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National Cancer Institute
Last Modified: June 22, 2012
Estimated new cases and deaths from cervical (uterine cervix) cancer in the United States in 2012: 1
The prognosis for patients with cervical cancer is markedly affected by the extent of disease at the time of diagnosis. A vast majority (>90%) of these cases can and should be detected early through the use of the Pap test and human papillomavirus (HPV) testing; however, 2 the current death rate is far higher than it should be, which reflects that, even today, the Pap test and HPV testing are not done on approximately 33% of eligible women. Clinical stage, however, as a prognostic factor must be supplemented by several gross and microscopic pathologic findings in surgically treated patients. These include: volume and grade of tumor, histologic type, lymphatic spread, and vascular invasion.
In a large surgicopathologic staging study of patients with clinical stage IB disease reported by the Gynecologic Oncology Group (GOG) (GOG-49), the factors that predicted most prominently for lymph node metastases and a decrease in disease-free survival were capillary-lymphatic space involvement by tumor, increasing tumor size, and increasing depth of stromal invasion, with the latter being most important and reproducible. 3 4 In a study of 1,028 patients treated with radical surgery, survival rates correlated more consistently with tumor volume (as determined by precise volumetry of the tumor) than clinical or histologic stage. 5
A multivariate analysis of prognostic variables in 626 patients with locally advanced disease (primarily stages II, III, and IV) studied by the GOG identified several variables that were significant for progression-free interval and survival: 6
The study confirmed the overriding importance of positive periaortic nodes and suggested further evaluation of these nodes in locally advanced cervical cancer. The status of the pelvic nodes was important only if the periaortic nodes were negative. This was also true for tumor size.
In a large series of cervical cancer patients treated by radiation therapy, the incidence of distant metastases (most frequently to lung, abdominal cavity, liver, and gastrointestinal tract) was shown to increase as the stage of disease increased, from 3% in stage IA to 75% in stage IVA. 7 A multivariate analysis of factors influencing the incidence of distant metastases showed stage, endometrial extension of tumor, and pelvic tumor control to be significant indicators of distant dissemination. 7
GOG studies have indicated that prognostic factors vary whether clinical or surgical staging are utilized, and with treatment. Delay in radiation delivery completion is associated with poorer progression-free survival when clinical staging is used. It is unclear whether stage, tumor grade, race, and age hold up as prognostic factors in studies utilizing chemoradiation. 8
Whether adenocarcinoma of the cervix carries a significantly worse prognosis than squamous cell carcinoma of the cervix remains controversial. 9 Reports conflict about the effect of adenosquamous cell type on outcome. 10 11 One report showed that approximately 25% of apparent squamous tumors have demonstrable mucin production and behave more aggressively than their pure squamous counterparts, suggesting that any adenomatous differentiation may confer a negative prognosis. 12 The decreased survival is mainly the result of more advanced stage and nodal involvement rather than cell type as an independent variable. Women with human immunodeficiency virus have more aggressive and advanced disease and a poorer prognosis. 13 A study of patients with known invasive squamous carcinoma of the cervix found that overexpression of the C-myc oncogene was associated with a poorer prognosis. 14 The number of cells in S phase may also have prognostic significance in early cervical carcinoma. 15 HPV type 18 DNA has been found to be an independent adverse molecular prognostic factor. Two studies have shown a worse outcome when identified in cervical cancers of patients undergoing radical hysterectomy and pelvic lymphadenectomy. 16 17
Molecular techniques for the identification of HPV DNA are highly sensitive and specific. More than 6 million women in the United States are estimated to have HPV infection, and proper interpretation of these data is important. Epidemiologic studies convincingly demonstrate that the major risk factor for development of preinvasive or invasive carcinoma of the cervix is HPV infection, which far outweighs other known risk factors such as high parity, increasing number of sexual partners, young age at first intercourse, low socioeconomic status, and positive smoking history. 18 19 Some patients with HPV infection appear to be at minimal increased risk for development of cervical preinvasive and invasive malignancies, while others appear to be at significant risk and are candidates for intensive screening programs and/or early intervention.
HPV DNA tests are unlikely to separate patients with low-grade squamous intraepithelial lesions into those who do and those who do not need further evaluation. A study of 642 women found that 83% had one or more tumorigenic HPV types when cervical cytologic specimens were assayed by a sensitive (hybrid capture) technique. 20 The authors of the study and of an accompanying editorial concluded that using HPV DNA testing in this setting does not add sufficient information to justify its cost. 20 HPV DNA testing has proven useful in triaging patients with atypical squamous cells of undetermined significance to colposcopy and has been integrated into current screening guidelines. 20 21 22 Patients with an abnormal cytology of a high-risk type (Bethesda classification) should be thoroughly evaluated with colposcopy and biopsy.
Other studies show patients with low-risk cytology and high-risk HPV infection with types 16, 18, and 31 are more likely to have cervical intraepithelial neoplasia (CIN) or microinvasive histopathology on biopsy. 19 23 24 25 One method has also shown that integration of HPV types 16 and 18 into the genome, leading to transcription of viral and cellular messages, may predict patients who are at greater risk for high-grade dysplasia and invasive cancer. 26 Studies suggest that acute infection with HPV types 16 and 18 conferred an 11- to 16.9-fold risk of rapid development of high-grade CIN, 19 27 but there are conflicting data requiring further evaluation before any recommendations may be made. Patients with low-risk cytology and low-risk HPV types have not been followed long enough to ascertain their risk. At present, studies are ongoing to determine how HPV typing can be used to help stratify women into follow-up and treatment groups. HPV typing may prove useful, particularly in patients with low-grade cytology or cytology of unclear abnormality. At present, how therapy and follow-up should be altered with low- versus high-risk HPV type has not been established.
Squamous cell (epidermoid) carcinoma comprises approximately 90%, and adenocarcinoma comprises approximately 10% of cervical cancers. Adenosquamous and small cell carcinomas are relatively rare. Primary sarcomas of the cervix have been described occasionally, and malignant lymphomas of the cervix, primary and secondary, have also been reported.
Cervical carcinoma has its origins at the squamous-columnar junction whether in the endocervical canal or on the portion of the cervix. The precursor lesion is dysplasia or carcinoma in situ (cervical intraepithelial neoplasia [CIN]), which can subsequently become invasive cancer. This process can be quite slow. Longitudinal studies have shown that in untreated patients with in situ cervical cancer, 30% to 70% will develop invasive carcinoma over a period of 10 to 12 years. However, in about 10% of patients, lesions can progress from in situ to invasive in a period of less than 1 year. As it becomes invasive, the tumor breaks through the basement membrane and invades the cervical stroma. Extension of the tumor in the cervix may ultimately manifest as ulceration, exophytic tumor, or extensive infiltration of underlying tissue including bladder or rectum.
In addition to local invasion, carcinoma of the cervix can spread via the regional lymphatics or bloodstream. Tumor dissemination is generally a function of the extent and invasiveness of the local lesion. While cancer of the cervix generally progresses in an orderly manner, occasionally a small tumor with distant metastasis is seen. For this reason, patients must be carefully evaluated for metastatic disease.
Pretreatment surgical staging is the most accurate method to determine the extent of disease. 1 Because there is little evidence to demonstrate overall improved survival with routine surgical staging, the staging usually should be performed only as part of a clinical trial. Pretreatment surgical staging in bulky but locally curable disease may be indicated in select cases when a nonsurgical search for metastatic disease is negative. If abnormal nodes are detected by computed tomography scan or lymphangiography, fine-needle aspiration should be negative before a surgical staging procedure is performed.
The Féderation Internationale de Gynécologie et d'Obstétrique (FIGO) and the American Joint Committee on Cancer (AJCC) have designated staging to define cervical cancer; the FIGO system is most commonly used. 2 3
|I||The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded).|
|IA||Invasive carcinoma, which can be diagnosed only by microscopy with deepest invasion 5 mm and largest extension 7 mm.|
|IA1||Measured stromal invasion of 3.0 mm in depth and extension of 7.0 mm.|
|IA2||Measured stromal invasion of >3.0 mm and not >5.0 mm with an extension of not >7.0 mm.|
|IB||Clinically visible lesions limited to the cervix uteri or preclinical cancers greater than stage IA.b|
|IB1||Clinically visible lesion 4.0 cm in greatest dimension.|
|IB2||Clinically visible lesion >4.0 cm in greatest dimension.|
|II||Cervical carcinoma invades beyond the uterus but not to the pelvic wall or to the lower third of the vagina.|
|IIA||Without parametrial invasion.|
|IIA1||Clinically visible lesion 4.0 cm in greatest dimension.|
|IIA2||Clinically visible lesion >4.0 cm in greatest dimension.|
|IIB||With obvious parametrial invasion.|
|III||The tumor extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or nonfunctioning kidney.c|
|IIIA||Tumor involves lower third of the vagina with no extension to the pelvic wall.|
|IIIB||Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney.|
|IV||The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to stage IV.|
|IVA||Spread of the growth to adjacent organs.|
|IVB||Spread to distant organs.|
|The involvement of vascular/lymphatic spaces should not change the stage allotment.|
Five randomized phase III trials (GOG-85, RTOG-9001, GOG-120, GOG-123, and SWOG-8797) have shown an overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy, 1 2 3 4 5 6 while one trial examining this regimen demonstrated no benefit. 7 The patient populations in these studies included women with Féderation Internationale de Gynécologie et d'Obstétrique (FIGO) stages IB2 to IVA cervical cancer treated with primary radiation therapy and women with FIGO stages I to IIA disease found to have poor prognostic factors (metastatic disease in pelvic lymph nodes, parametrial disease, or positive surgical margins) at the time of primary surgery. Although the positive trials vary in terms of the stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrate significant survival benefit for this combined approach. The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy. Based on these results, strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer. 1 2 3 4 5 6 7 8 9
Surgery and radiation therapy are equally effective for early-stage small-volume disease. 10 Younger patients may benefit from surgery in regard to ovarian preservation and avoidance of vaginal atrophy and stenosis.
Patterns of care studies clearly demonstrate the negative prognostic effect of increasing tumor volume. Treatment, therefore, may vary within each stage as currently defined by FIGO and will depend on tumor bulk and spread pattern. 11
Therapy of patients with cancer of the cervical stump is effective, yielding results comparable to those seen in patients with an intact uterus. 12
Cervical cancer during pregnancy
During pregnancy, no therapy is warranted for preinvasive lesions of the cervix, including carcinoma in situ, though expert colposcopy is recommended to exclude invasive cancer. Treatment of invasive cervical cancer during pregnancy depends on the stage of the cancer and gestational age at diagnosis. The traditional approach is to recommend immediate therapy appropriate for the disease stage when the cancer is diagnosed before fetal maturity and to delay therapy only if the cancer is detected in the final trimester. 13 14 However, other reports suggest that deliberate delay of treatment to allow improved fetal outcome may be a reasonable option for patients with stage IA and early IB cervical cancer. 15
Consensus guidelines have been issued for managing women with cervical intraepithelial neoplasia or adenocarcinoma in situ. 1 Properly treated, tumor control of in situ cervical carcinoma should be nearly 100%. Either expert colposcopic-directed biopsy or cone biopsy is required to exclude invasive disease before therapy is undertaken. A correlation between cytology and colposcopic-directed biopsy is also necessary before local ablative therapy is done. Even so, unrecognized invasive disease treated with inadequate ablative therapy may be the most common cause of failure. 2 Failure to identify the disease, lack of correlation between the Pap smear and colposcopic findings, adenocarcinoma in situ, or extension of disease into the endocervical canal makes a laser, loop, or cold-knife conization mandatory. The choice of treatment will also depend on several patient factors including age, desire to preserve fertility, and medical condition. Most importantly, the extent of disease must be known.
In selected cases, the outpatient loop electrosurgical excision procedure (LEEP) may be an acceptable alternative to cold-knife conization. This quickly performed in-office procedure requires only local anesthesia and obviates the risks associated with general anesthesia for cold-knife conization. 3 4 However, controversy exists as to the adequacy of LEEP as a replacement for conization. 5 A trial comparing LEEP with cold-knife cone biopsy showed no difference in the likelihood of complete excision of dysplasia. 6 However, two case reports suggested that the use of LEEP in patients with occult invasive cancer led to an inability to accurately determine depth of invasion when a focus of the cancer was transected. 7
Standard treatment options:
When the endocervical canal is involved, laser or cold-knife conization may be used for selected patients to preserve the uterus and avoid radiation therapy and/or more extensive surgery.
Total abdominal or vaginal hysterectomy is an accepted therapy for the postreproductive age group and is particularly indicated when the neoplastic process extends to the inner cone margin. For medically inoperable patients, a single intracavitary insertion with tandem and ovoids for 5,000 mg hours (80 Gy vaginal surface dose) may be used. 12
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IA cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Either radiation therapy or radical hysterectomy and bilateral lymph node dissection results in cure rates of 85% to 90% for women with Féderation Internationale de Gynécologie et d'Obstétrique (FIGO) stages IA2 and IB1 small-volume disease. The choice of either treatment depends on patient factors and available local expertise. A randomized trial reported identical 5-year overall survival (OS) and disease-free survival rates when comparing radiation therapy to radical hysterectomy. 1 The size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy. 2 For adenocarcinomas that expand the cervix more than 4 cm, the primary treatment should be concomitant chemotherapy and radiation therapy. 3
After surgical staging, patients found to have small volume para-aortic nodal disease and controllable pelvic disease may be cured with pelvic and para-aortic radiation therapy and concomitant chemotherapy. 4 The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative chemotherapy and radiation therapy. 5 Treatment of patients with unresected periaortic nodes with extended-field radiation therapy and chemotherapy leads to long-term disease control in those patients with low volume (<2 cm) nodal disease below L3. 6 A single study (RTOG-7920) showed a survival advantage in patients with tumors larger than 4 cm who received radiation therapy to para-aortic nodes without histologic evidence of disease. 7 Toxic effects were greater with para-aortic radiation therapy than with pelvic radiation therapy alone but were mostly confined to patients with prior abdominopelvic surgery. 7 Patients who underwent extraperitoneal lymph node sampling had fewer bowel complications than those who had transperitoneal lymph node sampling. 6 8 9 Patients with close vaginal margins (<0.5 cm) may also benefit from pelvic radiation therapy. 10
Five randomized phase III trials have shown an OS advantage for cisplatin-based therapy given concurrently with radiation therapy, 11 12 13 14 15 16 while one trial examining this regimen demonstrated no benefit. 17 The patient populations in these studies included women with FIGO stages IB2 to IVA cervical cancer treated with primary radiation therapy, and women with FIGO stages I to IIA disease who, at the time of primary surgery, were found to have poor prognostic factors, which included the following:
Although the positive trials vary somewhat in terms of the stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrate significant survival benefit for this combined approach. The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy. Based on these results, strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer. 11 12 13 14 15 16 17 18 19
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IB cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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