Alice Lytwyn

The role of cytology (Pap tests) and human papillomavirus testing in anal cancer screening.

Objective:To assess anal oncogenic human papillomavirus (HPV) and anal cytology as screening tests for detecting high-grade anal intraepithelial neoplasia (AIN 2+), as this is an immediate anal cancer precursor. Design:Cross-sectional study of 401 HIV-positive men who have sex with men (MSM). The endpoint was histologically confirmed AIN 2+ obtained by high-resolution anoscopy. Cytology and biopsy specimens were assigned random numbers and independently assessed by two pathologists. Methods:We did concomitant anal cytology, anal HPV testing and HRA with directed biopsies without knowing the results of each intervention. The main outcome measures were the sensitivity, specificity, negative predictive value and positive predictive value of anal cytology and oncogenic HPV for the detection of AIN 2+. Results:Cytology was abnormal in 67% of patients: high-grade squamous intraepithelial lesion, 12%; low-grade squamous intraepithelial lesion, 43% and atypical squamous cells of undetermined significance, 12%. Biopsies were abnormal in 68% of patients: AIN 2+, 25% and AIN 1, 43%. HPV was detected in 93% with multiple HPV types in 92% and oncogenic HPV types in 88%. Test performance characteristics for the detection of AIN 2+ using any abnormality on anal cytology were: sensitivity 84%, specificity 39%, negative predictive value 88% and positive predictive value 31%; using oncogenic HPV: sensitivity 100%, specificity 16%, negative predictive value 100% and positive predictive value 28%. Conclusion:Anal cytology and HPV detection have high sensitivity but low specificity for detecting AIN 2+. HIV-positive men who have sex with men have a high prevalence of AIN 2+ and require high-resolution anoscopy for optimal detection of high-grade anal dysplasia.

Frequency of serous tubal intraepithelial carcinoma in various gynecologic malignancies: a study of 300 consecutive cases.

Serous tubal intraepithelial carcinoma (STIC) has been implicated in the pathogenesis of pelvic serous carcinoma. We hypothesized that, if this is the case, the frequency of STIC should be substantially lower in endometrial serous carcinomas, in nonserous gynecologic malignancies, and in benign gynecologic neoplasms than in ovarian or peritoneal serous carcinomas. From 2007 to 2009 the fallopian tubes of 342 consecutive gynecologic cases were entirely submitted for histology using the Sectioning and Extensively Examining the FIMbriated end protocol. This study included 300 of these cases (277 TAH-BSO, 23 BSO) after exclusion. The hematoxylin and eosin-stained slides from the fallopian tubes were independently reviewed by 2 gynecologic pathologists who were blinded to all other findings; disagreements were resolved by a third pathologist. Among 46 cases of ovarian malignancies, STIC was identified in 6 (18.8%) of 32 cases of serous carcinoma, but not in any other subtype. Similarly, STIC coexisted in 4 (14.3%) of 28 cases of endometrial serous carcinoma; however, no STIC was identified in any of the 74 cases of nonserous endometrial malignancies. STIC was identified in 2 (28.6%) of 7 cases of peritoneal serous carcinoma. No STIC was identified among 15 nongynecologic malignancies, 90 cases of benign conditions, and 27 cases of other conditions including 4 cases of cervical adenocarcinoma in situ and high-grade cervical intraepithelial lesions, 8 cases of endometrial atypical complex hyperplasias, and 15 cases of ovarian borderline tumors. In conclusion, the fallopian tube may be the origin of some pelvic serous carcinomas. Other possibilities that may explain the origin of pelvic high-grade serous carcinoma are discussed. Given that STIC coexisted with 14% of endometrial serous carcinomas, a more unifying theory may be that gynecologic serous carcinomas and STIC are multifocal lesions.

Screening for HIV-Associated Anal Cancer: Correlation of HPV Genotypes, p16, and E6 Transcripts with Anal Pathology

Background: HIV-positive men with a history of anal-receptive intercourse are at risk for anal cancer. We determined whether human papilloma virus (HPV) biomarkers were correlated with anal pathology in these men. Methods: HPV genotype was determined by PCR/line blot assay. Real-time PCR assays were done for viral load, E6 transcripts for HPV genotypes 16, 18, and 31, and p16 transcripts. Results: The most common oncogenic HPV types were HPV 16 (38%), 18 (19%), 45 (22%), and 52 (19%). HPV types 16, 18, 31, 52, 59, and 68 were associated with high-grade histology. The number of HPV genotypes per anal swab was higher for anal intraepithelial neoplasia (AIN) 2/3 than for normal or AIN 1 histology [median, 5 types (interquartile range) (IQR), 3-7 versus 3.5 (IQR), 2-6; P = 0.0005]. HPV 16 viral load was also associated with AIN 2/3 histology. There was no difference in p16 or E6 transcripts between histologic grades. In the multivariable logistic regression model, HPV genotypes 16 [odds ratio, 2.58; 95% confidence interval (95% CI), 1.31-5.08; P = 0.006] and 31 (odds ratio, 4.74; 95% CI, 2.00-11.22; P = 0.0004), baseline CD4 count < 400 cells/mm3 (odds ratio, 2.96; 95% CI, 1.46-5.99; P = 0.0025), and Acquired Immunodeficiency Syndrome (AIDS)-defining illness (odds ratio, 2.42; 95% CI, 1.22-4.82; P = 0.01) were associated with high-grade histology after adjusting for age. Conclusions: The presence of high-grade anal pathology (AIN 2/3) in HIV-positive men was associated with multiple HPV genotypes, HPV genotypes 16 and 31, and HPV 16 viral load. (Cancer Epidemiol Biomarkers Prev 2009;18(7):1986–92)

Self-collection for vaginal human papillomavirus testing: systematic review of studies asking women their perceptions.

Objectives. To systematically review literature on womens acceptance, preference, willingness, and attitudes toward human papillomavirus DNA vaginal self-sampling and assess study validity using the STROBE statement. Materials and Methods. From September to October 2008, Ovid MEDLINE, EMBASE, and CINAHL databases were searched systematically over all years available. Participants were women who either completed vaginal self-sampling or were described the procedure. Studies were required to report womens acceptance, preference, willingness or attitudes toward self-sampling. Two independent reviewers assessed abstracts and articles for inclusion and collected study data. Disagreements were resolved by consensus. Results. Twenty studies were included. Of 8 studies, 7 reported that women found self-sampling acceptable. Of the 13 studies, 8 found that more women (63%-94%) preferred self-sampling to clinician-collected sampling. Most women were also receptive to self-sampling as part of future screening. Common opinions expressed by women included an uncertainty if they had or could perform the self-test properly and greater confidence in clinician sampling. Only 2 studies used questionnaires that had been validated, and selection bias favoring self-sampling could not be ruled out in most studies. Conclusions. Vaginal human papillomavirus DNA self-sampling is generally well received among women. However, the possibility of selection bias and survey instrument measurement error may have led to an overestimate of womens favorable opinions for self-sampling. A self-sampling option may increase screening coverage, but concerns of women must also be addressed.

Bilateral lymphangiomas of the ovary : An immunohistochemical characterization and review of the literature

Lymphangiomas of the ovary are rare tumors, with only 13 cases reported. The diagnoses of these tumors have been based on histologic findings without immunohistochemical confirmation of endothelial cell origin. It is uncertain if these tumors are true neoplasms or if some represent reactive lesions. In this report, the literature is reviewed, and a 53-year-old woman with bilateral ovarian lymphangiomas is described. The ovarian masses were composed of numerous, thin-walled, cystic spaces containing a proteinaceous fluid, mature lymphocytes, and occasional erythrocytes. The cyst walls were lined by flat, benign-appearing cells that were immunoreactive for factor VIII-related antigen, CD34, and CD31. Further examination of the specimen showed absent fallopian tube fimbriae, tuboovarian adhesions, and chronic follicular salpingitis, suggesting that the lymphatic proliferation in the ovaries was a reactive change secondary to impaired regional lymphatic drainage.

Characterization of androgenetic/biparental mosaic/chimeric conceptions, including those with a molar component: Morphology, p57 immnohistochemistry, molecular genotyping, and risk of persistent gestational trophoblastic disease

Recent studies have demonstrated the value of ancillary techniques, including p57 immunohistochemistry and short tandem repeat genotyping, for distinguishing hydatidiform moles (HM) from nonmolar specimens and for subtyping HMs as complete hydatidiform moles (CHM) and partial hydatidiform moles (PHM). With rare exceptions, CHMs are p57-negative and androgenetic diploid; partial hydatidiform moles are p57-positive and diandric triploid; and nonmolar specimens are p57-positive and biparental diploid. Androgenetic/biparental mosaic/chimeric conceptions can have morphologic features that overlap with HMs but are genetically distinct. This study characterizes 11 androgenetic/biparental mosaic/chimeric conceptions identified in a series of 473 products of conception specimens subjected to p57 immunohistochemistry and short tandem repeat genotyping. Fluorescence in situ hybridization was performed on 10 to assess ploidy. All cases were characterized by hydropically enlarged, variably sized and shaped villi. In 5 cases, the villi lacked trophoblastic hyperplasia, whereas in 6 there was a focal to extensive villous component with trophoblastic hyperplasia and features of CHM. The villi lacking trophoblastic hyperplasia were characterized by discordant p57 expression within individual villi (p57-positive cytotrophoblast and p57-negative stromal cells), whereas the villous components having trophoblastic hyperplasia were uniformly p57-negative in both cell types. Short tandem repeat genotyping of at least 2 villous areas in each case demonstrated an excess of paternal alleles in all regions, with variable paternal:maternal allele ratios (usually >2:1); pure androgenetic diploidy was identified in those cases with a sufficiently sized villous component having trophoblastic hyperplasia and features of CHM. Fluorescence in situ hybridization demonstrated uniform diploidy in 7 cases, including 4 of 5 tested cases with trophoblastic hyperplasia and 3 of 5 cases without trophoblastic hyperplasia. Two cases without trophoblastic hyperplasia had uniformly diploid villous stromal cells but 1 had triploid and 1 had tetraploid cytotrophoblast; 1 case with trophoblastic hyperplasia had uniformly diploid villous stromal cells but a mixture of diploid, triploid, and tetraploid cytotrophoblast. In 3 cases with a CHM component, persistent gestational trophoblastic disease developed. These results indicate that androgenetic/biparental mosaic/chimeric conceptions are most often an admixture of androgenetic diploid (p57-negative) and biparental diploid (p57-positive) cell lines but some have localized hyperdiploid components. Recognition of their distinctive p57 expression patterns and genotyping results can prevent misclassification as typical CHMs, PHMs, or nonmolar specimens. The presence of androgenetic cell lines, particularly in those with a purely androgenetic CHM component, warrants follow-up because of some risk of persistent gestational trophoblastic disease.

Trends in incidence and survival of women with invasive vulvar cancer in the United States and Canada: A population-based study

AIM The aim of this study is to estimate trends in incidence and relative survival in women diagnosed with invasive squamous cell vulvar cancer in the United States (U.S.) and Canada over the periods of 1973-2010 for U.S. and 1992-2008 for Canada. METHODS We identified patients with primary invasive squamous cell vulvar cancers in the Surveillance, Epidemiology, and End Results cancer registry database and the Canadian Cancer Registry dataset. Women younger than 40 years were excluded because of the small number of patients in this age group. A flexible parametric model was used to estimate two- and five-year relative survival ratios and excess mortality rate. RESULTS In total 15,041 patients diagnosed with invasive squamous cell vulvar cancer were included in this analysis. The incidence rate of vulvar cancer increased in both U.S. and Canada. Two- and five-year relative survival ratios decreased over time for both countries, particularly for patients 80 years and over. CONCLUSIONS The incidence rate of invasive vulvar cancer continued to increase in U.S. and Canada while its two- and five-year relative survival ratios gradually decreased for all age groups over the last few decades. Also, excess mortality rate reaches to its peak after about 6 months from diagnosis and then starts to decline. This is the first report that examine relative survival ratio for vulvar cancer in Canada and U.S. and serves as a basis for future similar studies.

Adjunctive Human Papillomavirus Testing in the 2-Year Follow-up of Women With Low-Grade Cervical Cytologic Abnormalities: A Randomized Trial and Economic Evaluation

CONTEXT Although human papillomavirus (HPV) testing may aid in managing low-grade abnormality on screening cervical cytology, patient compliance with repeat testing programs requires consideration. OBJECTIVES To determine effectiveness and costs of repeated Papanicolaou (Pap) test and oncogenic HPV testing for detecting cervical intraepithelial neoplasia 2 or 3. DESIGN We conducted a randomized controlled trial of combined Pap test and cervical HPV testing by Hybrid Capture 1 test compared with Pap test alone; tests were performed every 6 months for up to 2 years. The study end point was colposcopic examination performed on all women at 2 years, or earlier if an HPV test was positive or if a Pap test showed high-grade squamous intraepithelial lesion. SETTING Sixty-six community family practices. PARTICIPANTS Two hundred fifty-seven women with atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion on screening cervical cytology. MAIN OUTCOME MEASURES Detection of histologically confirmed cervical intraepithelial neoplasia 2 or 3, fully allocated costs, and loss to follow-up. RESULTS Combined Pap test and HPV testing detected 11 (100%) of 11 cases of cervical intraepithelial neoplasia 2/3, whereas Pap test alone detected 7 (63.6%) of these 11 cases (P =.14); corresponding specificities were 39 (46.4%) of 84 and 45 (71.4%) of 63 (P =.005). The cost-effectiveness ratio was Can

Reproducibility of the histological diagnosis of cervical dysplasia among pathologists from 4 continents.

4456 per additional case of high-grade cervical intraepithelial neoplasia. Sixty-nine (26.8%) of the 257 women (24.6% combined group vs 29.1% Pap test only group, P =.41) defaulted from testing or from colposcopy when referred with an abnormal result. CONCLUSIONS Combined testing was more costly but may detect more cases of cervical intraepithelial neoplasia 2/3 than Pap test alone. However, poor adherence limits usefulness of a management strategy that requires repeated follow-up.

Do deeper sections increase the frequency of detection of serous tubal intraepithelial carcinoma (STIC) in the "sectioning and extensively examining the FIMbriated end" (SEE-FIM) protocol?

Summary The reliable histological diagnosis of cervical squamous intraepithelial lesions (SILs), especially low-grade SIL, is known to be problematic. Poor diagnostic reproducibility can complicate studies addressing its appropriate management. As part of an international study comparing expectant management of histologically proven low-grade SIL with immediate loop electrocautery excisional procedure, this study was carried out to assess interobserver agreement on the histological diagnosis of SILs among a group of 22 pathologists from 5 countries and the intraobserver reliability among a subset of 7 Canadian pathologists. Fifty-six histological slides from colposcopically obtained cervical biopsies were circulated to each of the 22 pathologists. To assess intraobserver reliability, 7 Canadian pathologists assessed 40 of the slides once and 16 of the slides twice. Kappa values were used to measure interobserver agreement with an overall &kgr; value of 0.61 (95% confidence interval, 0.60-0.62) corresponding to moderate reliability. The weighted &kgr; values for interobserver agreement ranged from 0.46 to 0.88 (median, 0.79). The intraobserver reliability of 7 Canadian pathologists ranged from substantial to excellent based upon the weighted &kgr; values ranging from 0.62 to 0.94 (median, 0.72). This degree of reliability is comparable to that found in similar studies. In an individual case, there can be considerable disparity in diagnosis that can result in disparate management strategies. This adds a layer of complexity to any trial that attempts to assess optimal treatment strategies or the natural history of this disease.