Näytönastekatsaukset

Risk of recurrent cervical intraepithelial neoplasia (CIN) grade 2 or higher based on HPV genotyping before and after treatment

Näytönastekatsaukset
1.9.2026
Bianca Arrhenius and Ilkka Kalliala

Level of evidence: C

High-risk HPV positivity after treatment and persistence of the same HPV genotype before and after treatment, particularly genotype HPV16, seems to increase the risk of recurrent cervical intraepithelial neoplasia grade 2 or higher.

Table 1. Description of the included studies
ReferenceStudy typePopulationExposure variablesOutcomesRisk of bias
RCT=randomized controlled trial; SR=systematic review; MA=meta-analysis
Graca et al. «Graça J, Preti M, Pollano B, et al. Performance of Different Follow-Up Strategies and Genotype-Based Recurrence Risk After Treatment of Cervical High-Grade Squamous Intraepithelial Lesion. J Low Genit»1Retrospective registerbased cohort721 women (age >25 years) who had an excision of the tranformation zone for CIN 2 or CIN 3 in 2011-2022
Single center, Portugal		Baseline HPV status and genotype, HPV genotype at 6-12 months after treatment (and cytology, biopsy, colposcopy results from follow-up visits)Recurrenceor persistence of CIN 2 or worse Moderate
Bruno et al. 2Retrospective registerbased cohort956 women undergoing cervical conization (LEEP) for CIN in 2012-2018.
Multicenter, Italy		HPV genotype before and 6 months after LEEPRecurrence or residual disease (CIN 2 or worse) Moderate
Söderlund-Strand «Söderlund-Strand A, Kjellberg L, Dillner J. Human papillomavirus type-specific persistence and recurrence after treatment for cervical dysplasia. J Med Virol 2014;86(4):634-41 »3Cohort195 women aged 20-59 identified from population-based Pap smear screening and undergoing conization after that in 2001-2003.
Sweden		HPV testing before and 3, 6, 12, 24 and 36 months after treatmentRecurrence or residual disease (CIN 2 or worse)High
Kocken «Kocken M, Helmerhorst TJ, Berkhof J, et al. Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: a long-term multi-cohort study. Lancet Oncol 2011;12(5):441-50 »4Cohort435 women aged 21-70 treated for CIN 2+ with loop excision or cold knife conization 1988-2004.
Based on three cohorts, the Netherlands		HPV testing (and cytology) at 6,12 and 24 months Cumulative risk of CIN 2+ by the end of 2009Moderate
Heymans «Heymans J, Benoy IH, Poppe W, et al. Type-specific HPV geno-typing improves detection of recurrent high-grade cervical neoplasia after conisation. Int J Cancer 2011;129(4):903-9 »5Retrospective case-control studyOut of 823 women treated for CIN 2+ with conization 2001-2007, 21 cases with CIN 2+ recurrence were compared to 42 women without recurrence
Belgium		HPV genotyping before and 6 months after treatmentNumber of cases vs controls with different HPV infections after treatment, number of cases vs controls with persistent infectionsModerate
Kreimer «Kreimer AR, Guido RS, Solomon D, et al. Human papillomavirus testing following loop electrosurgical excision procedure identifies women at risk for posttreatment cervical intraepithelial neoplasia gra»6Cohort610 women who underwent loop electrosurgical excision procedure (LEEP) for a CIN 2+ lesion. Study subjects enrolled in 1997-1998
Multisite, USA		HPV genotyping before and 6 months after treatmentCumulative incidence of CIN 2+ lesion during 2-year follow-upModerate
Table 2. Additional comments for included studies
ReferenceComments
«Graça J, Preti M, Pollano B, et al. Performance of Different Follow-Up Strategies and Genotype-Based Recurrence Risk After Treatment of Cervical High-Grade Squamous Intraepithelial Lesion. J Low Genit»1 Persistent HPV positivity and different genotype persistency rates were not reported, only baseline and follow-up data separately. Data was gathered from one center, and it was unknown how many patients moved their follow-up to other institutions. Long inclusion time (2011-2022), follow-up procedures changed during that time.
«Bruno MT, Valenti G, Ruggeri Z, et al. Correlation of the HPV 16 Genotype Persistence in Women Undergoing LEEP for CIN3 with the Risk of CIN2+ Relapses in the First 18 Months of Follow-Up: A Multicent»2Retrospective design, small number of subjects with recurrences.
«Söderlund-Strand A, Kjellberg L, Dillner J. Human papillomavirus type-specific persistence and recurrence after treatment for cervical dysplasia. J Med Virol 2014;86(4):634-41 »3Conization was not based on histopathological findings in all cases (see-and-treat 39%). 46/195 patients (23.6%) were lost to follow-up. HPV persistence was not reported according to genotype. Recurrence rates were small (N=9), introducing bias and imprecision.
«Kocken M, Helmerhorst TJ, Berkhof J, et al. Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: a long-term multi-cohort study. Lancet Oncol 2011;12(5):441-50 »4Condom-users were excluded from one of the three cohorts. Some of the hrHPV tests were done by the patients themselves at home, however, the proportion of home-testing was not reported. Follow-up strategies varied somewhat across treatment sites.
«Heymans J, Benoy IH, Poppe W, et al. Type-specific HPV geno-typing improves detection of recurrent high-grade cervical neoplasia after conisation. Int J Cancer 2011;129(4):903-9 »5Retrospective design. Small case-control sample.
«Kreimer AR, Guido RS, Solomon D, et al. Human papillomavirus testing following loop electrosurgical excision procedure identifies women at risk for posttreatment cervical intraepithelial neoplasia gra»6 Small sample for genotyping. Persistent HPV positivity and different genotype persistency rates were not clearly reported.

Results

Table 3. HPV infection in follow-up after treatment, effect on recurrence of CIN 2+
ReferenceNumber of patients Follow-up timeRecurrence/relapse: number of events or number of cases vs controlsAbsolute risk or odds ratio
Level of evidence: low
I= intervention; C=comparison; CI=confidence interval, NR=not reported
*HPV 31,33, 35, 39, 45, 51, 52, 56, 58, 59, 68
Graca «Graça J, Preti M, Pollano B, et al. Performance of Different Follow-Up Strategies and Genotype-Based Recurrence Risk After Treatment of Cervical High-Grade Squamous Intraepithelial Lesion. J Low Genit»1HPV genotype 6-12 months after treatment:
  1. 1) HPV 16: 54
  2. 2) HPV 18: 13
  3. 3) HPV other: 147
  4. 4) HPV negative: NR
Median 24 monthsRecurrence:
  1. 1) HPV 16: 23
  2. 2) HPV 18: 1
  3. 3) HPV other: 15
  4. 4) HPV neg: NR
  1. 1)16: 42.6% (23/54)
  2. 2)18: 7.7% (1/13)
  3. 3)HPV other:10.2% (15/147)
  4. 4) HPV neg: NR
Kocken «Bruno MT, Valenti G, Ruggeri Z, et al. Correlation of the HPV 16 Genotype Persistence in Women Undergoing LEEP for CIN3 with the Risk of CIN2+ Relapses in the First 18 Months of Follow-Up: A Multicent»2HPV status at 6 months:
positive 87, of which
  1. 1) HPV 16: 56
  2. 2) other HPV type than 16: 31
  3. 3) HPV negative: 337
Median 15-24 months depending on cohortRecurrence
  1. 1) HPV 16: 40
  2. 2) other HPV than 16: 13
  3. 3) NR
  1. 1) 71.4% (40/56)
  2. 2) 41.9% (13/31)
  3. 3) NR, but 5-year cumulative risk was reported in HPV negative women at 6 months: 4.4% (95% CI 2.5-7.5) compared to HPV-positive women 56.9% (95% CI 46.0-67.2)
Heymans «Heymans J, Benoy IH, Poppe W, et al. Type-specific HPV geno-typing improves detection of recurrent high-grade cervical neoplasia after conisation. Int J Cancer 2011;129(4):903-9 »5At least 24 monthsHigh risk HPV (hrHPV-test+ among cases with recurrence at 6 months: 21/21 (100%)
hrHPV-test + among controls without recurrence at 6 months: 18/42 (44.9%)		The odds ratios for detecting
recurrent disease was 4.54 for abnormal follow-up
cytology, 6.25 for hrHPV positivity of follow-up samples.
Kreimer «Kreimer AR, Guido RS, Solomon D, et al. Human papillomavirus testing following loop electrosurgical excision procedure identifies women at risk for posttreatment cervical intraepithelial neoplasia gra»6HPV status post-LEEP:
  1. 1) HPV 16: 66
  2. 2) HPV 18: 14
  3. 3) Other carcinogenic HPV* type: 115
  4. 4) Other noncarcinogenic HPV type: 107
  5. 5) Negative: 227
24 monthsRecurrence:
  1. 1) HPV 16: 20
  2. 2) HPV 18: 2
  3. 3) Other carcinogenic HPV* type: 10
  4. 4) Other noncarcinogenic HPV type: 1
  5. 5) Negative: 0
  1. 1) HPV 16: 30.3% (20/66)
  2. 2) HPV 18: 14.3% (2/14)
  3. 3) Other carcinogenic HPV* type: 8.7% (10/115)
  4. 4) Other noncarcinogenic HPV type: 0.9% (1/107)
  5. 5) Negative: 0.0%
Table 4. HPV persistence before and after treatment, effect on recurrence of CIN 2+
ReferenceNumber of patients with HPV infections Follow-up timeAbsolute number of events or number of cases vs controlsAbsolute risk or odds ratio
Level of evidence: low
I= intervention; C=comparison; CI=confidence interval, NR= not reported
Bruno «Bruno MT, Valenti G, Ruggeri Z, et al. Correlation of the HPV 16 Genotype Persistence in Women Undergoing LEEP for CIN3 with the Risk of CIN2+ Relapses in the First 18 Months of Follow-Up: A Multicent»2Persistent infections (at 6 months):
  1. 1) HPV 16: 118
  2. 2) HPV 18: 32
  3. 3) HPV 31: 52
  4. 4) other HPV: 83

Non-persistent at 6 months:
  1. 5) Transient HPV after LEEP: 48
  2. 6) HPV-negative: 526
 4 years
  1. 1) 31
  2. 2) 3
  3. 3) 2
  4. 4) 3
  1. 5) 0
  2. 6) NR
  1. 1) 26.3% (31/118)
  2. 2) 9.4% (3/32)
  3. 3) 3.8% (2/52)
  4. 4) 3.6% (3/83)
  5. 5) 0.0% (0/48)
Söderlund-Strand «Söderlund-Strand A, Kjellberg L, Dillner J. Human papillomavirus type-specific persistence and recurrence after treatment for cervical dysplasia. J Med Virol 2014;86(4):634-41 »3
  1. 1) Persistence of the same HPV type at all visits during follow-up: 18
  2. 2) Transient or recurring HPV infections during follow-up: 33
 3 years
  1. 1) 9
  2. 2) 0
  1. 1) 50% (9/18)

Kocken «Kocken M, Helmerhorst TJ, Berkhof J, et al. Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: a long-term multi-cohort study. Lancet Oncol 2011;12(5):441-50 »4
  1. 1) Persistence of the same HPV genotype at baseline and 6 months: 65
  2. 2) New HPV genotype at 6 months: 22
Median 15-24 months depending on cohort
  1. 1) 46
  2. 2) 7
  1. 1) 70.7% (46/65)
  2. 2) 31.8% (7/22)
Heymans «Heymans J, Benoy IH, Poppe W, et al. Type-specific HPV geno-typing improves detection of recurrent high-grade cervical neoplasia after conisation. Int J Cancer 2011;129(4):903-9 »5Persistence of same hrHPV genotype before and 6 months after treatmentAt least 24 monthsCases with recurrence:
21/21 (100%)
Controls without recurrence: 12/42 (28.6%)		Odds ratio for detecting recurrent disease: 12.5 for follow-up samples after treatment with the same HPV
type as found at the time of diagnosis of the primary lesion.

References

  1. Graça J, Preti M, Pollano B, et al. Performance of Different Follow-Up Strategies and Genotype-Based Recurrence Risk After Treatment of Cervical High-Grade Squamous Intraepithelial Lesion. J Low Genit Tract Dis 2024;28(2):131-136 «PMID: 38465957»PubMed
  2. Bruno MT, Valenti G, Ruggeri Z, et al. Correlation of the HPV 16 Genotype Persistence in Women Undergoing LEEP for CIN3 with the Risk of CIN2+ Relapses in the First 18 Months of Follow-Up: A Multicenter Retrospective Study. Diagnostics (Basel) 2024;14(5): «PMID: 38472983»PubMed
  3. Söderlund-Strand A, Kjellberg L, Dillner J. Human papillomavirus type-specific persistence and recurrence after treatment for cervical dysplasia. J Med Virol 2014;86(4):634-41 «PMID: 24123176»PubMed
  4. Kocken M, Helmerhorst TJ, Berkhof J, et al. Risk of recurrent high-grade cervical intraepithelial neoplasia after successful treatment: a long-term multi-cohort study. Lancet Oncol 2011;12(5):441-50 «PMID: 21530398»PubMed
  5. Heymans J, Benoy IH, Poppe W, et al. Type-specific HPV geno-typing improves detection of recurrent high-grade cervical neoplasia after conisation. Int J Cancer 2011;129(4):903-9 «PMID: 21064091»PubMed
  6. Kreimer AR, Guido RS, Solomon D, et al. Human papillomavirus testing following loop electrosurgical excision procedure identifies women at risk for posttreatment cervical intraepithelial neoplasia grade 2 or 3 disease. Cancer Epidemiol Biomarkers Prev 2006;15(5):908-14 «PMID: 16702369»PubMed