Cervical Cancer AAFP.pdf

Cervical Cancer: Evaluation and Management Jennifer Wipperman, MD, MPH; Tara Neil, MD; and Tracy Williams, MD University of Kansas School of Medicine–Wichita, Wichita,...

Cervical Cancer: Evaluation and Management Jennifer Wipperman, MD, MPH; Tara Neil, MD; and Tracy Williams, MD University of Kansas School of Medicine–Wichita, Wichita, Kansas Human papillomavirus infection is the precursor for the development of cervical cancer and is detect- able in 99.7% of squamous cell carcinoma and adenocarcinoma cases. Early detection of precancerous lesions with Papanicolaou testing remains the primary mechanism for cancer prevention. Once cer- vical cancer is diagnosed, treatment may involve surgery, radiation therapy, chemotherapy, or a combination. The choice of therapy depends on the stage of disease, lymph node involvement, patient comorbidities, and risk factors for recurrence. Early-stage, microinvasive disease may be treated with surgery alone if margins are negative and there is no lymph node involvement; adjuvant chemoradia- tion should be considered for other early-stage disease. Locally advanced disease is often treated with chemoradiation. The addition of bevacizumab, an antivascular endothelial growth factor monoclonal antibody, to combination chemotherapy improves survival among patients with recurrent, persistent, or metastatic cervical cancer. Disease stage and lymph node involvement are the most prognostic factors. Pregnancy status and desire to preserve fertility should be considered when developing a treat- ment strategy. After treatment, close follow-up with a gynecologist-oncologist for pelvic examinations at regular intervals is recommended to assess for recurrence. (Am Fam Physician. 2018;97(7):449-454. Copyright © 2018 American Academy of Family Physicians.) Every year, nearly 13,000 cases of cervical can- Papanicolaou (Pap) testing is the primary mech- cer are diagnosed, with more than 4,000 deaths.1 anism for cancer prevention.5 Although the highest incidence of cervical cancer is among women 40 to 49 years of age (14 cases Pathogenesis per 100,000 women per year), 40% of women are HPV is detected in 99.7% of squamous cell car- older than 40 years at diagnosis.2 Rates of cervical cinomas and adenocarcinomas,6 the most com- cancer are higher in the southern region of the mon types of cervical cancer (Table 1).4 There United States.2 There are significant disparities in are 15 known oncogenic strains of HPV, with cervical cancer–related mortality among racial types 16 and 18 involved in 70% of cervical can- and ethnic groups. Black women are more than cer cases.7 Most sexually active adults will be twice as likely to die from cervical cancer than exposed to HPV, and more than 50% of adults white women.3 Mortality rates are also higher 20 to 24 years of age are currently infected.8 among Hispanic women.1 However, the immune system clears the virus Human papillomavirus (HPV) infection is the within six months in 50% of women with the precursor for the development of cervical can- infection and within two years in up to 90% of cer.4 Early detection of precancerous lesions with women.9,10 When HPV infection persists in the metaplas- tic epithelium of the cervical transformation See related article about cervical cancer zone, it can lead to dysplastic cellular changes. screening on page 441. Although low-grade dysplasia (cervical intraep- CME This clinical content conforms to AAFP ithelial neoplasia 1 [CIN1]) usually regresses, criteria for continuing medical education (CME). See CME Quiz on page 439. it can progress to high-grade dysplasia (CIN2 Author disclosure: No relevant financial or CIN3).11 Cervical cancer occurs when high- affiliations. grade lesions extend beyond the basement mem- brane of the cervical epithelium. Approximately Downloaded from April 1, 2018 the American ◆ Volume Family Physician 97, Number 7 website at www.aafp.org/afp. Copyright © 2018 American Academy of Family www.aafp.org/afp Physicians. American For the Family 449 private, noncom- Physician mercial use of one individual user of the website. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests.  CERVICAL CANCER MANAGEMENT 20% of women with high-grade dyspla- biopsied regardless of cervical cytology. sia will develop invasive cervical cancer TABLE 1 Adenocarcinomas may not lead to an within five years if left untreated.12 identifiable lesion if located in the endo- Histopathologic Types cervical canal. Risk Factors of Cervical Cancer Most cervical cancer risk factors Squamous cell carcinoma Staging relate to increased exposure to HPV (71% of cervical cancers) Cervical cancer spreads via direct exten- or decreased ability to clear the virus Keratinizing sion, and lymphatic and hematogenous immunologically.13 Smoking is associ- Nonkeratinizing routes. Staging is determined using the ated with an increased risk of squamous Verrucous International Federation of Gynecology cell carcinoma but not adenocarci- Adenocarcinoma (25%) and Obstetrics 2014 guideline (Table noma. This risk decreases by one-half Clear cell 3).21,22 Cervical cancer is the only gyne- 10 years after smoking cessation. Evi- 14 Endometrioid cologic cancer staged clinically before dence suggests a genetic susceptibility surgery, based on tumor size, depth of to cervical cancer, and several genetic Adenosquamous carcinoma (4%) invasion, spread into surrounding tis- alterations have been implicated.15 Adenoid cystic sue, and distant metastases (usually In addition, a large prospective cohort Small cell lung, liver, and bone).21 In suspected study found that use of oral contracep- Undifferentiated microinvasive disease, conization is tives for five to nine years was associated Information from reference 4. used to determine depth of invasion. with increased risk of cervical cancer Additional diagnostic studies may aid (hazard ratio = 2.0; 95% confidence in determining spread and prognosis, interval, 1.3 to 3.0). The mechanism appears to be hor- and in planning treatment. Computed tomography or mag- monal rather than behavioral and may be due to the effect netic resonance imaging assesses tumor size and spread, of sex steroids on oncogene expression.16 The risk appears to and computed tomography with or without positron emis- decline after cessation of oral contraceptives. However, CIN sion tomography is used to evaluate lymphovascular space is not currently a contraindication to oral contraceptive use invasion (LVSI). per the U.S. Medical Eligibility Criteria or cervical cancer treatment guidelines.17 Table 2 includes risk factors for cer- Management vical squamous cell carcinoma.1,13-16,18,19 Management of cervical cancer depends on stage, lymph node involvement, patient comorbidities, and risk factors Diagnosis for recurrence.23 Treatment may include surgical resection, Cervical cancer may be detected after a Pap test result is radiation, chemotherapy, or a combination. There are sev- abnormal, a lesion is visualized on pelvic examination, or eral types of hysterectomy procedures that are used to treat clinical symptoms develop. Management of abnormal Pap cervical cancer depending on stage (Table 4), and a mini- test results should follow the American Society for Colpos- mally invasive approach (laparoscopic or robotic) is often copy and Cervical Pathology guideline.20 If colposcopy is possible.24 Microinvasive disease (stage IA1) and no LVSI indicated because of an abnormal Pap test result or visible may be treated with simple hysterectomy if margins are lesion, cervical cancer may be diagnosed by colposcopy-directed biopsy or by an excisional procedure. BEST PRACTICES IN ONCOLOGY Although early cervical cancer is usu- ally asymptomatic, it may cause abnormal uterine bleeding or postcoital bleeding. Recommendations from the Choosing Wisely Campaign Advanced lesions can cause bladder outlet Recommendation Sponsoring organization obstruction, resulting in bladder or bowel Avoid routine imaging for cancer surveillance in Society of Gyneco- symptoms, back or pelvic pain, hematuria, women with gynecologic cancer, specifically ovarian, logic Oncology or renal failure. On pelvic examination, endometrial, cervical, vulvar, and vaginal cancers. cervical cancer may manifest as superfi- Source: For more information on the Choosing Wisely Campaign, see http://www. cial ulceration, an exophytic tumor, or an choosingwisely.org. For supporting citations and to search Choosing Wisely recommenda- enlarged, indurated cervix. Any abnor- tions relevant to primary care, see http://www.aafp.org/afp/recommendations/search.htm. mal lesion visible on the cervix should be 450 American Family Physician www.aafp.org/afp Volume 97, Number 7 ◆ April 1, 2018  TABLE 2 TABLE 3 Risk Factors for Cervical Squamous Cell International Federation of Gynecology Carcinoma and Obstetrics Staging of Cervical Cancer Relative risk (95% Stage (five- Risk factor confidence interval) year survival) Characteristics Number of sex partners I Carcinoma strictly confined to the cervix 2 to 5 2.00 (1.91 to 2.09) (extension to the uterine corpus should be disregarded) ≥6 2.98 (2.62 to 3.40) IA (93%) Invasive cancer identified only micro- Age at first intercourse < 18 years 2.24 (2.11 to 2.38) scopically; all gross lesions, even with superficial invasion, are stage IB cancers; Number of full-term pregnancies invasion is limited to measured invasion 1 to 2 1.00 (0.94 to 1.07) of stroma ≤ 5 mm in depth and ≤ 7 mm in 3 to 4 1.50 (1.43 to 1.59) horizontal spread ≥5 2.08 (1.95 to 2.23) IA1 Measured invasion of stroma ≤ 3 mm in depth and ≤ 7 mm in horizontal spread Age at first parity (years) IA2 Measured invasion of stroma > 3 mm to 17 to 19 2.16 (2.03 to 2.30) ≤ 5 mm in depth, and ≤ 7 mm in horizontal < 17 2.72 (2.42 to 3.05) spread IB (80%) Clinical lesions confined to the cervix or Current smoker 1.50 (1.38 to 1.63) microscopic lesions greater than IA2 IB1 Clinical lesion ≤ 4 cm in size Additional risk factors: black or His- — panic race, current oral contraceptive IB2 Clinical lesion > 4 cm in size use with a duration of more than 5 II Carcinoma extends beyond uterus but not years, history of sexually transmitted to pelvic wall or to lower one-third of the infections, immunosuppression, low vagina socioeconomic status, family history IIA (63%) No parametrial invasion Information from references 1, 13 through 16, 18, and 19. IIA1 Clinical lesion ≤ 4 cm in size IIA2 Clinical lesion > 4 cm in size IIB (58%) Parametrial invasion negative.25 Women with early disease (stage IA-IB1) may be treated with radical hysterectomy and pelvic lymphadenec- III Carcinoma extends to pelvic wall and/or tomy. A 2016 Cochrane review of 401 women with early dis- involves the lower one-third of the vagina, and/or causes hydronephrosis or non- ease (stage IA2-IIA) and risk factors for recurrence found functioning kidney that after surgery, adjuvant platinum-based chemoradiation IIIA (35%) Involves lower one-third of the vagina, no significantly reduced mortality compared with radiation extension to the pelvic wall alone (hazard ratio = 0.56; 95% confidence interval, 0.36 IIIB (32%) Extends to pelvic wall and/or causes to 0.87).26 Women who are not surgical candidates may be hydronephrosis or nonfunctioning kidney treated with primary radiation therapy or chemoradiation. IV Carcinoma extends beyond the true pelvis Locally advanced cervical cancer is often treated with or has clinically involved the mucosa of primary chemoradiation.27 Currently, treatment is based the bladder or rectum on combination therapy with platinum-based regimens. IVA (16%) Spread to adjacent organs Radiation involves external beam and high-dose intracavity IVB (15%) Spread to distant organs brachytherapy.28 Posttreatment hysterectomy is not associ- ated with increased survival rates and therefore is generally Information from references 21 and 22. not recommended.29 However, hysterectomy may be per- formed in patients who have large, bulky tumors or high posttreatment tumor volumes. or without hysterectomy, and it has a 50% cure rate.30 How- Treatment of recurrent disease includes medical or sur- ever, the procedure has a 3% to 5% mortality rate, 50% of gical options. For women with local recurrence, surgical patients have major complications, and there are no con- resection with hysterectomy or pelvic exenteration is an trolled trials to evaluate its effectiveness.31 option. Exenteration is an ultraradical surgical proce- Women with advanced metastatic disease are treated dure that involves en bloc removal of female reproductive with chemotherapy (and radiation if not previously organs, the lower urinary tract, and a portion of the rec- offered). Bevacizumab (Avastin) is an antivascular endo- tosigmoid. Exenteration is generally used for women who thelial growth factor monoclonal antibody that inhibits have had previous unsuccessful radiation treatment, with tumor angiogenesis. A 2017 double-blind, randomized trial April 1, 2018 ◆ Volume 97, Number 7 www.aafp.org/afp American Family Physician 451  CERVICAL CANCER MANAGEMENT disease have a 93% five-year survival rate,22 but TABLE 4 LVSI reduces this by approximately 50%.34 Types of Hysterectomy Adenocarcinoma Type Definition The incidence of adenocarcinoma has increased Simple/extrafascial Uterus is removed with the cervix, but without by 35% over the past 35 years.4 Although risk hysterectomy the parametria or vagina (class I) factors, diagnosis, staging, and treatment of ade- nocarcinoma are generally the same as for squa- Modified radical Uterus is removed with the cervix, parametria, mous cell carcinoma, there are some additional hysterectomy and upper one-fourth of the vagina (class II) considerations. Ovarian metastases are more Radical Uterus is removed with the cervix and: common with adenocarcinoma, and thus oopho- hysterectomy Additional parametria and upper one-half of rectomy is recommended in early-stage disease.35 the vagina (class III) Larger adenocarcinomas (greater than 2 cm) are Upper three-fourths of the vagina (class IV) more likely to involve lymph nodes and have Additional resection of a portion of the blad- higher recurrence rates compared with squa- der (class V) mous cell carcinomas of the same size.36 Note: This table includes the Piver-Rutledge-Smith surgical classification system, which is commonly used. Many other classification systems exist, including the Fertility Preservation Querleu-Morrow system. Fertility-sparing options are available for women Information from reference 24. with early-stage cervical cancer. Stage IA1 can be treated with conization if margins are negative. More advanced disease can be treated with radical of 452 patients with recurrent, persistent, or metastatic cer- trachelectomy (removal of the cervix) and pelvic lymph node vical cancer found that adding bevacizumab to combina- dissection. Fertility-sparing treatments for disease beyond tion chemotherapy was associated with a 23% improvement stage IB1 and greater than 2 cm are not recommended.25 in overall survival (hazard ratio = 0.77; 95% confidence Women should be counseled regarding future pregnancy risk, interval, 0.62 to 0.95; P =.007) and an extension of median including preterm birth, and need for obstetric consultation. overall survival from 13.3 months to 16.8 months compared with combi- nation chemotherapy alone. This trial SORT: KEY RECOMMENDATIONS FOR PRACTICE confirms persisting benefit of bevaci- zumab that was previously shown in Evidence an interim survival analysis.32 Clinical recommendation rating References Physicians should consider refer- Cervical cancer is staged clinically before surgery, C 21 ring patients to regional cancer cen- based on tumor size, depth of invasion, spread into ters. A 2012 Cochrane review found surrounding tissue, and distant metastases. that women with gynecologic cancer Adjuvant platinum-based chemoradiation should be A 26 had prolonged survival when treated considered after surgery for women with early cervical at facilities with centralization of ser- cancer (stage IA2-IIA) and risk factors for recurrence vices, such as regional cancer centers because it has been shown to reduce mortality. or academic institutions, compared Adding bevacizumab (Avastin) to combination che- B 32 with women treated at community motherapy should be considered for women with hospitals.33 recurrent, persistent, or metastatic cervical cancer because it has been shown to improve overall survival. Prognosis Patients with cervical cancer should be referred to B 33 Prognosis is impacted by stage, tumor regional cancer centers with centralization of services. volume, depth of cervical stromal inva- A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality sion, metastases, and LVSI (Table 321,22). patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert Disease stage and lymph node status opinion, or case series. For information about the SORT evidence rating system, go to http:// are the two most prognostic factors. www.aafp.org/afpsort. For example, women with stage IA 452 American Family Physician www.aafp.org/afp Volume 97, Number 7 ◆ April 1, 2018  CERVICAL CANCER MANAGEMENT Pregnancy should receive annual pelvic examinations to monitor for Colposcopy without endocervical curettage is safe during local recurrence and radiation-induced pelvic cancer.38,40 pregnancy and preferred at 20 weeks’ gestation if indicated based on the American Society for Colposcopy and Cer- Patient Counseling vical Pathology guideline for managing an abnormal Pap Patients should be educated about symptoms of potential test result.37 Stage IA1 disease may be treated with coniza- recurrence and adverse effects of cervical cancer treatments tion.25 In women with more advanced disease, management (Table 5). Patients undergoing treatment may struggle with should be individualized based on stage, gestational age, sexual, bowel, and urinary dysfunction, especially after and desire for continuation of the pregnancy. Imaging for radiation.27 Women with ovarian failure may be treated staging should consider risk of fetal exposure to radiation with hormone therapy; however, there is limited evidence and contrast media, and the value of diagnostic accuracy of of its safety in cervical cancer survivors. the test compared with potentially safer studies. This article updates a previous article on this topic by Canavan and Doshi.41 Recurrence Data Sources: General searches were done using Essential Evi- Recurrence of cervical cancer occurs locoregionally dence Plus, UpToDate, DynaMed, the U.S. Preventive Services or as metastatic disease, usually within three years of Task Force website, and the Cochrane database. The American treatment.38 Therefore, initial close follow-up with a Society for Colposcopy and Cervical Pathology, Journal of Lower Genital Tract Disease, and Obstetrics and Gynecology gynecologist-oncologist for pelvic examinations at regu- websites were also searched for disease-specific information lar three- to six-month intervals is recommended for the and guidelines. A PubMed search was completed in Clinical first two to five years following treatment, depending on Queries using the key terms cervical cancer, fertility, pregnancy, risk of recurrence. Women with local recurrence may pres- and human papillomavirus. Search dates: January 5 through ent with vaginal discharge, vaginal bleeding, dyspareunia, November 10, 2017. or pelvic pain. On physical examination, physicians may palpate or visualize a mass at the vaginal cuff. Metastatic The Authors symptoms may be vague or related to the affected site, such JENNIFER WIPPERMAN, MD, MPH, is an assistant professor as bone pain. Imaging is not recommended unless other- in the Department of Family and Community Medicine at the wise indicated based on symptoms or physical examina- University of Kansas School of Medicine–Wichita. tion findings. TARA NEIL, MD, is an assistant professor in the Department After regular follow-up with a gynecologist-oncologist, of Family and Community Medicine at the University of Kan- low-risk women with early-stage disease may resume care sas School of Medicine–Wichita. with their primary care physicians after two to three years. TRACY WILLIAMS, MD, is an associate professor in the Annual cytology is performed for detection of lower geni- Department of Family and Community Medicine at the Uni- tal tract dysplasia, which occurs more often in women with versity of Kansas School of Medicine–Wichita. a history of cervical cancer.39 Cervical cancer survivors Address correspondence to Jennifer Wipperman, MD, MPH, University of Kansas School of Medicine, 1010 N. Kansas, TABLE 5 Wichita, KS 67214 (e-mail: jennifer.wipperman1@ascension. org). Reprints are not available from the authors. Patient Education Topics for Cervical Cancer Survivors References Symptoms of local recurrence: vaginal discharge, vaginal 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29. bleeding, dyspareunia, pelvic pain 2. Viens LJ, Henley SJ, Watson M, et al. Human papillomavirus-associated Sexual health: vaginal lubrication, vaginal dilators after cancers—United States, 2008-2012. MMWR Morb Mortal Wkly Rep. radiation, pelvic floor therapy, psychotherapy 2016;65(26):661-666. Long-term effects of treatment: cystitis, proctitis, ovarian 3. Beavis AL, Gravitt PE, Rositch AF. Hysterectomy-corrected cervical can- failure, chronic pelvic pain cer mortality rates reveal a larger racial disparity in the United States. Smoking cessation Cancer. 2017;123(6):1044-1050. Depression screening 4. Adegoke O, Kulasingam S, Virnig B. 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