85.
Correspondence: Dr. Rosalynn M. Nazarian at rmnazarian@partners.org
Baseline prostate inflammation relative to risk of prostate cancer in repeat biopsy
The authors conducted a study to evaluate whether baseline acute and chronic prostate inflammation among men with an initial negative biopsy for prostate cancer increased the risk of subsequent prostate cancer detection in a clinical trial with systematic biopsies. The study involved a retrospective analysis of 6,238 men aged 50 to 75 years who had prostate-specific antigen levels between 2.5 and 10 ng/mL and a prior negative biopsy in the Reduction by Dutasteride of PCa Events, or REDUCE, study and completed a two-year repeat biopsy. Prostate cancer, acute prostate inflammation, and chronic prostate inflammation were assessed by central review. The association between inflammation in baseline prostate biopsies and positive two- and four-year repeat biopsies was evaluated with the chi-square test and logistic regression analysis adjusting for baseline covariates. Acute inflammation, chronic inflammation, and a combination of both were detected in 46 baseline biopsies (one percent), 3,931 baseline biopsies (63 percent), and 892 baseline biopsies (14 percent), respectively. Acute and chronic inflammation were found to be significantly associated with each other (P<0.001). Acute inflammation at baseline biopsy was associated with younger age, lower prostate-specific antigen levels, and a smaller prostate (all P<0.01), whereas chronic inflammation was associated with older age and larger prostate glands (all P<0.01). At the two-year biopsy, the prevalence of prostate cancer was 14 percent (n=900 patients). On univariable and multivariable analysis, both acute and chronic inflammation were found to be significantly associated with a lower prostate cancer risk (acute univariable: odds ratio [OR], 0.65 [P<0.001] and multivariable: OR, 0.75 [P=0.012]; and chronic univariable: OR, 0.61 [P<0.001] and multivariable: OR, 0.65 [P<0.001]). At the time of four-year biopsy, only acute inflammation was found to be associated with a lower prostate cancer risk. The authors concluded that baseline acute and chronic inflammation were independently associated with a lower prostate cancer risk. From a clinical standpoint, inflammation in negative biopsies for prostate cancer may lower the risk of subsequent prostate cancer detection.
Moreira DM, Nickel JC, Gerber L, et al. Baseline prostate inflammation is associated with a reduced risk of prostate cancer in men undergoing repeat prostate biopsy: Results from the REDUCE study. Cancer. 2014;120:190–196.
Correspondence: D. M. Moreira at dmoreira@nshs.edu
Classifying serrated lesions of the colon based on detection of BRAF V600E
BRAF V600E mutation in serrated lesions of the colon has been implicated as an important mutation and a specific marker for the serrated carcinogenic pathway. Recent findings point to microvesicular hyperplastic polyps that have similar histologic and molecular features to sessile serrated adenomas/polyps as potential colorectal precursors. The authors conducted a study to evaluate BRAF V600E mutation status by immunohistochemistry in serrated lesions of the colon with regard to histomorphology. They investigated 194 serrated lesions of the colon, comprising 42 sessile serrated adenomas/polyps, 16 traditional serrated adenomas, 136 hyperplastic polyps, and 20 tubular/tubulovillous adenomas (conventional adenomas) with the novel BRAF V600E mutation-specific antibody VE1. In addition, BRAF exon 15 and KRAS exon 2 status was investigated by capillary sequencing in selected cases. All sessile serrated adenomas/polyps (42 of 42; 100 percent), 15 of 16 (94 percent) traditional serrated adenomas, and 84 of 136 (62 percent) hyperplastic polyps were VE1+. None of the VE1- serrated lesions showed BRAF V600E mutation. Forty of 42 (95 percent) sessile serrated adenomas/polyps displayed areas with microvesicular hyperplastic polyp-like features. In microvesicular hyperplastic polyps, VE1 positivity was significantly associated with nuclear atypia (P=0.003); however, nuclear atypia was also present in VE1- cases. Immunostaining with VE1 allows not only the detection of BRAF V600E mutation but also correlation with histomorphology on a cellular level in serrated lesions. VE1 allows for the subclassification of microvesicular hyperplastic polyps according to mutation status. This improved classification of serrated lesions including immunohistochemical evaluation of BRAF V600E mutation may be the key to identifying lesions with higher potential for progressing to sessile serrated adenoma/polyp and then to BRAF V600E-mutated colorectal cancer.
Mesteri I, Bayer G, Meyer J, et al. Improved molecular classification of serrated lesions of the colon by immunohistochemical detection of BRAF V600E. Mod Pathol. 2014;27:135–144.
Correspondence: Dr. P. Birner at peter.birner@meduniwien.ac.at
Molecular phenotype offoci in multifocal invasive breast carcinomas
Multiple synchronous, ipsilateral, invasive foci of breast carcinomas are frequent. Few studies have investigated the prognostic and therapeutic implications of heterogeneity of such foci. The authors reviewed the tumor type, grade, and size of all invasive foci in a series of 110 multifocal breast carcinomas documented on large-format slides. Molecular phenotype was determined by immunohistochemistry in tissue microarray blocks using three classification systems. The survival rates of patients who had tumors with microscopic (tumor type or grade, or both) heterogeneity and patients who had tumors with phenotypic heterogeneity were compared, using Kaplan-Meier curves, with the survival rates of patients who had multifocal homogeneous tumors. The hazard ratio of dying from breast cancer was also calculated. The authors found that intertumoral heterogeneity in tumor type and grade was detected in 16 of 110 tumors (14.6 percent) and six of 110 tumors (5.5 percent), respectively. The molecular phenotype of invasive tumor foci within the same breast differed in 10 to 12.7 percent of patients (11 to 14 of 110 tumors), depending on the classification system used. Patients who had phenotypically heterogeneous, multifocal cancers had a greater risk of dying from disease (hazard ratio, 2.879; 95 percent confidence interval, 1.084–7.649; P=0.034) and had significantly shorter survival rates (P=0.016). Phenotypic differences were most common in patients who had tumors that were homogeneous in terms of tumor type (11 of 18 tumors) and histology grade (14 of 18 tumors). Phenotyping additional tumor foci had the potential to influence therapeutic decisions in up to eight patients. The authors concluded that phenotyping more than one invasive focus of multifocal breast carcinomas only if the individual foci deviate microscopically appears to be insufficient because phenotypic intertumoral heterogeneity may be observed in microscopically identical foci and has potential prognostic and therapeutic consequences.
Pekar G, Gere M, Tarjan M, et al. Molecular phenotype of the foci in multifocal invasive breast carcinomas: intertumoral heterogeneity is related to shorter survival and may influence the choice of therapy. Cancer. 2014;120:126–134.
Correspondence: Dr. Gyula Pekar at gyula.pekar@ltdalarna.se
Mutation profiles of ovarian and endometrial endometrioid carcinomas
Ovarian endometrioid carcinomas and endometrial endometrioid carcinomas share many histological and molecular alterations. These similarities are likely due to a common endometrial epithelial precursor cell of origin, with most ovarian endometrioid carcinomas arising from endometriosis. To directly compare the mutation profiles of two morphologically similar tumor types—endometrial endometrioid carcinomas (n=307) and ovarian endometrioid carcinomas (n=33)—the authors performed select exon-capture sequencing on the genes ARID1A, PTEN, PIK3CA, KRAS, CTNNB1, PPP2R1A, and TP53. They found that PTEN mutations were more frequent in low-grade endometrial endometrioid carcinomas (67 percent) than in low-grade ovarian endometrioid carcinomas (17 percent). By contrast, CTNNB1 mutations were more frequent in low-grade ovarian endometrioid carcinomas (53 percent) than in low-grade endometrial endometrioid carcinomas (28 percent). This difference in CTNNB1 mutation frequency may be reflective of the distinct microenvironments—the epithelial cells lining an endometriotic cyst within the ovary are exposed to a highly oxidative environment that promotes tumorigenesis. Understanding the distinct mutation patterns found in the PI3K and Wnt pathways of ovarian and endometrial endometrioid carcinomas may provide opportunities for stratifying patients for targeted therapeutics.
McConechy MK, Ding J, Senz J, et al. Ovarian and endometrial endometrioid carcinomas have distinct CTNNB1 and PTEN mutation profiles. Mod Pathol. 2014;27:128–134.
Correspondence: Dr. C. B. Gilks at blake.gilks@vch.ca or Dr. D. G. Huntsman at dhuntsma@bccancer.bc.ca