Guidelines for Cervical Cancer Screening in Immunosuppressed Women Without HIV Infection.

EXECUTIVE SUMMARY: The risk of cervical cancer (CC) among women immunosuppressed for a variety of reasons is well documented in the literature. Although there is improved organ function, quality of life and life expectancy gained through use of immunosuppressant therapy, there may be increased long-term risk of cervical neoplasia and cancer and the need for more intense screening, surveillance, and management. Although guidance for CC screening among HIV-infected women (see Table 1) has been supported by evidence from retrospective and prospective studies, recommendations for CC screening among non-HIV immunosuppressed women remains limited because quality evidence is lacking. Moreover, CC screening guidelines for HIV-infected women have changed because better treatments evolved and resulted in longer life expectancy.The objective of this report was to summarize current knowledge of CC, squamous intraepithelial lesions, and human papillomavirus (HPV) infection in non-HIV immunocompromised women to determine best practices for CC surveillance in this population and provide recommendations for screening. We evaluated those with solid organ transplant, hematopoietic stem cell transplant, and a number of autoimmune diseases.A panel of health care professionals involved in CC research and care was assembled to review and discuss existing literature on the subject and come to conclusions about screening based on available evidence and expert opinion. Literature searches were performed using key words such as CC, cervical dysplasia/squamous intraepithelial lesion, HPV, and type of immunosuppression resulting in an initial group of 346 articles. Additional publications were identified from review of citations in these articles. All generated abstracts were reviewed to identify relevant articles. Articles published within 10 years were considered priority for review. Reviews of the literature were summarized with relevant statistical comparisons. Recommendations for screening generated from each group were largely based on expert opinion. Adherence to screening, health benefits and risks, and available clinical expertise were all considered in formulating the recommendations to the degree that information was available. RESULTS: Solid Organ Transplant: Evidence specific for renal, heart/lung, liver, and pancreas transplants show a consistent increase in risk of cervical neoplasia and invasive CC, demonstrating the importance of long-term surveillance and treatment. Reports demonstrate continued risk long after transplantation, emphasizing the need for screening throughout a woman's lifetime.Hematopoietic Stem Cell Transplant: Although there is some evidence for an increase in CC in large cohort studies of these patients, conflicting results may reflect that many patients did not survive long enough to evaluate the incidence of slow-growing or delayed-onset cancers. Furthermore, history of cervical screening or previous hysterectomy was not included in registry study analysis, possibly leading to underestimation of CC incidence rates.Genital or chronic graft versus host disease is associated with an increase in high-grade cervical neoplasia and posttransplant HPV positivity.Inflammatory Bowel Disease: There is no strong evidence to support that inflammatory bowel disease alone increases cervical neoplasia or cancer risk. In contrast, immunosuppressant therapy does seem to increase the risk, although results of observational studies are conflicting regarding which type of immunosuppressant medication increases risk. Moreover, misclassification of cases may underestimate CC risk in this population. Recently published preventive care guidelines for women with inflammatory bowel disease taking immunosuppressive therapy recommend a need for continued long-term CC screening.Systemic Lupus Erythematosus and Rheumatoid Arthritis: The risk of cervical high-grade neoplasia and cancer was higher among women with systemic lupus erythematosus than those with rheumatoid arthritis (RA), although studies were limited by size, inclusion of women with low-grade neoplasia in main outcomes, and variability of disease severity or exposure to immunosuppressants. In studies designed to look specifically at immunosuppressant use, however, there did seem to be an increase in risk, identified mostly in women with RA. Although the strength of the evidence is limited, the increase in risk is consistent across studies.Type 1 DM: There is a paucity of evidence-based reports associating type 1 DM with an increased risk of cervical neoplasia and cancer. RECOMMENDATIONS: The panel proposed that CC screening guidelines for non-HIV immunocompromised women follow either the (1) guidelines for the general population or (2) current center for disease control guidelines for HIV-infected women. The following are the summaries for each group reviewed, and more details are noted in accompanying table:Solid Organ Transplant: The transplant population reflects a greater risk of CC than the general population and guidelines for HIV-infected women are a reasonable approach for screening and surveillance.Hematopoietic Stem Cell Transplant: These women have a greater risk of CC than the general population and guidelines for HIV-infected women are a reasonable approach for screening. A new diagnosis of genital or chronic graft versus host disease in a woman post-stem cell transplant results in a greater risk of CC than in the general population and should result in more intensive screening and surveillance.Inflammatory Bowel Disease: Women with inflammatory bowel disease being treated with immunosuppressive drugs are at greater risk of cervical neoplasia and cancer than the general population and guidelines for HIV-infected women are a reasonable approach for screening and surveillance. Those women with inflammatory bowel disease not on immunosuppressive therapy are not at an increased risk and should follow screening guidelines for the general population.Systemic Lupus Erythematosus and Rheumatoid Arthritis: All women with systemic lupus erythematosus, whether on immunosuppressant therapy or not and those women with RA on immunosuppressant therapy have a greater risk of cervical neoplasia and cancer than the general population and should follow CC screening guidelines for HIV-infected women. Women with RA not on immunosuppressant therapy should follow CC screening guidelines for the general population.Type 1 Diabetes Mellitus: Because of a lack of evidence of increased risk of cervical neoplasia and cancer among women with type 1 DM, these women should follow the screening guidelines for the general population.

Clinical Utility of Molecular Biomarkers in Cervical Squamous Intraepithelial Lesions in a Young Adult Population.

OBJECTIVE: Although human papillomavirus (HPV) infection is necessary for cervical squamous intraepithelial lesion (SIL/CIN) and cancer to develop, exposure to HPV is not predictive of which women will develop SIL/CIN and cancer. This study examines mRNA expression of several potential biomarkers in exfoliated cervical cells collected from college-aged women. MATERIALS AND METHODS: Freshman female students were recruited into the Carolina Women's Care Study, which was designed to prospectively evaluate factors that contribute to persistent HPV infections. One component of this study was to extract mRNA from exfoliated cervical cells. In this study, mRNA expression of Frizzled (FZD), growth differentiating factor 15, interleukin 1 beta (IL1ß), and N-cadherin was assessed through real-time polymerase chain reaction. Statistical analysis was performed with a Student t test; all results were standardized with glyceraldehyde 3-phosphate dehydrogenase. RESULTS: Fifty samples were selected that reflected the demographics of the Carolina Women's Care Study participants. IL1ß mRNA expression was 9.4-fold higher in cervical cells from women with abnormal Pap tests (p = .0018); low-grade squamous intraepithelial lesion had 12.7-fold higher expression than negatives (p = .0011). The FZD mRNA expression was 5.7-fold higher in CIN 2 as compared with CIN 1 (p = .0041) and 8.5-fold higher compared with cytology/pathology negative (p = .0014). Other differences in mRNA expression showed trends but not reaching statistical significance for each condition. CONCLUSIONS: It seems that several biomarkers involved in the cytokine/inflammatory pathway (IL1ß), cell adhesion pathway (N-cadherin), growth factor (growth differentiating factor 15), and Wingless (WNT) signaling pathway (FZD) may be potential biomarkers in conjunction with the Pap test and HPV that help predict which women are at highest risk for developing CIN 3 and cervical cancer.

Delaying Pap test screening in the adolescent population: an evidence-based approach.

Cervical cancer screening guidelines have evolved significantly over the past ten years in the adolescent population. The objective of this article is to review the cervical screening guidelines in the adolescent population as well as examine the evidence and studies that support delaying screening until 21 years old. Delaying HPV and Papanicolaou testing until 21 years old is safe and will not increase cervical cancer rates in the adolescent population.

Keratinizing squamous dysplasia pap test: a case for colposcopy.

OBJECTIVE: This study characterized women with Pap tests showing keratinizing squamous dysplasia (KSD) and helped develop management strategies in these patients. METHODS: This is a retrospective chart review of women presenting to Palmetto Health Women's Center with KSD on a Pap test from 1999 to 2009. Data analysis was performed with standard statistical computer programming; null hypothesis was rejected for p values .05 or less. RESULTS: A total of 65 Pap tests with KSD were identified. We found that women with KSD were statistically older (35 vs 26.8 y) and were more likely African American and less likely Hispanic than the general clinic population at Palmetto Health Women's Center. There were no statistical differences in body mass index or history of teen pregnancy. Interestingly, 41% of the women with KSD were immunosuppressed (e.g., human immunodeficiency virus infection, end-stage renal disease, long-term steroid use). All women with KSD were referred for colposcopy; 24% of patients failed to follow-up. Pathology distribution on cervical biopsies were similar to what is found after high-grade squamous intraepithelial lesion findings in Pap tests, with 58% cervical intraepithelial neoplasia (CIN) 2/3 or cancer, 32% CIN 1, and 10% negative biopsies. Of the women who had CIN 1 on cervical biopsy, 80% had persistent dysplasia or abnormal Pap test. Also, 60% had CIN 1 and 20% progressed to CIN 2/3 or carcinoma in situ. CONCLUSIONS: Our data suggest that women with KSD on Pap test should be managed aggressively with immediate colposcopy and cervical biopsies and not with expectant management.