Cervical Carcinomas: Diagnosis and Management
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
Globally, cervical cancer is a major health problem, with a yearly incidence of 371,000 cases and an annual death rate of 190,000. 78% of cases occur in developing countries where cervical cancer is the second most frequent cause of cancer-related death in women. Invasive cervical carcinoma, once the most common reproductive-tract cancer in the United States, has recently fallen to the rank of third most common. The American Cancer Society estimates that 12,900 new cases of cervical cancer would be diagnosed in the United States in 2001 and 4,400 deaths from cervical cancer would result. The substantial decrease in incidence and mortality in developed countries is thought to be a result of effective screening (1).
The purpose of this document is to describe staging criteria and treatment for cervical carcinoma. For practical purposes, it will focus on the squamous and adenocarcinoma histologies only. In addition, new evidence has documented conclusively that survival rates for women with cervical cancer improve when radiotherapy is combined with cisplatin-based chemotherapy in advanced cases.
Human papilloma-virus (HPV) is considered the most important factor contributing to the development of cervical neoplasia and cervical cancer. High-risk types of HPV (16, 18, 31, 33, 35, 39,45, 51, 52, 56, 58) are detected in more than 85% of all cervical cancers. Other risk factors include history of sexual intercourse at an early age, multiple sexual partners, sexually transmitted diseases (including chlamydia) and smoking. Additional risk factors include a male partner or partners who have had multiple sexual partners; previous history of squamous dysplasia of the cervix, vagina or vulva; and immunosuppression such as after organ transplantation or patients with HIV/AIDS.
The two major histologic types of invasive cervical carcinomas are squamous cell carcinomas and adenocarcinomas. Squamous cell carcinomas comprise 80% of cases, and adenocarcinoma or adenosquamous carcinoma comprise approximately 15%. The remaining cases are made up of various rare histologies, which may have very different biologic behavior. In 1994, FIGO, in an attempt to better qualify the definition of microinvasive carcinoma of the cervix, adopted the following definition for microinvasive carcinoma of the cervix. Stage Ia1 cancers would be those with stromal invasion up to 3 mm in depth and no greater than 7 mm. Stage Ia2 would be when invasion is present at 3-5 mm in depth and no greater than 7 mm. Lymphatic vascular space involvement would not exclude a patient from this definition (2).
Diagnosis and Guidelines for Clinical Staging of Invasive Cervical Carcinoma:
The signs and symptoms of early cervical carcinoma include watery discharge, intermittent spotting, and post-coital bleeding. Often the symptoms go unrecognized by the patient. Because of the accessibility of the cervix, accurate diagnosis often can be made with cytologic screening, colopscopically directed biopsy, or biopsy of a gross or palpable lesion. In cases of suspected microinvasive and early-stage carcinoma, cone biopsy of the cervix is indicated to evaluate the possibility of invasion or to define the depth and extent of microinvasion. Cold knife cone biopsy provides the most accurate evaluation of the margins. Staging of gynecologic cancers attempts to define the anatomic extent of a given cancer. Staging of invasive cervical cancer with the FIGO (International Federation of Gynecology and Obstetrics) system is achieved by clinical evaluation. The key points in staging the disease are (2):
- Examination should include inspection, palpation, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, inravenous pyelography, and X-ray examination of lungs and skeleton.
- Conization of the cervix is considered a clinical examination.
- Suspected bladder or rectal involvement should be confirmed histologically.
- If there is a question about the most appropriate stage, the earlier stage should be assigned.
Staging of Cervical Carcinomas:
The three major staging systems are those of FIGO, the American Joint Committee on Cancer, and the International Union Against Cancer. Cancer registries approved by the American College of Surgeons use the American Joint Committee on Cancer's TNM (tumor, nodes, metastasis) staging system. However, the scientific literature reports gynecologic oncology statistics using the FIGO system. It is recommended that the FIGO system be used to facilitate comparisons of international data.
FIGO Nomenclature: Carcinoma of the cervix
Stage 0 Carcinoma in situ, cervical intraepithelial neoplasia Grade III
Stage I The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded) Ia Invasive carcinoma that can be diagnosed only by microscopy. All macroscopically visible lesions-even with superficial invasion- are allotted to stage Ib carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5.0 mm and a horizontal extension of not more than 7.0 mm. Depth of invasion should not be more than 5.0 mm taken from the base of the epithelium of the original tissue - superficial or glandular. The involvement of vascular spaces - venous or lymphatic - should not change the stage allotment.
Ia1 Measured stromal invasion of not more than 3.0 mm in depth and extension of not more than 7.0 mm.
Ia2 Measured stromal invasion of more than 3.0 mm and not more than 5.0 mm with an extension of not more than 7.0 mm.
Ib Clinically visible lesions limited to the cervix uteri or pre-clinical cancers greater than Stage Ia.
Ib1 Clinically visible lesions not more than 4.0 cm.
Ib2 Clinically visible lesions more than 4.0 cm.
Stage II Cervical carcinoma invades beyond the uterus, but not to the pelvic wall or to the lower third of the vagina.
IIa No obvious parametrial involvement.
IIb Obvious parametrial involvement.
Stage III The carcinoma has extended to the pelvic wall. On rectal examination, there is no cancer-free space between the tumor and the pelvic wall. The tumor involves the lower third of the vagina. All cases with hydronephrosis or non-functioning kidney are included, unless they are known to be due to other causes.
IIIa Tumor involves lower third of the vagina, with no extension to the pelvic wall.
IIIb Extension to the pelvic wall or hydronephrosis or non-functioning kidney
Stage IV The carcinoma has extended beyond the true pelvis, or has involved (biopsy proved) the mucosa of the bladder or rectum. Bullous edema, as such, does not permit a case to be allotted to Stage IV.
IVa Spread of the growth to adjacent organs (bladder or rectum or both)
IVb Spread to distant organs.
Distinction between stage Ib1 and stage Ib2:
In 1994, FIGO revised its staging criteria, subdividing stage Ib carcinoma of the cervix into stage Ib1 (<4 cm in diameter) and stage Ib2 (>4 cm diameter). When the tumor is confined to the cervix, the size of the primary tumor has been shown to have a significant impact on survival rates in stage Ib cervical cancer, regardless of primary treatment modalities (3). Retrospective analysis has evaluated patients who had radical hysterectomies and lymph node dissections for stage Ib1 and Ib2 cancers of cervix. Patients with stage Ib2 disease had a significantly worse 5-year survival rate (72.8%) when compared with those who had stage Ib1 tumors (90%). Also in this study, in 38.7% of cases of stage Ib1 disease and 72.9% of cases of stage Ib2 disease patients received postoperative radiation therapy for high-risk indications such as positive lymph nodes, parametrial disease, positive surgical margins, and deep stromal invasion involving the outer third of cervix. The high percentage of postoperative radiation required in patients with stage Ib2 disease suggests that primary radiation should be considered for these patients and may be supplemented by surgical or radiologic evaluation to access retroperitoneal nodal status.
Another study demonstrated the effect of tumor size on outcomes in patients treated with radiation therapy alone (ie, without surgery or chemotherapy). Five-year disease-free survival rates for women with stage Ib cancer were 100% for lesions less than 1 cm in diameter, 98% for those 1-1.9 cm, 93% for those 2-2.9 cm, 83% for those 3-3.9 cm, and 76% for lesions of 4 cm or more (4).
Early carcinomas of the cervix usually can be managed by surgical techniques or radiation therapy. The more advanced carcinomas require primary treatment with radiation therapy. As discussed earlier, the results of surgical evaluation should not influence the stage determined by using the FIGO clinical staging system. However, it is well recognized that the presence of lymph node metastasis is the most important adverse predictor of survival. Retroperitoneal surgical lymph node dissection of the pelvic and paraaortic lymph nodes provides important information about treatment planning and prognosis. Resection of positive lymph nodes is thought to provide therapeutic benefit. Therefore, surgical evaluation allows individualization of therapy and may result in better clinical outcomes.
Microinvasive Cervical Caner - Diagnosis and Treatment:
The premise for this specific diagnosis is to define a subset of patients with early carcinomas of the cervix who had a favorable prognosis. It is important to remember these lesions are defined microscopically and cannot be visualized on gross inspection. The main issues affecting the definition are the maximum depth of stromal invasion, the significance of lymphatic-vascular space invasion, tumor volume, and confluence of the invasion pattern as related to the frequency of pelvic node metastasis, vaginal recurrence, and ultimate survival. Understanding the concepts behind definition and diagnosis of microinvasive carcinoma of the cervix is important to understanding the biology and behavior of the disease. Nodal metastasis is the most consistent and strongest predictor of survival for patients with early invasive cervical cancers. There is a relationship between depth of invasion and nodal metastasis. Minimally invasive lesions - those with invasion up to 3 mm - have a lymph node metastatic risk rate of 1.2% and a depth rate of less than 1%. However, lesions greater than 3 mm and no greater than 5 mm of invasion have a 7.8% rate of nodal metastasis and a depth rate of 2.4%. According to the FIGO criteria, patients with stage Ia1 carcinoma could be treated with simple hysterectomy without nodal dissection or conization in selected cases. Those patients with invasion greater than 3 mm and no greater than 5 mm (stage Ia2) should undergo radical hysterectomy and pelvic lymphadenectomy. Although lymphatic-vascular invasion should not alter the FIGO stage, it is an important factor in treatment decisions. The risk of recurrence with lymphatic-vascular involvement is 3.1% if the extent of invasion is 3 mm or less and 15.7% if it is greater than 3 mm and no greater than 5 mm (5).
Preservation of fertility has become increasingly important as more women are delaying having families. A treatment dilemma arises for women with cervical carcinoma who have not started or completed childbearing but desire the option to become pregnant. For both ethical and medico-legal reasons, patients who opt for conservative management should fully understand the risks involved.
Early-stage (Ib-IIa) invasive cervical carcinoma management:
Both treatment strategies for stage Ib and early-stage IIa invasive carcinoma include:
- a primary surgical approach with radical hysterectomy and pelvic lymphadenectomy or
- primary radiation therapy with external beam radiation and either high-dose-rate or low-dose-rate brachytherapy
Although the two modalities were found to be similarly effective in the randomized trials, the rate and types of complications differ. The preference of treatment depends on the situation, the physician's input, and the patient's age, health, and tumor characteristics. Those who favor radical surgery point out that it leaves the vagina in more functional condition, while radiation therapy results in a reduction in length, caliber, and lubrication of the vagina. In premenopausal women, ovarian function can be preserved with surgery. The surgical approach also provides the opportunity for pelvic and abdominal exploration and provides better clinical and pathologic information with which to individualize treatment. Surgery may be preferred over radiation therapy in women who have diverticular disease, tuboovarian abscess, or appendiceal abscess; have had prior radiation therapy; have congenital pelvic located kidney; or are psychotic or non-compliant. Proponents of radiation therapy advocate primary radiation to avoid surgical morbidity or mortality, risk of blood loss and transfusion, and excessive anesthesia time.
More careful analysis of patterns of failure following radical hysterectomy has led to better stratification of patients into risk groups and incorporated testing of systemic chemotherapy agents in those considered at high-risk of distant failure. Role of adjuvant therapy following primary surgery in early-stage carcinoma is greatly advanced in two randomized clinical trials (6). Patients with histologically documented extra-cervical disease- specifically those with pelvic nodal involvement, positive margins, or parametrial extension- are treated with concurrent pelvic radiation therapy and cisplatin-based chemotherapy. It improves relapse-free survival and overall survival rates when compared with radiation therapy alone. Following radical hysterectomy, a subset of node negative patients who have a constellation of primary risk factors (large tumors, depth of stromal infiltration, and lympho-vascular space involvement) may be defined as having intermediate risk for relapse. For these patients adjuvant pelvic radiation therapy provides clear therapeutic benefit, with significantly improved relapse-free survival rates when compared with those who had no further therapy.
Late-stage (IIb or later) cervical carcinoma management:
Historically, primary radiation therapy has been used to treat patients with bulky or locally advanced cervical cancer. The approach generally consists of external beam radiation to achieve primary tumor reduction and provide coverage to the parametria and regional nodes at risk, supplemented by brachytherapy to increase radiation dose delivery to the central residual tumor. Earlier attempts to improve outcome results from primary radiation therapy by the addition of agents such as hydroxyurea or hypoxic cell sensitizers met with mixed success.
Results from five randomized trials on cervical cancer have established the role of concurrent cisplatin-based chemotherapy and radiation therapy for high-risk or locally advanced disease (7). The various studies had different eligibility criteria, but in total included a broad spectrum of clinical presentations:
- patients with locally advanced tumors for whom chemo-radiation represented primary therapy
- bulky early-stage cancers in which chemo-radiation was delivered prior to adjuvant hysterectomy
- post-radical hysterectomy cases with high-risk pathologic factors (positive lymph nodes, positive parametria, positive margins) for whom adjuvant chemo-radiation was given.
Although the optimal cisplatin-based chemotherapeutic regimen has not yet been fully defined, many are choosing to use weekly cisplatin because of its ease of delivery and favorable toxicity profile. However, it is clear that the previously controversial use of hydroxyurea can be abandoned. Furthermore, it should be remembered that the advantages of chemo-radiation are obtained only in the setting of concurrent therapy. At present, women with locally advanced cervical cancer in North America should receive cisplatin-based chemotherapy concurrent with radiation therapy.
Should squamous cell cancer and adenocarcinoma be treated differently?
Underlying this question is the continuing debate regarding the independent prognostic implications of adenocarcinoma versus squamous cell histologies in cervical cancer, especially in early-stage disease. In a study done by Gynecology Oncology Group revealed no significant differences were found among the cell types with regard to the patient's age at presentation, performance status, pelvic nodal metastases, depth of cervical invasion, uterine extension, surgical margins, or parametrial infiltration. Relapse- free survival rates were similar for all three histologies, but adenosquamous cell was associated with a small, statistically significant reduction in overall survival, even after adjusting for associated pathologic risk factors (8). Despite the ongoing discussion regarding cell type and prognosis, there is no evidence to support differences in treatment of invasive squamous cell cancer versus adenocarcinoma of the cervix. The only exception to this is the management of microinvasive disease, where guidelines have been developed for more conservative management of patients with FIGO stage Ia1 squamous cell cancer, corresponding with the Society of Gynecologic Oncologists' working definition for minimally invasive tumors discussed previously.
For patients with frankly invasive disease, regardless of squamous cell or adenocarcinoma histology, the primary options for treatment are radical hysterectomy with lymphadenectomy or definitive radiation therapy. In patients, undergoing primary surgery who has positive nodes, positive margins, or parametrial infiltration, adjuvant radiation concurrent with cisplatin-based chemotherapy is indicated on the basis of positive results. The addition of chemotherapy to radiation appeared to overcome the worse prognosis associated with adenocarcinoma cell components, when compared with patients receiving adjuvant radiation therapy only.
Invasive Cervical Cancer during Pregnancy:
This clinical problem requires attention to the health of the woman as well as the safety of the fetus. Ethical concerns, cultural and religious issues, and whether the patient wishes to continue the pregnancy after being informed of the potential risks and benefits of the treatment influence the appropriate treatment. Optimal counseling and therapy require an interdisciplinary approach. Between 2.7% and 3.5% of cases of cervical cancer occur in pregnant women. The diagnosis of invasive carcinoma during pregnancy presents a therapeutic dilemma. The survival rate of patients with stage I cervical cancer is excellent regardless of the time of diagnosis during pregnancy, with recent reported survival rates of 85% and 95%. The overall survival rate for women who were pregnant and had invasive cervical cancer is 80% (9).
Pregnant women are 3.1 times more likely than nonpregnant women to have diagnosed Stage I disease, probably because of regular examination. A pregnant patient with carcinoma-in-situ and microinvasive squamous carcinoma of 3 mm or less can deliver vaginally and be reevaluated and treated at 6 weeks postpartum. Pregnant patients with invasive carcinoma of the cervix may choose early termination or choose to continue the pregnancy. Those who have mature fetus at the time of diagnosis also may wish to delay treatment, if the patient opts to continue the pregnancy, pre-delivery assessment of fetal lung maturity by amniotic fluid analysis should be strongly considered, taking into account the availability of neonatal support to optimize fetal outcome and to avoid the potentially severe complications of prematurity, both in the neonatal period and in long-term development. Even those patients with early-stage disease should be aware that delaying treatment carries an undefined, but likely small, risk of disease progression. However, delaying treatment to optimize fetal maturity provides a major, quantifiable benefit for the infant.
The mode of delivery for those patients who choose to delay treatment to allow fetal maturation is controversial. Patents with small-volume, early-stage lesions may be candidates for vaginal delivery. Whether vaginal delivery promotes disease progression is not clear. If possible, the patient should give birth by cesarean delivery at the time of planned radical surgery, and vaginal delivery should be reserved for those patients with pre-invasive disease or stage Ia invasive disease with planned postpartum fertility-sparing therapy. It is prudent not to attempt vaginal delivery of women with large or friable tumors, given the risk of obstructing the progress of labor or the risk of bleeding with potentially life-threatening hemorrhage that might require emergency hysterectomy. Post-treatment follow-up should include inspection and palpation of the episiotomy site. Treatment of recurrent disease in the episiotomy consists of excision followed by radiation.
When radical cesarean hysterectomy is performed, a classical uterine incision is preferred. Bilateral ovariopexy is a reasonable consideration at the time of surgery in the event that adjuvant radiation might be indicated for patients with high-risk histopathologic features. Most pregnant patients who are candidates for radical surgery will benefit from surgery rather than radiation therapy, given the advantage of ovarian preservation and the avoidance of radiation-associated vaginal fibrosis. Planning radiation treatment for pregnant patients with cervical cancer requires careful adaptation to adjust for the anatomic distortion created by the gravid state. Patients opting for primary radiation therapy with the intent of pregnancy termination should begin with external-beam therapy.
Surveillance after primary therapy for invasive carcinoma of cervix is universally recommended. Approximately 35% of patients will have persistent or recurrent disease. The main goal of surveillance is early detection of recurrent disease so that patients can be offered potentially curative salvage therapy. The average1-year survival for patients with recurrent cervical cancer is 10-20%. Post-therapy surveillance and proposed schedule involving thrice- yearly follow-up visits for the first 2 years, and twice-yearly visits subsequently to year 5, with Pap tests and chest X-ray on a yearly basis. Common approach includes examinations and Pap tests every 3-4 months for the first 3 years, decreasing to twice yearly in the fourth and fifty year (10).
Post-treatment follow-up also is beneficial for reasons other than the diagnosis of recurrence. The psychological support and reassurance of continued contact with the treating team is vitally important. Annual health maintenance visits for mammography, blood pressure, and evaluation of other medical problems are important. Many of these patients undergo bilateral salpingo-oopherectomy or radiation therapy, and hormone replacement therapy should be considered in such patients. Cervical adenocarcinoma is not a contraindication to hormone replacement therapy.
The Gynecologic Oncology Group (GOG) conducted a phase III study of cisplatin compared with cisplatin plus dibromodulcitol or ifosfamide. Compared with cisplatin alone, cisplatin plus ifosfamide had a significantly higher response rate and progression-free interval, with no significant difference in survival. Furthermore, adverse effects (leukopenia, nephrotoxicity, central and peripheral neurotoxicity) were significantly increased in the ifosfamide-containing arm. Lessons learned from this trial included the need to assess quality of life. Results with palliative chemotherapy for metastatic cervical cancer are steadily improving, but no treatment may be considered "optimal", and therefore the preferred therapy should be, whenever possible, participation in a clinical trial. Clinical trials have produced better, although more complex therapies. Except for subsets of patients with early-stage disease, almost all patients with cervical cancer will receive multimodality therapy. The search for the optimal drug(s) to combine with radiation therapy should continue (11).
Operative laparoscopy has long been a mainstay in the treatment of benign gynecologic conditions. In the 1990s gynecologic oncologists began to use laparoscopy to perform hysterectomies and lymph-node dissections in women with endometrial cancer. Total laparoscopic radical hysterectomy (TLRH) for the treatment of patients with cervical cancer was also first described in the early 1990s. This procedure although technically difficult to perform, is a feasible and safe procedure that has fewer intraoperative and postoperative morbidity than abdominal radical hysterectomy and long-term outcomes that are likely equivalent to the those of abdominal radical hysterectomy. As laparoscopic technology and equipment improve and as surgeons become more comfortable with minimally invasive techniques, TLRH will be performed more commonly (12).
For stage Ib and selected IIa carcinomas of the cervix, either radical hysterectomy and lymph node dissection or radiation therapy with cisplatin-based chemotherapy should be considered. Adjuvant radiation therapy may be required in those treated surgically, based on pathologic risk factors, especially in those with stage Ib2 carcinoma. Stage IIb and greater should be treated with external-beam and brachytherapy radiation and concurrent cisplatin-based chemotherapy.
For stage Ia1 microinvasive squamous carcinoma of the cervix, treatment with conization of the cervix or simple extra-facial hysterectomy may be considered. Stage Ia2 invasive squamous carcinoma of the cervix should be treated with radical hysterectomy with lymph node dissection or radiation therapy, depending on clinical circumstances. Stage Ib1 should be distinguished from stage Ib2 carcinoma of the cervix because the distinction predicts nodal involvement and overall survival and may therefore, affect treatment and outcome. Patients with squamous cell cancers and those with adenocarcinomas should be managed similarly, except for those with microinvasive disease. Criteria for microinvasive adenocarcinomas have not been established.
Following treatment for cervical carcinoma, patients should be monitored regularly, for example, with thrice-yearly follow-up examinations for the first 2 years and twice-yearly visits subsequently to year 5, with Pap tests annually and chest X-rays annually for up to 5 years. Treatment for pregnant patients with invasive carcinoma of the cervix should be individualized on the basis of evaluation of maternal and fetal risks.
- World Health Organization
Cervical Cancer Screening in Developing Countries (pdf)
Planning and Implementing Cervical Cancer Prevention and Control Programs (pdf)
- National Cancer Institute
- Center for Disease Control and Prevention
National Breast and Cervical Cancer Early Detection Program
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- keys HM, Bundy BN, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 1999;340:1154-1161 (Level I).
- Look KY, Brunetto VL, et al. An analysis of cell type in patients with surgically staged stage IB carcinoma of the cervix: a Gynecologic Oncology Group study. Gyecol Oncol 1996;63:304-311 (Level II-3).
- Goff BA, Paley PJ, et al. Cancer in the pregnant patient. In Hoskins WJ, Perez CA, Young RC, eds. Principles and practice of gynecologic oncology. Philadelphia: Lippincott Williams & Wilkins, 2000:501-528 (Level III).
- National Comprehensive Cancer Network. NCCN practice guidelines for cervical cancer. In: The complete library of NCCN oncology practice guidelines (CD-ROM), version 2000, Revision date June 1, 2000 (Level-III).
- Moore DH. Cervical cancer. Obstet Gynecol 2006;107:1152-1161.
- Frumovitz M, Reis RD, Sun CC, Milam MR et al. Comparison of total laparoscopic and abdominal radical hysterectomy for patients with early-stage cervical cancer. Obstet Gynecol 2007;110:96-102.
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