Jeffrey Killeen

Pathology and classification of ovarian tumors.

*This article is a US Government work and, as such, is in the public domain of the United States of America. Knowledge of the embryology and microscopic anatomy of the ovary is fundamental to the understanding of the various cancer types that originate in this organ. A complete description of the embryology and anatomy of the ovary is beyond the scope of this monograph; however, comprehensive reviews are available for those who seek more detail. The current discussion focuses on key developmental events and anatomic features that shed light on the natural history of ovarian cancers. At approximately five weeks of gestation, thickenings of the lining of the posterior embryonic body cavity, the coelomic epithelium, form the genital ridges. Continued proliferation of the coelomic epithelium into the underlying primitive connective tissue, known as the mesenchyme, leads to the formation of the primordial indifferent gonads. Cells from adjacent transient embryonic structures, known as mesonephros, concurrently invade the mesenchyme, and the primordial germ cells arrive after a long journey that starts at their place of origin in the yolk sac and takes the cells along the distal embryonic intestine and the posterior wall of the embryonic body cavity. The different tumor types that arise in the ovary are linked to the different cell types that are present at this stage of development: coelomic epithelial, mesenchymal, mesonephric, and germ cells. Ovaries and testes develop in similar fashion until approximately the fourth month of embryonic life. This finding explains the origin of tumors that are commonly associated with testicular tissue but appear in the ovaries and vice versa. At two months gestation, the primitive gonad is recognized as an ovary because of the lack of development of the well-defined testicular sex cords. Instead, mesonephric cells and germ cells remain closely associated, forming illdefined ovarian sex cords embedded in the primitive mesenchyme. The coelomic epithelium remains at the periphery, enwrapping the developing ovary. In the adult, the ovaries are flat, nodular, oval structures that measure between 3 and 5 cm in their greatest dimension and weigh between 2 and 4 g. They are suspended by peritoneal folds and ligaments on either side of the uterus and attached to the back of the broad ligament of the uterus, behind and below the uterine tubes. A single layer of cells, the surface epithelium, which is derived from the coelomic epithelium, lines their external surface. A dense, fibrous tissue, the stroma, which is derived from the mesenchyme, makes up most of their internal substance. The germ cells, also known as oocytes, are located near the periphery of the stroma. The granulosa cells, specialized cells of probable mesonephric origin that are derived from the sex cords, surround the germinal cells that form the follicles. The stroma immediately surrounding the follicles differentiates into plum elongated cells known as theca cells. When stimulated, theca 2631

Anal Human Papillomavirus Infection in Women and Its Relationship with Cervical Infection

Human papillomavirus (HPV), the primary cause of cervical cancer, is also associated with the development of anal cancer. Relatively little is known about the epidemiology of anal HPV infection among healthy females and its relationship to cervical infection. We sought to characterize anal HPV infection in a cohort of adult women in Hawaii. Overall, 27% (372 of 1,378) of women were positive for anal HPV DNA at baseline compared with 29% (692 of 2,372) with cervical HPV DNA. Among women with paired anal and cervical samples, anal infection without accompanying cervical infection was observed in 14% (190 of 1,363). Concurrent anal and cervical HPV infections were observed in 13% (178 of 1,363) of women. Women with cervical HPV infection had >3-fold increased risk of concurrent anal infection. Concurrent anal and cervical HPV infection was most prevalent among the youngest women and steadily decreased through age 50 years. By contrast, the prevalence of anal infection alone remained relatively steady in all age groups. Compared with cervical infections, the overall distribution of HPV genotypes in the anus was more heterogeneous and included a greater proportion of nononcogenic types. A high degree of genotype-specific concordance was observed among concurrent anal and cervical infections, indicating a common source of infection. Nevertheless, the association of anal intercourse with anal HPV infection was limited to those women without accompanying cervical infection. The relationship of anal to cervical infection as described in this study has implications for the development of anal malignancies in women.

Prevalence, Acquisition, and Clearance of Cervical Human Papillomavirus Infection among Women with Normal Cytology: Hawaii Human Papillomavirus Cohort Study

Few natural history studies of cervical human papillomavirus (HPV) incidence and duration have been conducted among older women, especially from multiethnic populations. Viral and nonviral determinants of HPV acquisition and clearance were examined among 972 sexually active women, ages 18 to 85 years, recruited from clinics on Oahu, Hawaii, and followed for a mean duration of 15 months (range, 2-56 months). Interviews and cervical cell specimens for cytology and HPV DNA detection by PCR, using the PGMY09/PGMY11 primer system, were obtained at baseline and at 4-month intervals. The prevalence of cervical HPV infection was 25.6% at study entry. A total of 476 incident genotype-specific infections were observed during the follow-up period. The incidence of high-risk (HR) HPV types (9.26 per 1,000 woman-months) was similar to low-risk (LR) HPV types (8.24 per 1,000 woman-months). The most commonly acquired HR-HPV types were HPV-52, HPV-16, and HPV-31; and their incidence was increased significantly with a coexisting cervical HPV infection. Cervical HPV acquisition decreased with age, income, and long-term use of oral contraceptives and increased with number of sexual partners, use of hormonal creams, alcohol drinking, and condom use by a sexual partner. Cohort participants cleared 265 of the 476 incident infections during follow-up. LR-HPV infections cleared more rapidly than did HR-HPV infections (median, 180 days versus 224 days). Clearance times were enhanced among older women and women with multiple infections. Our data suggest several viral and nonviral determinants of cervical HPV acquisition and clearance that might be used in cervical cancer prevention programs.

Acquisition of Anal Human Papillomavirus (HPV) Infection in Women: the Hawaii HPV Cohort Study

BACKGROUND The majority of anal cancer is associated with human papillomavirus (HPV) infection, yet little is known about womens risk of acquisition of anal HPV infection. METHODS Risk factors for the acquisition of anal HPV infection were examined in a longitudinal cohort study of 431 women, via repeated measurement of HPV DNA. RESULTS Seventy percent of women were positive for anal HPV infection at one or more clinic visits from baseline through a follow-up period that averaged 1.3 years. The incidence of a high-risk (HR) infection was 19.5 (95% confidence interval [CI], 16.0-23.6) per 1000 woman-months. The most common incident HR HPV types were HPV-53, -52 and -16. The presence of an HR anal HPV infection at baseline increased the risk of an incident anal infection by 65%. Baseline HR cervical HPV infection also predicted the acquisition of an HR anal HPV infection (odds ratio, 1.81 [95% CI, 1.09-3.02]). Nonviral risk factors for acquisition of HR HPV infection included younger age, lower socioeconomic status, greater lifetime number of sexual partners, past use of hormones, and condom use. CONCLUSIONS The results of this study suggest that womens risk of anal HPV infection is as common as their risk of cervical HPV infection.

Sequential Acquisition of Human Papillomavirus (HPV) Infection of the Anus and Cervix: The Hawaii HPV Cohort Study

BACKGROUND Relatively little is known about the epidemiology of anal human papillomavirus (HPV) infection in healthy women and its association with cervical HPV infection. METHODS he association of an incident cervical (or anal) HPV infection with the subsequent risk of a genotype-concordant incident anal (or cervical) HPV infection was examined in a longitudinal cohort study of 751 sexually active women. Age-adjusted hazard ratios, obtained using Cox regression, served as measurements of relative risk (RR). RESULTS Among women, the RR of acquiring an anal HPV infection after a cervical infection with HPV of the same genotype was 20.5 (95% confidence interval, 16.3-25.7), and the RR of acquiring a cervical HPV infection after an anal infection with HPV of the same genotype was 8.8 (95% confidence interval, 6.4-12.2), compared with women without a previous anal/cervical infection with HPV of a concordant genotype. RRs varied by phylogenetic species, with HPV alpha3/alpha15 and alpha1/alpha8/alpha10 types having a greater likelihood than other types of HPV infecting the anus among women with a previous infection at the cervix with HPV of the same genotype. CONCLUSIONS It appears common for anal and cervical HPV infections to occur consecutively. The high degree of genotype-specific concordance suggests that the cervix (vagina) and anus may serve as reservoirs for HPV infection at the other anatomical site.

Duration and Clearance of Anal Human Papillomavirus (HPV) Infection among Women: The Hawaii HPV Cohort Study

BACKGROUND The association of anal cancer with human papillomavirus (HPV) infection is well established; however, little is known about the epidemiology of anal HPV in healthy women. We investigated patterns of duration and clearance of anal HPV infection in a cohort of healthy women in Hawaii. METHODS Viral and nonviral determinants of anal HPV clearance were examined in a longitudinal cohort study of 431 sexually active women. At baseline and at 4-month intervals, interviews were conducted and cervical and anal cell specimens were obtained for detection of HPV DNA. RESULTS Of the 431 women, 50% experienced a total of 414 incident anal HPV infections, reported at 1 clinic visits from baseline through a follow-up period of average duration of 1.2 years. Of these infections, 58% cleared during follow-up. The clearance rate for a high-risk anal infection was 9.2 per 100 woman-months (95% confidence interval [CI], 6.9-11.9 per 100 woman-months), with a median duration of 150 days (95% CI, 132-243 days). The slowest clearing high-risk HPV types were HPV-59 (median clearance time, 350 days) and HPV-58 (median clearance time, 252 days). The median clearance times for HPV-16 and HPV-18, the predominant types associated with anal cancer, were 132 days and 212 days, respectively. Nonviral factors that delayed clearance of anal HPV included douching, long-term tobacco smoking, and anal sex. CONCLUSIONS The majority of anal HPV infections resolve in a relatively short time. Although anal HPV is commonly acquired in healthy women, its rapid clearance suggests limited efficacy of HPV testing as an anal cancer screening tool.

A relaxin-mediated pathway to preterm premature rupture of the fetal membranes that is independent of infection.

OBJECTIVE This study was designed to show whether the overexpression of relaxin in the decidua of patients with preterm premature rupture of the membranes is independent of or a consequence of chorioamnionitis. STUDY DESIGN Two experiments were conducted. In the first experiment fetal membranes and decidua were collected from patients with preterm premature rupture of the membranes (n = 17) or preterm labor (n = 17) and were divided according to their degree of histologic infection. Messenger ribonucleic acid was isolated from the tissues and quantitative, sequential Northern analyses were carried out for the expression of human relaxin, interleukin-1beta, interleukin-6, and interleukin-8. The second experiment was aimed at increasing the numbers of messenger ribonucleic acid preparations in the two extreme categories, uninfected and severely infected tissues, with preterm premature rupture of the membranes and preterm labor. Some samples of messenger ribonucleic acid from the first experiment were rerun with the Northern analyses in the second experiment. These repeat samples showed no statistical differences in the results run at different times. Therefore the data from the respective groups of patients in both experiments were pooled for statistical analysis. RESULTS In both the first experiment and in the pooled data of the two experiments the expression of the relaxin genes was significantly greater (P < .005) in the tissues from patients with preterm premature rupture of the membranes compared with those with preterm labor, in the absence of infection. No effect of the level of infection on the expression of relaxin was noted. In contrast, interleukin-6 gene expression was significantly increased (P < .05) in severely infected tissues, which was independent of whether the delivery was from preterm premature rupture of the membranes or preterm labor. The expression of the interleukin-1beta and interleukin-8 genes were only marginally increased even in severe infection. Marked patient variability in expression of the interleukin genes, especially in severe infection, was noted. CONCLUSION A relaxin-mediated pathway that leads to preterm premature rupture of the membranes may exist independent of infection.

Cervical cytokines and clearance of incident human papillomavirus infection: Hawaii HPV cohort study.

Mechanisms for the control and resolution of human papillomavirus (HPV) infection of the cervix include the local production of cytokines, which control recruitment and function of cells integral to pathogen control. We established a cohort of women for long‐term follow‐up to examine the mucosal expression of antiviral (IFN‐α2), Type‐1 (IFN‐γ, IL‐12), regulatory (IL‐10), and proinflammatory (IL‐1α, IL‐1β, IL‐6, IL‐8, MIP‐1α, and TNF) cytokines in association with the clearance of incident cervical HPV infection. Interviews and specimens for HPV DNA analysis and cytokine protein measurement were obtained at baseline and at 4‐month intervals. A Cox proportional hazards model was used to study the relationship between clearance of 107 high‐risk and 111 low‐risk incident HPV infections and cytokine levels among 154 women. Positive changes from baseline levels of IL‐10, IL‐12, MIP‐1α, and TNF were associated with significantly longer times to type‐specific HPV clearance. Inverse trends in the hazard ratios associated with clearance of high‐risk HPV infections were monotonic and significant for IL‐12 (ptrend = 0.02) and TNF (ptrend = 0.02); the likelihood of high‐risk HPV clearance was reduced by 65% and 67%, respectively, among women in the highest as compared with the lowest quartile of change from baseline. Our results suggest that in women with a nontransient cervical HPV infection, proinflammatory, Type‐1, and regulatory cytokines are elevated, underscoring the long‐term commitment of local immune mediators to viral eradication.

Rapid enzymatic urine screening test to detect bacteriuria in pregnancy

Objective To determine the sensitivity, specificity, and positive and negative predictive values of an enzymatic urine screening test for diagnosing bacteriuria in pregnancy. Methods Clean-catch midstream urine samples were collected from 383 women who had routine prenatal screening for bacteriuria. Sensitivity, specificity, and positive and negative predictive values for each screening test (enzyme activity, nitrites or leukocytes on dipstick, and bacteria or pyuria on microscopic examination) were estimated using urine culture as the criterion standard. Urine cultures were considered positive if they grew 104 colony-forming units of a single uropathogen. Standard deviations used to calculate 95% confidence intervals were based on binomial distribution. A sample of 30 urine specimens was selected to evaluate interrater agreement using Cohens kappa statistic. Results Five of 383 samples were contaminated, leaving 378 samples for evaluation. Thirty of 43 specimens with positive urine culture had positive enzyme activity. Of 335 samples with no growth, 150 had negative enzyme activity. Sensitivity, specificity, and positive and negative predictive values for the Uriscreen enzymatic screening test (Bard Patient Care Division, Murray Hill, NJ) were 70%, 45%, 14%, and 92%, respectively. Sensitivity of the Uriscreen was lower than that of bacteria alone. Interrater agreement for Uriscreen testing was high among the three testers (κ = .86). Conclusion The Uriscreen enzymatic screening test had inadequate sensitivity for rapid screening for bacteriuria in pregnancy.

Mammographic density and epithelial histopathologic markers

BackgroundWe explored the association of mammographic density, a breast cancer risk factor, with hormonal and proliferation markers in benign tissue from tumor blocks of pre-and postmenopausal breast cancer cases.MethodsBreast cancer cases were recruited from a case-control study on breast density. Mammographic density was assessed on digitized prediagnostic mammograms using a computer-assisted method. For 279 participants of the original study, we obtained tumor blocks and prepared tissue microarrays (TMA), but benign tissue cores were only available for 159 women. The TMAs were immunostained for estrogen receptor alpha (ERα) and beta (ERβ), progesterone receptor (PR), HER2/neu, Ki-67, and Proliferating Cell Nuclear Antigen (PCNA). We applied general linear models to compute breast density according to marker expression.ResultsA substantial proportion of the samples were in the low or no staining categories. None of the results was statistically significant, but women with PR and ERβ staining had 3.4% and 2.4% higher percent density. The respective values for Caucasians were 5.7% and 11.6% but less in Japanese women (3.5% and -1.1%). Percent density was 3.4% higher in women with any Ki-67 staining and 2.2% in those with positive PCNA staining.ConclusionThis study detected little evidence for an association between mammographic density and expression of steroid receptors and proliferation markers in breast tissue, but it illustrated the problems of locating tumor blocks and benign breast tissue samples for epidemiologic research. Given the suggestive findings, future studies examining estrogen effects in tissue, cell proliferation, and density in the breast may be informative.