Background
Methods
Scope of review
Literature Review Design
Category | Search terms | Articles Retrieved | Articles Selected for this Review |
---|---|---|---|
Duration and progression of cervical HPV infection and natural immunity | <human papillomavirus and cervical> OR <human papillomavirus and cervix> | 7,454 | 8 |
Progression and regression of cervical intraepithelial neoplasia | <cervical intraepithelial neoplasia and progression> OR <CIN and progression> OR <cervical intraepithelial neoplasia and natural history> OR <CIN and natural history> OR <cervical intraepithelial neoplasia and regression> OR <CIN and regression> OR <cervical intraepithelial neoplasia and clearance> OR <CIN and clearance> | 1,321 | 5 |
Natural history of cervical cancer | <cervical and cancer and natural history> OR <cervix and cancer and natural history> OR <cervical and cancer and progression> OR <cervix and cancer and progression> | 2,538 | 4 |
Hysterectomy | <hysterectomy and rate and United States> | 270 | 1 |
Cervical cytology screening | <Pap and rate and United States> OR <cervical and screening and rate and United States> OR <cervix and screening and rate and United States> OR <cervical and cytology and rate and United States> OR <cervix and cytology and rate and United States> | 848 | 3 |
Cervical cytology sensitivity and specificity | For literature published up to October 1999 we consulted a prior systematic review: | 559 | 2 |
Nanda K, McCrory DC, Myers ER, Bastian LA, Hasselblad V, Hickey JD, Matchar DB. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med. 2000 May 16;132(10):810–9. | |||
For literature published from October 1999 forward we used search terms of: | |||
<Pap and cervical intraepithelial neoplasia and sensitivity> OR <cytology and cervical intraepithelial neoplasia and sensitivity> OR <screening and cervical intraepithelial neoplasia and sensitivity> OR <Pap and cervical intraepithelial neoplasia and specificity> OR <cytology and cervical intraepithelial neoplasia and specificity> OR <screening and cervical intraepithelial neoplasia and specificity> OR <Pap and CIN and sensitivity> OR <cytology and CIN and sensitivity> OR <screening and CIN and sensitivity> OR <Pap and CIN and specificity> OR <cytology and CIN and specificity> OR <screening and CIN and specificity> | |||
Symptom development for cervical cancer | <cervical and cancer and symptom> OR <cervix and cancer and symptom> | 255 | 0 |
Eradication of disease with treatment | <cervical intraepithelial neoplasia and treatment and loop excision and recurrence> OR <cervical intraepithelial neoplasia and treatment and LEEP and recurrence> OR <cervical intraepithelial neoplasia and treatment and LLETZ and recurrence> OR <cervical intraepithelial neoplasia and treatment and loop excision and residual> OR <cervical intraepithelial neoplasia and treatment and LEEP and residual> OR <cervical intraepithelial neoplasia and treatment and LLETZ and residual> OR <cervical intraepithelial neoplasia and treatment and loop excision and failure> OR <cervical intraepithelial neoplasia and treatment and LEEP and failure> OR <cervical intraepithelial neoplasia and treatment and LLETZ and failure> OR <genital wart and treatment and recurrence> | 362 | 10 |
HPV persistence following treatment | <human papillomavirus and treatment and persistence> OR <human papillomavirus and treatment and clearance> | 162 | 2 |
Anogenital wart patients seeking physican care | <genital wart and untreated> OR <genital wart and undiagnosed> OR <genital wart and care seeking> | 36 | 0 |
General Methodologic Criteria
Parameter Group | Study Selection Criteria |
---|---|
General criteria for stud y selection
| • Nationally representative studies meeting selection criteria |
➢ If unavailable, then select broad population-based studies | |
▪ If unavailable, then select local studies | |
• Specificity of results to HPV type groupings of interest (16/18 or 6/11) | |
➢ If studies specific to HPV 16/18 or 6/11 infection or disease are unavailable, then select studies of all high-risk or all low-risk HPV types, respectively | |
▪ If unavailable then select studies for all infections or disease | |
• PCR-based methods for HPV detection in infections | |
Progression of HPV infection and disease | • Histologic confirmation of cervical disease |
• Data available for outcomes reported over a 12-month time horizon | |
HPV infection mean duration in absence of detectable disease | • Specificity of results to HPV type groupings of interest (16/18 or 6/11) |
• Truncation of infection duration at time of disease detection via histology | |
• Limited degree of censoring beyond longest infection follow-up time | |
Regression of HPV infection and disease | • Histologic confirmation of cervical disease at baseline |
• Biopsy confirmation of cervical HPV-type specific disease absence during follow-up to connote regression | |
➢ If unavailable for all cases, then select studies with either biopsy confirmed HPV-type specific disease absence for a portion of cases, with negative cytology for non-biopsied cases, OR biopsy confirmed disease absence, irrespective of HPV-type | |
• Data available for outcomes reported over a 12-month time horizon | |
Cervical cancer mortality | • Data available on an age- and stage-specific basis |
• Nationally representative or broad population-based studies in unscreened women | |
➢ If unavailable, then select nationally representative or broad population-based studies in screened and unscreened women | |
• Data available for outcomes reported over a 12-month time horizon | |
Hysterectomy for non-HPV related conditions | • Age-specific annual hysterectomy rates reported |
Cytology screening rates | • Age-specific annual routine cervical cytology screening rates reported |
➢ Routine screening reported separately from follow-up screening | |
➢ Cervical cytology reported separately from vaginal cytology | |
• Data based on documented screening utilization in a population-based study if available | |
➢ If unavailable, then select studies based on patient self-report | |
Cytology sensitivity | • Liquid-based cytology evaluated |
• Cervical biopsy performed on all women | |
➢ If unavailable, then select studies in which cervical biopsy was performed on at least a random sample of women with negative cytology and colposcopy results | |
Cytology specificity | • Liquid-based cytology evaluated |
• Cervical colposcopy performed on all women, with biopsy performed if abnormalities suspected | |
• Biopsy results reported for all grades of cervical disease (≥ CIN 1) | |
Colposcopy sensitivity/specificity | • Colposcopy performed following abnormal cytology |
• Colposcopically directed cervical biopsy performed on all women | |
• Biopsy results reported for all grades of cervical disease (≥ CIN 1) | |
Symptom development among cancer patients | • Stage-specific symptom development |
• Representative cross-section of patients with cervical cancer at each stage including patients who may harbor occult cancers | |
➢ If unavailable, then rely upon expert opinion from the literature | |
Eradication of CIN with treatment | • Representative study of CIN therapies used in practice if available |
➢ If unavailable then select studies of LEEP (most common modality) | |
• Stratified reporting of outcomes by pre-treatment CIN grade | |
• Post-treatment follow-up of all women within 12 months via colposcopy and/or biopsy | |
• Definition of recurrent or residual disease as CIN 1 or more severe histology | |
Eradication of cervical cancer with treatment | • Nationally representative or broad population-based studies of 5-year disease-free survival by cancer stage |
➢ If unavailable, then select nationally representative or broad population-based studies of 5-year relative survival by cancer stage | |
Eradication of genital warts with treatment | • Representative study of genital wart treatments used in clinical practice |
• Physician ascertained clearance following treatment for all subjects | |
Persistence of HPV following cervical disease eradication | • Representative study of therapies used in practice if available |
➢ If unavailable, then select studies of LEEP (most common modality) for CIN, and hysterectomy or radiation therapy for cervical cancer | |
• Histologic confirmation of disease pre-treatment and post-treatment (for exclusionary study purposes) | |
• HPV typing of pre- or post-treatment lesion tissue specimens or both | |
➢ If unavailable, then select studies with HPV typing of any cervical specimen | |
• Follow-up for all women within 6 months post-treatment | |
➢ If unavailable, then select studies with less prompt follow-up | |
• Colposcopy performed on all women post-treatment to assist in confirming disease eradication | |
Persistence of HPV following genital wart eradication | • Representative study of genital wart treatments used in clinical practice |
• Testing for HPV infection across a range of anogenital sites post-treatment (not just at the former wart site) | |
• Follow-up for all women within 6 months post-treatment | |
➢ If unavailable, then select studies with less prompt follow-up | |
Care seeking behavior for genital warts | • Population-based studies of patients with genital warts, including both those who have, and who have not, chosen to seek physician care |
➢ If unavailable, then rely upon expert opinion from the literature |
Cytology vs. Histology
Classification and Quality of HPV Testing and Typing
Interval of Follow-up
Age-specific Natural History Modeling
Risks vs. Rates
Results
Epidemiologic Natural History
Parameter | Estimate |
---|---|
Progression in the presence of HPV 16/18, % per year | |
Normal to CIN1[43] | 9.4 |
5.8 | |
3.5 | |
CIN1 to CIN 2* | 13.6 |
14.0 | |
43.0 | |
CIN 3 (CIS) to LCC | 4.1 |
10.0 | |
RCC to DCC [22] | 30.0 |
Progression in the presence of HPV 6/11, % per year | |
Normal to CIN1 [43] | 8.5 |
Normal to CIN 1 to CIN 2 [43] | 1.9 |
0.0 | |
CIN 1 to CIN2 * | 0.0 |
Normal to genital warts [41] | 57 |
Mean HPV infection duration with CIN absent, years | |
HPV 16/18 infection [42] | 1.2 |
HPV 6/11 infection [42] | 0.7 |
Duration of acquired immunity following HPV infection | 10 years to Lifelong |
Regression of HPV 16/18+ disease, % per year | |
CIN1 to Negative/HPV 16/18 [40]* | 32.9 |
21.0 | |
CIN 2 to CIN 1 [65] | 13.3 |
CIN 3 (severe dysplasia) to Negative/HPV 16/18 [49] | 11.0 |
3.0 | |
3.0 | |
Regression of HPV 6/11+ disease, % per year | |
CIN1 to Negative/HPV 6/11* | 55.2 |
87.5 | |
Age and stage-specific cervical cancer mortality, 1997–2002, % per year [69] | |
for LCC | |
15–29 years | 0.7 |
30–39 years | 0.6 |
40–49 years | 0.8 |
50–59 years | 1.9 |
60–69 years | 4.2 |
≥ 70 years | 11.6 |
for RCC | |
15–29 years | 13.4 |
30–39 years | 8.9 |
40–49 years | 11.0 |
50–59 years | 10.1 |
60–69 years | 17.6 |
≥ 70 years | 28.6 |
for DCC | |
15–29 years | 42.9 |
30–39 years | 41.0 |
40–49 years | 46.7 |
50–59 years | 52.7 |
60–69 years | 54.6 |
≥ 70 years | 70.3 |
Progression of HPV 16/18 infection to Histologically Detectable CIN
HPV 16/18 infection to CIN 1
HPV 16/18 infection to CIN 2/3
Progression of HPV 16/18-positive CIN and Cancer
HPV 16/18-positive CIN 1 to CIN 2
HPV 16/18-positive CIN 2 to CIN 3 (severe dysplasia)
HPV 16/18-positive CIN 3 (severe dysplasia) to CIN 3 (CIS)
HPV 16/18-positive CIN 3 (CIS) to Localized Cervical Cancer
HPV 16/18-positive LCC to Regional and Distant Cervical Cancer
Progression of HPV 6/11 infection to Histologically Detectable CIN and Anogenital Warts
HPV 6/11 infection to CIN 1
HPV 6/11 infection to CIN 2/3
HPV 6/11-positive CIN 1 to CIN 2
HPV 6/11 infection to Anogenital Warts
Duration of HPV 6/11 and HPV 16/18 infections in the Absence of CIN
Duration of HPV 16/18 Infections
Duration of HPV 6/11 Infections
Existence and duration of acquired immunity following HPV infection
Regression of HPV 16/18 positive CIN
HPV 16/18-positive CIN 1 to Negative/HPV 16/18
HPV 16/18-positive CIN 2 to Negative/HPV16/18
HPV 16/18 positive CIN 2 to CIN 1
HPV 16/18 positive CIN 3 (severe dysplasia) to Negative/HPV 16/18
HPV 16/18 positive CIN 3 (severe dysplasia) to CIN 2 or CIN1
Regression of HPV 6/11 positive CIN and anogenital warts
HPV 6/11-positive CIN 1 to Negative/HPV 6/11
HPV 6/11-positive Anogenital Warts to Negative/HPV 6/11
Cervical Cancer Mortality (As a % of women within each cervical cancer stage and age grouping)
Clinical Diagnosis and Treatment
Parameter | Parameter estimate |
---|---|
Hysterectomy for non-HPV-related conditions, % per year [93] | |
15–24 years | 0.02 |
25–29 years | 0.26 |
30–34 years | 0.53 |
35–39 years | 0.89 |
40–44 years | 1.17 |
45–54 years | 0.99 |
≥ 55 years | 0.36 |
Cervical cytology screening, % per year (excluding those with hysterectomy) [47] | |
10–14 years | 0.6 (0.6) |
15–19 years | 21.0 (21.0) |
20–24 years | 44.6 (44.8) |
25–29 years | 60.4 (61.6) |
30–34 years | 52.4 (54.9) |
35–39 years | 46.0 (50.5) |
40–44 years | 41.0 (48.1) |
45–49 years | 39.1 (49.1) |
50–54 years | 38.0 (51.1) |
55–59 years | 33.2 (46.7) |
60–64 years | 29.4 (42.5) |
65–69 years | 26.2 (38.9) |
70–74 years | 19.4 (29.6) |
75–79 years | 12.9 (20.1) |
80–84 years | 7.0 (11.1) |
85+ | 3.4 (5.5) |
Women never screened, % | 5.0 |
Liquid-based cytology sensitivity, % | |
for CIN 1 [114] | 28 |
for ≥ CIN 2/3 [115] | 59 |
94 | |
Colposcopy sensitivity, % [117] | 96 |
Colposcopy specificity, % [117] | 48 |
Symptom development, % per year | |
for LCC | 4 |
for RCC | 18 |
for DCC | 90 |
Eradication with treatment, % | |
97 | |
93 | |
93 | |
for LCC [89] | 92 |
for RCC [89] | 55 |
for DCC [89] | 17 |
for anogenital warts [41] | 87.5/year |
Persistence of HPV following eradication of CIN, % [127] | 34 |
Persistence of HPV following eradication of cervical cancer, % [129] | 47 |
Persistence of HPV following eradication of genital warts | 34 |
Anogenital wart patients seeking physician care, % [71] | 75 |