OBJECTIVE:To describe the natural history of cervical intraepithelial neoplasia (CIN) 2 in a prospective study of adolescents and young women, and to examine the behavioral and biologic factors ...associated with regression and progression.
METHODS:Adolescents and women aged 13 to 24 years who were referred for abnormal cytology and were found to have CIN 2 on histology were evaluated at 4-month intervals. Risks for regression were defined as three consecutive negative cytology and histology visits, and progression to CIN 3 was estimated using Cox proportional hazards regression models.
RESULTS:Ninety-five patients with a mean age of 20.4 years (±2.3) were entered into the analysis. Thirty-eight percent resolved by year 1, 63% resolved by year 2, and 68% resolved by year 3. Multivariable analysis found that recent Neisseria gonorrhoeae infection (hazard ratio 25.27; 95% confidence interval CI 3.11–205.42) and medroxyprogesterone acetate use (per month) (hazard ratio 1.02; 95% CI 1.003–1.04) were associated with regression. Factors associated with nonregression included combined hormonal contraception use (per month) (hazard ratio 0.85; 95% CI 0.75–0.97) and persistence of human papillomavirus (HPV) of any type (hazard ratio 0.40; 95% CI 0.22–0.72). Fifteen percent of patients showed progression by year 3. HPV 16/18 persistence (hazard ratio 25.27; 95% CI 2.65–241.2; P=.005) and HPV 16/18 status at last visit (hazard ratio 7.25; 95% CI 1.07–49.36; P<.05) were associated with progression Because of the small sample size, other covariates were not examined.
CONCLUSION:The high regression rate of CIN 2 supports clinical observation of this lesion in adolescents and young women.
LEVEL OF EVIDENCE:II
In March 2012, the College of American Pathologists and American Society for Colposcopy and Cervical Pathology, in collaboration with 35 stakeholder organizations, convened a consensus conference ...called the Lower Anogenital Squamous Terminology (LAST) Project. The recommendations of this project include using a uniform, two-tiered terminology to describe the histology of human papillomavirus-associated squamous disease across all anogenital tract tissues: vulva, vagina, cervix, penis, perianus, and anus. The recommended terminology is "low-grade" or "high-grade squamous intraepithelial lesion (SIL)." This terminology is familiar to clinicians, because it parallels the terminology of the Bethesda System cytologic reports. Biopsy results using SIL terminology may be further qualified using "intraepithelial neoplasia" (IN) terminology in parentheses. Laboratory p16 tissue immunostaining is recommended to better classify histopathology lesions that morphologically would earlier have been diagnosed as IN 2. p16 is also recommended for differentiating between high-grade squamous intraepithelial lesions and benign mimics. The LAST Project recommendations potentially affect the application of current guidelines for managing cervical squamous intraepithelial lesions. The authors offer interim guidance for managing cervical lesions diagnosed using this new terminology with special attention paid to managing young women with cervical high-grade squamous intraepithelial lesions on biopsy. Clinicians should be aware of the LAST Project recommendations, which include important changes from prior terminology.
The incidence of anal cancer is increasing, especially in high-risk groups, such as PLWH. HPV 16, a high-risk (HR) HPV genotype, is the most common genotype in anal high-grade squamous ...intraepithelial lesions (HSIL) and squamous cell carcinoma (SCC) in the general population. However, few studies have described the distribution of HR HPV genotypes other than HPV 16 in the anus of PLWH. HPV genotyping was performed by DNA amplification followed by dot-blot hybridization to identify the HR and low-risk (LR) genotypes in benign anal lesions (n = 34), HSIL (n = 30), and SCC (n = 51) of PLWH and HIV-negative individuals. HPV 16 was the most prominent HR HPV identified, but it was less common in HSIL and SCC from PLWH compared with HIV-negative individuals, and other non-HPV 16 HR HPV (non-16 HR HPV) types were more prevalent in samples from PLWH. A higher proportion of clinically normal tissues from PLWH were positive for one or more HPV genotypes. Multiple HPV infection was a hallmark feature for all tissues (benign, HSIL, SCC) of PLWH. These results indicate that the development of anal screening approaches based on HPV DNA testing need to include non-16 HR HPVs along with HPV 16, especially for PLWH. Along with anal cytology, these updated screening approaches may help to identify and prevent anal disease progression in PLWH.
The incidence of anal cancer is elevated in human immunodeficiency virus (HIV)‐infected men‐who‐have‐sex‐with‐men (MSM) compared to the general population. Anal high‐grade squamous intraepithelial ...lesions (HSIL) are common in HIV‐infected MSM and the presumed precursors to anal squamous cell cancer; however, direct progression of HSIL to anal cancer has not been previously demonstrated. The medical records were reviewed of 138 HIV‐infected MSM followed up at the University of California, San Francisco, who developed anal canal or perianal squamous cancer between 1997 and 2011. Men were followed up regularly with digital anorectal examination (DARE), high‐resolution anoscopy (HRA) and HRA‐guided biopsy. Although treatment for HSIL and follow‐up were recommended, not all were treated and some were lost to follow‐up. Prevalent cancer was found in 66 men. Seventy‐two HIV‐infected MSM developed anal cancer while under observation. In 27 men, anal cancer developed at a previously biopsied site of HSIL. An additional 45 men were not analyzed in this analysis due to inadequate documentation of HSIL in relation to cancer location. Of the 27 men with documented progression to cancer at the site of biopsy‐proven HSIL, 20 men progressed from prevalent HSIL identified when first examined and seven men from incident HSIL. Prevalent HSIL progressed to cancer over an average of 57 months compared to 64 months for incident HSIL. Most men were asymptomatic, and cancers were detected by DARE. Anal HSIL has clear potential to progress to anal cancer in HIV‐infected MSM. Early diagnosis is facilitated by careful follow‐up. Carefully controlled studies evaluating efficacy of screening for and treatment of HSIL to prevent anal cancer are needed.
What's new?
The elevated incidence of anal cancer seen among HIV‐infected men‐who‐have‐sex‐with‐men (MSM) is presumably linked to the common occurrence of anal high‐grade squamous intraepithelial lesions (HSIL) in this population. This study provides some of the first evidence for direct progression of the postulated HSIL precursors to anal cancer. MSM were followed for a period of more than 20 years with high‐resolution anoscopy and biopsy. The data provide conclusive evidence of the malignant potential of anal HSIL and underscore the potential to reduce anal cancer through targeted removal of anal HSIL.
Although anal squamous cell carcinoma (SCC) and adenocarcinoma (ADC) are generally combined in cancer surveillance, their etiologies likely differ. Here, we describe demographic characteristics and ...trends in incidence rates (IR) of anal cancer by histology (SCC, ADC) and behavior (invasive, in situ) in the United States.
With data from the Surveillance, Epidemiology, and End Results (SEER) Program, we estimated age-adjusted anal cancer IRs across behavior/histology by demographic and tumor characteristics for 2000-2011. Trends in IRs and annual percent changes during 1977-2011 were also estimated and compared with rectal cancer.
Women had higher rates of SCC rate ratio (RR), 1.45; 95% confidence interval (CI), 1.40-1.50 and lower rates of ADC (RR, 0.68; 95% CI, 0.62-0.74) and squamous carcinoma in situ (CIS; RR, 0.36; 95% CI, 0.34-0.38) than men. Blacks had lower rates of SCC (RR, 0.82; 95% CI, 0.77-0.87) and CIS (RR, 0.90; 95% CI, 0.83-0.98) than non-Hispanic whites, but higher rates of ADC (RR, 1.48; 95% CI, 1.29-1.70). Anal cancer IRs were higher in men and blacks aged <40 years. During 1992-2011, SCC IRs increased 2.9%/year, ADC IRs declined nonsignificantly, and CIS IRs increased 14.2%/year. SCC and ADC IR patterns and trends were similar across anal and rectal cancers.
Rates of anal SCC and CIS have increased strongly over time, in contrast to rates of anal ADC, similar to trends observed for rectal SCC and ADC.
Anal SCC and ADC likely have different etiologies, but may have similar etiologies to rectal SCC and ADC, respectively. Strong increases in CIS IRs over time may reflect anal cancer screening patterns.
Objective The objective of the study was to estimate the impact of human immunodeficiency virus (HIV) infection on the incidence of high-grade cervical intraepithelial neoplasia (CIN). Study Design ...HIV-seropositive and comparison seronegative women enrolled in a prospective US cohort study were followed up with semiannual Papanicolaou testing, with colposcopy for any abnormality. Histology results were retrieved to identify CIN3+ (CIN3, adenocarcinoma in situ, and cancer) and CIN2+ (CIN2 and CIN3+). Annual detection rates were calculated and risks compared using a Cox analysis. Median follow-up (interquartile range) was 11.0 (5.4–17.2) years for HIV-seronegative and 9.9 (2.5–16.0) for HIV-seropositive women. Results CIN3+ was diagnosed in 139 HIV-seropositive (5%) and 19 HIV-seronegative women (2%) ( P < .0001), with CIN2+ in 316 (12%) and 34 (4%) ( P < .0001). The annual CIN3+ detection rate was 0.6 per 100 person-years in HIV-seropositive women and 0.2 per 100 person-years in seronegative women ( P < .0001). The CIN3+ detection rate fell after the first 2 years of study, from 0.9 per 100 person-years among HIV-seropositive women to 0.4 per 100 person-years during subsequent follow-up ( P < .0001). CIN2+ incidence among these women fell similarly with time, from 2.5 per 100 person-years during the first 2 years after enrollment to 0.9 per 100 person-years subsequently ( P < .0001). In Cox analyses controlling for age, the hazard ratio for HIV-seropositive women with CD4 counts less than 200/cmm compared with HIV-seronegative women was 8.1 (95% confidence interval, 4.8–13.8) for CIN3+ and 9.3 (95% confidence interval, 6.3–13.7) for CIN2+ ( P < .0001). Conclusion Although HIV-seropositive women have more CIN3+ than HIV-seronegative women, CIN3+ is uncommon and becomes even less frequent after the initiation of regular cervical screening.
Histopathological diagnosis of colposcopically identified cervical lesions is a critical step for the recognition of cervical cancer precursors requiring treatment. Although there have been efforts ...to standardize the histologic diagnosis of cervical biopsy specimens, in terms of terminology and use of biomarkers, there is no uniform approach in the pathology community. Adjunctive p16 immunohistochemistry (IHC) can highlight precancer diagnoses, with use recommendations outlined by the Lower Anogenital Squamous Terminology project.
We assessed the diagnostic reproducibility of cervical histopathological biopsy specimens with and without p16 staining among 2 expert pathologists.
Interpretation of p16 IHC as positive vs negative was highly reproducible (92.5% agreement, κ = 0.85); greater variation was seen in the choice of which biopsy specimens required adjunctive p16 staining (78.0% agreement, κ = 0.43). Adjunctive p16 IHC did not significantly increase diagnostic agreement under multitiered grading systems (benign vs cervical intraepithelial neoplasia CIN 1/low-grade squamous intraepithelial lesion vs atypical squamous metaplasia vs CIN2/high-grade squamous intraepithelial lesion HSIL vs CIN3/HSIL-CIN3 vs cancer) (65.5% agreement, κ = 0.56 without p16; 70.0% agreement, κ = 0.58 with p16). However, when dichotomizing diagnoses based on clinical management (less than HSIL vs HSIL+), diagnostic agreement increased with p16 IHC (90.5% agreement, κ = 0.79 without p16; 92.0% agreement, κ = 0.84 with p16). For biopsy specimens taken from women positive for human papillomavirus (HPV) type 16, agreement was similar with or without adjunctive p16 (κ = 0.80 without p16; κ = 0.78-0.80 with p16). In contrast, p16 IHC substantially improved diagnostic agreement for cervical biopsy specimens taken from women positive for other high-risk HPV strains, producing improvements in κ from 0.03 to 0.24.
Adjunctive p16 immunostaining provides useful information in the evaluation of cervical biopsies for precancer. In our study, we have demonstrated that it is highly reproducible between 2 pathologists, although the decision of which biopsies warrant its use is less so. Furthermore, although p16 IHC showed a limited increase in diagnostic reproducibility for all biopsies included in our study, it did demonstrate a more sizable gain in biopsies negative for HPV 16 but positive for other high-risk genotypes. Further studies are needed to clarify the role of p16 IHC and how it can be optimized for the detection of cervical precancer, particularly in HPV-vaccinated populations where types other than HPV 16 are relatively more important.
To report quantitative and qualitative results on cervical cancer human papillomavirus (HPV)-based screening and treatment algorithms, with/out triage with visual inspection after acetic acid (VIA), ...followed by ablative treatment (AT).
Women 30 to 54 years old from Durban, South Africa were recruited, regardless of human immunodeficiency virus (HIV) status, randomized into one of two study arms and screened for HPV. VIA triage arm: HPV-positive women were triaged using VIA, biopsied and received AT if VIA positive and eligible; no triage arm: eligible HPV-positive women received AT. Women ineligible for AT were referred to colposcopy. Women were asked about side effects immediately and 1 week after AT. Retention to screening and treatment algorithms was compared between arms.
A total of 350 women 275 HIV-uninfected and 75 women living with HIV, (WLWH) were allocated to receive HPV testing with VIA triage (n = 175) or no triage (n = 175). HPV prevalence was 28% 95% confidence interval (CI) = 23-33; WLWH: 52% (95% CI = 40-64) versus HIV-uninfected: 21% (95% CI = 17-27; P < 0.05). Among women who underwent VIA triage with histologic diagnosis, 3/17 were VIA negative with cervical intraepithelial neoplasia (CIN)2+; 14/18 were VIA positive with <CIN2. Retention to screening and treatment algorithms was high (92%).
This pilot demonstrated the feasibility of implementing screening and treatment algorithms, including performing triage and treatment in one visit; however, VIA triage did not reduce overtreatment and missed some precancerous lesions.
This study reports on implementation feasibility of two World Health Organization screening and treatment algorithms (with/out VIA triage). Although the retention to screening and treatment algorithms was high in both arms, the question of how best triaging HPV-positive women deserves further consideration, particularly for WLWH. See related In the Spotlight, p. 763.
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