Cervical Dysplasia

Cervical Dysplasia 

Cervical dysplasia refers to the atypical development of intraepithelial cells of the cervix that do not cross the basement membrane and is a precursor to cervical cancer.

It is caused by persistent infection with human papillomavirus (HPV), most commonly types 16 and 18. Characteristics include increased cellularity, nuclear abnormalities, and increased nuclear/cytoplasmic ratio.

A progressive loss of squamous differentiation begins adjacent to the basement membrane and progresses to the most advanced stage (severe dysplasia), which encompasses the entire thickness of the squamous epithelial layer.

The revised 2001 Bethesda System terminology was used in a National Institutes of Health consensus conference, sponsored by the American Society for Colposcopy and Cervical Pathology (ASCCP) and its partner professional organizations in 2006.

The conference updated therapeutic options for women based on studies such as the 

A SC-US (atypical squamous cells of undetermined significance)/ L SIL (low-grade squamous intraepithelial lesions) Triage S tudy (ALTS) that appeared after revision of the Bethesda classification. 

Here is the comparison of grading systems for cervical squamous dysplasia.

Comparison of grading systems. CIN, Cervical intraepitheial neoplasia; HPV, human papilloma virus; WHO, World Health Organization.

From Young B et al: Female reproductive system. In Wheater’s basic pathology, Philadelphia, 2011, Elsevier, pp. 216-315.

In 2012, the American Cancer Society (ACS), ASCCP, and American Society for Clinical Pathology (ASCP) published a new set of recommendations for lifetime assessment and early diagnosis of cervical dysplasia and cancer. The recommendations attempted to reduce the number of lifetime screenings, thereby reducing the possible morbidity associated with excess testing and also optimizing the co-evaluation with Pap smear and HPV testing. In 2019, the ASCCP published updated consensus guidelines for the management of cervical cancer screening abnormalities, which shifted the focus of management recommendations from test results–based algorithms to risk-based guidelines.

Screening Protocol (2012 recommendations)

• •Women younger than 21 yr of age should not have cervical cancer screening unless HIV positive. If HIV positive, screening should start within 1 yr of coitarche.
• •Women 21 to 29 yr of age should have testing every 3 yr with cytology only. With negative cytology or HPV-negative ASC-US, patients can repeat every 3 yr. For HPV-positive ASC-US or cytology with LG-SIL or greater, follow-up is as per the 2006 guidelines, typically with a colposcopy as the initial step with follow-up steps depending on the findings.
• •Women between the ages of 30 and 65 yr should have co-testing every 5 yr with both Pap cytology and HPV testing. Alternatively, it is also acceptable to perform cytology alone; however, the testing interval should be every 3 yr. With negative cytology or HPV-negative ASC-US, patients can repeat with co-testing every 5 yr. For HPV-positive ASC-US or cytology with LG-SIL, follow-up is as per the 2006 guidelines, as previously documented. For patients with positive HPV but negative cytology, the patient can repeat testing 12 mo later with co-testing. Patients can also specifically test for HPV 16 or HPV 16/18 genotypes and, if positive, should be referred for colposcopy. Patients with positive HPV but negative 16 and/or 18 should be retested in 12 mo with co-testing.
• •Women older than the age of 65 and those with a history of hysterectomy (including removal of cervix) should no longer be tested unless they had previous diagnosis of cervical intraepithelial neoplasia (CIN) 2 or greater; these women should be tested for at least 20 yr.
• •Women who have been vaccinated for HPV should still use age-specific recommendations for screening.

Bethesda 2001 Updated Classification

The Bethesda 2001 System was the result of a year-long iterative process held to update the original 1991 system and to broaden participation in the consensus process, clarify reporting of abnormalities, and incorporate data that had been collected since the initial system was created.

The reporting system includes the following areas:

• •Specimen adequacy: The system defines the specimen as either satisfactory for evaluation or unsatisfactory, and then specifies the reason for inadequacy if necessary.
• •General categorization (optional): This serves to triage the specimen into normal finding (negative for intraepithelial lesion or malignancy) or identifies it as an “epithelial abnormality.” The descriptions are meant to be mutually exclusive.
• •Interpretation/result: Makes a distinction between “interpretation” and “diagnosis” of the specimen so that the interpretation may be incorporated into the overall clinical context for the particular patient being evaluated.
• •Negative for intraepithelial lesion or malignancy: In this screening test, no intraepithelial lesion or malignancy is identified. Nonneoplastic findings such as organisms or reactive cellular findings may be specified but are still considered to be a negative result.
• •Epithelial cell abnormalities:
  • 1.Squamous cell:
    • a.Atypical squamous cell (ASC) of undetermined significance (ASC-US) emphasizing the unusual but still possible association with underlying CIN II/III and extremely rare possibility of squamous cell carcinoma.
    • b.ASC cannot exclude high-grade squamous intraepithelial lesion (ASC-H), suggesting a risk for CIN II/III that is intermediate between ASC-US and HSIL.
    • c.Low-grade squamous intraepithelial lesion (LSIL) suggests a transient viral infection with a greater likelihood for regression, more likely to encompass HPV infection and CIN I histologically.
    • d.High-grade squamous intraepithelial lesion (HSIL) suggestive of a more persistent viral infection and with a greater risk for progressive disease, more likely to encompass CIN II/III and carcinoma in situ (CIS) histologically.
    • e.Squamous cell carcinoma.
  • 2.Glandular cell:
    • a.Atypical glandular cells (should specify endocervical, endometrial, or not otherwise specified).
    • b.Atypical glandular cell, favor neoplasia (should specify endocervical or not otherwise specified).
    • c.Endocervical adenocarcinoma in situ (AIS).
    • d.Adenocarcinoma.
  • 3.Other: Because menopausal status is sometimes uncertain, age >40 yr was chosen to discriminate women who might warrant further evaluation with endometrial sampling in those with findings of endometrial cells on cytology.

Updated 2019 ASCCP Risk-Based Management Consensus Guidelines

• •Recommendations of colposcopy, treatment, or surveillance will be based on a patient’s risk of CIN 3 or greater as determined by a combination of current results and past history.
• •Repeat HPV testing or co-testing at 1 yr is recommended for patients with minor screening abnormalities indicating HPV infection with low risk of underlying CIN 3+ (e.g., HPV-positive, low-grade cytologic abnormalities after a documented negative screening HPV test or co-test).
• •Expedited treatment was an option for patients with HSIL cytology in the 2012 guidelines; this guidance is now better defined in the 2019 recommendations.
  • 1.For nonpregnant patients 25 yr or older, expedited treatment, defined as treatment without preceding colposcopic biopsy demonstrating CIN 2+, is preferred when the immediate risk of CIN 3+ is ≥60%, and is acceptable for those with risks between 25% and 60%.
  • 2.Expedited treatment is preferred for nonpregnant patients 25 yr or older with high-grade squamous intraepithelial lesion (HSIL) cytology and concurrent positive testing for HPV genotype 16 (HPV 16) (i.e., HPV 16–positive HSIL cytology) and never or rarely screened patients with HPV-positive HSIL cytology regardless of HPV genotype.
  • 3.Shared decision-making should be used when considering expedited treatment, especially for patients with concerns about the potential impact of treatment on pregnancy outcomes.
• •Excisional treatment is preferred to ablative treatment for histologic HSIL (CIN 2 or CIN 3) in the U.S. Excision is recommended for adenocarcinoma in situ (AIS).
• •For CIN1, observation is preferred to treatment.
• •Histopathology reports based on Lower Anogenital Squamous Terminology (LAST)/World Health Organization (WHO) recommendations for reporting histologic HSIL should include CIN 2 or CIN 3 qualifiers, i.e., HSIL (CIN 2) and HSIL (CIN 3).
• •All positive primary HPV screening tests, regardless of genotype, should have additional reflex triage testing performed from the same laboratory specimen (e.g., reflex cytology).
  • 1.Additional testing from the same laboratory specimen is recommended because the findings may inform colposcopy practice. For example, those HPV-16 positive HSIL cytology qualify for expedited treatment.
  • 2.HPV 16 or 18 infections have the highest risk for CIN 3 and occult cancer, so additional evaluation (e.g., colposcopy with biopsy) is necessary even when cytology results are negative.
  • 3.If HPV 16 or 18 testing is positive, and additional laboratory testing of the same sample is not feasible, the patient should proceed directly to colposcopy.
• •Continued surveillance with HPV testing or co-testing at 3-yr intervals for at least 25 yr is recommended after treatment and initial post-treatment management of histologic HSIL, CIN 2, CIN 3, or AIS.
• •Continued surveillance at 3-yr intervals beyond 25 yr is acceptable for as long as the patient’s life expectancy and ability to be screened are not significantly compromised by serious health issues.
  • 1.The 2012 guidelines recommended return to 5-yr screening intervals and did not specify when screening should cease. New evidence indicates that risk remains elevated for at least 25 yr, with no evidence that treated patients ever return to risk levels compatible with 5-yr intervals.
• •Surveillance with cytology alone is acceptable only if testing with HPV or cotesting is not feasible.
• •Cytology is less sensitive than HPV testing for detection of precancer and is therefore recommended more often. Cytology is recommended at 6-mo intervals when HPV testing or cotesting is recommended annually. Cytology is recommended annually when 3-yr intervals are recommended for HPV or cotesting.
• •Human papillomavirus assays that are Food and Drug Administration (FDA)–approved for screening should be used for management according to their regulatory approval in the U.S. (note: All HPV testing in this document refers to testing for high-risk HPV types only.)
  • 1.For all management indications, HPV mRNA and HPV DNA tests without FDA approval for primary screening alone should only be used as a co-test with cytology, unless sufficient, rigorous data are available to support use of these particular tests in management.

Key Points

• •The cytologic distinctions of low grade (LSIL) and high grade (HSIL) do not necessarily equate to the histologic classifications CIN I and CIN II/III.
• •The 2006 conference noted that one cytologic abnormality can have different histologic risk in different women and highlights “special populations” such as adolescent and young women, and those women who are pregnant. In young women, spontaneous HPV clearance rates are exceptionally high. The testing recommendations essentially removed the possibility of testing women younger than 21 yr of age.
• •DNA testing for high-risk HPV types is incorporated into the evaluation and treatment algorithms for women with cytologic cervical abnormalities.

Epidemiology & Demographics

Predominant Age

• •Dysplasia: Peak age, 26 yr (3600 cases/100,000 persons)
• •CIS: Peak age, 32 yr (1100 cases/100,000 persons)
• •Invasive cancer: Peak age <60 yr (800 cases/100,000 persons)

Peak Incidence

• •Age 35
• •Abnormal Pap smear rate revealing dysplasia approximates 2% to 5% depending on population risk factors and false-negative rate variance
• •False-negative rate approaching 40%
• •Average age-adjusted incidence of severe dysplasia is 35 cases/100,000 persons
• •Approximately half of the cases of new cervical cancer had never been screened, and another 10% had not been screened in more than 5 yr. Given that many of these women come from underserved or underresourced communities, reduction of the morbidity and mortality from cervical cancer would necessitate addressing these health disparities.

Physical Findings & Clinical Presentation of Cervical Dysplasia 

• •Cervical lesions associated with dysplasia often are not visible to the naked eye;therefore, physical findings are best viewed by colposcopy of a 3% acetic acid-prepared or Lugol solution–prepared cervix
• •Patients evaluated by colposcopy are identified by abnormal cervical cytology screening from Pap smear screening
• •Colposcopic findings:
  • 1.Leukoplakia (white lesion seen by the unaided eye that may represent condyloma, dysplasia, or cancer)
  • 2.Acetowhite epithelium with or without associated punctation, mosaicism, abnormal vessels
  • 3.Abnormal transformation zone (abnormal iodine uptake, “cuffed” gland openings)
• •Studies have looked at the benefit of taking random biopsies at time of colposcopy and have shown that there may be increased detection of CIN II or greater if biopsies are taken at random rather than only directed toward abnormal appearing lesions

What causes Cervical Dysplasia?

• •Strongly associated and initiated by oncogenic HPV infection (high-risk HPV types are 16, 18, 31, 33, 35, 45, 51, 52, 56, and 58; low-risk HPV types are 6, 11, 42, 43, and 44)
• •Risk factors:
  • 1.HPV
  • 2.Any heterosexual coitus
  • 3.Coitus during puberty (transformation-zone metaplasia peak)
  • 4.Diethylstilbestrol exposure
  • 5.Multiple sexual partners
  • 6.Lack of prior Pap smear screening
  • 7.History of STD
  • 8.Other genital tract neoplasia
  • 9.HIV
  • 10.Tuberculosis
  • 11.Substance abuse
  • 12.“High-risk” male partner (HPV)
  • 13.Low socioeconomic status
  • 14.Early first pregnancy
  • 15.Tobacco use

Differential Diagnosis

• •Metaplasia
• •Hyperkeratosis
• •Condyloma
• •Microinvasive carcinoma
• •Glandular epithelial abnormalities
• •Vulvar intraepithelial neoplasm
• •Vaginal intraepithelial neoplasm
• •Metastatic tumor involvement of the cervix

How is Cervical Dysplasia diagnosed?

• •Periodic history and physical examination (including cytologic screening) depending on age, risk factors, and history of preinvasive cervical lesions
• •Consider screening for sexually transmitted disease (gonorrhea, Chlamydia, herpes, HIV, HPV)
• •Abnormal cytology (HSIL/LSIL, initial ASC/ASC-US/ASC-H in high-risk patients, recurrent in low-risk/postmenopausal patients) and grossly evident suspicious lesions should be referred for colposcopy and possible directed biopsy/endocervical curettage (ECC). Examination should include cervix, vagina, vulva, and anus.
• •For glandular cell abnormalities (AGCs): Refer for colposcopy and possible directed biopsy/ECC, and consider endometrial sampling
• •In pregnancy: Abnormal cytology followed by colposcopy in the first trimester and at 28 to 32 wk; only high-grade lesions suspicious for carcinoma biopsied; ECC is contraindicated

Laboratory Tests

• •Gonorrhea, chlamydia nucleic-acid amplification tests to rule out STD
• •Pap cytology screening (requires appropriate sampling, preparation, cytologist interpretation, and reporting)
• •HPV DNA typing
• •Colposcopy, directed cervical biopsy, and ECC
• •As compared with Pap testing, HPV testing has greater sensitivity for the detection of intraepithelial neoplasia

Imaging Studies

• •Cervicography
• •Computer-enhanced Pap cytology screening (e.g., PAPNET)

Management

Refer to the literature for a more comprehensive approach. The following treatment paradigms in the below table give a general outline for care.

Summary of Recommendations

Modified from Saslow D et al: American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer, J Low Gen Tract Dis 16(3):175-204, 2012.

Population	Recommended Screening Method	Management of Screen Results	Comments
<21 yr	No screening
21-29 yr	Cytology alone every 3 yr	HPV-positive ASC-US or cytology of LSIL or more severe: Refer to ASCCP Guidelines Cytology Negative or HPV-Negative ASC-US; Rescreen with cytology in 3 yr
30-65 yr	HPV and cytology “co-testing” every 5 yr (preferred)	HPV-positive ASC-US or cytology of LSIL or more severe: Refer to ASCCP guidelines	Screening by HPV testing alone is not recommended for most clinical settings.
		HPV positive, cytology negative: Option 1: Y 12-mo follow-up with co-testing
		Option 2: Y test for HPV16 or HPV16/18 genotypes. If HPV16 or HPV16/18 positive, refer to colposcopy. If HPV16 or HPV16/18 negative, 12-mo follow-up with co-testing
		Co-test negative or HPV-negative ASC-US: Rescreen with co-testing in 5 yr
	Cytology alone every 3 yr (acceptable)	HPV-positive ASC-US or cytology of LSIL or more severe: Refer to ASCCP guidelines
		Cytology negative or HPV-negative ASC-US: Rescreen with cytology in 3 yr
>65 yr	No screening following adequate negative prior screening		Women with a history of CIN2 or a more severe diagnosis should continue routine screening for at least 20 yr
After hysterectomy	No screening		Applies to women without a cervix and without a history of CIN2 or a more severe diagnosis in the past 20 yr or cervical cancer ever.
HPV vaccinated	Follow age-specific recommendations (same as unvaccinated women)

ASCCP, American Society for Colposcopy and Cervical Pathology; ASC-US, atypical squamous cells of undetermined significance; CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus; LSIL, low-grade squamous intraepithelial lesions.

Disposition

• •Because of the large number of women in high-risk groups, the prevalence of HPV, and the high false-negative Pap smear rate, routine Pap smear screening should be strongly encouraged for all women, especially those with a history of cervical dysplasia. Primary HPV testing with reflex cytology and using risk-based guidelines reduces the incidence of CIN II or III, or cancer detected by subsequent screening.
• •Success rates for treatment approach 80% to 90%.
• •Detection of persistence or recurrence requires careful follow-up.
• •Cervical treatment can increase risk for poor obstetric outcomes (cervical incompetence with subsequent miscarriage or preterm birth), which requires careful consideration and discretion for use of loop electrosurgical excision procedure and cone biopsy in women desiring future childbearing.
• •Appropriate counseling and informed consent are needed when considering any form of management of cervical dysplasia.

Referral

• •Patients with abnormal Pap cytology should be referred to a provider, preferably a trained obstetrician/gynecologist, who can appropriately treat the patient in an age-specific manner and also perform a colposcopy or excisional procedure if indicated as part of the new recommendations. Given the morbidity associated with both under evaluation and treatment, as well as reacting excessively to cytologic findings, a provider who is intimately familiar with ASCCP guidelines should be sought.
• •If treatment is required, patient should be referred to a gynecologist or gynecologic oncologist skilled in the diagnosis and treatment of preinvasive cervical disease.

Comments

• •Testing for human papillomavirus by Hybrid capture 2 DNA test will identify 91% of the small proportion of women with post-treatment residual or recurrent disease, but 30% of all women who are tested will test positive and need colposcopy.
• •HPV vaccination is recommended for males and females from ages 9 to 26. As of June 2019, ACIP recommends HPV vaccination based on shared clinical decision-making for individuals ages 27 through 45 yr who are not adequately vaccinated.

Seek Additional Information

• Curry S.J., et al.: Screening for cervical cancer. JAMA 2018; 320 (7): pp. 674.
• Feldman S.: Making sense of the new cervical cancer screening guidelines. N Engl J Med 2011; 365 (23): pp. 2148.
• Kizer N., Peipert J.F.: Cervical cancer screening: primum non nocere. Ann Intern Med 2012; 156: pp. 896-897.
• Perkins R.B., et al.: 2019 ASCCP Risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2020; 24 (2): pp. 102-131.
• Saslow D., et al.: American Cancer Society, American Society For Colposcopy and Lower Cervical Pathology, and American Society For Clinical Pathology screening guidelines for the prevention and detection of early cervical cancer. J Low Genit Tract Dis 2012; 16 (3): pp. 1-29.
• Vesco U., et al.: Risk factors and other epidemiologic considerations for cervical cancer screening: a narrative review for the U.S. Preventive Services Task Force. Ann Intern Med 2011; 155: pp. 698-705.