Cervical Cancer

Carcinoma of the cervix is a common cause of cancer in women worldwide but has decreased in prominence in the U.S. with advances in cervical cancer screening. Screening guidelines differ depending upon age group. Pap smear and HPV screening tests are the most common laboratory tests used for early detection of cervical cancer.  

  • Key Points
  • Diagnosis
  • Screening
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Persistent human papillomavirus (HPV) infection is the most important factor in the development of cervical cancer. HPV types 16 and 18 cause 70% of all cervical cancers and precancerous cervical lesions (WHO, 2016). Cervical cytology screening has been proven to decrease the incidence and mortality of squamous cell cervical cancer and to increase the cure rate of cervical cancer. Use of DNA testing for high-risk subtypes of HPV is also a useful adjunct to cervical cytology screening in select patients (National Comprehensive Cancer Network [NCCN], 2017),

Human Papillomavirus Testing in Women

Screening Guidelines

ARUP Laboratories’ Cervical Cancer and HPV Screening Tests

Screening Guidelines for the Prevention and Early Detection of Cervical Cancer (ACS/ASCCP/ASCP, 2012)

Indications for Testing

  • Watery vaginal discharge (National Comprehensive Cancer Network [NCCN], 2017)
  • Abnormal vaginal bleeding or a significant unexplained change in menstrual cycle
  • Friable cervix that bleeds easily following intercourse or contact (eg, insertion of a diaphragm, collection of a Pap smear)
  • Pain during sexual intercourse
  • Abnormal vaginal discharge containing blood-tinged mucous

Laboratory Testing

Refer to Key Points section

Epidemiology

  • Incidence – >12,000 new cases in the U.S. in 2016 (National Comprehensive Cancer Network [NCCN], 2017)
  • Prevalence – fourth most common cancer in women worldwide (NCCN, 2017)
  • Age – median age of onset is 49 (SEER, 2016)
    • Infection with oncogenic strain of human papillomavirus (HPV) associated with earlier age of onset
      • High-grade dysplasia in 30s
      • Invasive carcinoma in 40s

Risk Factors (NCCN, 2017)

  • HPV infection
  • History of smoking
  • Sexual activity
    • History of early sexual activity, especially with multiple sex partners
    • Sexual partner who began sexual activity at an early age or who had many previous sexual partners
    • History of sexually transmitted infections (STIs)
  • Parity
  • Oral contraceptive use
  • Certain autoimmune diseases
  • Chronic immunosuppression
  • Family history of cervical cancer

Pathophysiology

  • Etiology – HPV, particularly the oncogenic types
    • HPV 16 and 18 are responsible for >70% of invasive cervical cancers
  • Tumor types – 80% are squamous cell carcinoma, 20% are adenocarcinomas (NCCN, 2017)
    • Increased incidence of adenocarcinomas over last 30 years
      • Cytologic screening methods are less effective for adenocarcinomas, but HPV testing may improve detection rates
  • Usually evolves from cervical dysplasia
    • 30-35% of high-grade dysplasias progress to invasive carcinoma

Clinical Presentation

  • Earliest stage may be asymptomatic or associated with a watery vaginal discharge (NCCN, 2017)
  • Abnormal vaginal bleeding or a significant unexplained change in menstrual cycle
  • Friable cervix that bleeds easily following intercourse or contact (eg, insertion of a diaphragm, collection of a Pap smear)
  • Pain during sexual intercourse
  • Abnormal vaginal discharge containing blood-tinged mucous

Prevention

  • HPV vaccine – recommended for males and females in 2- or 3-dose schedules, depending on age (CDC, 2017)
    • 2-dose schedule – for ages 9-14
    • 3-dose schedule –  for ages 15-26 and for immunocompromised persons
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Cytology, ThinPrep Pap Test and Human Papillomavirus (HPV), High Risk by Transcription-Mediated Amplification (TMA) (for routine co-testing in women over 30) 2000136
Method: Microscopy/Qualitative Transcription-mediated Amplification

Limitations 

Pap test has an inherent false-negative rate

Follow-up 

Refer to Key Points section

Human Papillomavirus (HPV), High Risk with 16 and 18 Genotype by PCR, ThinPrep 2011940
Method: Qualitative Polymerase Chain Reaction

Follow-up 

Refer to Key Points section

Human Papillomavirus (HPV), High Risk by Transcription-Mediated Amplification (TMA) with Reflex to HPV Genotypes 16 and 18/45 by TMA, ThinPrep 2007890
Method: Qualitative Transcription-Mediated Amplification

Follow-up 

Refer to Key Points section

Cytology, ThinPrep Pap Test with Reflex to Human Papillomavirus (HPV), High Risk, E6/E7 mRNA by Transcription-Mediated Amplification (TMA) 2000138
Method: Microscopy/Qualitative Transcription-mediated Amplification

Limitations 

Pap test has an inherent false-negative rate

Follow-up 

Refer to Key Points section

Cytology, SurePath Liquid-Based Pap Test 2000134
Method: Microscopy

Limitations 

Test does not include HPV testing

Test has an inherent false-negative rate

Follow-up 

Refer to Key Points section

Cytology, ThinPrep Pap Test 2000137
Method: ThinPrep 2000 System/Routine Cytopathologic Evaluation

Limitations 

Test has an inherent false-negative rate

Follow-up 

Refer to Key Points section

Human Papillomavirus (HPV), High Risk by Transcription-Mediated Amplification (TMA), ThinPrep 2007893
Method: Qualitative Transcription-Mediated Amplification

Follow-up 

Refer to Key Points section

Human Papillomavirus (HPV), High Risk by PCR, ThinPrep 2011947
Method: Qualitative Polymerase Chain Reaction

Follow-up 

Refer to Key Points section

Human Papillomavirus (HPV) Genotypes 16 and 18/45 by Transcription-Mediated Amplification (TMA), ThinPrep 2007894
Method: Qualitative Transcription-Mediated Amplification

Follow-up 

Refer to Key Points section

Human Papillomavirus (HPV), High Risk with 16 and 18 Genotype by PCR, SurePath 2011933
Method: Qualitative Polymerase Chain Reaction

Follow-up 

Refer to Key Points section

Human Papillomavirus (HPV), High Risk by PCR, SurePath 2011942
Method: Qualitative Polymerase Chain Reaction

Follow-up 

Refer to Key Points section

Cytology, SurePath Liquid-Based Pap Test and Human Papillomavirus (HPV), High Risk by PCR, SurePath (for routine co-testing in women over 30) 2000133
Method: Microscopy/Qualitative Polymerase Chain Reaction

Limitations 

Pap test has an inherent false-negative rate

Follow-up 

Refer to Key Points section

Squamous Cell Carcinoma Antigen, Serum 0081054
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Limitations 

Results obtained with different assay methods or kits cannot be used interchangeably

Follow-up 

SCC antigen levels alone should not be interpreted as evidence of the presence or absence of malignant disease; in patients with known or expected cancer, other tests and procedures must be considered for diagnosis and patient management

Guidelines

Apgar BS, Kittendorf AL, Bettcher CM, Wong J, Kaufman AJ. Update on ASCCP consensus guidelines for abnormal cervical screening tests and cervical histology. Am Fam Physician. 2009; 80(2): 147-55. PubMed

Cervical Cancer Screening Guidelines. Centers for Disease Control and Prevention. Atlanta, GA [Accessed: Feb 2017]

Cervical Cancer Screening Recommendations, 2012. The American Society for Colposcopy and Cervical Pathology. Frederick, MD [Accessed: Feb 2017]

Choosing Wisely. An initiative of the ABIM Foundation. [Accessed: Oct 2017]

Committee on Practice Bulletins—Gynecology. Practice Bulletin No. 168: Cervical Cancer Screening and Prevention. Obstet Gynecol. 2016; 128(4): e111-30. PubMed

Huh WK, Ault KA, Chelmow D, Davey DD, Goulart RA, Garcia FA, Kinney WK, Massad S, Mayeaux EJ, Saslow D, Schiffman M, Wentzensen N, Lawson HW, Einstein MH. Use of primary high-risk human papillomavirus testing for cervical cancer screening: interim clinical guidance. Obstet Gynecol. 2015; 125(2): 330-7. PubMed

James RM, Cruickshank ME, Siddiqui N, Guideline Development Group. Management of cervical cancer: summary of SIGN guidelines. BMJ. 2008; 336(7634): 41-3. PubMed

Massad S, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M, Solomon D, Wentzensen N, Lawson HW, 2012 ASCCP Consensus Guidelines Conference. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013; 121(4): 829-46. PubMed

Meites E, Kempe A, Markowitz LE. Use of a 2-Dose Schedule for Human Papillomavirus Vaccination — Updated Recommendations of the Advisory Committee on Immunization Practices. December 16, 2016 / 65(49);1405–1408. Centers for Disease Control and Prevention. Atlanta, GA [Last updated Aug 2017; Accessed: Oct 2017]

Moyer VA, U.S. Preventive Services Task Force. Screening for cervical cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012; 156(12): 880-91, W312. PubMed

NCCN Clinical Practice Guidelines in Oncology, Cervical Cancer. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Sep 2017]

Protocol for the Examination of Specimens from Patients with Carcinoma of the Uterine Cervix. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Jan 2016. College of American Pathologists (CAP). Northfield, IL [Revised Jan 2016; Accessed: Sep 2017]

Salani R, Khanna N, Frimer M, Bristow RE, Chen L. An update on post-treatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncology (SGO) recommendations. Gynecol Oncol. 2017; 146(1): 3-10. PubMed

Saslow D, Solomon D, Lawson HW, Killackey M, Kulasingam SL, Cain J, Garcia FA, Moriarty AT, Waxman AG, Wilbur DC, Wentzensen N, Downs LS, Spitzer M, Moscicki A, Franco EL, Stoler MH, Schiffman M, Castle PE, Myers ER, American Cancer Society, American Society for Colposcopy and Cervical Pathology, American Society for Clinical Pathology. 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. Am J Clin Pathol. 2012; 137(4): 516-42. PubMed

Sawaya GF, Kulasingam S, Denberg TD, Qaseem A, Clinical Guidelines Committee of American College of Physicians. 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(12): 851-9. PubMed

Smith RA, Manassaram-Baptiste D, Brooks D, Doroshenk M, Fedewa S, Saslow D, Brawley OW, Wender R. Cancer screening in the United States, 2015: a review of current American cancer society guidelines and current issues in cancer screening. CA Cancer J Clin. 2015; 65(1): 30-54. PubMed

Trimble EL. Cervical cancer state-of-the-clinical-science meeting on pretreatment evaluation and prognostic factors, September 27-28, 2007: proceedings and recommendations. Gynecol Oncol. 2009; 114(2): 145-50. PubMed

Wright TC, Massad S, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D, 2006 American Society for Colposcopy and Cervical Pathology-sponsored Consensus Conference. 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol. 2007; 197(4): 346-55. PubMed

General References

Arbyn M, Roelens J, Cuschieri K, Cuzick J, Szarewski A, Ratnam S, Reuschenbach M, Belinson S, Belinson JL, Monsonego J. The APTIMA HPV assay versus the Hybrid Capture 2 test in triage of women with ASC-US or LSIL cervical cytology: a meta-analysis of the diagnostic accuracy. Int J Cancer. 2013; 132(1): 101-8. PubMed

Feldman S. Making sense of the new cervical-cancer screening guidelines. N Engl J Med. 2011; 365(23): 2145-7. PubMed

Jarboe EA, Hunt JP, Layfield LJ. Cytomorphologic diagnosis and HPV testing of metastatic and primary oropharyngeal squamous cell carcinomas: a review and summary of the literature. Diagn Cytopathol. 2012; 40(6): 491-7. PubMed

Laudadio J. Human papillomavirus detection: testing methodologies and their clinical utility in cervical cancer screening. Adv Anat Pathol. 2013; 20(3): 158-67. PubMed

Pyne MT, Hamula CL, Tardif K, Law C, Schlaberg R. High-risk HPV detection and genotyping by APTIMA HPV using cervical samples. J Virol Methods. 2015; 221: 95-9. PubMed

Rebolj M, Bonde J, Njor SH, Lynge E. Human papillomavirus testing in primary cervical screening and the cut-off level for hybrid capture 2 tests: systematic review. BMJ. 2011; 342: d2757. PubMed

Schiffman M, Solomon D. Clinical practice. Cervical-cancer screening with human papillomavirus and cytologic cotesting. N Engl J Med. 2013; 369(24): 2324-31. PubMed

Solomon D, Papillo JL, Davey DD, Cytopathology Education and Technology Consortium. Statement on HPV DNA test utilization. Am J Clin Pathol. 2009; 131(6): 768-9; discussion 770-3. PubMed

Wentzensen N, Doeberitz Mv. Biomarkers in cervical cancer screening. Dis Markers. 2007; 23(4): 315-30. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Bentz JS, Hughes JH, Fatheree LA, Schwartz MR, Souers RJ, Soures RJ, Wilbur DC, Cytopathology Resource Committee, College of American Pathologists. Summary of the 2006 College of American Pathologists Gynecologic Cytology Proficiency Testing Program. Arch Pathol Lab Med. 2008; 132(5): 788-94. PubMed

Bentz JS. Liquid-based cytology for cervical cancer screening. Expert Rev Mol Diagn. 2005; 5(6): 857-71. PubMed

Bishop JW, Marshall CJ, Bentz JS. New technologies in gynecologic cytology. J Reprod Med. 2000; 45(9): 701-19. PubMed

Erali M, Pattison DC, Wittwer CT, Petti CA. Human papillomavirus genotyping using an automated film-based chip array. J Mol Diagn. 2009; 11(5): 439-45. PubMed

Holladay B, Logan S, Arnold J, Knesel B, Smith D. A comparison of the clinical utility of p16(INK4a) immunolocalization with the presence of human papillomavirus by hybrid capture 2 for the detection of cervical dysplasia/neoplasia. Cancer. 2006; 108(6): 451-61. PubMed

Hughes JH, Bentz JS, Fatheree L, Souers RJ, Wilbur DC, Cytopathology Resource Committee, College of American Pathologists. Changes in participant performance in the "test-taking" environment: observations from the 2006 College of American Pathologists Gynecologic Cytology Proficiency Testing Program. Arch Pathol Lab Med. 2009; 133(2): 279-82. PubMed

Layfield LJ, Qureshi N. HPV DNA testing in the triage of atypical squamous cells of undetermined significance (ASCUS): cost comparison of two methods. Diagn Cytopathol. 2005; 33(2): 138-43. PubMed

Pyne MT, Hamula CL, Tardif K, Law C, Schlaberg R. High-risk HPV detection and genotyping by APTIMA HPV using cervical samples. J Virol Methods. 2015; 221: 95-9. PubMed

Pyne MT, Law C, Hillyard DR, Schlaberg R. Testing and genotyping of high-risk human papillomavirus by the cobas HPV Test and the Hybrid Capture 2 high-risk HPV DNA test using cervical and vaginal samples. J Clin Microbiol. 2014; 52(5): 1720-3. PubMed

Renshaw AA, Mody DR, Walsh M, Bentz JS, Colgan TJ, Cytopathology Resource Committee, College of American Pathologists. The significance of certification in liquid-based cytology and performance in the College of American Pathologists interlaboratory comparison program in cervicovaginal cytopathology. Arch Pathol Lab Med. 2006; 130(9): 1269-72. PubMed

Rowe LR, Aldeen W, Bentz JS. Prevalence and typing of HPV DNA by hybrid capture II in women with ASCUS, ASC-H, LSIL, and AGC on ThinPrep Pap tests. Diagn Cytopathol. 2004; 30(6): 426-32. PubMed

Tardif KD, Pyne MT, Malmberg E, Lunt TC, Schlaberg R. Cervical Cytology Specimen Stability in Surepath Preservative and Analytical Sensitivity for HPV Testing with the cobas and Hybrid Capture 2 Tests. PLoS One. 2016; 11(2): e0149611. PubMed

Tardif KD, Simmon KE, Kommedal O, Pyne MT, Schlaberg R. Sequencing-based genotyping of mixed human papillomavirus infections by use of RipSeq software. J Clin Microbiol. 2013; 51(4): 1278-80. PubMed

Wilson AR, Welch RJ, Hashibe M, Greenwood J, Jackson B, She RC. Surveillance of human papilloma virus using reference laboratory data for the purpose of evaluating vaccine impact. Online J Public Health Inform. 2014; 6(3): e194. PubMed

Witt BL, Factor RE, Jarboe EA, Layfield LJ. Negative loop electrosurgical cone biopsy finding following a biopsy diagnosis of high-grade squamous intraepithelial lesion: frequency and clinical significance. Arch Pathol Lab Med. 2012; 136(10): 1259-61. PubMed

Medical Reviewers

Content Reviewed: 
September 2017

Last Update: October 2017