■ Cervical Cancer

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Cervical Cancer

Sharon Romano Fitzgerald, Michael P. Stany, and Chad A. Hamilton

EPIDEMIOLOGY

■Worldwide, cervical cancer is the third most common cancer and the fourth leading cause of cancer death in women.

■In 2008, more than 529,800 new cases were diagnosed worldwide; an estimated 275,100 women die each year of this disease.

■In the United States, cervical cancer is the third most common cancer of the female reproductive tract, with more than 12,170 new cases and 4,220 deaths estimated in 2012.

■Introduction of Papanicolaou (Pap) smear screening has reduced the incidence and mortality of invasive cervical cancer by almost 75% over the last 50 years; however, 86% of cases occur in developing countries where screening may not be available.

■Cervical cancer incidence in the United States is decreasing but remains disproportionately high among subgroups of the population (Asians, African Americans, Latinos, Native Americans).

■In more developed areas, the cumulative risk of developing cervical cancer by age 75 is 0.9% and the mortality risk is 0.3%; in less developed areas, those risks are 1.9% and 1.1%, respectively.

RISK FACTORS

Human Papillomavirus

■Persistent human papillomavirus (HPV) infection is the most important factor in developing cervical cancer and greater than 99% of cervical cancers harbor HPV DNA.

■Approximately 40 distinct HPV types are known to infect the genital tract, and at least 15 types have been associated with cancer.

■HPV viruses of high oncogenic potential that are associated with cervical cancer include types 16, 18, 31, 33, 35, 45, 52, and 58. HPV types 16, 18, and 45 presented at a younger mean age than other HPV subtypes.

■HPV types 16 and 18 account for 70% of cervical cancer.

■In the United States, up to 50% of sexually active young women will be HPV (+) within 36 months of sexual activity; however, most women clear the infection within 8 to 24 months.

■Prevalence of HPV in countries with high incidence of cervical cancer is 10% to 20% and in countries with lower incidence of cervical cancer is 5% to 10%.

■The oncogenic effect of the high-risk HPV subtypes appears to be mediated by E6 and E7 proteins, which have been shown to inactivate tumor-suppressor genes p53 and pRb, respectively. The subsequent loss of the cell-cycle regulatory mechanism leads to malignant transformation.

■Current clinical data show no evidence that determining whether an invasive cervical cancer harbors HPV influences clinical outcome or management. Therefore, routine HPV typing of cancers is not recommended except in clinical trials. For patients with cervical intraepithelial neoplasia (CIN), the presence of high-risk HPV serotypes increases the risk of invasive disease.

Demographic, Personal, or Sexual Risk Factors

■Risk of invasive cervical cancer is largely influenced by HPV exposure, vaccination, and screening as well as immune response to HPV infection.

■Demographic risk factors include race (higher in Hispanic/Latino, African American, and Native American women), lower socioeconomic status, and immigration from HPV high-prevalence or low-screening countries.

■Personal risk factors include early onset of coitus (relative risk [RR] is twofold for younger than 18 years compared to 21 years or older), multiple sex partners (RR is threefold with six or more partners compared to one partner), and a history of sexually transmitted infections.

■Among males with multiple sex partners (a known risk factor for HPV infection), penile circumcision appears to reduce the risk of cervical cancer for their female partners.

■Smoking increases the RR of squamous cell cervical cancer fourfold and has been shown to accelerate progression of dysplasia to invasive carcinoma twofold.

■Additional risk factors include multiparity (RR = 3.8), use of oral contraceptives for more than 5 years (RR of 1.90), and immunosuppression.

■Renal transplantation (RR = 5.7) and HIV infection (RR = 2.5) increase the risk of cervical cancer. (Cervical cancer is an indicator condition in the case definition of AIDS in HIV-positive women according to the 1993 Centers for Disease Control and Prevention criteria.)

SCREENING

■Joint national guidelines provide the following consensus screening recommendations:

•Cervical cancer screening of women in the general population should begin no sooner than age 21.

•Women aged 21 to 29 should be screened with cervical cytology alone every 3 years.

•In women aged 30 to 65, cotesting with cervical cytology and HPV testing every 5 years is preferred. Continued screening with cervical cytology every 3 years is acceptable.

•Screening should end at age 65 in women with negative prior screening and no history of CIN 2 or greater. Likewise, it should end in women who have had a (total) hysterectomy with removal of the cervix and no prior history of CIN 2 or greater.

■Cervical cytology should be described using the 2001 Bethesda System detailing specimen adequacy and interpretation.

■Interpretation is divided into nonmalignant findings and epithelial cell abnormalities including squamous and glandular abnormalities.

■Adenocarcinoma incidence has been increasing over past three decades because Pap screening is often inadequate for detecting endocervical lesions; however, HPV screening and vaccine may decrease both squamous and adenocarcinoma rates.

PRECURSOR LESIONS

■Mild, moderate, and severe cervical dysplasias are categorized as CIN 1, 2, and 3, respectively.

■Mild-to-moderate dysplasias are more likely to regress than progress. Nevertheless, the rate of progression of mild dysplasia to severe dysplasia is 1% per year; the rate of progression of moderate dysplasia to severe dysplasia is 16% within 2 years and 25% within 5 years.

■Untreated carcinoma in situ (CIN 3) has a 30% probability of progression to invasive cancer within 30 years.

SIGNS AND SYMPTOMS

■CIN and early cervical cancer are often asymptomatic.

■In symptomatic patients, abnormal vaginal bleeding (i.e., postcoital, intermenstrual, or menorrhagia) is the most common symptom and may lead to anemia-related fatigue.

■Vaginal discharge (serosanguinous or yellowish, sometimes foul smelling) may represent a more advanced lesion.

■Pain in the lumbosacral or gluteal area may suggest hydronephrosis caused by tumor, or tumor extension to lumbar roots.

■Urinary or rectal symptoms (hematuria, rectal bleeding, etc.) may indicate bladder or rectal involvement.

■Persistent, unilateral, or bilateral leg edema may indicate lymphatic and venous blockage caused by extensive pelvic-wall disease.

■Leg pain, edema, and hydronephrosis are characteristic of advanced-stage disease (IIIB).

DIAGNOSTIC WORKUP

■History and physical examination should include bimanual pelvic and rectovaginal examinations. These are usually normal with stage IA disease (microscopic invasion only).

■The most frequent examination abnormalities include visible cervical lesions or abnormalities on bimanual pelvic examination.

■About 15% of adenocarcinomas have no visible lesion because the carcinoma is within the endocervical canal.

Standard Diagnostic Procedures

■Cervical cytology for routine screening and in the absence of a gross lesion

■Cervical biopsy of any gross lesion (may be colposcopically guided)

■Conization for subclinical tumor or after negative biopsy if malignancy is suspected

■Conization for microinvasive cancer to determine appropriate treatment

■Endocervical curettage for suspected endocervical lesions

■Cystoscopy and proctoscopy for symptoms concerning for bladder or rectal extension

Radiologic Studies

■Because of limits of low-resource countries, International Federation of Gynecology and Obstetrics (FIGO) limits imaging for staging purposes to chest x-ray, intravenous pyelography (IVP), and barium enema.

■When available for treatment planning purposes, recommended imaging may include CT or combined PET/CT and MRI.

■MRI is the best imaging modality for determining soft-tissue and parametrial involvement.

■CT or PET/CT is useful to evaluate nodal involvement and/or volume.

Laboratory Studies

■Complete blood count

■Blood chemistries

■Liver and renal function tests

HISTOLOGY

■Cervical carcinoma originates at the squamo-columnar junction, or transformation zone, of the cervix.

■Seventy-five percent to 80% of cervical cancers are of squamous cell histology; the remaining 20% to 25% are mostly adenocarcinomas or adenosquamous carcinomas.

STAGING

■Because the global burden of cervical cancer is in low-resource countries where abilities to surgically stage may be limited, cervical cancer is clinically staged according to the 2010 FIGO definitions and staging system. This system has been approved by the American Joint Committee on Cancer (AJCC) (see AJCC Cancer Staging Manual, seventh edition).

■Laparoscopy, lymphangiography, CT, MRI, and FDG-PET may be used for treatment planning.

PROGNOSTIC FACTORS

■Major prognostic factors are stage, nodal involvement, tumor volume, depth of cervical stroma invasion, lymphovascular space invasion (LVSI), and to a lesser extent histologic type and grade.

■Stage is the most important prognostic factor followed by lymph node involvement. The prognostic impact of squamous carcinoma versus adenocarcinoma remains controversial.

■Five-year survival based on extent of tumor at diagnosis:

•Localized: 92%

•Regional: 56%

•Distant spread: 16.5%

•Unstaged at diagnosis: 60%

MODE OF SPREAD

■Spread is usually orderly along lymphovascular planes into the parametria. It may extend to the vaginal mucosa or endomyometrium, or by direct extension into adjacent structures.

■Ovarian involvement by direct extension of cervical cancer is rare (0.5% of squamous cell carcinomas, 1.7% adenocarcinomas).

■Lymphatic spread most commonly involves pelvic and para-aortic lymph nodes.

■Hematogenous spread is typically a late occurrence but most commonly involves lung, liver, and bone.

■Risk of pelvic lymph node metastasis increases with increasing depth of tumor invasion and size, and presence of LVSI.

TREATMENT

(High-Grade Dysplasia/Carcinoma In Situ)

■AJCC includes stage 0 for in situ disease (Tis), while FIGO no longer includes stage 0 (Tis).

■Noninvasive lesions can be treated with electrosurgical excision, cryotherapy, laser excision or ablation, surgical conization, or other surgical procedures.

■A one-step diagnostic and therapeutic option is the loop electrosurgical excision procedure (LEEP), which allows excision of the entire transformation zone of the cervix with a low-voltage diathermy loop.

■A cold-knife conization (CKC) excises the transformation zone with a scalpel, avoiding cautery artifact on the surgical margins. In the majority of situations, LEEP may be an acceptable alternative to CKC because it is a quick, outpatient procedure requiring only local anesthesia.

■When margin status will dictate the need for, and type of, additional therapy, as in cases of adenocarcinoma in situ or microinvasive squamous cell carcinoma, a CKC is preferred.

■Extrafascial (i.e., simple or total) hysterectomy is preferred for management of adenocarcinoma in situ in women who have completed childbearing. If preservation of fertility is desired, conization with negative margins followed by surveillance is reasonable.

Invasive Cervical Cancer

■Treatment in each stage may vary depending on the size of the tumor. Smaller tumors may be treated surgically or with radiation. Larger tumors are usually only treated with radiation.

■Results from five randomized phase 3 trials demonstrated an overall survival (OS) advantage for cisplatin-based chemotherapy given concurrently with radiation when compared to radiation-only therapy. These trials have demonstrated a 30% to 50% overall reduction in risk of death in patients with FIGO stage IB2 to IVA tumors and in patients with FIGO I to IIA tumors with poor prognostic factors (i.e., pelvic lymph node involvement, parametrial disease, and positive surgical margins) compared to radiation alone.

■Based on these data, the National Cancer Institute issued a clinical announcement stating that strong consideration should be given to adding chemotherapy to radiation therapy (RT) in the treatment of invasive cervical cancer.

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