Cervical Dysplasia

• Anthony Sciscione, D.O.

 Basic Information

Definition

Cervical dysplasia refers to atypical development of immature squamous epithelium that does not penetrate the basement epithelial membrane. Characteristics include increased cellularity, nuclear abnormalities, and increased nuclear/cytoplasmic ratio. A progressive loss of squamous differentiation exists beginning adjacent to the basement membrane and progressing to the most advanced stage (severe dysplasia), which encompasses the complete squamous epithelial layer thickness. 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 ASC-US (atypical squamous cells of undetermined significance)/LSIL (low-grade squamous intraepithelial lesions) Triage Study (ALTS) that appeared after revision of the Bethesda classification. Fig. 1 provides a comparison of grading systems for cervical squamous dysplasia.

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 assessments, thereby reducing the possible morbidity associated with excess testing and also optimizing the co-evaluation with Pap smear and HPV testing. In brief, women younger than 21 yr of age should not have any screening. Women 21-29 yr of age should have testing every 3 yr with only cytology. With negative cytology or HPV-negative ASC-US, patients can repeat every 3 yr. For HPV-positive ASC-US or cytology with LG-SIL, follow-up is as per the 2006 guidelines (essentially a colposcopic examination 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, but then 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 months 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 months with co-testing.

Women older than the age of 65 yr 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 more severe; 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:

1. •

   Specimen adequacy: The system defines the specimen as either satisfactory for evaluation or unsatisfactory and then specifies the reason for inadequacy if necessary.

2. •

   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.

3. •

   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.

4. •

   Negative for intraepithelial lesion or malignancy: In this screening test, no intraepithelial lesion or malignancy is identified. Non-neoplastic findings such as organisms or reactive cellular findings may be specified but are still considered to be a negative result.

5. •

   Epithelial cell abnormalities:

   1. 1.

      Squamous cell:

      1. ▪

         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

      2. ▪

         ASC cannot exclude high-grade squamous intraepithelial lesion (HSIL) (ASC-H), suggesting a risk for CIN II/III that is intermediate between ASC-US and HSIL

      3. ▪

         Low-grade squamous intraepithelial lesion (LSIL) suggests a transient viral infection with a greater likelihood for regression, more likely to encompass human papillomavirus (HPV) infection and CIN I histologically

      4. ▪

         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

      5. ▪

         Squamous cell carcinoma

   2. 2.

      Glandular cell:

      1. ▪

         Atypical glandular cells (should specify endocervical, endometrial, or not otherwise specified)

      2. ▪

         Atypical glandular cell, favor neoplasia (should specify endocervical or not otherwise specified)

      3. ▪

         Endocervical adenocarcinoma in situ (AIS)

      4. ▪

         Adenocarcinoma

   3. 3.

      Other: Endometrial cells in a woman ≥>40 yr of age. Because menopausal status is sometimes uncertain, age was chosen to discriminate women who might, with the findings of endometrial cells on cytology, warrant further evaluation with endometrial sampling

Key Points

1. •

   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.

2. •

   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.

3. •

   DNA testing for high-risk HPV types is incorporated into the evaluation and treatment algorithms for women with cytologic cervical abnormalities.

Histologically, a two-tiered system is developed in this guideline that distinguishes between the lower-risk CIN I and higher-risk CIN II/III diagnoses.

ICD-10CM CODES
N87.9	Dysplasia of cervix uteri, unspecified
R87.610	Atypical squamous cells of undetermined significance on cytologic smear of cervix (ASC-US)
R87.611	Atypical squamous cells cannot exclude high grade squamous intraepithelial lesion on cytologic smear of cervix (ASC-H)
R87.612	Low grade squamous intraepithelial lesion on cytologic smear of cervix (LGSIL)
R87.613	High grade squamous intraepithelial lesion on cytologic smear of cervix (HGSIL)
R87.614	Cytologic evidence of malignancy on smear of cervix
R87.615	Unsatisfactory cytologic smear of cervix
R87.618	Other abnormal cytological findings on specimens from cervix uteri
R87.619	Unspecified abnormal cytological findings in specimens from cervix uteri
Z12.4	Encounter for screening for malignant neoplasm of cervix

Epidemiology & Demographics

Predominant Age

1. •

   Dysplasia: peak age, 26 yr (3600 cases/100,000 persons)

2. •

   CIS: peak age, 32 yr (1100 cases/100,000 persons)

3. •

   Invasive cancer: peak age <60 yr (800 cases/100,000 persons)

Peak Incidence

1. •

   Age 35 yr

2. •

   Abnormal Pap smear rate revealing dysplasia approximates 2% to 5% depending on population risk factors and false-negative rate variance

3. •

   False-negative rate approaching 40%

4. •

   Average age-adjusted incidence of severe dysplasia is 35 cases/100,000 persons

5. •

   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. Many of these women come from underserved or underresourced communities. The single biggest impact in reducing the morbidity and mortality from cervical cancer would come from appropriately addressing these health disparities.

Physical Findings & Clinical Presentation

1. •

   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 cervix.

2. •

   Patients evaluated by colposcopy are identified by abnormal cervical cytology screening from Pap smear screening.

3. •

   Colposcopic findings:

   1. 1.

      Leukoplakia (white lesion seen by the unaided eye that may represent condyloma, dysplasia, or cancer)

   2. 2.

      Acetowhite epithelium with or without associated punctation, mosaicism, abnormal vessels

   3. 3.

      Abnormal transformation zone (abnormal iodine uptake, “cuffed” gland openings)

Etiology

1. •

   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)

2. •

   Risk factors:

   1. 1.

      HPV

   2. 2.

      Any heterosexual coitus

   3. 3.

      Coitus during puberty (transformation-zone metaplasia peak)

   4. 4.

      Diethylstilbestrol exposure

   5. 5.

      Multiple sexual partners

   6. 6.

      Lack of prior Pap smear screening

   7. 7.

      History of STD

   8. 8.

      Other genital tract neoplasia

   9. 9.

      HIV

   10. 10.

       Tuberculosis

   11. 11.

       Substance abuse

   12. 12.

       “High-risk” male partner (HPV)

   13. 13.

       Low socioeconomic status

   14. 14.

       Early first pregnancy

   15. 15.

       Tobacco use

        

    

Diagnosis

Differential Diagnosis

1. •

   Metaplasia

2. •

   Hyperkeratosis

3. •

   Condyloma

4. •

   Microinvasive carcinoma

5. •

   Glandular epithelial abnormalities

6. •

   Vulvar intraepithelial neoplasm

7. •

   Vaginal intraepithelial neoplasm

8. •

   Metastatic tumor involvement of the cervix

Workup

1. •

   Periodic history and physical examination (including cytologic screening) depending on age, risk factors, and history of preinvasive cervical lesions

2. •

   Consider screening for sexually transmitted disease (gonorrhea, Chlamydia, herpes, HIV, HPV)

3. •

   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; refer for colposcopy and possible directed biopsy/endocervical curettage (ECC; examination should include cervix, vagina, vulva, and anus)

4. •

   For glandular cell abnormalities (AGCs): refer for colposcopy and possible directed biopsy/ECC, and consider endometrial sampling

5. •

   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

1. •

   Gonorrhea, chlamydia NAATs to rule out STD

2. •

   Pap cytology screening (requires appropriate sampling, preparation, cytologist interpretation, and reporting)

3. •

   Colposcopy and directed biopsy, ECC for indications (see “Workup”)

4. •

   HPV DNA typing if identified abnormal cytology

5. •

   As compared with Pap testing, HPV testing has greater sensitivity for the detection of intraepithelial neoplasia

Imaging Studies

1. •

   Cervicography

2. •

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

Management

Refer to the literature for a more comprehensive approach. The following treatment paradigms in Table 1 give a general outline for care.

Disposition

1. •

   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. The addition of an HPV test to the Pap test reduces the incidence of CIN II or III, or cancer detected by subsequent screening.

2. •

   Success rates for treatment approach 80% to 90%.

3. •

   Detection of persistence of recurrence requires careful follow-up.

4. •

   Cervical treatment possibly results in infertility (cervical stenosis or incompetence), which requires careful consideration and discretion for use of LEEP and cone biopsy.

5. •

   Appropriate counseling and informed consent are needed when considering any form of management of cervical dysplasia.

Referral

1. •

   Patients with abnormal Pap cytology should be referred to a provider, likely a trained obstetrician/gynecologist, who can appropriately treat the patient in an age-specific manner and also perform a colposcopy if indicated as part of the new recommendations. Given the morbidity associated with both underevaluating and treating as well as reacting excessively to cytologic findings, a provider who is intimately familiar with ASCCP guidelines should be sought.

2. •

   If treatment is required, patient should be referred to a gynecologist or gynecologic oncologist skilled in the diagnosis and treatment of preinvasive cervical disease.

Pearls & Considerations

Comments

1. •

   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.

2. •

   HPV vaccination is recommended for males and females from ages 9 to 26.

Suggested Readings

• S. Feldman: Making sense of the new cervical cancer screening guidelines. N Engl J Med. 365 (23):2148 2011

• N. Kizer, J.F. Peipert: Cervical cancer screening: primum non nocere. Ann Intern Med. 156:896–897 2012 22711084

• D. Saslow, 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. 16 (3):1–29 2012 22020407

• U. Vesco, 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. 155:698–705 2011 22006929

Related Content

1. Cervical Dysplasia (Patient Information)

2. Pap Smear Abnormalities (Patient Information)

3. Cervical Cancer (Related Key Topic)

4. Cervical Polyps (Related Key Topic)