Cervical Cancer

INTRODUCTION

Background: Cervical cancer is the second most common malignancy in women worldwide, and it remains a leading cause of cancer-related death for women in developing countries. In the United States, it is the fourth most common malignant neoplasm in women, after carcinoma of the breast, colorectum, and endometrium. The incidence of invasive cervical cancer has declined steadily in the United States over the past few decades; however, it continues to rise in many developing countries. The change in the epidemiological trend in the United States has been attributed to mass screening with Pap smears.

Frequency:
　

• In the US: In the United States, 12,800 new cases of invasive cervical cancer are diagnosed each year, in addition to more than 50,000 cases of carcinoma in situ.

• Internationally: Internationally, 500,000 new cases are diagnosed each year.

Mortality/Morbidity: Forty-eight hundred of the 12,800 patients (37.5%) will die from their disease each year in the United States. This represents 2% of all cancer deaths and 18% of deaths from gynecological cancers.

Race: In the United States, cervical cancer is more common in Hispanic, African American, and Native American women compared to whites.

Sex: Only found in women.

CLINICAL

History:

• Because women are routinely screened, the most common finding is an abnormal Pap smear.

• Clinically, the first symptom is abnormal vaginal bleeding, usually postcoital.

• Vaginal discomfort, malodorous discharge, and dysuria are not uncommon.

• Tumor grows by extending upward to the endometrial cavity, downward to the vagina, and laterally to the pelvic wall. It can directly invade the bladder and rectum.

• Symptoms that can evolve, such as constipation, hematuria, fistula, and ureteral obstruction with or without hydroureter or hydronephrosis, reflect local organ involvement.

• The triad of leg edema, pain, and hydronephrosis suggests pelvic wall involvement.

• The common sites for distant metastasis include extrapelvic lymph nodes, liver, lung, and bone.

Physical:

• In patients with early-stage cervical cancer, physical examination can be relatively normal.

• As the disease progresses, the cervix may become abnormal in appearance, with gross erosion, ulcer, or mass. These abnormalities can extend to the vagina.

• Rectal exam may reveal an external mass or gross blood from tumor erosion.

• Bimanual exam will often find pelvic metastasis.

  　

• Leg edema suggests lymphatic/vascular obstruction from tumor.

• If the disease involves the liver, hepatomegaly will be found in some patients.

• Pulmonary metastasis is usually hard to detect on physical exam unless pleural effusion or bronchial obstruction becomes apparent.

Causes: Early epidemiological data demonstrated a direct causal relationship between cervical cancer and sexual activity. Major risk factors observed include sex at young age, multiple sexual partners, promiscuous male partners, and history of STD. However, the search for a potential sexually transmitted carcinogen had been unsuccessful until the last decade when a breakthrough in molecular biology enabled scientists to detect viral genome in cervical cells.

Strong evidence now implicates human papillomaviruses (HPV) as prime suspects. HPV viral DNA has been detected in more than 80% of squamous intraepithelial lesions (SIL) and invasive cervical cancers compared to a consistently lower percentage of control women. Both animal data and molecular biologic evidence confirm the malignant transformation potential of papilloma virus-induced lesions. SILs are found predominantly in younger women, while invasive cancers are more often detected in women 10-15 years older, suggesting slow progression of cancer.

HPV infection occurs in a high percentage of sexually active women. Most of these infections clear spontaneously within months to a few years, and only a small proportion progress to cancer. This means that other crucial factors must be involved in the process of carcinogenesis.

Three kinds of factors have been postulated to influence the progression of low-grade SIL to high-grade SIL. These include the type and duration of viral infection, with high-risk HPV type and persistent infection predicting a higher risk for progression; host conditions that compromise immunity, such as multiparity or poor nutritional status; and environmental factors such as smoking, oral contraceptive use, or vitamin deficiencies. In addition, various gynecologic factors, including age of menarche, age of first intercourse, and number of sexual partners, significantly increase the risk for cervical cancer.

• Human papilloma virus (HPV)

• HPV is a heterogeneous group of viruses that contain closed, circular double-strand DNA. The viral genome encodes 6 early open reading frame proteins (E1, E2, E3, E4, E6, and E7), which function as regulatory proteins, and 2 late open reading frame proteins (L1 and L2) that make up the viral capsid.

• So far, 77 different genotypes of HPV have been identified and cloned, among which, types 6, 11, 16, 18, 26, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 58, 59, 66, and 68 have the propensity to infect anogenital tissues.

• The HPVs that infect the human cervix fall into 2 broad categories. The low-risk types consist of HPV 6b and 11, which are associated with low-grade SIL but are never found in invasive cancer. The high-risk types, mostly HPV 16 and 18, are found in 50-80% of SIL and in up to 90% of invasive cancers. The major difference between the 2 types is that after infection, the low-risk HPVs are maintained as extrachromosomal DNA episomes, while the high-risk HPV genome is found integrated into the host cellular DNA. The recombination event often leaves E6 and E7 directly coupled to the viral promoter and enhancer sequences, allowing their continued expression after integration. Because E7 binds and inactivates the Rb protein while E6 binds p53 and directs its degradation, the functional loss of both p53 and the RB genes leads to resistance to apoptosis, causing uncensored cell growth after DNA damage. This ultimately results in progression to malignancy.

• Human immunodeficiency virus (HIV)

• The role of human immunodeficiency virus infection in the pathogenesis of cervical cancer is not fully understood. Studies have shown a higher prevalence of HPV in HIV-seropositive women than in seronegative women, and the HPV prevalence was directly proportional to the severity of immunosuppression as measured by CD4 counts.

• It is postulated that impaired lymphocyte function enhances latent or subclinical HPV activity, resulting in a higher rate of persistent infection.

• It is not clear whether HIV has a synergistic effect on HPV infection either by direct molecular interaction or through indirect immunologic effect.

WORKUP

Lab Studies:
　

• A Pap smear should be done in every patient who is suspected of the diagnosis of cervical cancer.

• Patient should be referred to a gynecologist for colposcopy, direct biopsies, and endocervical curettage.

• After the diagnosis is established, complete blood count and serum chemistry for renal and hepatic functions should be ordered to look for abnormalities from possible metastatic disease.

Imaging Studies:
　

• Once the diagnosis is established, imaging studies are done for staging. Table 1 lists the International Federation of Gynecology and Obstetrics (FIGO) staging system.

• A routine chest radiograph should be obtained to rule out pulmonary metastasis.

• CT scan of the abdomen and pelvis is performed to look for metastasis in the liver, lymph nodes, or other organs and to rule out hydronephrosis/hydroureter.

• In patients with bulky primary tumor, barium enema can be used to evaluate extrinsic rectal compression from the cervical mass.

Procedures:
　

• In patients with bulky primary tumor, cystoscopy and proctoscopy should be performed to rule out local invasion of the bladder and the colon.

• Clinical staging can fail to detect pelvic and aortic lymph node involvement in 20-50% and 6-30% of patients, respectively. For that reason, surgical staging is frequently recommended.

• Pretreatment surgical staging is the most accurate method to determine the extent of disease. However, there is little evidence to suggest an improvement in overall survival with routine surgical staging. Therefore, pretreatment surgical staging should be individualized after a thorough nonsurgical workup, including fine needle aspiration of lymph nodes, has failed to demonstrate metastatic disease.

Histologic Findings: Precancerous lesions of the cervix are usually detected with Pap smear. The Pap smear classification system has evolved over the years. The traditional numerical system defined class I as normal, class II as atypical cells, class III as cervical dysplasia, class IV as carcinoma in situ, and class V as invasive cancer. In 1972, the cervical intraepithelial neoplasia (CIN) system replaced the numerical system. CIN I stands for mild dysplasia, CIN II is moderate dysplasia, and CIN III is severe dysplasia or carcinoma in situ. Since 1988, the National Cancer Institute (NCI) has sponsored a workshop to standardize Pap smear reporting, and Table 2 shows the revised Bethesda Pap smear system.

• Atypical squamous cells of undetermined significance (ASCUS)

  　

  • Found in approximately 5% of Pap smears, they usually represent squamous metaplasia and HPV lesions.

    　

  • About 50% of them will spontaneously regress; therefore, repeat smears should be performed every 4-6 months for 2 years until 3 consecutive negative smears are documented.

    　

  • For those who are noncompliant or with persistent ASCUS, colposcopy and biopsy should be done.

    　

  • Postmenopausal women should be treated with topical estrogens for 2 months prior to repeating Pap smear.

    　

  • Infection if found should be treated.

  　

• Low-grade squamous intraepithelial lesions (LGSIL)

  　

  • CIN II-III is seen in about 5-40% of LGSIL Pap smears. The majority of these (78.3%) spontaneously regress.

    　

  • The options for management include immediate colposcopy with biopsy or repeat Pap smear every 4-6 months. If persistent LGSIL is found, colposcopy is indicated.

  　

• High-grade squamous intraepithelial lesions (HGSIL)

  　

  • Patients with HGSIL smears should undergo colposcopy and direct biopsy.

    　

  • If the entire lesion and transformational zone is visualized, either excisional or ablative therapy is indicated. If the entire lesion or the transformational zone cannot be seen, a cone biopsy is indicated.

  　

• Atypical glandular cells of undetermined significance (AGCUS)

  　

  • Glandular cells with abnormalities more severe than changes of a reactive or inflammatory process but not severe enough to qualify for neoplasia are called atypical glandular cells of undetermined significance.

    　

  • These cells may originate from endocervix, endometrium, fallopian tubes, or ovaries.

  　

• Complete evaluation should include Pap smear with cytobrush and endocervical and endometrial samplings. If the smear is suspicious for adenocarcinoma in situ, a cone biopsy should be done. If the pathology is still unclear after the above workup, the patient should have dilatation and curettage (D&C).

  　

• Consideration should be given to an ultrasound that adequately defines the fallopian tubes and ovaries prior to define uterine curettage to help identify primary malignancies of these organs.

  　

• Invasive cervical cancer

  　

  • The histology of cervical malignancy is predominantly of epithelial origin, with squamous cell carcinoma as the major group (85%).

    　

  • Less common histologies include adenocarcinoma, small cell carcinoma, melanoma, and lymphoma.

TREATMENT

Medical Care: The treatment of cervical cancer varies with disease stage. For early invasive cancer, surgery is the treatment of choice. In more advanced cases, radiation combined with chemotherapy is the current standard of care. In patients with disseminated disease, chemotherapy or radiation provides symptom palliation. Treatment of choice for stage Ia disease is surgery.

• Stage IB or IIA

• For patients with stage IB or IIA disease, treatment options are either combined external beam radiation with brachytherapy or radical hysterectomy with bilateral pelvic lymphadenectomy.

  　

• Most retrospective studies have shown equivalent survival rates for both procedures, although such studies are usually flawed due to patient selection bias and other compounding factors. However, a recent randomized study showed identical overall and disease-free survival.

  　

• Quality of life data, particularly in the psychosexual area, is relatively lacking.

  　

• Postoperative radiation to the pelvis decreases the risk of local recurrence in patients with high-risk factors.

  　

• A recent randomized trial showed that patients with parametrial involvement, positive pelvic nodes, or positive surgical margins benefit from postoperative combination of cisplatin-containing chemotherapy with pelvic radiation.

• Stage IIB-IVA

• For locally advanced cervical carcinoma (stages IIB, III and IVA), radiation therapy has traditionally been the treatment of choice.

  　

• For treatment with radiation alone, 5-year survival rates reportedly are 65-75%, 35-50%, and 15-20% for stages IIB, III, and IVA patients, respectively.

  　

• Treatment begins with a course of external beam radiation to reduce tumor mass to enable subsequent intracavitary application. Brachytherapy is delivered using afterloading applicators that are placed in the uterine cavity and vagina.

• Combined chemotherapy plus radiation therapy for cervical cancer

• Recently, the report of 3 well-conducted studies of concurrent chemoradiation has changed the standard of care in this group of patients.

  　

• In the Radiation Therapy Oncology Group (RTOG) trial, 403 patients with bulky IB and IIB-IVA cancers were randomized to either radiotherapy to a pelvic and para-aortic field or pelvic radiation with concurrent cisplatin and fluorouracil. Both disease-free survival and overall survival were significantly higher in the group that received combination treatment.

  　

• Rose and associates conducted a Gynecologic Oncology Group (GOG) trial for patients with stages IIB, III, or IVA cancer, comparing the combination of radiation with 3 different chemotherapy regimens (cisplatin alone, cisplatin/5-FU/hydroxyurea, and hydroxyurea alone). Overall survival was significantly higher in the 2 groups that received cisplatin-containing regimens.

  　

• In another GOG trial, patients with bulky stage IB disease were randomized to either radiation alone or combination of weekly cisplatin and radiation. All patients had adjuvant hysterectomy. Both disease-free survival and overall survival were significantly higher in the combined-therapy group at 4 years of follow-up.

  　

• Based on above studies, it is now reasonable to use cisplatin-based chemotherapy in combination with radiation for patients with locally advanced cervical cancer.

Surgical Care:

• Carcinoma in situ (stage 0) is treated with local ablative measures such as cryosurgery, laser ablation, and loop excision.

• Hysterectomy should be reserved for patients with other gynecologic indications to justify the procedure.

  　

• After local treatment, lifelong surveillance of these patients is required.

• The treatment for disseminated cervical cancer is mainly palliation because cure is not possible.

• Chemotherapy with single agents such as cisplatin or ifosfamide causes response rates of approximately 20%. Combination regimens have higher response rate and can prolong disease-free survival. However, toxicity is increased and there is no survival advantage. In addition, the duration of response is usually short.

• Palliative radiation is often used individually to control bleeding, pelvic pain, or urinary for partial large bowel obstructions from pelvic disease.

  　

• Invasive procedures such as nephrostomy or diverting colostomy are sometimes performed in this group of patients to improve the quality of life.

• Special effort should be made to ensure comprehensive palliative care including adequate pain control for these patients.

• The standard treatment for microinvasive disease (stage IA) is total hysterectomy.

• Lymph node dissection is not required if the depth of invasion is less than 3 mm and no lympho-vascular invasion is noted.

• Selected patients with stage IA1 disease but no lympho-vascular space invasion who desire to maintain fertility may have a therapeutic conization with close follow-up, including cytology, colposcopy, and endocervical curettage.

• Patients with medical comorbidities who are not surgical candidates can be successfully treated with radiation.

Consultations: The treatment of cervical cancer will frequently require a multidisciplinary approach involving gynecologist oncologist, radiation oncologist, and medical oncologist.

Diet:

• Nutrition is important for patients with cervical cancer. Every attempt should be made to encourage and provide adequate oral food intake.

• Nutritional supplements such as Ensure or Boost are used when patient has had significant weight loss or cannot tolerate regular food due to nausea caused by radiation or chemotherapy.

• In patients with severe anorexia, appetite stimulants such as Megace can be prescribed.

• For patients who are unable to tolerate any oral intake, percutaneous endoscopic gastrostomy (PEG) tubes are placed for nutritional purposes.

• In patients with extensive bowel obstruction as a result of metastatic cancer, hyperalimentation is sometimes used.

MEDICATION

Chemotherapy should be administered in conjunction with radiation therapy to most patients with stage IB (high risk)-IVA. Cisplatin is most commonly used agent, although 5-fluorouracil is also used frequently. For patients with metastatic disease, cisplatin remains the most active agent. Ifosfamide and paclitaxel also have significant activity in this setting. In patients with recurrent or metastatic disease, there is no evidence that combined chemotherapy produces an improvement in survival compared to single-agent therapy.
　

Drug Category: Chemotherapy agents -- Inhibit cell growth and proliferation.

FOLLOW-UP

Deterrence/Prevention:
　

• Screening of cervical cancer

• Retrospective data have shown that screening with Pap smear reduces the incidence of cervical cancer by 60-90% and death rate by 90%.

• Since 1988, the American Cancer Society and the National Cancer Institute have recommended that a Pap smear and pelvic examination be performed annually after the onset of sexual activity or at the age of 18. After 3 consecutive negative results, the screening interval may be prolonged at the discretion of the physician and patient. Women over the age of 60 should continue to have Pap smear screening.

• In 1995, the American College of Obstetricians and Gynecologists recommended that women with risk factors such as HIV, HPV infection, cervical dysplasia, and multiple sexual partners have annual Pap smear screening.

• The false-negative rate of Pap smear is 20%, which mostly results from sampling error. Physicians can reduce sampling error by ensuring adequate material is taken from both endocervical canal and ectocervix. Smears without endocervical or metaplastic cells must be repeated. Suspicious or grossly abnormal cervical lesions on physical exam should be biopsied regardless of cytologic finding.

Complications:
　

• Complications from radiation alone

• During the acute phase of pelvic radiation, the surrounding normal tissues such as the intestines, the bladder, and the perineum skin are often affected.

• Acute gastrointestinal side effects include diarrhea, abdominal cramping, rectal discomfort, or bleeding. Diarrhea is usually controlled by either loperamide (Imodium) or atropine sulfate (Lomotil). Steroid-containing, small enemas are prescribed to alleviate symptoms from proctitis.

• Cystourethritis can also occur, which leads to dysuria, frequency, and nocturia. Antispasmodics are often helpful for symptom relief.

• Urine should be examined for possible infection. If urinary tract infection is diagnosed, therapy should be instituted without delay.

• Proper skin hygiene should be maintained for the perineum and topical lotion used in case erythema or desquamation occurs.

• Late sequelae of radiation usually appear from 1-4 years after treatment. The major sequelae include rectal or vaginal stenosis, small bowel obstruction, malabsorption, and chronic cystitis.

• Complications from surgery

• The most frequent complication of radical hysterectomy is urinary dysfunction as a result of partial denervation of the detrusor muscle.

• Other complications include foreshortened vagina ureterovaginal fistula, hemorrhage, infection, bowel obstruction, stricture and fibrosis of the intestine or rectosigmoid colon, and bladder and rectovaginal fistulas.

Prognosis:
　

• Prognosis of cervical cancer depends on disease stage. In general, the 5-year survival rate for stage I disease is above 90%, for stage II is 60-80%, for stage III is around 50%, and for stage IV disease it is below 30%.

Patient Education:
　

• Cervical cancer is over represented among underserved and minority groups in the US. It is imperative to increase awareness in these groups about the benefits of the Pap smear screening.