Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis
- Michael Frumovitz, MD, MPH
Michael Frumovitz, MD, MPH
- Professor of Gynecologic Oncology
- MD Anderson Cancer Center
- Section Editors
- Barbara Goff, MD
Barbara Goff, MD
- Section Editor — Gynecologic Oncology
- Professor of Gynecologic Oncology
- University of Washington
- Don S Dizon, MD, FACP
Don S Dizon, MD, FACP
- Section Editor – Gynecologic Oncology
- Head of Women's Cancers, Lifespan Cancer Institute
- Director of Medical Oncology, Rhode Island Hospital
- Associate Professor of Medicine, Warren Alpert Medical School of Brown University
Cancer of the uterine cervix is the third most common gynecologic cancer diagnosis and cause of death among gynecologic cancers in the United States . Cervical cancer has lower incidence and mortality rates than uterine corpus and ovarian cancer, as well as many other cancer sites. These rankings are similar to global estimates for other developed countries . Unfortunately, in countries that do not have access to cervical cancer screening and prevention programs, cervical cancer remains the second most common type of cancer (17.8 per 100,000 women) and cause of cancer deaths (9.8 per 100,000) among all types of cancer in women.
Human papillomavirus (HPV) is central to the development of cervical neoplasia and can be detected in 99.7 percent of cervical cancers . The most common histologic types of cervical cancer are squamous cell (69 percent of cervical cancers) and adenocarcinoma (25 percent) .
The epidemiology, risk factors, clinical manifestations, and diagnosis of invasive cervical cancer will be reviewed here. Screening and prevention, staging, and the management of cervical cancer and preinvasive disease are discussed separately. (See "Screening for cervical cancer" and "Invasive cervical cancer: Staging and evaluation of lymph nodes" and "Management of early-stage cervical cancer" and "Management of locally advanced cervical cancer" and "Cervical intraepithelial neoplasia: Management of low-grade and high-grade lesions".)
EPIDEMIOLOGY AND RISK FACTORS
Incidence and mortality — Globally, cervical cancer accounted for an estimated 528,000 new cancer cases worldwide and for 266,000 deaths in 2012 .
Global incidence and mortality rates depend upon the presence of screening programs for cervical precancer and cancer and of human papillomavirus (HPV) vaccination, which are most likely to be available in developed countries. Due to these interventions, there has been a 75 percent decrease in the incidence and mortality of cervical cancer over the past 50 years in developed countries [6,7].
- Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011; 61:212.
- Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015; 65:87.
- Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189:12.
- Ries LAG, Melbert D, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2004. National Cancer Institute; Bethesda, MD 2007.
- Cervical cancer. Estimated incidence, mortality and prevalence worldwide in 2012. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx (Accessed on March 18, 2015).
- Quinn M, Babb P, Jones J, Allen E. Effect of screening on incidence of and mortality from cancer of cervix in England: evaluation based on routinely collected statistics. BMJ 1999; 318:904.
- Willoughby BJ, Faulkner K, Stamp EC, Whitaker CJ. A descriptive study of the decline in cervical screening coverage rates in the North East and Yorkshire and the Humber regions of the UK from 1995 to 2005. J Public Health (Oxf) 2006; 28:355.
- WHO/ICO Information Center of HPV and Cervical Cancer (HPV Information Center). Human Papillomavirus and Related Cancers in the World. Summary Report 2010. http://www.who.int/hpvcentre/en/ (Accessed on September 19, 2011).
- Beavis AL, Gravitt PE, Rositch AF. Hysterectomy-corrected cervical cancer mortality rates reveal a larger racial disparity in the United States. Cancer 2017; 123:1044.
- Van Kriekinge G, Castellsagué X, Cibula D, Demarteau N. Estimation of the potential overall impact of human papillomavirus vaccination on cervical cancer cases and deaths. Vaccine 2014; 32:733.
- Brotherton JM, Fridman M, May CL, et al. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study. Lancet 2011; 377:2085.
- Niccolai LM, Julian PJ, Meek JI, et al. Declining rates of high-grade cervical lesions in young women in Connecticut, 2008-2011. Cancer Epidemiol Biomarkers Prev 2013; 22:1446.
- International Collaboration of Epidemiological Studies of Cervical Cancer. Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer 2007; 120:885.
- Castellsagué X, Bosch FX, Muñoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med 2002; 346:1105.
- Anttila T, Saikku P, Koskela P, et al. Serotypes of Chlamydia trachomatis and risk for development of cervical squamous cell carcinoma. JAMA 2001; 285:47.
- Wallin KL, Wiklund F, Luostarinen T, et al. A population-based prospective study of Chlamydia trachomatis infection and cervical carcinoma. Int J Cancer 2002; 101:371.
- Hawes SE, Kiviat NB. Are genital infections and inflammation cofactors in the pathogenesis of invasive cervical cancer? J Natl Cancer Inst 2002; 94:1592.
- Castle PE, Wacholder S, Lorincz AT, et al. A prospective study of high-grade cervical neoplasia risk among human papillomavirus-infected women. J Natl Cancer Inst 2002; 94:1406.
- International Collaboration of Epidemiological Studies of Cervical Cancer, Appleby P, Beral V, et al. Carcinoma of the cervix and tobacco smoking: collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies. Int J Cancer 2006; 118:1481.
- Muñoz N, Franceschi S, Bosetti C, et al. Role of parity and human papillomavirus in cervical cancer: the IARC multicentric case-control study. Lancet 2002; 359:1093.
- International Collaboration of Epidemiological Studies of Cervical Cancer. Cervical carcinoma and reproductive factors: collaborative reanalysis of individual data on 16,563 women with cervical carcinoma and 33,542 women without cervical carcinoma from 25 epidemiological studies. Int J Cancer 2006; 119:1108.
- International Collaboration of Epidemiological Studies of Cervical Cancer, Appleby P, Beral V, et al. Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet 2007; 370:1609.
- Waggoner SE, Darcy KM, Tian C, Lanciano R. Smoking behavior in women with locally advanced cervical carcinoma: a Gynecologic Oncology Group study. Am J Obstet Gynecol 2010; 202:283.e1.
- Singh GK, Miller BA, Hankey BF, Edwards BK. Area Socioeconomic Variations in U.S. Cancer Incidence, 1975-1999. National Cancer Institute; Bethesda, MD 2003.
- Saraiya M, Ahmed F, Krishnan S, et al. Cervical cancer incidence in a prevaccine era in the United States, 1998-2002. Obstet Gynecol 2007; 109:360.
- Gierisch JM, Coeytaux RR, Urrutia RP, et al. Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review. Cancer Epidemiol Biomarkers Prev 2013; 22:1931.
- Franco EL, Schlecht NF, Saslow D. The epidemiology of cervical cancer. Cancer J 2003; 9:348.
- Green J, Berrington de Gonzalez A, Sweetland S, et al. Risk factors for adenocarcinoma and squamous cell carcinoma of the cervix in women aged 20-44 years: the UK National Case-Control Study of Cervical Cancer. Br J Cancer 2003; 89:2078.
- Hemminki K, Chen B. Familial risks for cervical tumors in full and half siblings: etiologic apportioning. Cancer Epidemiol Biomarkers Prev 2006; 15:1413.
- Liu L, Yang X, Chen X, et al. Association between TNF-α polymorphisms and cervical cancer risk: a meta-analysis. Mol Biol Rep 2012; 39:2683.
- Grimm C, Watrowski R, Baumühlner K, et al. Genetic variations of interleukin-1 and -6 genes and risk of cervical intraepithelial neoplasia. Gynecol Oncol 2011; 121:537.
- Wang Q, Zhang C, Walayat S, et al. Association between cytokine gene polymorphisms and cervical cancer in a Chinese population. Eur J Obstet Gynecol Reprod Biol 2011; 158:330.
- Craveiro R, Bravo I, Catarino R, et al. The role of p73 G4C14-to-A4T14 polymorphism in the susceptibility to cervical cancer. DNA Cell Biol 2012; 31:224.
- Wang L, Gao R, Yu L. Combined analysis of the association between p73 G4C14-to-A4T14 polymorphisms and cancer risk. Mol Biol Rep 2012; 39:1731.
- Wang K, Zhou B, Zhang J, et al. Association of signal transducer and activator of transcription 3 gene polymorphisms with cervical cancer in Chinese women. DNA Cell Biol 2011; 30:931.
- Schiffman M, Castle PE, Jeronimo J, et al. Human papillomavirus and cervical cancer. Lancet 2007; 370:890.
- Manhart LE, Holmes KK, Koutsky LA, et al. Human papillomavirus infection among sexually active young women in the United States: Implications for developing a vaccination strategy. Sex Transm Dis 2006; 33:502.
- Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015; 64:1.
- Kayes O, Ahmed HU, Arya M, Minhas S. Molecular and genetic pathways in penile cancer. Lancet Oncol 2007; 8:420.
- Parkin DM, Bray F. Chapter 2: The burden of HPV-related cancers. Vaccine 2006; 24 Suppl 3:S3/11.
- Li N, Franceschi S, Howell-Jones R, et al. Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: Variation by geographical region, histological type and year of publication. Int J Cancer 2011; 128:927.
- Society of Gynecologic Oncologists Education Resource Panel Writing group, Collins Y, Einstein MH, et al. Cervical cancer prevention in the era of prophylactic vaccines: a preview for gynecologic oncologists. Gynecol Oncol 2006; 102:552.
- Jones C. Cervical cancer: is herpes simplex virus type II a cofactor? Clin Microbiol Rev 1995; 8:549.
- Smith JS, Herrero R, Bosetti C, et al. Herpes simplex virus-2 as a human papillomavirus cofactor in the etiology of invasive cervical cancer. J Natl Cancer Inst 2002; 94:1604.
- Lehtinen M, Koskela P, Jellum E, et al. Herpes simplex virus and risk of cervical cancer: a longitudinal, nested case-control study in the nordic countries. Am J Epidemiol 2002; 156:687.
- Kjaer SK, de Villiers EM, Cağlayan H, et al. Human papillomavirus, herpes simplex virus and other potential risk factors for cervical cancer in a high-risk area (Greenland) and a low-risk area (Denmark)--a second look. Br J Cancer 1993; 67:830.
- Kurman RJ, Norris HJ, Wilkinson EJ. Atlas of tumor pathology: Tumors of the cervix, vagina, and vulva, 3rd, Armed Forces Institute of Pathology, Washington, DC 1992.
- Eifel PJ, Burke TW, Morris M, Smith TL. Adenocarcinoma as an independent risk factor for disease recurrence in patients with stage IB cervical carcinoma. Gynecol Oncol 1995; 59:38.
- Smith HO, Tiffany MF, Qualls CR, Key CR. The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in the United States--a 24-year population-based study. Gynecol Oncol 2000; 78:97.
- Adegoke O, Kulasingam S, Virnig B. Cervical cancer trends in the United States: a 35-year population-based analysis. J Womens Health (Larchmt) 2012; 21:1031.
- Look KY, Brunetto VL, Clarke-Pearson DL, et al. An analysis of cell type in patients with surgically staged stage IB carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 1996; 63:304.
- Grisaru D, Covens A, Chapman B, et al. Does histology influence prognosis in patients with early-stage cervical carcinoma? Cancer 2001; 92:2999.
- Lea JS, Coleman RL, Garner EO, et al. Adenosquamous histology predicts poor outcome in low-risk stage IB1 cervical adenocarcinoma. Gynecol Oncol 2003; 91:558.
- Albores-Saavedra J, Gersell D, Gilks CB, et al. Terminology of endocrine tumors of the uterine cervix: results of a workshop sponsored by the College of American Pathologists and the National Cancer Institute. Arch Pathol Lab Med 1997; 121:34.
- Behtash N, Mousavi A, Tehranian A, et al. Embryonal rhabdomyosarcoma of the uterine cervix: case report and review of the literature. Gynecol Oncol 2003; 91:452.
- Villella JA, Bogner PN, Jani-Sait SN, et al. Rhabdomyosarcoma of the cervix in sisters with review of the literature. Gynecol Oncol 2005; 99:742.
- Dursun P, Gultekin M, Bozdag G, et al. Primary cervical lymphoma: report of two cases and review of the literature. Gynecol Oncol 2005; 98:484.
- Kendrick JE 4th, Straughn JM Jr. Two cases of non-Hodgkin's lymphoma presenting as primary gynecologic malignancies. Gynecol Oncol 2005; 98:490.
- Wright JD, Rosenblum K, Huettner PC, et al. Cervical sarcomas: an analysis of incidence and outcome. Gynecol Oncol 2005; 99:348.
- Sutton GP, Bundy BN, Delgado G, et al. Ovarian metastases in stage IB carcinoma of the cervix: a Gynecologic Oncology Group study. Am J Obstet Gynecol 1992; 166:50.
- Pilleron JP, Durand JC, Hamelin JP. Prognostic value of node metastasis in cancer of the uterine cervix. Am J Obstet Gynecol 1974; 119:458.
- Metcalf KS, Johnson N, Calvert S, Peel KR. Site specific lymph node metastasis in carcinoma of the cervix: Is there a sentinel node? Int J Gynecol Cancer 2000; 10:411.
- Levenback C, Coleman RL, Burke TW, et al. Lymphatic mapping and sentinel node identification in patients with cervix cancer undergoing radical hysterectomy and pelvic lymphadenectomy. J Clin Oncol 2002; 20:688.
- Bader AA, Winter R, Haas J, Tamussino KF. Where to look for the sentinel lymph node in cervical cancer. Am J Obstet Gynecol 2007; 197:678.e1.
- Lee YN, Wang KL, Lin MH, et al. Radical hysterectomy with pelvic lymph node dissection for treatment of cervical cancer: a clinical review of 954 cases. Gynecol Oncol 1989; 32:135.
- Lagasse LD, Creasman WT, Shingleton HM, et al. Results and complications of operative staging in cervical cancer: experience of the Gynecologic Oncology Group. Gynecol Oncol 1980; 9:90.
- Arends MJ, Buckley CH, Wells M. Aetiology, pathogenesis, and pathology of cervical neoplasia. J Clin Pathol 1998; 51:96.
- Hughes RR, Brewington KC, Hanjani P, et al. Extended field irradiation for cervical cancer based on surgical staging. Gynecol Oncol 1980; 9:153.
- Sevin BU, Nadji M, Averette HE, et al. Microinvasive carcinoma of the cervix. Cancer 1992; 70:2121.
- DiSaia PJ, Creasman WT. Invasive cervical cancer. In: Clinical Gynecologic Oncology, 7th ed., Mosby Elsevier, Philadelphia 2007. p.55.
- Partridge EE, Abu-Rustum NR, Campos SM, et al. Cervical cancer screening. J Natl Compr Canc Netw 2010; 8:1358.
- EPIDEMIOLOGY AND RISK FACTORS
- Incidence and mortality
- Age distribution
- Risk factors
- ROUTES OF SPREAD
- CLINICAL MANIFESTATIONS
- Physical examination
- Cervical cytology
- Cervical biopsy and colposcopy
- Other diagnostic modalities
- Differential diagnosis
- SCREENING AND PREVENTION
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS