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

Näytönastekatsaus | Julkaistu: 01.09.2026 Tulosta
Bianca Arrhenius ja Ilkka Kalliala

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

Näytönastekatsaukset
Bianca Arrhenius and Ilkka Kalliala
1.9.2026

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
Reference Study type Population Exposure variables Outcomes Risk 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...»1 Retrospective registerbased cohort 721 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. Retrospective registerbased cohort 956 women undergoing cervical conization (LEEP) for CIN in 2012-2018.
Multicenter, Italy		 HPV genotype before and 6 months after LEEP Recurrence or residual disease (CIN 2 or worse) Moderate
Söderlund-Strand «Söderlund-Strand A, Kjellberg L, Dillner J. Human ...»3 Cohort 195 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 treatment Recurrence or residual disease (CIN 2 or worse) High
Kocken «Kocken M, Helmerhorst TJ, Berkhof J, et al. Risk o...»4 Cohort 435 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 2009 Moderate
Heymans «Heymans J, Benoy IH, Poppe W, et al. Type-specific...»5 Retrospective case-control study Out 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 treatment Number of cases vs controls with different HPV infections after treatment, number of cases vs controls with persistent infections Moderate
Kreimer «Kreimer AR, Guido RS, Solomon D, et al. Human papi...»6 Cohort 610 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 treatment Cumulative incidence of CIN 2+ lesion during 2-year follow-up Moderate
Table 2. Additional comments for included studies
Reference Comments
«Graça J, Preti M, Pollano B, et al. Performance of...»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...»2 Retrospective design, small number of subjects with recurrences.
«Söderlund-Strand A, Kjellberg L, Dillner J. Human ...»3 Conization 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 o...»4 Condom-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...»5 Retrospective design. Small case-control sample.
«Kreimer AR, Guido RS, Solomon D, et al. Human papi...»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+
Reference Number of patients Follow-up time Recurrence/relapse: number of events or number of cases vs controls Absolute 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...»1 HPV 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 months Recurrence:
  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...»2 HPV 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 cohort Recurrence
  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...»5 At least 24 months High 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 papi...»6 HPV 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 months Recurrence:
  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+
Reference Number of patients with HPV infections Follow-up time Absolute number of events or number of cases vs controls Absolute 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...»2 Persistent 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 ...»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 o...»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...»5 Persistence of same hrHPV genotype before and 6 months after treatment At least 24 months Cases 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
Article ID: nak08758 (050.049)
© 2026 The Finnish Medical Society Duodecim

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