Evaluation of Different Guidelines for Cervical Cancer Screening and Management of Abnormal Cervical Cytology

ACOG: American College of Obstetricians and Gynecologists; USPSTF: United States Preventive Services Task Force; ACS: American Cancer Society; ASCCP: American Society for Colposcopy and Cervical Pathology; ASCP: American Society for Clinical Pathology; CDC: Centers for Disease Control and Prevention; ACP: American College of Physicians; NICE: National Institute for Health and Care Excellence; NHS: National Health Service; VIA: Visual Inspection with Acetic Acid; HPV: Human Papillomavirus; ASCUS: Atypical Squamous Cells of Undetermined Signifi cance; LSIL: Low Grade Squamous Intraepithelial Lesion; HSIL: High Grade Squamous Intraepithelial Lesion; ASC-H: Atypical Squamous Cells in which HSIL cannot be excluded; AGC: Atypical Glandular Cells; AIS: Adenocarcinoma in Situ; CIN: Cervical Intraepithelial Neoplasia; SCC: Squamous Cell Carcinoma; LEEP/LLETZ: Large Loop Excision of The Transformation Zone; CKC: Cold Knife Conization Abstract


Introduction
The introduction of cervical cancer screening programs has accounted for a signifi cant reduction in the incidence and mortality of cervical cancer [1]. In countries where cervical cancer screening is not available, cervical cancer remains the second most common cause of cancer as well as the second most common cause of cancer deaths among women [2]. Therefore, it is widely established that cervical cancer screening is undoubtedly essential as it permits early discovery of the disease and hence, early treatment and better prognosis. It also allows the detection of pre-malignant states, thus prevent the progression into invasive cancer [3].
Globally, various guidelines exist for cervical cancer screening as different countries and societies have developed different algorithms for screening. Those algorithms may agree about or vary in the age at which screening should be initiated and ceased, the intervals of screening as well as the steps involved in management of any abnormal screening result. Yet, there is no universe screening guideline that all countries, worldwide, may follow. This article will discuss different cervical cancer screening programs that exist. It will highlight the key differences and resemblances between those guidelines with regards to the age of screening initiation and cessation, the screening intervals and management of abnormal screening results. Society for Colposcopy and Cervical Pathology, agree to start routine screening for cervical cancer at the age of 21years [4].

Discussion
However, the guidelines of Singapore and Canada, as well as the NICE and NHS guidelines, recommend starting screening at the age of 25years [5][6][7][8]. The World Health Organization (WHO), on the other hand, recommends beginning screening at age 30 for HIV-negative women [9]. Nevertheless, those guidelines give similar rationales behind their recommendations; cervical cancer is uncommon among younger women and to offer screening for that age group may lead to over-treatment and ultimately, more harm than good.

Age of screening cessation
The American guidelines for cervical screening, recommend that screening shall be ceased once a woman is above 65years of age and has no history of CIN2 or higher. However, this would be applicable only if either of the following is true; having 3 previous consecutive negative cytology results, or; having 2 previous consecutive negative co-test results, in the previous 10years with the most recent test being within 5years. Furthermore, screening shall also be discontinued for women who have had total hysterectomy with removal of the cervix and no history of CIN 2 or higher 4. The guidelines of Singapore are similar, as they recommend no further screening for women aged above 65 if there was a previous negative smear in the last 3years [6]. As per the NICE guidelines and the NHS, women above the age of 65 shall only undergo cervical screening if there has been no screening done up to the age of 50years or if there is a recent abnormal cytology result.
Otherwise, no screening should be offered in older women due to the infrequency of cervical cancer in this age group [7].
The Canadian guidelines, on the other hand, suggest stopping screening at the age of 70 for women who have had satisfactory screening, for instance 3 consecutively negative Pap test results in the previous 10years, as there is limited evidence of benefi t to continue screening in this age group.
Nevertheless, for women at 70years of age or older who have not yielded 3 negative test results, the recommendation is to continue adequate screening until these results have been obtained [5].

Screening intervals
The American guidelines recommend screening via cytology (Pap smear or liquid-based cytology) every 3years. However, if the woman wishes to lengthen the screening interval, a combination of cytology and HPV testing can be done every 5years instead. However, it is not recommended to do HPV testing for average-risk women in the age group between 20 and 31. Moreover, there is insuffi cient evidence to support longer screening intervals for women between the age of 21 and 30 with 2 or more consecutive negative cytology results 4.
The screening intervals recommended by the NICE guidelines and the NHS are as follows: 3-yearly for women between the ages of 25-49years and 5-yearly for women between the ages of 50-65years [7]. (Please see Table 1, which summarizes   the NHS guideline and Table 2, which summarizes the NHS guidelines). The Canadian guidelines recommend a 3-yearly screening interval for women between the ages 25-69years.
This recommendation is based on 13 case-control and 2 cohort studies, which established that a screening interval of 5years or less provides a signifi cant protection against cervical cancer [5], (Please see table 3, which summarizes The Canadian Task Force on Preventive Health Care screening for cervical cancer guidelines). The guidelines of Singapore recommend a 3-yearly screening interval as well for women between the ages 25-65years, however, more frequent screening if highrisk [6]. is positive, the patient should be referred to colposcopy. On the other hand, if the latter is negative, HPV co-testing should be repeated in 12months time [4,8]. If screening via   HPV co-testing: current recommendations do not recommend so. But decision will be revisited once more data available cytology revealed atypical squamous cells of undetermined signifi cance (ASCUS) and HPV co-testing was negative, it is recommended to preform routine age-based screening only. This is simply explained by the low risk of pre-cancerous or invasive lesions seen in HPV-negative women with ASCUS, as studies have shown [8]. However, if the result of the cytology were as either; atypical squamous cells-cannot exclude HSIL (ASC-H), Low Grade Squamous Intraepithelial Lesion (LSIL), high Grade Squamous Intraepithelial Lesion (HSIL) or Atypical Glandular Cells (AGC), it is recommended to do HPV cotesting after 12months with referral for colposcopy [4,8]. In addition, for women with history of CIN 2 or higher, the ACOG recommends to screen via cytology every 3years for a period of 20years after the initial post-treatment surveillance period. This would also be applicable if the woman underwent a total or supra-cervical hysterectomy [4,8]. The American Society for Colposcopy and Cervical Pathology: The main 2 categories of population regarding this guideline is based on age group, that is, people younger than 21years old and people older than 21years old. Initiation of screening is recommended 3years after fi rst sexual intercourse or at the age of 21, whichever comes fi rst in the less than 21years old population. Screening is advised every 3years in the older group. For any age group, if HPV test is positive and cytology is negative, a conservative approach should be considered, that is repeating both test in 12months' time. However, if both HPV test and cytology are positive, referral to colposcopy is recommended. In the <21year old patients, a cytology revealing ASCUS or LSIL needs to be repeated in 12months and if the change still persists for more than 24months, then referral to colposcopy is indicated. If the lesion shows HSIL, colposcopy is recommended. In the event of a cytology showing AGC initially and on repeated cytology in 24months, referral for colposcopy is advised. Patients having CIN 1 lesions on colposcopy will need repeat cytology in 12months and if the changes still persist for 24months, colposcopy will be required. In the >21year old population, in case cytology shows ASCUS, 3 options are available, HPV test, cytology in 6 or 12months and colposcopy. In case colposcopy is chosen and revealed negative, repeat cytology in 6 or 12months or HPV test in 12months. If HPV test done is positive or repeated cytology done in 6 or 12months shows ASCUS or HPV test done in 12months is positive, colposcopy is advisable. Any LSIL changes noted on cytology should be referred to colposcopy. If colposcopy is found to be positive for any changes except for CIN 2 and CIN 3, cytobrush and endocervical curette is recommended; otherwise HPV test is recommended in 12months or cytology in 6 and 12months. If HSIL is found on cytology, the initial test recommended are diagnostic procedures (immediate loop electrosurgical excision) or colposcopy with endocervical assessment. If no CIN 2 or 3 was found on colposcopy and endometrial sampling is negative, diagnostic procedures or cytology or colposcopy every 6months can be considered. However, if HSIL persists at 6 or 12months, referral for excision should be considered. In cytology showing AGC, colposcopy with endocervical sampling and HPV test are recommended, especially in the suspicion of high risk of endometrial cancer. In the event of a cytology showing AIS, diagnostic excisional procedure is recommended. For CIN 1 persisting for 2years, observe the changes but if it was preceded by HSIL or AGC-NOS, then diagnostic excision or cytology and colposcopy in 6 and 12months are recommended.
If there is any unsatisfactory colposcopy or positive sampling or previous treatment, refer for excision. Please see summary tables 4-9, which covers each of the six discussed guidelines.
In addition, please see Table 10, which compares cervical cancer screening guidelines based on cytology and Table 11, which compares cervical cancer screening guidelines based on histology.

NICE guidelines
If cytology reveals ASCUS or LSIL, the following action depends on the HPV co-testing result. If HPV is positive, colposcopy should be done within 8weeks. However, if HPV CIN 2 Treatment will be given and later, the patient will return back to routine age-based screening for a period of 20years from the initial post-treatment surveillance (past age 65years if necessary) For women with total hysterectomy and history of either CIN 2 or higher in previous 20years or cervical cancer ever, screen with cervical cytology alone every 3years for 20years after initial post-treatment surveillance period For women with a supracervical hysterectomy and history of CIN 2 or higher perform routine screening every 3years for 20years after initial post treatment surveillance period  [7]. Please see Table 7 at the end of this review article, which summarizes the discussed guideline. If a longer screening interval is desired, screening with a combination of cytology and HPV co-testing may be done every 5years No screening is recommended if there were adequate normal previous screening tests and the women is no other-wise at high risk for cervical cancer Adequate previous screening may be defi ned as 3 consecutive negative cytology results or 2 consecutive negative co-test results over the past 10years, with the most recent test being done within the last 5years Screening is also stopped for women who have undergone total hysterectomy with removal of the cervix and have no history of ≥ CIN 2 Table 6: American College of Physicians (ACP) on screening for cervical cancer.

Classifi cation American College of Physicians (ACP)
Overview <21year old 21-30year old 31-65year old >65year old No screening is done Start screening asymptomatic average-risk women at the age of 21years Do a 3-yearly screen with cytology Do not screen more frequently than once every 3years Do not perform HPV testing in average-risk women < 30years old Do a 3-yearly screen with cytology A combination of Pap smear and HPV testing once every 5years may be used in women who prefer screening less frequently than once every 3years Screening is ceased in women above the age of 65years with no history of ≥ CIN 2 with either 3 consecutive negative cytology results or 2 consecutive negative co-test results over the past 10years, with the most recent test being done within the last 5years  if a lesion was to be found and the transformation zone could not be seen and the endocervical curettage and/or biopsy were negative; a diagnostic excisional procedure will be required.

Whenever atypical glandular cells or adenocarcinoma in-situ
were to be found on cytology, colposcopy and endocervical curettage are to be done within 6weeks. Besides, if the age is above 35years and per-vaginal bleeding is evident, endometrial sampling will be required. If the colposcopy shows no lesion, a diagnostic excisional procedure will be done. Furthermore, if histology then shows CIN1, the patient will be kept under observation and either cytology at 12months or colposcopy at 12months will be done. On the other hand, a CIN2 or 3 in an age group more than 25years will necessitate treatment via excision. If a positive margin was found, colposcopy and directed Bx and/or endocervical curettage will be required. In case of any recurrence or persistent lesions, excision will be required as well. Please see Table 12, which summarizes the discussed guideline.

Singapore guidelines
Firstly, based on the cytology result, if atypical squamous cells of undetermined signifi cance were found (ASCUS), PAP Repeat cytology in 12months, if the change persists for more than 24months then refer to colposcopy 1) If persistent for 2years, observe the changes -if preceded by HSIL OR AGC-NOS, then diagnostic excision is recommended OR cytology and colposcopy in 6months and 12months 2) If unsatisfactory colposcopy OR positive sampling OR previous treatment, refer for excision  smear will be repeated in 6months. If the repeated smear was positive, patient will be referred to colposcopy, however, if negative, it will be repeated again in 6months, then if a persistent negative smear was found, the patient will be referred back to routine screening. Moreover, if atypical squamous cells in which HSIL (ASC-H) cannot be excluded, the patient will be referred immediately to colposcopy 6.

For Low Grade Squamous Intraepithelial Lesion (LSIL)
• If mild dyskaryosis was found or not otherwise specifi ed, the patient will be referred to colposcopy.
• If a HPV effect was found, cytology will be repeated in 6months. If the repeated cytology was negative, it will be repeated again in 1year after which if persistent negative smear was found, routine screening schedule will be resumed. However, if the initial repeated cytology showed a HPV effect or more signifi cant abnormality, colposcopy will be done.

For High Grade Squamous Intraepithelial Lesion (HSIL)
Moderate or severe dyskaryosis: referral to colposcopy will be done and an urgent referral if severe dyskaryosis in which invasive carcinoma cannot be ruled out 6. If atypical glandular cells or endocervical adenocarcinoma in-situ was found, the patient will be referred to colposcopy.

Any infl ammatory smear will require the following actions
• Treatment of any infection or atrophy then repetition of smear in 4-6months. • If 2 nd smear has similar changes, the same action as per 1st smear will be done.
• If 3 rd smear has again similar changes, the patient will be referred to a gynecologist.
• If changes resolve after 1st or 2nd smears, routine screening will be resumed.
Regarding the recommended approaches towards histological fi ndings, the management of a grade 1 cervical intraepithelial lesion is controversial. One possible approach is to treat the lesion via ablation or excision then follow it up with PAP smear at 3-6months then PAP smear and colposcopy at 12months then a yearly PAP smear (four smears) and then fi nally return to routine screening. The other option is to observe the lesion and repeat PAP smear and colposcopy +/biopsy in 6months [6].
Grade 2 and 3 cervical intraepithelial lesions will require treatment. Following treatment, screening via PAP smear will be done at 3-6months then PAP smear and colposcopy at 12months then PAP smear 6monthly for the 2nd year and fi nally a yearly PAP smear [6].
Please see table 13, which summarizes the discussed guideline.

The WHO Guidelines for Screening and Treatment of Precancerous Lesions for Cervical Cancer Prevention:
The new WHO guidelines recommend a screen-and treat approach for cervical neoplasms. As the name suggests, this strategy involves screening followed by initiation of appropriate treatment once screening is positive [9]. Screening is initiated at the age of 30. There are no recommendations to preform screening for women aged less than 30years of age [9]. The guidelines suggest that screening via HPV testing is superior to screening with cytology (PAP smear). However, the guidelines provide algorithms for both screening methods (9).
First, if screening with HPV was done, the following steps are taken • If HPV negative: repeat screening every 5years minimum.
• If HPV positive> do VIA to assess eligibility for treatment with cyotherpay and to exclude a cervical cancer.
• If VIA negative: repeat screening in 1-year time and then 3-5yearly .
• If VIA positive: Treat with cryotherpay if eligible or with LEEP if not. Later, do a follow-up screen in a 1year time.
• If cancer was suspected: refer the patient for appropriate diagnosis and treatment.

Alternatively, if HPV test was positive, colposcopy can be done instead of VIA
• If colposcopy was negative: Repeat screening in 3years' time.

• If colposcopy was positive and no biopsy was done:
Treat with cryotherapy if eligible or with LEEP if not.
Later, do a follow-up screen in a 1year time.

• If colposcopy was positive and no biopsy was done:
Treat with cryotherapy if eligible or with LEEP if not. Later, do a follow-up screen in a 1 year time.

If colposcopy was positive and biopsy was done
For ≥ CIN2 treat with cryotherapy or LEEP and then do a follow-up screen in a 1-year time. However, if biopsy shows a ≤CIN1 repeat screening in 3-year time.
If cancer was suspected: Refer the patient for appropriate diagnosis and treatment [9].
For those recommendations, cryotherapy is the superior treatment method. However, the WHO specifi es eligibility criteria for cryotherapy that requires the entire lesion and the squamocolumnar junction to be visible and the lesion should not cover more than 75% of the ectocervix. If this criteria was not met, LEEP would be the alternative option [9]. Please see table 14 which summarizes the discussed guideline.

The European guidelines for quality assurance in cervical cancer screening
The recent guidelines published in 2015 indicate that the use of HPV alone as a screening test for cervical cancer is more benefi cial than cytology. They also show that co-testing is not superior to HPV testing alone as it may lead to an increase in costs and unnecessary referrals to colposcopy. However, this is only applicable for the ages between 30-65, as beyond this range, cytology remains the primary screening tool [10]. If a HPV test was negative, re-screening should be done at least 5-yearly. Moreover, not all HPV-positive tests will be referred to colposcopy. Cytology will be done on the same sample collected. If cytology was negative, the test will be repeated in 6-12months' time. If cytology indicated ASC-H, HSIL or AIS, the patient will be referred immediately to colposcopy. If cytology indicated ASCUS, AGC or LSIL, either the test will be repeated in 6-12months' time or the patient will be referred Citation: Ismail

Classifi cation WHO Guidelines
The new WHO guidelines recommend a screen-and-treat approach for cervical neoplasms. This strategy compromise of screening for cervical cancer via one of the following methods; HPV test, VIA or cytology (Pap smear). Once a screening test has been done and showed a positive result, treatment will be initiated via one of the following methods; cryotherapy, LEEP/LLETZ or CKC. • Not only is HPV linked to cervical cancer, but also to vaginal, vulvular, oropharyngeal and anal cancers.
• The timing for vaccination relies on the age. The best time to start vaccination is prior to sexual intercourse.
The target age group for HPV vaccination is young girls between the ages 9years and 14years.
• The vaccine regimen depends on the age at which the vaccine is to be given. For example, if the female was less than 15years of age, the vaccine is given as 2 doses 6-months apart. However, if the female was more than 15years of age, a 3-doses regimen is recommended [14].
• Regardless of the vaccination status, women will still have to be screened as per the routine screening guidelines. This is explained by the fact that 10%-30% of the cervical cancer cases are caused by other types of HPV that are not included in the vaccines. Also, there is a possibility that the vaccinated woman was already  infected with the virus before the vaccine was delivered [10][11][12][13][14][15].
• The effi cacy of vaccination depends on whether the individual was previously infected or not. The best protection lies in those who were never infected. Vaccination is more effective in younger women than older ones though older women would still benefi t from vaccination. The immunoprotection of HPV vaccine lasts approximately 84months. Antibodies developed against HPV after vaccination is found to last about 10years.
• HPV vaccination is not recommended in pregnancy due to few data concerning its safety. However, no increased risk of adverse pregnancy outcomes was noted in patients who have been vaccinated.
• HPV vaccination is recommended in immunocompromised patients. 3 doses should be administered for all patients through 26years old.
• The risks associated with vaccination are minimal.
Parents might think that vaccination might lead to sexual disinhibition but surveys performed suggest that there was no increase in risky sexual behavior. Hence, HPV vaccination should be promoted and administered to both men and women.

Cervical cancer screening and HPV in Bahrain
In Bahrain, a recent report was published with local statistics of cervical cancer and HPV. It indicated an annual incidence Bahrain is one of the countries with an established screening program for cervical cancer. The guidelines state to screen all women between the ages 30 and 65years once every 5years.
However, currently, there is no established HPV vaccination program in Bahrain [16].