We previously have shown that a portion of CIN2 diagnoses are also due to misclassification of disease (3
) and to HPV infections by non-HR HPV genotypes (3
). Here, we present data from ALTS showing that a significant portion of CIN2 diagnosed by central panel review, even caused by HR HPV genotypes, may represent only regressive lesions. Similar patterns were observed in the ASCUS referral population, in the ASCUS referrals that tested hc2 positive, and in the LSIL referral population. We estimated that approximately 40% of rigorously-defined CIN2 diagnoses in primarily young women (mean age = 24.8 years, median age = 23 years, range = 18–62 years) were destined to resolve on their own by using a “subtractive” analytic approach that compared the fraction found in the least sensitive (CM) and most sensitive (IC) study arm (by virtue of the proportion of women in arm referred to colposcopy) for detection of cervical abnormalities. The differences in CIN2 detection are due to the delay in the colposcopic evaluation of patients. Importantly, the time difference in diagnostic evaluation was assigned by the randomization, which created comparable populations. By comparison, 27% (20
) and 19% (21
) of histologically-confirmed CIN2 regressed over approximately 2 years of follow-up in the placebo arms of two chemoprevention trials.
We used ≥CIN3 as a reference to show that the study arms were roughly equivalent in cancer risk, and the differences in the criteria for enrollment colposcopy primarily affected the fraction of women diagnosed with CIN2. However, we note that, in addition to some CIN2 regressing, some HPV infections may have caused incident CIN2 while some CIN2 may have “progressed” to CIN3. Thus CIN2 regression cannot be precisely determined although reasonable estimations can be derived.
It is also worth mentioning that CIN2 is the least reproducible of all cervical diagnoses (19
), and it is possible that the regressive nature of CIN2 will depend somewhat on the individual pathologist diagnosing it. As shown in , this lack of agreement is directly related to the regression of CIN2: the likelihood of regression correlated with the severity of the second (original) diagnosis by the clinical center. For scientific rigor, we used the histopathologic diagnoses rendered by the Pathology Quality Control Group review in our analysis. Yet, we observed a similar difference in the fraction of CIN2 as diagnosed by the clinical center pathologists between the CM and IC arms.
In real-world settings, some clinical pathologists equivocate on the use of a CIN2 diagnosis, relying on non-standard diagnoses such as "CIN1-2” or “CIN2-3”. Their use may reflect further the uncertain nature of CIN2. It is plausible that each diagnosis will represent different likelihoods of regression although it is unclear how reliable such distinctions are, given how generally unreliable a CIN2 diagnosis is (19
). The inclusion of lesions of an even more ambiguous nature in the definition of CIN2 would be expected to increase the overall regressive potential of CIN2. The use of equivocations like CIN1/2 should probably be discouraged given the lack of evidence of utility, unproven reliability, and the possible increase in the number of women receiving unnecessary therapy.
We point out that the CIN2 diagnosed at enrollment followed an ASCUS or LSIL Pap smear, which led to referral into the study. That is, women were not referred into ALTS because of a HSIL Pap smear. In ALTS, we previously found that women with biopsy-diagnosed CIN2 following the HSIL enrollment cytology (n.b., women enrolled into ALTS had cytology repeated at the enrollment visit) were more apt to have an underlying CIN3 than those with a less severe enrollment cytology (3
). We therefore hypothesize that CIN2 following a HSIL cytology may be on average less regressive than that observed for CIN2 diagnosed in the ALTS population.
A CIN2 diagnosis on biopsy is the clinical threshold for treatment in the U.S., its treatment provides a margin of safety against cancer risk. However, a greater recognition of the true equivocal nature of CIN2 is needed. Aggressive clinical management of young women (median age = 25 years; mean age = 27.5 years in ALTS) who have ASCUS or LSIL cytology will lead to over-diagnosis of CIN2 and over-treatment of a significant number of regressive lesions. This is an important clinical issue since most CIN2 is diagnosed in women following ASCUS or LSIL cytology (23
From these data, we suggest that strategies that send more women to colposcopy, such as immediate colposcopy for LSIL or ASC-US or HPV triage of ASC-US, offer the benefit of early detection of CIN3 at the cost of increased detection of CIN2, some proportion of which is destined to resolve and its treatment translates into patient morbidity without benefit. Repeat cytology at an ASCUS threshold as recommended, rather than a HSIL threshold as used in CM arm of ALTS, would be expected to yield different results, with more women going to colposcopy and higher proportion of CIN2 i.e., more akin to the IC and HPV arms of ALTS. However, this is only speculative since we did not evaluate this clinical algorithm in ALTS.
HPV16-positive CIN2 appears less likely to regress, perhaps as the result of its greater tendency to persist and its greater oncogenic potential to progress to precancerous lesions than other HPV genotypes (24
). When HPV genotyping from validated tests becomes routinely available, detection of HPV16 may be a useful stratifier of risk (25
) for deciding the clinical management of CIN2 diagnoses: HPV16-negative CIN2 diagnosed in young women with ASCUS or LSIL cytology could be managed less aggressively through increased surveillance rather than immediate treatment (1
) while HPV16-positive CIN2, the most strongly linked with CIN3 (3
) and least regressive, probably warrants inclusion with CIN3 for management.
More generally, a clinical trial to determine the best management strategies for CIN2, akin to ALTS for ASCUS and LSIL Pap smears, is needed. Several biomarkers, such as HPV genotyping and p16INK4A
), warrant evaluation for determining which women with CIN2 need immediate treatment versus surveillance. Key outcomes for any triage strategy for CIN2 would be the timely detection of CIN3 (misclassified as CIN2 (3
) or progression of a carcinogenic HPV infection, diagnosed as CIN2, to CIN3), safety against cancer, and the reduction in the number of women with CIN2 treated as compared to the current standard-of-care (4
) of excising treatment for all women diagnosed with CIN2.