Carcinoma of the lower uterine segment: association with Lynch syndrome
Adjunctive human papillomavirus DNA testing for disease-risk assessment and triage of females with ASC-H Pap results
Pathologic predictors of microsatellite instability in colorectal cancer
Diagnosing epithelial mesothelioma using tree-based regression analysis and minimal antibodies
Significance of IGF2BP3 as a biomarker in ovarian clear-cell carcinoma
Endometrial carcinoma of the lower uterine segment is a poorly described cancer that can be confused with endocervical carcinoma. The authors performed a case-comparison study to document the clinicopathologic characteristics of lower uterine segment (LUS) tumors and their association with risk factors for endometrial cancer. They reviewed the clinical records and pathology reports from women who underwent hysterectomy for endometrial or endocervical adenocarcinoma at their institution during an 11-year interval. The LUS group consisted of women with endometrial tumors that clearly originated between the lower uterine corpus and upper endocervix. The authors performed immunohistochemistry and microsatellite instability and MLH1 methylation assays. They determined that 35 of 1,009 (3.5 percent) women had endometrial carcinoma of the LUS. They also found that, compared with patients with corpus tumors, LUS patients were younger, had higher stage tumors, and had more invasive tumors. Preoperative diagnosis of LUS tumors more frequently included the possibility of endocervical adenocarcinoma. Seventy-three percent of the LUS tumors had an immunohistochemical expression pattern typical of conventional endometrioid adenocarcinoma. Ten of 35 (29 percent) women with LUS tumors were confirmed to have Lynch syndrome or were strongly suspected of having Lynch syndrome on the basis of tissue-based molecular assays. The authors concluded that the prevalence of Lynch syndrome in patients with LUS endometrial carcinoma (29 percent) is much greater than in the general endometrial cancer patient population (1.8 percent) or in endometrial cancer patients younger than 50 years (eight to nine percent). Therefore, the possibility of Lynch syndrome should be considered in women with LUS tumors.
Westin SN, Lacour RA, Urbauer DL, et al. Carcinoma of the lower uterine segment: a newly described association with Lynch syndrome. J Clin Oncol. 2008;26:5965–5971.
Correspondence: Dr. Russell R. Broaddus at firstname.lastname@example.org
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Recent guidelines recommend colposcopy for women with atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H). The au-thors conducted a study to determine whether adjunctive high-risk human papillomavirus (hrHPV) testing is useful for assessing disease risk in females with ASC-H test results. They analyzed high-risk HPV prevalence and histopathologic follow-up data on 1,187 females with ASC-H ThinPrep Pap test results and hrHPV test results. ASC-H was reported in 1,646 of 277,400 (0.59 percent; 270,338 ThinPrep and 7,062 conventional) Pap test results. The difference in ASC-H detection rates between the ThinPrep and conventional Pap smears was statistically significant (0.60 versus 0.38 percent; P=.02). High-risk HPV was detected in 589 (49.6 percent) of 1,187 females with ASC-H ThinPrep and hrHPV testing. The hrHPV DNA-positive rate in females younger than 40 years was 54.7 percent, significantly higher than the 36.5 percent in women 40 years and older. Among 505 females with histopathologic followup, cervical intraepithelial neoplasia 2/3 was identified in 32.7 percent of hrHPV-positive and 1.2 percent of hrHPV-negative females. The sensitivity, specificity, positive predictive value, and negative predictive value of ASC-H cytology in conjunction with hrHPV DNA testing results for detecting cervical intraepithelial neoplasia 2/3 were 96.1 versus 100 percent, 54 versus 68.4 percent, 35.8 versus 20.8 percent, and 98.1 versus 100 percent in females younger than 40 years and women 40 years and older, respectively. The authors concluded that reflex hrHPV testing is a highly useful option for women with ASC-H Pap tests. Females with ASC-H and negative hrHPV testing may be more efficiently managed by followup with regular Pap and hrHPV testing than with universal colposcopy, especially women 40 years and older.
Bandyopadhyay S, Austin RM, Dabbs D, et al. Adjunctive human papillomavirus DNA testing is a useful option in some clinical settings for disease risk assessment and triage of females with ASC-H Papanicolaou test results. Arch Pathol Lab Med. 2008;132:1874–1881.
Correspondence: Dr. Chengquan Zhao at email@example.com
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Identifying microsatellite unstable colorectal cancers is important not only for recognizing hereditary nonpolyposis colorectal cancer syndrome but also because microsatellite instability-high (MSI-H) colorectal cancers have a better prognosis and may respond differently to 5-fluorouracil-based chemotherapy. The authors pre-sented two nearly equivalent logistic regression models for clinical use that predict microsatellite instability based on reviewing 1,649 colorectal cancers from patients of all ages collected in a population-based case control study in northern Israel. One hundred ninety-eight of the 1,649 (12 percent) tumors demonstrated a high degree of microsatellite instability. Multivariate analysis found that more than two tumor-infiltrating lymphocyte (TIL) cells per high-powered field, lack of dirty necrosis, presence of a Crohn-like reaction, right-sided location, mucinous differentiation (mucinous or focally mucinous) and well or poor differentiation, and age younger than 50 years were independent predictors of MSI-H. The authors developed two logistic regression models that differ based only on the statistical approach used to analyze the number of TIL cells per high-powered field, for which the slightly more accurate and complex model uses the log of the total number of TIL cells. The simpler clinical model uses a cutoff of two or more TIL cells per high-powered field. The accuracy of both models is high, with an 85.4 versus 85 percent probability of correctly classifying tumors as MSI-H. By employing the simpler model, pathologists can predict the likelihood of microsatellite instability by compiling the MSI probability score from simple histologic and clinical data available during sign-out. The model shows that approximately 43 percent of colorectal cancers have an MSI probability score of one or less and therefore have little likelihood (less than three percent) of being MSI-H. The authors concluded that although this model is not perfect in predicting microsatellite instability, it could improve the efficiency of expensive diagnostic testing.
Greenson JK, Huang SC, Herron C, et al. Pathologic predictors of microsatellite instability in colorectal cancer. Am J Surg Pathol. 2009;33:126–133.
Correspondence: Dr. Joel K. Greenson at firstname.lastname@example.org
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Immunohistochemistry with panels of antibodies is a standard procedure to distinguish between malignant mesothelioma and metastatic adenocarci-noma. However, most studies assess only the sensitivity and specificity for single antibodies, even when an antibody panel is recommended. The authors conducted a study of a novel statistical approach to identify a minimal panel of antibodies that would distinguish between malignant mesothelioma and metastatic adenocarcinoma in the majority of cases. They investigated 200 consecutive cases of pleural malignancy (173 pleural mesothelio-mas of epithelial type and 27 cases of secondary adenocarcinoma) using a standard panel of 12 antibodies, including CAM5.2, CK 5/6, calretinin, HBME-1, thrombomodulin, WT1, EMA, CEA, CD15, B72.3, BG8, and TTF-1. They applied regression and classification tree-based methods to select the best combination of markers. The modeling procedures used employ successive, hierarchical predictions computed for individual cases to sort them into homogeneous classes. The authors found that labeling for calretinin and lack of labeling for BG8 were sufficient for definite correlation with a diagnosis of malignant mesothelioma. CD15 provided additional differentiating information in some cases. The authors concluded that a panel of three antibodies was sufficient in most cases to diagnose or exclude epithelial mesothelioma. Calretinin exhibits the strongest correlative power of the antibodies tested.
Klebe S, Nurminen M, Leigh J, et al. Diagnosis of epithelial mesothelioma using tree-based regression analysis and a minimal panel of antibodies. Pathology. 2009;41:140–148.
Correspondence: Sonja Klebe at email@example.com
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Clear-cell carcinoma is an uncommon subtype of ovarian carcinoma, accounting for 10 percent of cases, and typically presents with stage I or II disease. In this setting, prognostic markers could aid in management decisions, in particular the decision to treat with adjuvant chemotherapy. The authors tested whether ex-pression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3, also known as IMP3) can serve as a biomarker to predict outcome for patients with clear cell-carcinoma and other subtypes of ovarian carcinoma. They evaluated the expression of IGF2BP3 with immunohistochemistry in 475 ovarian carcinomas of different subtypes and correlated the findings with disease-specific survival rates. IGF2BP3 antibody specificity was validated by correlation of IGF2BP3 protein with mRNA expression level in a series of 35 ovarian carcinomas (r=0.849; P<.0001). IGF2BP3 protein expression was an independent marker of reduced disease-specific survival (risk ratio 2.9; 95 percent confidence interval [CI], 1.4–5.8) in the clear-cell subtype (n=128) but not in high-grade serous (n=198) or endometrioid (n=121) carcinomas. The prognostic significance of IGF2BP3 expression for reduced disease-specific survival (risk ratio, 2.6; 95 percent CI, 1.3–5.0) was confirmed in an independent series of cases (n=150) from three centers in North America. The authors concluded that IGF2BP3 is the first biomarker of prognostic signifi-cance for ovarian clear-cell carcinoma that has been validated in an independent case series.
Köbel M, Xu H, Bourne PA, et al. IGF2BP3 (IMP3) expression is a marker of unfavorable prognosis in ovarian carcinoma of clear cell subtype. Mod Pathol. 2009;22:269–475.
Correspondence: Dr. C. B. Gilks at firstname.lastname@example.org
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Carcinomas co-occur in the pancreas, extrahepatic bile ducts, and ampulla of Vater. The authors investigated whether cancers originating in these sites represent a field effect similar to that observed in the lung and upper aerodigestive tract. They specifically sought to determine whether a field effect for car-cinogenesis exists in the ampulla of Vater, extrahepatic bile ducts, gallbladder, and pancreas. The authors obtained data from the National Cancer Institute’s Surveillance Epidemiology and End Results Program from 1973 through 2005. Cases were compared by age-frequency density plots, age-specific incidence rates, and logarithmic plots of the age-specific incidence rates and age of diagnosis. Incidence rates were 11.71, 1.43, 0.88, and 0.49 per 100,000 people at risk for pancreatic, gallbladder, extrahepatic bile duct, and ampullary carcinomas, respectively. Age-frequency density plots were congruent for cancers originating in all four sites. Logarithmic plots of the age-specific incidence rates with age of diagnosis produced parallel linear rate patterns for the four sites indicative of similar populations for tumor development. However, density and logarithmic plots of pancreatic endocrine carcinomas, a tumor of different cellular differentiation and carcinogenic pathway, served as a comparison. The endocrine carcinomas showed a different age distribution and nonparallel rate patterns with ductal carcinomas. The authors concluded that carcinomas of the pancreas, gallbladder, extrahepatic bile ducts, and ampulla of Vater have a common embryonic cellular ancestry, differentiation pathways, mucosal histologic patterns, and population-related tumor development indicating a field effect in carcinogenesis. Parallel linear rate patterns indicated that the rate of cancer development is similar in all four sites, even though the absolute incidence rates vary, and that regardless of location, the ductal epithelium is equally susceptible to malignant transformation. If carcinogenic pathways to cancer are similar, then the varying incidence rates noted clinically may be linked to the relative surface area of the ductal system in these sites. Pancreatic cancers are the most common because the surface area of the ductal system of the pancreas is greater than that of the gallbladder, extrahepatic bile ducts, and ampulla of Vater.
Henson DE, Schwartz AM, Nsouli H, et al. Carcinomas of the pancreas, gallbladder, extrahepatic bile ducts, and ampulla of Vater share a field for carcinogenesis: a population-based study. Arch Pathol Lab Med. 2009;133:67–71.
Correspondence: Dr. Donald E. Henson at email@example.com
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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.