Sarah Feldman

A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer

Infection by carcinogenic human papillomaviruses (HPV) results in precancers [cervical intraepithelial neoplasia (CIN)] and cancers near the ectoendocervical squamocolumnar (SC) junction of the cervix. However, the specific cells targeted by HPV have not been identified and the cellular origin of cervical cancer remains elusive. In this study, we uncovered a discrete population of SC junctional cells with unique morphology and gene-expression profile. We also demonstrated that the selected junctional biomarkers were expressed by a high percentage of high-grade CIN and cervical cancers associated with carcinogenic HPVs but rarely in ectocervical/transformation zone CINs or those associated with noncarcinogenic HPVs. That the original SC junction immunophenotype was not regenerated at new SC junctions following excision, not induced by expression of viral oncoproteins in foreskin keratinocytes, and not seen in HPV-related precursors of the vagina, vulva, and penis further support the notion that junctional cells are the source of cervical cancer. Taken together, our findings suggest that carcinogenic HPV-related CINs and cervical cancers are linked to a small, discrete cell population that localizes to the SC junction of the cervix, expresses a unique gene expression signature, and is not regenerated after excision. The findings in this study uncover a potential target for cervical cancer prevention, provide insight into the risk assessment of cervical lesions, and establish a model for elucidating the pathway to cervical cancer following carcinogenic HPV infection.

Predicting risk of complications with gynecologic laparoscopic surgery

Objective To determine the incidence and predictors of risk for operative complications, conversions to laparotomy, and postoperative admissions after laparoscopic procedures. Methods We obtained demographic information on and medical histories of a consecutive series of 843 women who underwent laparoscopic surgery for all procedures other than tubal ligation at Brigham and Womens Hospital during 1994. All major complications after surgery were recorded. Major operative complications were defined as bowel, bladder, ureter, or vascular injuries or significant abdominal wall or other internal bleeding. Categorical analysis was used to compare differences in the rates of operative complications, conversions to laparotomy, and postoperative admissions after laparoscopy. We also estimated the influence of medical history and specific laparoscopic procedures on the risk of adverse complications after surgery. Results Operative complications and conversion to laparotomy occurred in 1.9% and 4.7% of laparoscopic procedures, respectively. Complications included four bowel, two bladder, one ureteral, two vascular, and five abdominal wall injuries. There were 165 patients (19.6%) admitted postoperatively. Aside from the type of operative procedure, increasing age was the most important predictor of complications. Relative to all other operative procedures, women treated for endometriosis or ovarian cystectomy had generally low rates of operative complications, conversions to laparotomy, and postoperative admissions. In contrast, 12.5% of women undergoing laparoscopically assisted vaginal hysterectomy experienced operative injuries or abdominal bleeding and 90% were hospitalized postoperatively. Conclusion Serious operative complications after gynecologic laparoscopy were rare in this patient population. The more complex laparoscopic procedures resulted in proportionately greater rates of operative complications, conversions to laparotomy, and postoperative admissions to the hospital.

China's 50% caesarean delivery rate: is it too high?

high? S Hellerstein, S Feldman, T Duan a Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA b Fish Women’s Health Center, Brigham and Women’s Hospital, Chestnut Hill, MA, USA c Department of Obstetrics and Gynaecology, Shanghai 1st Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China d Shanghai Woman’s Healthcare Institute, Shanghai, China Correspondence: Dr S Hellerstein, Harvard Medical School, Brigham and Women’s Hospital, Fish Women’s Health Center, 850 Boylston Street, Chestnut Hill, MA 02467, USA. Email shellerstein@partners.org

Risk of high-grade cervical dysplasia and cervical cancer in women with systemic inflammatory diseases: a population-based cohort study

Background Previous studies have suggested a potential risk of cervical cancer in patients with systemic inflammatory diseases (SID) such as inflammatory bowel disease (IBD) and systemic lupus erythematosus (SLE). Objectives To assess the risk of high-grade cervical dysplasia, a surrogate endpoint for cervical cancer and cervical cancer, in women with SID, including IBD, psoriasis, rheumatoid arthritis (RA) or SLE, compared with the risk in women without SID. Methods Using US insurance data (2001–2012), we conducted a cohort study of 133 333 women with SID, based on two or more diagnoses and one or more dispensed prescription for disease-specific treatment, and 533 332 women without SID. High-grade cervical dysplasia and cervical cancer was defined by a validated algorithm with a positive predictive value of ≥81%. Results Over the mean follow-up of 2.1 years, the crude incidence rate of high-grade cervical dysplasia and cervical cancer per 100 000 person-years was the highest at 141.1 in SLE and the lowest at 82.2 in psoriasis among women with SID, and 73.4 in women without SID. The multivariable HR adjusted for potential confounders was 1.07 (95% CI 0.79 to 1.45) in IBD, 0.96 (95% CI 0.73 to 1.27) in psoriasis, 1.49 (95% CI 1.11 to 2.00) in RA and 1.53 (95% CI 1.07 to 2.19) in SLE. Multivariable HRs were increased, but not statistically significant, in IBD, RA and SLE with baseline use of systemic immunosuppressive drugs or steroids. Conclusions The risk of high-grade cervical dysplasia and cervical cancer was 1.5 times higher in women with RA and SLE than in those without SID. The risk may be increased in IBD with use of systemic immunosuppressive drugs or steroids.

Cervical squamocolumnar junction-specific markers define distinct, clinically relevant subsets of low-grade squamous intraepithelial lesions

Low-grade cervical squamous abnormalities (low-grade squamous intraepithelial lesions [LSIL, CIN1]) can be confused with or followed by high-grade (HSIL, CIN2/3) lesions, expending considerable resources. Recently, a cell of origin for cervical neoplasia was proposed in the squamocolumnar junction (SCJ); HSILs are almost always SCJ+, but LSILs include SCJ+ and SCJ− subsets. Abnormal cervical biopsies from 214 patients were classified by 2 experienced pathologists (panel) as LSIL or HSIL using published criteria. SILs were scored SCJ+ and SCJ− using SCJ-specific antibodies (keratin7, AGR2, MMP7, and GDA). Assessments of interobserver agreement, p16ink4 staining pattern, proliferative index, and outcome were compared. The original diagnostician agreed with the panel diagnosis of HSIL and SCJ− LSIL in all cases (100%). However, for SCJ+ LSIL, panelists disagreed with each other by 15% and with the original diagnostician by 46.2%. Comparing SCJ− and SCJ+ LSILs, 60.2% and 94.9% were p16ink4 positive, 23% and 74.4% showed strong (full-thickness) p16ink4 staining, and 0/54 (0%) and 8/33 (24.2%) with follow-up had an HSIL outcome, respectively. Some SCJ+ LSILs are more likely to both generate diagnostic disagreement and be associated with HSIL. Conversely, SCJ− LSILs generate little observer disagreement and, when followed, have a very low risk of HSIL outcome. Thus, SCJ biomarkers in conjunction with histology may segregate LSILs with very low risk of HSIL outcome and conceivably could be used as a management tool to reduce excess allocation of resources to the follow-up of these lesions.

Fertility-sparing treatment in younger women with adenocarcinoma in situ of the cervix

OBJECTIVE For women who have completed childbearing, the treatment of choice for adenocarcinoma in situ (ACIS) of the cervix is hysterectomy. In women who desire future fertility, however, conservative therapy is an acceptable alternative. In this study we compare the outcomes for young women who underwent loop conization or were treated with cold knife conization. METHODS We performed a retrospective analysis in 112 patients with ACIS, age 30 or younger, treated with cold knife conization or loop conization between 1998 and 2010. Decision to perform office loop conization was based on the size of the cervix and the colposcopic lesion. Main outcomes were negative margins after the procedure and recurrence of ACIS. RESULTS Fifty-eight patients (52%) were treated with cold knife conization and 54 (48%) underwent loop conization. The odds ratio for cold knife conization to achieve negative cone margins compared with loop conization was 1.4 (95% CI 0.6-3.5). We observed no difference in residual or recurrent ACIS between patients treated with loop conization versus cold knife conization. CONCLUSIONS In select young patients who desire future fertility, loop conization and cold knife conization have equivalent rates of negative margins and negative follow-up. For optimal results, patients must have a lesion which can be removed in one pass of a loop, confirmed by expert colposcopy. Loop excision should be considered the treatment of choice in this specific group of patients.

Management and Care of Women With Invasive Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Clinical Practice Guideline

Purpose To provide evidence-based, resource-stratified global recommendations to clinicians and policymakers on the management and palliative care of women diagnosed with invasive cervical cancer. Methods ASCO convened a multidisciplinary, multinational panel of cancer control, medical and radiation oncology, health economic, obstetric and gynecologic, and palliative care experts to produce recommendations reflecting resource-tiered settings. A systematic review of literature from 1966 to 2015 failed to yield sufficiently strong quality evidence to support basic- and limited-resource setting recommendations; a formal consensus-based process was used to develop recommendations. A modified ADAPTE process was also used to adapt recommendations from existing guidelines. Results Five existing sets of guidelines were identified and reviewed, and adapted recommendations form the evidence base. Eight systematic reviews, along with cost-effectiveness analyses, provided indirect evidence to inform the consensus process, which resulted in agreement of 75% or greater. Recommendations Clinicians and planners should strive to provide access to the most effective evidence-based antitumor and palliative care interventions. If a woman cannot access these within her own or neighboring country or region, she may need to be treated with lower-tier modalities, depending on capacity and resources for surgery, chemotherapy, radiation therapy, and supportive and palliative care. For women with early-stage cervical cancer in basic settings, cone biopsy or extrafascial hysterectomy may be performed. Fertility-sparing procedures or modified radical or radical hysterectomy may be additional options in nonbasic settings. Combinations of surgery, chemotherapy, and radiation therapy (including brachytherapy) should be used for women with stage IB to IVA disease, depending on available resources. Pain control is a vital component of palliative care. Additional information is available at www.asco.org/rs-cervical-cancer-treatment-guideline and www.asco.org/guidelineswiki. It is the view of ASCO that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines.

Management of cervical precancers: a global perspective.

Cervical cancer incidence and mortality have decreased dramatically over the past 50 years in countries with access and resources to provide frequent screening, evaluation, and treatment of high-grade cervical cancer precursors. For countries with fewer resources and many competing health concerns, cervical cancer remains one of the most lethal and common cancers among women. With the advent of newer technology, such as low-cost HPV vaccines and self-administered HPV tests, followed by simple well-known techniques such as VIA and cryotherapy, cervical cancer rates may well start to decrease worldwide.

Making Sense of Cervical Cancer Screening Guidelines and Recommendations.

Opinion statementSince the publication of the American Cancer Society (ACS)/American Society for Colposcopy and Cervical Pathology (ASCCP)/American Society for Clinical Pathology (ASCP) clinical guidelines in 2012, the majority of practice organizations have reached a consensus on screening recommendations for a low-risk population. These guidelines were based on a thorough review of the evidence with reproducible methods to obtain high-quality, generalizable guidelines. Despite the strength of the evidence based recommendations comprising these guidelines, limitations in physician understanding and compliance remain with respect to reaching an unscreened population and defining and caring for women who are at “high risk.” “High-risk” patients are poorly characterized but should include women with a history of a prior abnormal screening, as data has shown a subsequent increased risk of cervical intraepithelial neoplasia grade 2 (CIN2) or greater, even after treatment. These women warrant more intense screening than the general population—though there are no evidence-based guidelines for optimized screening protocols in this population. Emerging data in cervical cancer screening this year includes the FDA approval of primary high-risk human papillomavirus (HPV) testing. While the data is promising, its role in clinical practice, impact on rates of colposcopy in a non-study population, and long-term outcomes are not fully understood, and ongoing research is needed. Challenges remain in this shifting environment on the optimal interval and modality for cervical cancer screening to provide the greatest benefit in detection of precancerous lesions while minimizing the harm of overtreatment. While rapid advancements in research provide improved knowledge on how to treat and prevent this disease, it is often difficult for providers across multiple specialties to remain abreast of these changes and to educate their patients about the most current recommendations. Ultimately, provider and patient education is critical both for improving primary prevention with HPV vaccination, as well as for the uptake of evidence-based screening and management guidelines aimed at detecting and treating precancerous changes of the cervix.

Potential effects of updated pap test screening guidelines and adenocarcinoma in situ of the cervix.

OBJECTIVE: To review cases of adenocarcinoma in situ (AIS) at our institution to examine how updated guidelines affect the timing of diagnosis. METHODS: We identified patients with AIS diagnosed between 1998 and 2010 using the International Classification of Diseases, 9th Revision, Clinical Modification, code 233.1. Diagnosis was confirmed by pathology review. We abstracted demographic data, dysplasia history, and modalities utilized for diagnosis and treatment. RESULTS: We identified 242 patients who met selection criteria. Two hundred eight (86%) had Pap test abnormalities at presentation. One hundred thirty-seven out of 208 (66%) patients with abnormal Pap test results had a squamous, rather than glandular, abnormality. The mean time from abnormal Pap test to diagnosis of AIS was 29 months in patients older than 30 years and was 21 months in patients 30 years or younger. In patients younger than 21 years, 16 out of 17 had abnormal screening Pap test results showing squamous lesions. Their subsequent treatment for squamous dysplasia ultimately led to the diagnosis of AIS. CONCLUSION: Updated screening guidelines may prevent the expeditious diagnosis of AIS in females younger than 21 years and those aged 21–29 years, many of whom had normal Pap test results within 3 years of diagnosis. LEVEL OF EVIDENCE: II