Appendix C

Clinical question list

Questions 1

Relevant guidelines content page: Oncogenic HPV types not 16/18

Question 1a

Primary PICO

For women who are positive for hr-HPV types other than 16 or 18 and have pLSIL/dLSIL reflex liquid based cytology (intermediate risk), what is the safety and effectiveness of immediate colposcopy compared to colposcopy delayed by 12 months based on later HPV test results (assuming referral to colposcopy if any HPV positive at 12 months)?

Population	Study design	Intervention	Control	Outcome
Women who are positive for hr-HPV types other than 16 or 18 and have pLSIL/dLSIL (ASC-US/LSIL) liquid based cytology (intermediate risk)	Randomised or pseudo randomized controlled trial	Immediate Colposcopy	Repeat HPV test in 12 months; Colposcopy if positive	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion detection

Secondary PICO (In the event that no randomised or pseudo-randomised controlled trials were identified that directly addressed the primary PICO)

For women undergoing routine cervical screening what is the risk of CIN3+ for women who are positive for HPV oncogenic types other than 16 and 18 and have p/dLSIL cytology compared with women who have p/d LSIL cytology regardless of HPV status, p/dHSIL cytology regardless of HPV status, or are HPV 16/18+ regardless of cytology?

Population	Study design	Exposure	Comparator	Outcome
Women undergoing routine cervical screening	Longitudinal or cross-sectional prognostic	Positive for HPV oncogenic types other than 16 and 18 and have p/dLSIL cytology	p/dLSIL or p/dHSIL or HPV 16/18+	CIN3+ CIN2+

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Question 1b

Primary PICO

For women who are positive for hr-HPV types other than 16 or 18 and have negative or pLSIL/dLSIL reflex liquid based cytology (intermediate risk), what is the safety and effectiveness of repeating HPV testing in 12 and 24 months compared to repeating HPV test at 12 months only before returning to 5 yearly screening?

Population	Study design	Intervention	Control	Outcomes
Women who are positive for hr-HPV types other than 16 or 18 and have negative or pLSIL/dLSIL (ASC-US/LSIL) liquid based cytology (intermediate risk)	Randomized or pseudo randomized controlled trial	Repeat HPV test in 12 and 24 months; Colposcopy and reflex LBC if positive or if both negative discharge back to screening	Repeat HPV test in 12 months; Colposcopy if positive and if negative discharge to screening	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion detection

Secondary PICO (In the event that no randomised or pseudo-randomised controlled trials were identified that directly addressed the primary PICO)

For women undergoing routine cervical screening what is the risk of subsequent CIN3+ for women who are positive for HPV oncogenic types other than 16 and 18 and have negative cytology compared with women who have p/d LSIL regardless of HPV status or who have p/d LSIL and are positive for HPV oncogenic types other that 16 and 18?

Population	Study design	Exposure	Comparator	Outcomes
Women undergoing routine cervical screening	Longitudinal prognostic	Positive for HPV oncogenic types other than 16 and 18 and have NILM cytology	p/dLSIL or positive for HPV oncogenic types other than 16 /18 and have p/dLSIL cytology	CIN3+ CIN2+

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Questions 2

Relevant guidelines content page: Normal colposcopic findings following LBC prediction of LSIL or HSIL

Question 2a

Primacy PICO

For HPV positive women who are not in treatment follow-up and who have negative or LSIL cytology and who have undergone colposcopy and the colposcopy was negative, what is the safety and effectiveness of testing with repeat HPV test at 12 months when compared with repeat cytology and HPV testing in 12 months?

Population	Study design	Intervention	Control	Outcomes
HPV positive women who have undergone colposcopy and the colposcopy was negative and cytology was: i. negative, ii. p/d LSIL	Randomized or pseudo randomized controlled trial	Repeat HPV test at 12 months; Colposcopy (and reflex LBC test) if positive If negative HPV test in 12 months	Repeat cytology and HPV testing at 12 months: Colposcopy if HPV positive test or if cytology pHSIL or worse, and another 12 months follow-up if HPV negative p/dLSIL; repeat HPV and cytology test in 12 months if HPV negative and cytology p/dLSIL or negative	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion detection

Secondary PICO (In the event that no randomised or pseudo-randomised controlled trials were identified that directly addressed the primary PICO)

For HPV positive women who are not in treatment follow-up and who have negative or p/dLSIL cytology on referral and who had colposcopy and the colposcopy was negative what are the predictors of subsequent detection of high-grade disease?

Population	Study design	Exposure	Comparator	Outcomes
Women who have p/dLSIL or negative cytology who have undergone colposcopy and no abnormalities were seen on colposcopy	Cohort	Referral cytology Referral HPV status Age	Other Referral cytology Referral HPV status Age	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion detection

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Question 2b

For women who are HPV positive with p/dHSIL referral cytology and p/dLSIL or less after cytologic review and colposcopy is negative, what is the safety and effectiveness of conservative management compared with excision of the transformation zone?

Population	Study design	Intervention	Control	Outcome
HPV positive women who have undergone colposcopy and the colposcopy was negative and referral cytology was p/d HSIL and review cytology was p/d LSIL or less	Randomized or pseudo randomized controlled trial	Conservative management	Excision of the transformation zone	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion detection

dHSIL = definite HSIL; dLSIL = definite LSIL; HSIL = high-grade squamous intraepithelial lesion; LSIL = low-grade squamous intraepithelial lesion pHSIL = possible HSIL; pLSIL = possible LSIL

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Question 2c

For women who are HPV positive with p/dHSIL referral cytology and p/dHSIL after cytologic review and colposcopy is negative, what is the safety and effectiveness of cytologic and colposcopic follow-up at 3-6 months compared with excision of the transformation zone?

Population	Study design	Intervention	Control	Outcome
HPV positive women who have undergone colposcopy and the colposcopy was negative and referral and review cytology was p/d HSIL	Randomized or pseudo randomized controlled trial	Conservative management; cytologic and colposcopic follow-up at 3-6 months	Excision of the transformation zone	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion detection

dHSIL = definite HSIL; HSIL = high-grade squamous intraepithelial lesion; pHSIL = possible HSIL

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Questions 3

Relevant guidelines content page: Type 3 TZ (previously termed ‘unsatisfactory’) colposcopy following LBC prediction of LSIL or HSIL

Question 3a

For HPV positive women currently not in treatment follow-up and have negative or LSIL cytology who have undergone colposcopy and the colposcopy was unsatisfactory what is the safety and effectiveness of repeat HPV test at 12 months compared with repeat cytology and HPV testing in 12 months?

Population	Study design	Intervention	Control	Outcomes
HPV positive women who have undergone colposcopy and the colposcopy was unsatisfactory and cytology was: i. negative, ii. p/d LSIL	Randomized or pseudo randomized controlled trial	Repeat HPV test at 12 months; Colposcopy (and reflex LBC test) if positive and if negative HPV test in 12 months	Repeat cytology and HPV testing at 12 month; Colposcopy if HPV positive test or if cytology pHSIL or worse, and another 12 months follow-up if HPV negative p/dLSIL; repeat HPV and cytology test in 12 months if HPV negative and cytology p/dLSIL or negative	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion detection

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Question 3b

For HPV-positive women with a referral cytology finding of p/dHSIL and who have an unsatisfactory colposcopy, what is the safety and effectiveness of conservative management compared with diagnostic excision of the transformation zone?

Population	Study design	Intervention	Control	Outcomes
HPV positive women who have undergone colposcopy and the colposcopy was unsatisfactory and cytology was: p/d HSIL	Randomized or pseudo- randomized controlled trial	Conservative management: Co-testing at 3-6 months or repeat HPV test at 12 months	Diagnostic excision of the transformation zone	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion detection

dHSIL = definite HSIL; HSIL = high-grade squamous intraepithelial lesion; pHSIL = possible HSIL

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Question 4

Relevant guidelines content page Chapter 9. Management of histologically confirmed low-grade squamous abnormalities

For HPV positive women currently not in treatment follow-up who have undergone colposcopy (without treatment) with colposcopy LSIL and CIN 1 or less on biopsy what is the safety and effectiveness of excisional treatment or testing with repeat HPV test at 12 months when compared with repeat cytology and HPV testing in 12 months?

Population	Study design	Intervention	Control	Outcomes
HPV positive women, who have undergone colposcopy and colposcopy LSIL, confirmed by biopsy CIN1 or less, and referral cytology was: i. negative or p/d LSIL or ii. p/dHSIL	Randomized or pseudo randomized controlled trial	Excisional treatment or Repeat HPV test at 12 months	i. Negative cytology or p/dLSIL: Repeat cytology and HPV testing at 12 months: Colposcopy if HPV positive test or if cytology pHSIL or worse, and another 12 months follow-up if HPV negative p/dLSIL; repeat HPV and cytology test in 12 months if HPV negative and cytology p/dLSIL or negative ii. p/dHSIL: repeat cytology and colposcopy in 6 months	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion detection

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Questions 5

Relevant guidelines content page: Investigation of cytological glandular abnormalities

Question 5a

For women who are HPV positive with atypical endocervical cells of undetermined significance (confirmed on review) and negative colposcopy what is the safety and effectiveness of repeating HPV and cytology testing when compared with treatment with excisional cone biopsy?

Population	Study design	Intervention	Control	Outcomes
Women who are HPV positive with atypical endocervical cells of undetermined significance (confirmed on review) and colposcopy negative	Randomized or pseudo randomized controlled trial	Repeat HPV and liquid based cytology testing at 6 months	Excisional cone biopsy cervix	Cervical cancer mortality Other gynaecologic cancer diagnosis (endometrial, ovarian) Cervical cancer diagnosis Precancerous high grade lesion (including AIS) detection

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Question 5b

For women who are HPV positive with atypical glandular cells of undetermined significance (AGUS) or possible high grade glandular lesion (confirmed on review) and negative colposcopy what is the safety and effectiveness of repeating HPV and cytology testing when compared with treatment with excisional cone biopsy?

Population	Study design	Intervention	Control	Outcomes
Women who are HPV positive with AGUS or possible HGGA (confirmed on review) and colposcopy negative	Randomized or pseudo randomized controlled trial	Repeat HPV and liquid based cytology testing at 6 months	Excisional cone biopsy cervix	Cervical cancer mortality Cervical cancer diagnosis Endometrial cancer diagnosis Ovarian cancer diagnosis Precancerous high grade lesion (including AIS) detection

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Question 6

Relevant guidelines content page: Treatment of HSIL CIN2

For women with biopsy confirmed CIN2 what is the safety and effectiveness of p16 immunohistochemistry and treating only p16 positive CIN2 while conservatively managing p16 negative CIN2 when compared with treating all CIN2 cases?

Population	Study design	Intervention	Control	Outcomes
Women with biopsy confirmed CIN2	Randomized or pseudo randomized controlled trial	Using p16 immunohistochemistry to stratify management: p16 positive cases treated with excision and p16 negative cases conservatively managed	Treat all CIN2 with excision of transformation zone.	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion detection

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Question 7

Relevant guidelines content page: Follow-up after excisional treatment for AIS

For women who are HPV positive with adenocarcinoma in situ (AIS) or possible high-grade glandular lesion cytology or biopsy confirmed AIS, what is the safety and effectiveness of large loop excision of the transformation zone (LLETZ), Fischer cone, laser cone or straight wire/needle excision of the transformation zone (SWETZ/NETZ) compared with cold knife cone biopsy?

Population	Study design	Intervention	Control	Outcomes
Women who are HPV positive with AIS or possible high-grade glandular lesion cytology or biopsy confirmed AIS	Randomized or pseudo randomized controlled trial	LLETZ or Fischer cone or laser cone or SWETZ or NETZ or Any electro-surgery of the transformation zone	Cold knife cone biopsy	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion (including recurrent AIS) detection Completeness of excision. Depth of excision

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Question 8

Relevant guidelines content page: Investigation of abnormal vaginal bleeding

For women with postcoital, intermenstrual bleeding or heavier periods (menorrhagia), what is the safety and effectiveness of direct colposcopy compared with HPV test and cytology?

Population	Study design	Intervention	Control	Outcomes
Women with postcoital (PCB) or intermenstrual bleeding (IMB) or menorrhagia	Randomized or pseudo randomized controlled trial	Direct referral to colposcopy	Cytology and HPV	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion detection

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Question 9

Relevant guidelines content page: Screening in immune-deficient women

For women who are at higher risk of cervical cancer due to immunosuppression what is the safety and effectiveness of screening using strategies other than those recommended for the general population compared to those recommended for the general population?

Population	Study design	Intervention	Control	Outcome
Chronically immuno-suppressed or immuno-compromised asymptomatic women or Potentially immune suppressed or immune compromised women	Screening randomized controlled or pseudo- randomized trial	Modified recommended screening strategy: starting at an age <25 years and/or screening intervals less than 5 years and/or referring all HPV positive women to colposcopy irrespective of reflex cytology result	Recommended screening strategy Primary HPV screening every 5 years from ages 25 – 69 years using partial genotyping with women positive for HPV16/18 referred to colposcopy and women positive for other oncogenic types undergoing cytology triage	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion detection

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Question 10

Relevant guidelines content page: Women who have experienced early sexual activity or have been victims of sexual abuse

For women with a history of sexual abuse or early sexual debut what is the safety and effectiveness of screening using strategies other than those recommended for the general population compared to those recommended for the general population?

Population	Study design	Intervention	Control	Outcome
History of sexual abuse or early sexual debut	Screening randomized or pseudo- randomized controlled trial	Modified recommended screening strategy: Starting at an age <25 years	Recommended screening strategy Primary HPV screening every 5 years from ages 25 – 69 years using partial genotyping with women positive for HPV16/18 referred to colposcopy and women positive for other oncogenic types undergoing cytology triage	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion detection

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Question 11

Relevant guidelines content page: Screening in DES-exposed women

For women who were exposed to diethylstilboestrol (DES) in utero and their daughters what is the safety and effectiveness of screening using strategies other than those recommended for the general population compared to those recommended for the general population?

Population	Study design	Intervention	Control	Outcome
Asymptomatic women exposed in utero to DES and their daughters	Screening randomized or pseudo- randomized controlled trial	Current practice: Annual vaginal examination, cervical and vaginal cytology test, HPV test and colposcopy of the lower genital tract	Recommended screening strategy for general population: Primary HPV screening every 5 years from ages 25 – 69 years using partial genotyping with women positive for HPV16/18 referred to colposcopy and women positive for other oncogenic types undergoing cytology triage	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion detection

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Question 12

Relevant guidelines content page: Screening in Aboriginal and Torres Strait Islander women

For women who are of Aboriginal or Torres Strait Islander descent what is the safety and effectiveness of screening using strategies other than those recommended for the general population compared to those recommended for the general population?

Population	Study design	Intervention	Control	Outcomes
Women of Aboriginal or Torres Strait Islander descent	Screening randomized or pseudo-randomized controlled trial	Modified recommended screening strategy: - starting at an age <25 years - other	Recommended screening strategy for general population: Primary HPV screening every 5 years from ages 25 – 69 years using partial genotyping with women positive for HPV16/18 referred to colposcopy and women positive for other oncogenic types undergoing cytology triage	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion detection

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Question 13

Relevant guidelines content page: Screening in pregnancy

For women who are pregnant update the literature of management of abnormal cytology in pregnancy p.74 from the old guidelines. Describe guidance for excluding presence of invasive cancer. How can we support the exclusion of the presence of the invasive cervical cancer? Are there any circumstances that you would manage or treat pregnant women differently to the general population?

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Questions 14

Relevant guidelines content page: After total hysterectomy

For groups of women (literature review or PICO) who have had a hysterectomy. What should the recommendation be in regard to further ‘screening’?

1. Women with total hysterectomy for benign conditions who have never had an abnormal HPV or cytology. Do they need any further screening?
2. Women who have had in the past been HPV positive with high grade abnormality (squamous or glandular) who have been treated satisfactorily and are on surveillance or have returned to normal screening, who then have a total hysterectomy with no evidence of abnormality on the hysterectomy specimen.
3. Women who have had a high grade abnormality treated by total hysterectomy, with complete excision of the lesion in the hysterectomy specimen. What follow up would be reasonable.
4. Women who have had a high grade lesion (CIN2+) who have been treated and have completed test of cure and returned to routine screening, subsequently have hysterectomy with no abnormality in the hysterectomy specimen. Is there any need for further screening?

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Question 16

Relevant guidelines content page: Test of Cure after treatment for HSIL (CIN2/3)

For women have been treated for a high grade precancerous squamous lesion what is the safety and effectiveness of testing with HPV test and cytology at 12 months after treatment and discharging if double-negative compared with testing at 12 and 24 months and discharging if double-negative at both 12 and 24 months?

Population	Study design	Intervention	Control	Outcome
Women who have been treated for high grade precancerous squamous lesions	Randomized or pseudo randomized controlled trial	Cytology and HPV testing 12 months after treatment with discharge if double negative	Cytology and HPV testing 12 and 24 months after treatment with discharge if double negative on both occasions	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion detection

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Question 17

Relevant guidelines content page: Follow-up after excisional treatment for AIS

For women have been treated for adenocarcinoma in situ (AIS) with cone excision or LEEP and with clear histologic margins what is the safety and effectiveness of cytology and HPV testing at 12 and 24 months and discharging if double-negative at both 12 and 24 months or completion hysterectomy compared to cytology?

Population	Study design	Intervention	Control	Outcome
Women treated for AIS with cone excision or LEEP with complete excision and clear histological margins	Randomized or pseudo randomized controlled trial	Cytology and HPV testing 12 and 24 months after treatment with discharge if double negative on both occasions Or Completion hysterectomy	Annual cytology	Cervical cancer mortality Cervical cancer diagnosis Precancerous high grade lesion (including recurrent AIS) detection

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