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.
■The most common regimen for concurrent chemotherapy is once-weekly cisplatin, 40 mg/m2 IV (maximum 70 mg) for six cycles, concurrent with radiation. Alternatively, cisplatin with 5-FU given every 3 to 4 weeks during radiation is acceptable.
Stage IA1
■Prior to treatment, the most important variables include (1) the patient’s fertility desires, (2) medical operability, and (3) presence of LVSI from the biopsy.
■For patients with no LVSI and negative margins on their LEEP or CKC specimen, and who have completed childbearing, a simple hysterectomy is indicated.
■For those with LVSI or positive margins, a modified radical hysterectomy with pelvic lymph node dissection is indicated.
■For those who wish to preserve fertility, a conization with negative margins, followed by observation is adequate therapy. However, if margins are positive, options include radical trachelectomy or repeat cone biopsy.
■Para-aortic lymph node dissection is reserved for patients with known or suspected nodal disease.
Stages IA2, IB1, IIA1 (Early-Stage Disease)
■General options for early-stage disease include the following:
•Fertility sparing—radical trachelectomy and pelvic lymph node dissection with (or without) para-aortic lymph node dissection
•Modified radical hysterectomy and pelvic lymph node dissection with para-aortic lymph node dissection for known or suspected nodal disease
•Definitive chemoradiotherapy (whole pelvic radiation and brachytherapy)
■All options are equally effective but differ in associated morbidity and complications.
■For early-stage cervical cancers, primary surgery is often recommended rather than primary chemoradiation to avoid the long-term toxicities of radiation.
■Optimal choice depends on patient’s age and childbearing plans, disease stage, current comorbidities, and presence of histologic characteristics associated with increased risk of recurrence.
Stage IB2 or IIA2 (Bulky Disease)
■General options for bulky disease include the following:
•Definitive chemoradiotherapy (whole pelvic radiation and brachytherapy) is generally preferred.
•Radical hysterectomy plus pelvic lymph node dissection with para-aortic lymph node dissection for known or suspected nodal disease
■Radiologic imaging (including PET/CT) is recommended for assessing bulky disease.
■Concurrent radiation and cisplatin-based chemotherapy has been shown to improve patient survival.
Surgery
■Adjuvant hysterectomy after primary chemoradiation appears to improve pelvic control, but not OS and has increased morbidity. Postradiation (adjuvant) surgery is not routinely performed but may be considered in patients with residual tumor confined to the cervix or in patients with suboptimal brachytherapy because of vaginal anatomy.
■Laparoscopic and robotic approaches are associated with shortened recovery time, decreased hospital stay, and less blood loss. They are used routinely in many institutions with promising early outcome data.
■Radical trachelectomy is a fertility-preserving surgery, which may be an option for small-volume, early-stage disease (IA1–IB1).
■Para-aortic lymph node sampling may be indicated in patients with positive pelvic nodes, clinically enlarged nodes, or patients with large-volume disease.
Indications for Adjuvant Therapy
■High risk for recurrent disease:
•Positive or close margins
•Positive lymph nodes
•Positive parametrial involvement
■Intermediate risk for recurrent disease:
•LVSI
•Deep stromal invasion (greater than one-third)
•Large tumor size (greater than 4 cm)
Adjuvant Therapy
■Women who undergo a modified radical hysterectomy should receive adjuvant chemoradiation treatment in the presence of risk factors (as above).
•For women with intermediate risk factors, a randomized trial demonstrated that adjuvant RT improved progression-free survival (PFS) with a trend toward improved OS.
•For women with high risk factors a randomized trial demonstrated that adjuvant chemoradiation was associated with an improved PFS and OS.
■If definitive RT is chosen over radical hysterectomy, concurrent cisplatin-based chemotherapy should be administered.
Stages IIB, III, IV
■Patients with stage IIB to IVA (locally advanced) disease should be treated with tumor volume–directed radiation and concurrent cisplatin-based chemotherapy.
■Radiologic imaging (PET/CT) and potentially surgical staging (i.e., extraperitoneal or laparoscopic lymph node dissection) are recommended to assess nodal involvement to guide radiotherapy.
■Patients with IVA disease (bowel or bladder mucosal involvement) who are poor candidates for chemoradiation (i.e., acute or chronic pelvic inflammatory disease, coexistent pelvic mass) may be candidates for primary exenterative surgery.
■Patients who have distant metastasis (IVB disease) should receive systemic chemotherapy with or without individualized radiation.
Radiation Therapy
■For definitive treatment, pelvic external beam radiation therapy (EBRT) with intracavitary brachytherapy is routinely used.
■Higher doses of radiation can be delivered to the central primary tumor with the combination of EBRT and brachytherapy than with EBRT alone.
■In select cases of very early disease (stage IA2) brachytherapy alone may be an option.
■Pelvic inflammatory disease, inflammatory bowel disease, and pelvic kidney are relative contraindications to pelvic radiation.
■CT-based treatment planning is considered standard of care for EBRT.
■EBRT should cover the gross disease (vaginal margin 3 cm from tumor), parametria, uterosacral ligaments, and presacral, external/internal iliac, obturator nodes. For patients at high risk of nodal involvement, the radiation field should also cover common iliac nodes. If documented common iliac/para-aortic nodal involvement, extended field radiation up to the level of renal vessels is recommended.
■Both high-dose brachytherapy (isotope Iridium 192; rate 200 to 300 cGy per hour) and low-dose brachytherapy (isotope Cesium 137; rate 40 to 70 cGy per hour) are currently being used. The relative merits of each are under evaluation.
■Determining maximum effective dose to the primary tumor, as well as to the bladder and rectum, is of primary importance. A typical regimen of EBRT is 40 to 50 Gy, followed by 30 to 40 Gy to point A with brachytherapy for a total dose of 80 to 90 Gy to point A.
■Point A is located 2 cm cephalad and 2 cm lateral to the cervical OS. Anatomically, it correlates with the medial parametrium or lateral cervix, the point where the ureter and uterine artery cross.
■Depending on the extent of disease, a parametrial boost (10 to 15 Gy) with EBRT to a total dose of 60 Gy may be applied to point B (5 cm lateral to OS, corresponding to the pelvic-wall nodes).
■Radiation treatment is equivalent to surgery for stages IB and IIA, with identical 5-year OS and disease-free survival. Expected cure rate is 75% to 80% (85% to 90% in small-volume disease).
■A study by the Radiation Therapy Oncology Group (RTOG 79-20) showed a 11% 10-year survival advantage for patients with IB2, IIA, and IIB disease treated with prophylactic para-aortic nodal (extended field RT) and total pelvic irradiation compared to those treated with pelvic irradiation alone.
■Multivariate analysis has shown that a total dose of >8,500 cGy intracavitary radiation to point A (advanced stage only), use of chemosensitizers, and overall treatment time of <8 weeks are associated with improved pelvic tumor control and survival in cervical cancer patients. Extending treatment time beyond 6 to 8 weeks can result in 0.5% to 1% decrease in recurrence-free survival for each day beyond treatment.
Palliative Chemotherapy
■No standard chemotherapy regimen has been shown to produce prolonged complete remissions.
■Combination platinum-based chemotherapy has demonstrated improved response rates in randomized trials compared to single-agent therapy.
■Cisplatin/paclitaxel demonstrated higher response rate and improved PFS compared to single-agent cisplatin in Gynecologic Oncology Group (GOG) 169. Preliminary data from a Japanese randomized trial demonstrate equivalency of carboplatin/taxol with cisplatin/taxol.
■Cisplatin/topotecan demonstrated superior response rate, PFS, and median survival compared to single-agent cisplatin in GOG 179.
■A comparison trial of cisplatin/topotecan, cisplatin/gemcitabine, and cisplatin/vinorelbine compared to a control arm of cisplatin/paclitaxel was halted when the experimental arms were not superior to the control. Cisplatin/paclitaxel had the best response rate, 29.1%.
■Based on the above, cisplatin/paclitaxel and carboplatin/paclitaxel are the most commonly used regimens for metastatic and recurrent cervical cancer. Cisplatin/topotecan, cisplatin/gemcitabine or single-agent therapies are reasonable alternatives.
■The most active single agents include
•Cisplatin (response rate 20% to 30%)
•Carboplatin (response rate 15% to 28%)
•Ifosfamide (response rate 15% to 33%)
•Paclitaxel (response rate 17% to 25%)
■Other agents with activity include irinotecan, vinorelbine, gemcitabine, bevacizumab, docetaxel, 5-FU, mitomycin, topotecan, pemetrexed.
■The benefit of chemotherapy with or without radiation versus best supportive care in this patient population has not yet been established.
Special Considerations
■Recent studies have clearly demonstrated the deleterious effect of anemia on patients receiving RT. Hemoglobin <12 g/dL at the time of RT results in increased local recurrence and decreased survival. However, the use of transfusions or erythropoietin-stimulating agents has not been associated with improved survival and is associated with their own risk of complications.
■Some patients with small-volume disease in para-aortic lymph nodes and controllable pelvic disease can potentially be cured. However, radiation is of little use in gross para-aortic disease because surrounding organs (bowel, kidney, spinal cord, etc.) cannot tolerate the high doses of radiation required. For this reason, removal of grossly involved nodes prior to radiotherapy is indicated.
■Toxicity from standard para-aortic lymph node radiation is greater than from pelvic radiation alone, but is seen mostly in patients with prior abdominopelvic surgery.
■Different surgical techniques affect the incidence of complications secondary to para-aortic lymph node radiation. For example, extraperitoneal lymph node sampling leads to fewer postradiation complications than transperitoneal sampling.
■Intensity-modulated radiation therapy (IMRT) is likely to reduce sequelae of extended field para-aortic nodal irradiation and is becoming more widely available. However, its utility in cervical cancer continues to be evaluated in several clinical trials.
Recurrent Disease
■A 10% to 20% recurrence rate has been reported following primary surgery or radiotherapy in patients with stage IB to IIA disease with negative nodes; up to 70% of patients with more advanced-stage disease with or without positive nodes exhibit recurrences.
■Majority of local/regional recurrences are symptomatic and 80% to 90% are detected within the first 2 years posttreatment.
■Favorable prognostic factors include localized, central pelvic recurrence, not fixed to the sidewall, disease-free interval >6 months, and size of tumor <3 cm.
■More than 90% of patients with distant recurrence will die of disease within 5 years.
■For early-stage disease, the predominant site of recurrence is local (vaginal apex) or regional (pelvic sidewall).
■Multiple studies have demonstrated the sites of recurrence as indicated:
•Central (vaginal apex)—22% to 56%
•Regional (pelvic sidewall)—28% to 37%
•Distant metastasis—15% to 61%
■Patients with positive nodes, particularly para-aortic, at primary diagnosis have higher risk of distant metastasis than patients with negative nodes.
■No curative therapy is available for distant recurrent disease. However, local recurrence can potentially be treated with curative intent.
■Surgical resection of limited metastatic disease, such as in the lung, may result in prolonged clinical remission.
■For patients with recurrence in the pelvis after radical surgery, radiation combined with cisplatin has a 40% to 50% cure rate.
■Pelvic exenteration (resection of the bladder, rectum, vagina, uterus/cervix) is the preferred treatment for centrally located recurrent disease after radiation, with a 32% to 62% 5-year survival in select patients. Reconstructive procedures include continent urinary conduit, end-to-end rectosigmoid reanastomosis, and myocutaneous graft for a neovagina.
■High-dose intraoperative RT combined with surgical resection is offered by some centers for patients whose tumors extend close to the pelvic sidewalls.
■Chemotherapy for distant recurrent disease is palliative, not curative, demonstrating low response rates, short response duration, and low OS rates (see the Palliative Chemotherapy section). Cisplatin is the most active single agent, with a median survival of 7 months.
■Factors associated with higher likelihood of failure to cisplatin-based combination chemotherapy include
•Black race
•Performance status 1 or 2
•Disease in the pelvis
•Prior treatment with cisplatin
•Recurrence within 1 year of diagnosis
■Chemotherapy-naive patients have a higher response rate than those exposed to chemotherapy as part of their initial treatment.
TREATMENT DURING PREGNANCY
■Cervical cancer is the most common gynecologic malignancy associated with pregnancy, ranging from 1 in 1,200 to 1 in 2,200 pregnancies.
■No therapy is warranted for preinvasive lesions; colposcopy, but not endocervical curettage, is recommended to rule out invasive cancer.
■Conization is reserved for suspicion of invasion or for persistent cytologic evidence of invasive cancer in the absence of colposcopic confirmation. Management of dysplasia is usually postponed until postpartum.
■Treatment of invasive cancer depends on the tumor stage and the fetus’s gestational age. If cancer is diagnosed before fetal maturity, immediate appropriate cancer therapy for the relevant stage is recommended. However, with close surveillance, delay of therapy to achieve fetal maturity is a reasonable option for patients with stage IA and early IB disease. For more advanced disease, delaying therapy is not recommended unless diagnosis is made in the final trimester. When the fetus reaches acceptable maturity, a cesarean section precedes definitive treatment.
TREATMENT OF HIV-POSITIVE PATIENTS
■HIV-infected women (or immunocompromised) should undergo cervical cancer screening twice in the first year after diagnosis and then annually.
■Each examination should include a thorough visual inspection of the anus, vulva, vagina, as well as the cervix.
■The American College of Obstetricians and Gynecologists and the Centers for Disease Control do not endorse HPV testing in the triage of HIV-infected patients. This conflicts with 2006 American Society for Colposcopy and Cervical Pathology Consensus Guidelines, which endorse similar management of patients irrespective of HIV status.
■Treatment of preinvasive lesions and cervical cancer in HIV-positive patients is the same as in HIV-negative patients, though response to therapy is usually poorer.
■Incidence of CIN is four to five times higher in HIV-positive women compared to HIV-negative women with high-risk behaviors.
■Among HIV-infected women, rates of oncogenic HPV and high-grade CIN increase with diminished CD4 counts and higher HIV RNA levels.
■Women with HIV are more likely to have persistent HPV and CIN than uninfected women.
■Although anti-retroviral therapy has altered the natural history of HIV, its effect on HPV and HPV-associated neoplasia is less clear.
FOLLOW-UP AFTER PRIMARY THERAPY
■Eighty percent to 90% of recurrences occur within 2 years of completing therapy suggesting a role for increased surveillance during this period.
■Follow-up visits, including thorough physical examination, should occur every 3 to 6 months in the first 2 years posttreatment, every 6 to 12 months for the following 3 years then annually to detect any potentially curable recurrences.
■Additionally, patients should have annual cervical or vaginal cytology, though an exception can be made for those that have undergone pelvic radiation.
■There are insufficient data to support the routine use of radiographic imaging; chest x-ray, CT, and PET should only be used if recurrence is suspected.
■Patients should be counseled about signs and symptoms of recurrence to include persistent abdominal and pelvic pain, leg symptoms such as pain or lymphedema, vaginal bleeding or discharge, urinary symptoms, cough, weight loss, and anorexia.
PREVENTION
■The efficacy of vaccination against HPV-16 and -18 to prevent high-grade CIN has been demonstrated in multiple studies since 2002. The Centers for Disease Control and Prevention now recommend that males and females aged 11 and 12 years be vaccinated. Vaccines may be administered as early as age 9 with catch up through age 26 in females and 21 in males (with “permissive use” through age 26). The vaccine is also recommended for gay, bisexual men, and men with compromised immune systems (including HIV) through age 26, if they did not get fully vaccinated when they were younger.
REVIEW QUESTIONS
1.A 35-year-old female has recently been diagnosed with cervical cancer. She is now in your office and after discussing her particular case, she asks about cervical cancer in the broader population. You tell her that all the following epidemiologic factors are true, EXCEPT:
A.Worldwide, cervical cancer is the fourth leading cause of cancer death in women.
B.Herpes simplex virus (HSV) is thought to be the causative agent in the majority of the cases.
C.Incidence of cervical cancer is higher in African American and Latino women compared to Caucasians in the United States.
D.During past 50 years, death rates from cervical cancer have decreased due to routine screening with Pap smears.
2.A 43-year-old patient is diagnosed with squamous cell cervical carcinoma after physical examination and cervical biopsy. All of the following risk factors are associated with metastatic disease EXCEPT:
A.Presence of microinvasion
B.Depth of invasion
C.Tumor size
D.Presence of LVSI
3.A 38-year-old patient presents with a 1-year history of bleeding after intercourse. She has not a Pap smear in 6 years. During a speculum examination, a 3 cm cervical lesion is seen and biopsied. The results of the biopsy show cervical adenocarcinoma. In regard to her staging all of the following are true EXCEPT:
A.If hydronephrosis was seen on CT scan, she would be stage IIIB.
B.MRI is the best imaging modality for determining soft-tissue and parametrial involvement.
C.Staging for cervical cancer is clinical, involving pelvic examination.
D.If enlarged lymph nodes were seen on CT scan, she would be at least a stage III.
4.A 51-year-old female with history of abnormal Pap smears presents with postcoital bleeding. On examination she has a 2 cm visible lesion on her cervix. A rectovaginal examination reveals no evidence of parametrial spread. After cervical biopsy and further evaluation she is diagnosed with stage IB1 squamous cervical cancer. The best treatment option for her includes
A.Simple hysterectomy
B.Radical hysterectomy with pelvic lymph node dissection or primary chemoradiation
C.Radical trachelectomy
D.Cervical conization
5.A 42-year-old patient with stage IIIB cervical cancer develops a recurrence in her cervix less than 2 years from the completion of treatment. She had received primary chemoradiation at the time of her initial diagnosis. Current imaging shows a central pelvic tumor with no metastatic disease. The only treatment option that has a chance for cure in this setting is
A.Chemotherapy with combined cisplatin and topotecan
B.Chemotherapy with combined cisplatin and paclitaxel
C.Referral back to radiation oncology for consideration of further radiation
D.Referral to gynecologic oncology for consideration of pelvic exenteration
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