Abnormal Pap smear

Diseases

Overview

Introduction

Worldwide, an estimated 660,000 new cases of cervical cancer were diagnosed in 2022, with approximately 350,000 deaths.WHO: cervical cancer Cervical cancer is the fourth most common cancer diagnosed in women and ranks second in resource-limited countries.

Cervical cancer is caused primarily by persistent infection of the cervix with human papillomavirus (HPV). HPV is a sexually transmitted infection and is common in sexually active individuals. Most infections resolve spontaneously, but persistent infection of the cervix, if untreated, can cause abnormal, precancerous cells to develop. Cervical screening can detect precancerous and cancerous lesions in asymptomatic women.[1] [2] [3] [4] [5]

Cervical cancer screening has been hailed as one of the most successful preventive medical strategies. It has been associated with a 70% reduction in cervical cancer mortality in developed countries since the introduction of the Papanicolaou (Pap) test in 1941.[6] [7] Cancer Research UK: cervical cancer mortality statisticsImage

HPV infection of cervical epithelial cells is associated with characteristic morphologic changes, and the presence of HPV can, therefore, be indicated by histopathologic observation. HPV tests, either alone or with cytology, are a newer method of cervical cancer screening.

Cervical cancer is rare in women under the ages 21 years. Routine screening is recommended for those with a cervix ages 21 years to 65 years. Screening may be clinically indicated in women over the ages 65 years who have not had adequate prior screening or are at high risk of cervical cancer. Women who have undergone total hysterectomy (i.e., their cervix has been removed) no longer need cervical cancer screening, as long as they have no previous history of cervical cancer or dysplasia. Women of any age who have a limited life expectancy can also discontinue cervical cancer screening.[1] [3] [4] [5]

National Cancer Institute: cervical cancer screening

ACOG: cervical cancer screening FAQs

See Cervical cancer

Cervical sampling techniques

Cervical screening samples cells from the junction of the ectocervix and endocervix (the transformation zone or squamocolumnar junction, where 90% of cervical neoplasias originate) to identify premalignant or malignant lesions.[8]

Epidemiologic, not randomized, data support the impact of cervical screening. The sequential introduction of screening in Canada, matched neighborhood controlled studies, and the introduction of screening to Finland, Sweden, and Iceland in the 1960s were associated with a fall in the incidence of cervical cancer.[9] [10] [11] More than half of cervical cancers diagnosed in the US occur in women who fail to get screening.[12]

Conventional cytology using fixed cells on a slide sampled by spatula has a reported sensitivity of 30% to 87% for dysplasia.[13] A meta-analysis suggested a sensitivity of 58% when used for population screening.[14] [15]

Since the mid-1990s, newer techniques have used a liquid transport medium (liquid-based cytology) based on ethanol to preserve cells. Several commercial products are available. The liquid sample has the advantage of allowing other diagnostic assessments for sexually transmitted diseases such as gonorrhea, chlamydia, and HPV to triage risk. Additionally, the proportion of unsatisfactory specimens has been reduced from 4.1% to 2.6%.[16] Standard slide cytology and liquid-based cytology have similar diagnostic accuracy, with reported sensitivity of liquid-based cytology ranging from 61% to 66% with a specificity of 80% to 91%.[17] [18]

Histology of cervical intraepithelial neoplasia

From the collection of Dr Richard Penson, Massachusetts General Hospital, Boston; used with permission

Cervical cytology

The US Preventive Services Task Force recommends screening of average-risk women with cytology (cytologic tests without human papillomavirus [HPV] tests) from the ages 21 years, and then once every 3 years, if the results are normal.[1] [5] Average-risk women should not be screened for cervical cancer with cytology more often than once every 3 years.[4] [5] Average risk is defined as those with no history of a precancerous lesion (cervical intraepithelial neoplasia [CIN] grade 2 or a more severe lesion) or cervical cancer, those who are not immunocompromised (including being HIV-infected), and those without in utero exposure to diethylstilbestrol.

Unsatisfactory cytology tests should be repeated in 2-4 months.[2] [19] Appropriate follow-up evaluation should be undertaken for women with abnormal cytology, irrespective of HPV testing status.[2] [5] [19] Screening of average-risk women should stop from the ages 65 years, if they have had three consecutive negative cytology results or two consecutive negative cytology plus HPV test results within 10 years, with the most recent test performed within 5 years.[1] [3] [4] [5]

Classification of test results, based on the Bethesda System for reporting cervical cytology, was first introduced in 1988 and revised in 2001 to define satisfactory samples and to standardize reporting.[20] Inadequate samples for evaluation include those tests that lack patient identifying information, broken slides, inadequate squamous component (defined as <5000 squamous cells on liquid-based medium or <8000 to 12,000 cells on conventional medium), or obscuring elements on over 75% of squamous cells (typically due to lubricant, inflammation, or blood).

The Bethesda System terminology for cytologic reporting classifies epithelial abnormalities as follows.[20]

Squamous cell abnormalities
- Atypical squamous cells (ASC)
- Atypical squamous cells of undetermined significance (ASC-US)
- Atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion (ASC-H)
- Low-grade squamous intraepithelial lesion (LSIL), encompasses those previously classified as koilocytic atypia (HPV changes) or cervical intraepithelial neoplasia (CIN) 1
- High-grade squamous intraepithelial lesion (HSIL), encompasses those formerly called CIN 2 or CIN 3
- Squamous cell carcinoma.

Glandular cell abnormalities
- Atypical glandular cells (AGC)
- Atypical glandular cells, favor neoplastic
- Endocervical adenocarcinoma in situ (AIS)
- Adenocarcinoma.

The Bethesda System classifies LSIL and HSIL as squamous cervical precursor lesions.

Although originally used as cytologic diagnoses, the squamous intraepithelial lesion terminology can be used for histologic classification as well. Generally, CIN grades 1 to 3 are used to classify histologic diagnoses. More than two-thirds of smears showing cellular atypia do not meet diagnostic criteria for dysplasia and are classified as ASC-US or as ASC-H. Studies have shown that up to 90% of LSIL will spontaneously regress.[21] [22] However, some estimates suggest LSIL may carry up to a 33% risk of harboring a higher-grade lesion (CIN 2 or 3). HSIL carries a risk of >70%.[23] [24]

HPV testing

HPV infection has been implicated in over 90% of high-grade cervical dysplasia and nearly 100% of cervical cancers.[25] [26] Failure to clear HPV is likely to be a primary factor in the subsequent development of dysplasia. Oncogenic or high-risk subtypes of HPV are 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68.[27] Investigations have shown that HPV-16 and HPV-18 are associated with significantly more high-grade (at least CIN 2) lesions than other high-risk subtypes.[28]

In the US, the Food and Drug Administration (FDA) has approved DNA-based testing for high-risk HPV (hrHPV) types as an option for primary cervical cancer screening in women ages 25 years and older. Because of the high prevalence of HPV infection in women younger than 30 years, and the fact that many infections are fleeting, HPV testing is not routinely recommended in average-risk women younger than 30 years.[4] HPV testing is more useful in older age groups because these women are more likely to have established infection. The US Preventive Services Task Force recommends screening of average-risk women with hrHPV testing alone or in combination with cytology (co-testing) every 5 years from the ages 30 years.[1] [5]

Management (return to routine screening, more or less frequent surveillance, colposcopy, or treatment) is determined by clearly defined risk thresholds for CIN 3+ lesions derived from the results of HPV testing, alone or in combination with cytology, and the patient's past history.[2] [19]

Primary hrHPV testing

The US is in a transition period from cytology testing to primary hrHPV testing. The American Cancer Society (ACS) has updated its guidance to recommend women ages 25-65 years should be screened with hrHPV testing alone every 5 years as an alternative to cytology-based screening; if hrHPV testing is unavailable, however, the ACS recommends individuals ages 25-65 years should be screened with co-testing (hrHPV testing in combination with cytology) every 5 years or cytology alone every 3 years.[3]

HPV testing may have a role in the rural setting of developing countries. One Indian study reported a reduction in advanced cervical cancer in women ages more than 30 years compared with those screened with cytology.[29]

HPV self-sampling has the potential to improve access to, and compliance with, cervical cancer screening. The World Health Organization recommends it as an additional approach for individuals ages 30-60 years, but the approach is still investigational in the US.[30]

Co-testing (hrHPV testing and cytology)

In co-testing, cytology and hrHPV testing are administered together from the same sample of cells taken from the cervix.

Reflex testing

Cytology samples that report either ASC-US or LSIL results should be tested for the presence of HPV types associated with CIN (reflex HPV testing or HPV triage). Multiple studies, including the ASCUS-LSIL Triage Study (ALTS), have demonstrated that HPV testing after ASC-US test results are obtained can improve detection of higher-grade lesions.[23] [28] [31] [32] At 10-year follow-up, one study reported finding CIN 3 in 21% and cervical cancer in 18% of women who were initially cytology-negative but HPV-16- or HPV-18-positive. High-grade lesions (CIN 3 and cervical cancer) were identified in only 1.5% of all other cytology-negative, hrHPV-positive women at 10-year follow-up.[28] Positive primary hrHPV tests should have an additional cytology review on the same sample (reflex cytology testing), to classify epithelial abnormalities and inform management.[2] [19]

HPV vaccination

The combination of HPV vaccination and cervical screening provides the greatest protection against developing cancers caused by HPV, including cervical cancer. Following the introduction of the vaccination programme in the US, there has been a reduction in HPV prevalence and cervical precancer incidence.[33] [34] [35][36] A reduction in HPV-16 and HPV-18-positive CIN 2+ lesions has also been observed in unvaccinated women, which suggests herd protection in these women.[37]

There are three HPV vaccines licensed to prevent HPV infection: bivalent (HPV-16 and HPV-18); quadrivalent (HPV-6, HPV-11, HPV-16, and HPV-18); and 9-valent (HPV-6, HPV-11, HPV-16, HPV-18, HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58). In the US, only the 9-valent vaccine is available and approved for use in females and males ages 9-45 years.[38] The quadrivalent vaccine is available in some other countries. A single dose of HPV vaccine is effective in preventing cervical infection with HPV-16 and HPV-18, the two types of HPV that cause 70% of cervical cancers.[39] [40] [41] Different HPV vaccine types have comparable efficacies and immunogenicity data suggests high levels of persistent antibody titers 10 years after immunization.[42] [43] [44]

The US Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP) recommends HPV vaccination for all children and adults ages 9-26 years.[45] [46] [47] The recommended age for vaccination is 11 to 12 years; however, the vaccination series can begin at age 9 years. The ACIP recommendation for HPV vaccination is for a two or three dose series, depending on age at initial vaccination or condition.[45] [46] [47] Shared clinical decision-making regarding HPV catch-up vaccination is recommended in people ages 27-45 years who were not adequately vaccinated when younger.[46] [47]

The vaccines are considered to be very safe, with typical side effects including pain, itching, irritation, erythema, and low-grade fever.[48]

Women who have received the HPV vaccine should be screened following the general population cervical screening recommendations.[5]

Images

Colposcopic view of cervical carcinoma
Histology of cervical intraepithelial neoplasia

Citations

Key Articles

Fontham ETH, Wolf AMD, Church TR, et al. Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society. CA Cancer J Clin. 2020 Sep;70(5):321-46.[Abstract][Full Text]
Sawaya GF, Kulasingam S, Denberg TD, et al. Cervical cancer screening in average-risk women: best practice advice from the clinical guidelines committee of the American College of Physicians. Ann Intern Med. 2015;162:851-9.[Abstract][Full Text]
US Preventive Services Task Force., Curry SJ, Krist AH, et al. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018 Aug 21;320(7):674-86.[Abstract][Full Text]

Other Online Resources

WHO: cervical cancer
Cancer Research UK: cervical cancer mortality statistics
National Cancer Institute: cervical cancer screening
ACOG: cervical cancer screening FAQs

Referenced Articles

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3. Fontham ETH, Wolf AMD, Church TR, et al. Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society. CA Cancer J Clin. 2020 Sep;70(5):321-46.[Abstract][Full Text]
4. Sawaya GF, Kulasingam S, Denberg TD, et al. Cervical cancer screening in average-risk women: best practice advice from the clinical guidelines committee of the American College of Physicians. Ann Intern Med. 2015;162:851-9.[Abstract][Full Text]
5. US Preventive Services Task Force., Curry SJ, Krist AH, et al. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018 Aug 21;320(7):674-86.[Abstract][Full Text]
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26. Muñoz N, Bosch FX, de Sanjosé S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003 Feb 6;348(6):518-27.[Abstract][Full Text]
27. Cuzick J, Beverly E, Ho L, et al. HPV testing in primary screening of older women. Br J Cancer. 1999;81:554-558.[Abstract][Full Text]
28. Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005;97:1072-9.[Abstract][Full Text]
29. Sankaranarayanan R, Nene BM, Shastri SS, et al. HPV screening for cervical cancer in rural India. N Engl J Med. 2009;360:1385-94.[Abstract][Full Text]
30. World Health Organization. self-care interventions for health and well-being. 2022 [internet publication].[Full Text]
31. ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol. 2003;188:1383-1392.[Abstract]
32. ASCUS-LSIL Triage Study (ALTS) Group. A randomized trial on the management of low-grade squamous intraepithelial lesion cytology interpretations. Am J Obstet Gynecol. 2003;188:1393-1400.[Abstract]
33. Markowitz LE, Hariri S, Lin C, et al. Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003-2010. J Infect Dis. 2013 Aug 1;208(3):385-93.[Abstract][Full Text]
34. Hariri S, Johnson ML, Bennett NM, et al. Population-based trends in high-grade cervical lesions in the early human papillomavirus vaccine era in the United States. Cancer. 2015 Aug 15;121(16):2775-81.[Abstract][Full Text]
35. Benard VB, Castle PE, Jenison SA, et al. Population-Based Incidence Rates of Cervical Intraepithelial Neoplasia in the Human Papillomavirus Vaccine Era. JAMA Oncol. 2017 Jun 1;3(6):833-837.[Abstract][Full Text]
36. Gargano JW, Park IU, Griffin MR, et al. Trends in high-grade cervical lesions and cervical cancer screening in 5 states, 2008-2015. Clin Infect Dis. 2019 Apr 8;68(8):1282-91.[Abstract][Full Text]
37. McClung NM, Gargano JW, Bennett NM, et al. Trends in human papillomavirus vaccine types 16 and 18 in cervical precancers, 2008-2014. Cancer Epidemiol Biomarkers Prev. 2019 Mar;28(3):602-9.[Abstract][Full Text]
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39. Barnabas RV, Brown ER, Onono M, et al. Single-dose HPV vaccination efficacy among adolescent girls and young women in Kenya (the KEN SHE Study): study protocol for a randomized controlled trial. Trials. 2021 Sep 27;22(1):661.[Abstract][Full Text]
40. Herrero R, Wacholder S, Rodríguez AC, et al. Prevention of persistent human papillomavirus infection by an HPV16/18 vaccine: a community-based randomized clinical trial in Guanacaste, Costa Rica. Cancer Discov. 2011 Oct;1(5):408-19.[Abstract][Full Text]
41. Basu P, Malvi SG, Joshi S, et al. Vaccine efficacy against persistent human papillomavirus (HPV) 16/18 infection at 10 years after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre, prospective, cohort study. Lancet Oncol. 2021 Nov;22(11):1518-29.[Abstract][Full Text]
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46. Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices adult immunization schedule by age: recommendations for ages 19 years or older - United States, 2024. Nov 2023 [internet publication].[Full Text]
47. American College of Obstetricians and Gynecologists. Committee opinion no.809: human papillomavirus vaccination. Aug 2020 [internet publication].[Full Text]
48. Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep 2019;68:698-702.[Full Text]
49. Szurkus DC, Harrison TA. Loop excision for high-grade squamous intraepithelial lesion on cytology: correlation with colposcopic and histologic findings. Am J Obstet Gynecol. 2003;188:1180-1182.[Abstract]
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