Mary Rubin

The epidemiology of anal human papillomavirus and related neoplasia.

The relationship between cervical cancer and human papillomavirus (HPV) is well known. Like cervical cancer, anal cancer is preceded by a series of precancerous changes, raising the possibility that like cervical cancer, anal cancer can be prevented. Further, given the known risk factors for anal cancer, prevention efforts could be targeted to high-risk groups, providing a unique example of a screening program targeted to high-risk individuals. This article describes the epidemiology of anal HPV infection, anal intraepithelial neoplasia, and anal cancer among men and women, as well as current efforts to prevent anal cancers.

HIV-associated disruption of mucosal epithelium facilitates paracellular penetration by human papillomavirus

The incidence of human papillomavirus (HPV)-associated epithelial lesions is substantially higher in human immunodeficiency virus (HIV)-infected individuals than in HIV-uninfected individuals. The molecular mechanisms underlying the increased risk of HPV infection in HIV-infected individuals are poorly understood. We found that HIV proteins tat and gp120 were expressed within the oral and anal mucosal epithelial microenvironment of HIV-infected individuals. Expression of HIV proteins in the mucosal epithelium was correlated with the disruption of epithelial tight junctions (TJ). Treatment of polarized oral, cervical and anal epithelial cells, and oral tissue explants with tat and gp120 led to disruption of epithelial TJ and increased HPV pseudovirion (PsV) paracellular penetration in to the epithelium. PsV entry was observed in the basal/parabasal cells, the cells in which the HPV life cycle is initiated. Our data suggest that HIV-associated TJ disruption of mucosal epithelia may potentiate HPV infection and subsequent development of HPV-associated neoplasia.

Antenatal exposure to DES: lessons learned...future concerns.

The short- and long-term effects of the widespread use of diethylstilbestrol (DES) over 3 decades have become a distant memory for many clinicians. Others are too young to remember the flurry of activity in the early 1970s on the part of many medical centers to identify the offspring of women who were prescribed DES during their pregnancies. This medication was given in an attempt to prevent multiple pregnancy-related problems such as miscarriage, premature birth, and abnormal bleeding. The recognition of the association of DES with an increased incidence of cervical and vaginal cancers in very young women led the Food and Drug Administration to ban its use during pregnancy in 1971. Other pregnancy-related problems for the daughters and genitourinary tract changes in the sons did not become apparent until years later. Ongoing follow-up of these offspring has raised concerns for their future as well as their mothers’ future. Clinicians need to be up-to-date with current knowledge regarding risks for cancer and other health-related issues. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the reader should be able to relate that since 1971 there has been an intense follow-up of DES-exposed daughters, explain that certain complications have no time limit, recall that pregnancy complications of these daughters is not insignificant, and state that continued follow-up is necessary.

Prospective Multicenter Randomized Intermediate Biomarker Study of Oral Contraceptive versus Depo-Provera for Prevention of Endometrial Cancer in Women with Lynch Syndrome

Women with Lynch syndrome have a 40% to 60% lifetime risk for developing endometrial cancer, a cancer associated with estrogen imbalance. The molecular basis for endometrial-specific tumorigenesis is unclear. Progestins inhibit estrogen-driven proliferation, and epidemiologic studies have shown that progestin-containing oral contraceptives (OCP) reduce the risk of endometrial cancer by 50% in women at general population risk. It is unknown whether they are effective in women with Lynch syndrome. Asymptomatic women ages 25 to 50 with Lynch syndrome were randomized to receive the progestin compounds Depo-Provera (depo-MPA) or OCP for three months. An endometrial biopsy and transvaginal ultrasound were conducted before and after treatment. Endometrial proliferation was evaluated as the primary endpoint. Histology and a panel of surrogate endpoint biomarkers were evaluated for each endometrial biopsy as secondary endpoints. A total of 51 women were enrolled, and 46 completed treatment. Two of the 51 women had complex hyperplasia with atypia at the baseline endometrial biopsy and were excluded from the study. Overall, both depo-MPA and OCP induced a dramatic decrease in endometrial epithelial proliferation and microscopic changes in the endometrium characteristic of progestin action. Transvaginal ultrasound measurement of endometrial stripe was not a useful measure of endometrial response or baseline hyperplasia. These results show that women with Lynch syndrome do show an endometrial response to short-term exogenous progestins, suggesting that OCP and depo-MPA may be reasonable chemopreventive agents in this high-risk patient population. Cancer Prev Res; 6(8); 774–81. ©2013 AACR.

A randomized study of the effectiveness of a brief psychosocial intervention for women attending a gynecologic cancer clinic

OBJECTIVES While there are many psychosocial interventions for cancer patients, few are brief in nature. The aim of this study was to investigate the usefulness of a single-visit psychosocial intervention for gynecologic cancer patients. METHODS One hundred women attending a gynecologic cancer clinic as new patients were randomized to receive no intervention or a one-time meeting with a psychologist who discussed issues and concerns the woman might have about her cancer diagnosis. Thirty-eight of the women had a current or previous cancer. The women were given questionnaires measuring mood and quality of life at baseline, two weeks and three months after the intervention. RESULTS At baseline, 43 of the women in the control group completed questionnaires, as did 45 women randomized to the intervention. 21 of these women received the intervention. Women who received the intervention had greater decreases in anxiety, depression and overall distress over time. The control group also had decreases in anxiety and overall distress over time, but had an increase in depression. The women in the intervention group increased in physical, emotional, functional, and overall well being, while the control group only had a slight increase in overall well being over time. The difference between the groups in emotional well being at Time 2 approached significance (p=.08). The intervention group had increases in positive coping at Time 2, while the control group decreased (ps ranged from .02-.10). Three month follow-up data were available for 23 women in the control group and 15 in the intervention group. At Time 3 functional well being was significantly higher in the intervention group (p=.04). Information seeking and affect regulation remained higher in the intervention than the control group (ps=.002 and .02, respectively). When the women with cancer or previous cancer were examined, significant differences were seen for affect regulation at baseline (p=.0007), and anger two weeks later (p=.04), with the women in the control group being more angry. Utilization of other cancer resources was low with 12% of the women reporting that they used the Cancer Resource Center. CONCLUSIONS The results of this study show that there was a positive effect towards coping and quality of life for a one-time psychosocial intervention after the first visit to a gynecologic oncology practice. Women who were randomized to the intervention but did not go were more distressed at baseline than the women who did go. This suggests that incorporating psychosocial services as an integrated part of the new patient consultation may be very important to address patients distress. Future studies with larger sample sizes may reveal more significant differences. Strategies to overcome the poor utilization of the cancer resource center are also clearly needed to improve awareness of these resources.

Six cases of women with diethylstilbestrol in utero demonstrating long-term manifestations and current evaluation guidelines.

Diethylstilbestrol (DES), a nonsteroidal estrogen, was widely used in the United States from 1940 through 1971 to prevent pregnancy loss. In the late 1960s, an association was made with an increased incidence of clear cell adenocarcinoma in young women exposed in utero to DES. Additional study of these women over the next 35 years has shown an increased risk of other health problems including intraepithelial neoplasia, ectopic pregnancy, first trimester spontaneous abortion and second trimester pregnancy loss. The National Institutes of Health continues to fund studies to follow cohorts of DES-exposed mothers, daughters, sons and third generation children. The Centers for Disease Control have conducted a large DES Education Project and have established guidelines for management. The following six cases studies illustrate common problems seen in DES exposed daughters and management of problems encountered.

Essentials of colposcopy education: the curriculum revised.

A young colleague recently described his colposcopy training. He had been exposed to colposcopy during his residency and had performed the procedure, when indicated and under supervision, on his continuity patients. He confided that he did not feel totally confident in his ability as a colposcopist. When asked about the curriculum used in his residency to teach colposcopy, he summed it up by quoting one of his attendings, “Apply acetic acid. Look for the area that turns white and biopsy it.” Colposcopy training is a standard part of obstetrics and gynecology residencies and is offered in 95% of family medicine residencies [1]. In addition, the art and science of colposcopy is increasingly being learned by advanced practice clinicians including certified nurse midwives, nurse practitioners, and physician assistants [2]. A recent survey by Spitzer et al. [3] showed that the specifics of colposcopy education and the volume of cases available to residents in obstetrics and gynecology and family medicine vary widely across the United States. This raises concerns that the limited training received by the young physician, cited above, may not be as uncommon as one might hope. The elements of colposcopy education have been variably described in the gynecology [4–6], family medicine [7–10], and advanced practice nursing [2] literature. These include a didactic curriculum, a period of supervised hands-on mentorship, an examination to assess knowledge and skill, and continuing education. Most residencies, both obstetrics and gynecology and family medicine, provide supervised hands-on experience. The didactic portion of training, however, is variable and inconsistent [3]. However, providers who are taught colposcopy at many of the free-standing colposcopy courses that have proliferated over the past two decades are exposed to a structured series of lectures but little, if any, mentored experience with patients. The mentorship experience intrinsic to a residency varies considerably in number of patients examined and pathologic results seen [3]. Recommendations as to the number of supervised cases needed to attain proficiency in colposcopy have ranged from 25 to 100 [2, 5, 6, 11]. The American Society for Colposcopy and Cervical Pathology (ASCCP) Mentorship Program provides a framework for the supervised patient care portion of colposcopy training. It is widely used by providers learning colposcopy outside of a residency program and by some residents as well. Participation as a mentor in the ASCCP Mentorship Program requires that the prospective mentor have an active colposcopy practice. In adReprint requests to: Alan G. Waxman, MD, MPH, Department of Obstetrics and Gynecology, MSC 10 5580, University of New Mexico School of Medicine, 1 University of New Mexico, Albuquerque, NM 87131-0001. E-mail: awaxman@salud.unm.edu

Perceived uncertainty, coping strategies, and adaptation in women with human papillomavirus on pap smear.

Objective. To explore, identify, and describe the perception of uncertainty over time in college-aged women experiencing the unexpected event of an abnormal Pap smear with human papillomavirus (HPV). Methods. Eighty-eight female patients, who had abnormal Pap smear and had indications for colposcopy, were recruited from a Student Health Service and consented for study participation. Uncertainty levels were measured over time. Relationships among uncertainty, knowledge of HPV, body attitude and moods, coping strategies, and follow-up were evaluated. Results. The relationship between uncertainty and coping strategies was supported in the emotion-focused path as predicted but not in the problem-focused path. Evidence of adaptation to uncertainty through emotion-focused coping was found in the significant relationship between emotion-focused coping and body attitude. Similarly, there was a significant relationship between emotion-focused coping and moods in the path analysis and in correlations with the subcategories of positive and negative moods. The problem-focused indirect path from uncertainty to adaptation showed no significant relationship. Likewise, uncertainty also had no significant direct effect on body attitude or promptness of follow-up but did have a direct impact on moods. The direct path from previous knowledge to uncertainty was not supported. Conclusions. The presence of uncertainty over time was established in this study population. Statistically significant relationships were confirmed among uncertainty, emotion-focused coping strategies, and adaptation in a group of young women experiencing a mildly abnormal Pap smear.

Prophylactic surgery to reduce the risk of gynecologic cancers in the lynch syndrome

Lynch syndrome, or hereditary nonpolyposis colorectal cancer, is a condition of susceptibility to cancer that is caused by a germline mutation in a DNA-mismatch repair gene. Cancers develop early in the colon and rectum, endometrium, ovary, small bowel, ureter, and renal pelvis. Affected women have a 40% to 60% chance of developing endometrial cancer and a 10% to 20% lifetime risk of ovarian cancer. Some have proposed removal of the uterus and ovaries on a preventive basis despite a lack of evidence that it is beneficial. This study examined the risk of endometrial and ovarian cancer in women found in 3 registries in the years 1973-2004 with MLH1, MSH2, or MSH6 germline mutations. Sixty-one women having prophylactic hysterectomy and 47 undergoing bilateral salpingo-oophorectomy in addition were matched, respectively, with 210 and 223 mutation-positive women of similar age who did not have prophylactic surgery. None of the women having prophylactic hysterectomy developed endometrial cancer compared with 33% of control women. Operated women were followed for approximately 13 years on average and control women for 7 years. The prevented fraction, or proportion of potential new cancers prevented, was 100% with a 95% confidence interval (CI) of 90% to 100%. Three of 25 women who died during follow up had undergone prophylactic surgery. Ovarian cancer developed in 5% of control women but in none of the 47 having bilateral salpingo-oophorectomy at the time of prophylactic hysterectomy. The prevented fraction was 100%, with a 95% CI of -62% to 100%. One woman (1.6%) had surgical complications. Prophylactic surgery effectively prevents gynecologic cancers in women with Lynch syndrome. In particular, hysterectomy with bilateral salpingo-oophorectomy can prevent both endometrial and ovarian cancers in affected women. These women should have an opportunity to discuss the tradeoff between a reduced risk of cancer and the risks and side effects of surgery.