Based on the 2001 Bethesda System for reporting cervical cytology results, Pap smear results are categorized as negative for intraepithelial lesion or malignancy (NILM), epithelial cell abnormalities, or other. Epithelial cell abnormalities include low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), atypical glandular cells (AGC), and atypical squamous cells (ASC).1 LSIL and HSIL are precancerous lesions that exist on a spectrum. The management of LSIL, HSIL, and ASC pap smears is based on the risk of developing high-grade cervical intraepithelial neoplasia (CIN-3) in five years. Because the human papillomavirus (HPV) is one of the main drivers of persistent cervical dysplasia, the presence or absence of HPV will affect this risk.
Low-grade dysplasia (LSIL)
Over 80% of people with LSIL also have HPV, although generally, the infection is transient.1–3 Patients aged 30 to 64 with LSIL and HPV positive test have a 6.9% risk of developing CIN3 within 5 years.4,5 For patients aged 30 to 64 with LSIL and HPV negative test, the 5-year risk of developing CIN3 is 2%.4 For patients aged 21 to 24, HPV testing is not recommended due to high rates of transient infections. In this group who have LSIL only, the 5-year risk of developing CIN3 is 2.4%.6
High-grade dysplasia (HSIL)
HSIL is associated with persistent HPV infection and carries a higher risk for progression to cancer.1 In one study of patients with HSIL pap smear, the risk of CIN3 was 29%, and the risk of cervical cancer was 3%.7 The risk of high-grade dysplasia is increased if HPV is present: for patients with HSIL/HPV positive Pap smear, the risk of underlying CIN3 is 49% compared to 25% for HSIL/HPV negative. The five-year risk is similarly affected: 53% for HSIL/HPV positive versus 27% for HSIL/HPV negative.4,5
Atypical Squamous Cells of Undetermined Significance (ASCUS)
ASCUS is defined as cellular abnormalities that are beyond those of reactive changes but do not meet the criteria for the diagnosis of squamous intraepithelial lesion.1 In this setting, HPV testing is useful to stratify patients who may be at higher risk of an underlying precancerous lesion. Different strains of HPV confer different risks: patients who are positive for HPV types 16 or 18 have a higher risk of having underlying high-risk dysplasia.8,9 The 5-year risk of developing CIN3+ in people with a cervix with ASCUS-HPV positive results is 7.3%, and the immediate risk of CIN3+ is 4.4%.4 Thus, patients in this population are recommended for immediate colposcopy.5 For patients with ASCUS-HPV negative results, the 5-year risk of CIN3+ is lower so early repeat co-testing in 3 years is recommended.4,5
Atypical Squamous Cells – Cannot exclude HSIL (ASC-H)
ASC-H includes cytology that does not meet the criteria for squamous intraepithelial lesion but demonstrates more characteristics concerning this diagnosis.1 Patients with ASC-H have a considerably higher risk of subsequently developing CIN2+ lesions compared to patients with ASCUS or LSIL. For patients with an ASC-H/HPV positive pap smear, the 5-year risk of CIN3 is 33%, and the immediate risk of CIN3 is 26%. For those with an ASC-H/HPV negative pap smear, these numbers are 3.8% and 3.4%, respectively.4,5
Atypical Glandular Cells (AGC)
Pap smear demonstrating AGC is concerning for underlying malignancy of either the inner cervix (endocervix) or uterine endometrium.10,11 In one study, 15.3% of patients with AGC on Pap smear had an underlying precancerous or cancerous lesion. Of these, 8.3% were cervical lesions and 6.3% were endometrial lesions.11 It is therefore recommended that, regardless of age or HPV status, all patients with this result undergo colposcopy with endocervical sampling. Further, given that the rates of underlying endometrial carcinoma in patients with AGC increase with age, endometrial sampling should also be done for patients who are older than 35.5,10
Negative cytology, HPV positive
When patients have a pap smear with negative cytology but HPV positive, further genotyping is recommended. If high-risk HPV types 16 or 18 are found, then patients require colposcopy. Otherwise, a repeat pap smear and HPV test in 1 year is recommended.12
References
- Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA. 2002;287(16):2114-2119. doi:10.1001/jama.287.16.2114
- ASCUS-LSIL Traige Study (ALTS) Group. A randomized trial on the management of low-grade squamous intraepithelial lesion cytology interpretations. Am J Obstet Gynecol. 2003;188(6):1393-1400. doi:10.1067/mob.2003.462
- Katki HA, Schiffman M, Castle PE, et al. Five-year risks of CIN 2+ and CIN 3+ among women with HPV-positive and HPV-negative LSIL Pap results. J Low Genit Tract Dis. 2013;17(5 Suppl 1):S43-9. doi:10.1097/LGT.0b013e3182854269
- Egemen D, Cheung LC, Chen X, et al. Risk estimates supporting the 2019 ASCCP risk-based management consensus guidelines. J Low Genit Tract Dis. 2020;24(2):132-143. doi:10.1097/LGT.0000000000000529
- Perkins RB, Guido RS, Castle PE, 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):102-131. doi:10.1097/LGT.0000000000000525
- Moore G, Fetterman B, Cox JT, et al. Lessons from practice: risk of CIN 3 or cancer associated with an LSIL or HPV-positive ASC-US screening result in women aged 21 to 24. J Low Genit Tract Dis. 2010;14(2):97-102. doi:10.1097/LGT.0b013e3181b8b024
- Massad LS, Collins YC, Meyer PM. Biopsy correlates of abnormal cervical cytology classified using the Bethesda system. Gynecol Oncol. 2001;82(3):516-522. doi:10.1006/gyno.2001.6323
- ASCUS-LSIL Traige 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(6):1383-1392. doi:10.1067/mob.2003.457
- Stoler MH, Wright TC, Sharma A, et al. High-risk human papillomavirus testing in women with ASC-US cytology: results from the ATHENA HPV study. Am J Clin Pathol. 2011;135(3):468-475. doi:10.1309/AJCPZ5JY6FCVNMOT
- Sharpless KE, Schnatz PF, Mandavilli S, Greene JF, Sorosky JI. Dysplasia associated with atypical glandular cells on cervical cytology. Obstet Gynecol. 2005;105(3):494-500. doi:10.1097/01.AOG.0000152350.10875.02
- Zhao C, Florea A, Onisko A, Austin RM. Histologic follow-up results in 662 patients with Pap test findings of atypical glandular cells: results from a large academic womens hospital laboratory employing sensitive screening methods. Gynecol Oncol. 2009;114(3):383-389. doi:10.1016/j.ygyno.2009.05.019
- Saslow D, Solomon D, Lawson HW, 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. CA Cancer J Clin. 2012;62(3):147-172. doi:10.3322/caac.21139