|
Cervical Cancer
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 Papanicolaou tests (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: Of the 12,800 patients, 4800
(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 than in
white women.
Sex: Cervical cancer is found only in women.
Age: Cervical cancers usually affect women of middle
age or older, but it may be diagnosed in any reproductive-aged woman.
History:
- Because women are screened routinely, the most common finding is an
abnormal Pap smear result.
- Clinically, the first symptom is abnormal vaginal bleeding, usually
postcoital.
- Vaginal discomfort, malodorous discharge, and dysuria are not
uncommon.
- The tumor grows by extending upward to the endometrial cavity,
downward to the vagina, and laterally to the pelvic wall. It can invade
the bladder and rectum directly.
- 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
findings 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 examination may reveal an external mass or gross blood from
tumor erosion.
- Bimanual examination findings often reveal pelvic
metastasis.
- Leg edema suggests lymphatic/vascular obstruction from
tumor.
- If the disease involves the liver, some patients develop
hepatomegaly.
- Pulmonary metastasis usually is difficult to detect upon physical
examination 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 a young age, multiple sexual
partners, promiscuous male partners, and history of sexually transmitted
diseases. 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 (HPVs) as prime
suspects. HPV viral DNA has been detected in more than 80% of squamous
intraepithelial lesions (SILs) and invasive cervical cancers compared to a
consistently lower percentage in controls. 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 detected more often in women aged 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 main factors have been postulated to influence the progression of
low-grade SILs to high-grade SILs. 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.
- HPV is a heterogeneous group of viruses that contain closed
circular double-stranded DNA. The viral genome encodes 6 early open
reading frame proteins (ie, E1, E2, E3, E4, E6, E7), which function as
regulatory proteins, and 2 late open reading frame proteins (ie, L1,
L2), which make up the viral capsid.
- To date, 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 SILs but are never found in invasive cancer.
The high-risk types, mostly HPV 16 and 18, are found in 50-80% of SILs
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 TP53 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
- The role of human immunodeficiency virus (HIV) 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.
- Impaired lymphocyte function has been postulated to enhance latent
or subclinical HPV activity, resulting in a higher rate of persistent
infection.
- Whether HIV has a synergistic effect on HPV infection, either by
direct molecular interaction or through an indirect immunologic
effect, remains unclear.
DIFFERENTIALS
Cervicitis
Endometrial Carcinoma
Pelvic
Inflammatory Disease
Uterine Cancer
Vaginitis
Other Problems to be Considered:
Cervicitis/infection, particularly granulomatous (rare)
Vaginal
cancer
Metastatic cancer to cervix (rare)
Lab Studies:
- A Pap smear should be performed in every patient suggested to have a
diagnosis of cervical cancer.
- The patient should be referred to a gynecologist for colposcopy,
direct biopsies, and endocervical curettage.
- After the diagnosis is established, a complete blood cell 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 performed for
staging purposes.
- A routine chest radiograph should be obtained to help 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 help rule
out hydronephrosis/hydroureter.
- In patients with bulky primary tumor, barium enema studies 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 help rule out local invasion of the bladder and
the colon.
- Clinical staging protocols can fail to demonstrate pelvic and aortic
lymph node involvement in 20-50% and 6-30% of patients, respectively.
For that reason, surgical staging frequently is recommended.
Pretreatment surgical staging is the most accurate method to determine
the extent of disease. However, little evidence suggests 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 usually are detected
via Pap smear. The Pap smear classification system has evolved over the
years. The traditional numerical system defined class I as normal cells,
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 indicates 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.
Atypical squamous cells of undetermined significance
Atypical squamous cells of undetermined significance (ASCUS) are found
in approximately 5% of Pap smear results. Usually, they represent squamous
metaplasia and HPV lesions. Approximately 50% of ASCUS spontaneously
regress; therefore, repeat smears should be performed every 4-6 months for
2 years until negative findings are documented on 3 consecutive smears.
For those who are noncompliant with therapy or those with persistent
ASCUS, colposcopy and biopsy should be performed. Postmenopausal women
should be treated with topical estrogens for 2 months prior to the repeat
Pap smear. Infection, if found, should be treated.
Low-grade squamous intraepithelial lesions
CIN II-III is seen in approximately 5-40% of low-grade squamous
intraepithelial lesion (LGSIL) Pap smears. The majority (78.3%) of these
spontaneously regress. The options for management include immediate
colposcopy with biopsy or repeat Pap smear every 4-6 months. If persistent
LGSILs are found, colposcopy is indicated.
High-grade squamous intraepithelial lesions
Patients with high-grade squamous intraepithelial lesions on 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
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 the endocervix, endometrium,
fallopian tubes, or ovaries.
General considerations
Complete evaluation should include Pap smear with cytobrush and
endocervical and endometrial samplings. If the smear result is suggestive
of adenocarcinoma in situ, a cone biopsy should be performed. If the
pathology still is unclear after the above workup, the patient should have
dilatation and curettage.
Consideration should be given to obtaining ultrasound findings that
adequately define the fallopian tubes and ovaries prior to defining
uterine curettage to help identify primary malignancies of these organs.
Regarding 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.
Medical Care: The
treatment of cervical cancer varies with the stage of the disease. 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. The treatment of choice for stage
Ia disease is surgery.
- 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 usually are flawed due to
patient selection bias and other compounding factors. However, a
recent randomized study showed identical overall and disease-free
survival rates.
- Quality-of-life data, particularly in the psychosexual area, is
relatively scant.
- 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 a postoperative combination of cisplatin-containing
chemotherapy and pelvic radiation.
- For locally advanced cervical carcinoma (stages IIB, III, and
IVA), radiation therapy traditionally has 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, 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 trial, 403 patients with
bulky IB and IIB-IVA cancers were randomized to either radiotherapy to
a pelvic and paraaortic field or pelvic radiation with concurrent
cisplatin and fluorouracil. Rates of 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 stage IIB, III, or IVA cancer, comparing the
combination of radiation with 3 different chemotherapy regimens
(cisplatin alone, cisplatin/5-fluorouracil/hydroxyurea, and
hydroxyurea alone). Overall survival rates were 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 a combination of weekly
cisplatin and radiation. All patients had adjuvant hysterectomy. Both
disease-free survival and overall survival rates were significantly
higher in the combined-therapy group at 4 years of follow-up.
- Based on the aforementioned study results, using cisplatin-based
chemotherapy in combination with radiation for patients with locally
advanced cervical cancer now is a reasonable option.
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, these patients require lifelong
surveillance.
- The treatment for disseminated cervical cancer primarily is
palliative in nature because cure is not possible.
- Chemotherapy with single agents such as cisplatin or ifosfamide
results in response rates of approximately 20%. Combination regimens
have higher response rates and can prolong disease-free survival.
However, toxicity is increased and no survival advantage is gained. In
addition, the duration of response usually is short.
- Palliative radiation often is used individually to control
bleeding, pelvic pain, or urinary or partial large bowel obstructions
from pelvic disease.
- Invasive procedures such as nephrostomy or diverting colostomy
sometimes are performed in this group of patients to improve their
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 lymphovascular invasion is noted.
- Selected patients with stage IA1 disease but no lymphovascular
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 frequently requires a
multidisciplinary approach involving a gynecologic oncologist, radiation
oncologist, and medical oncologist.
Diet:
- Proper 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
patients have 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 tubes are placed for nutritional
supplementation.
- In patients with extensive bowel obstruction as a result of
metastatic cancer, hyperalimentation sometimes is used.
MEDICATION
Chemotherapy should be administered in
conjunction with radiation therapy to most patients with stage IB (high
risk) to IVA. Cisplatin is the agent used most commonly, although
5-fluorouracil also is 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, no evidence indicates that combined
chemotherapy produces an improvement in survival compared to single-agent
therapy.
Drug Category: Chemotherapy agents --
Inhibit cell growth and proliferation.
Drug Name
|
Cisplatin (Platinol) -- Intrastrand
cross-linking of DNA and inhibition of DNA precursors are among
proposed mechanisms of action. Used in combination with radiation
therapy.
|
| Adult Dose |
50-100 mg/m2 IV
q3wk
40 mg/m2 IV qwk for 5 wk
|
| Pediatric Dose |
Not established
|
| Contraindications |
Documented hypersensitivity; renal
failure; peripheral neuropathy; bone marrow suppression
|
| Interactions |
Decreases elimination of bleomycin
|
| Pregnancy |
D - Unsafe in pregnancy
|
| Precautions |
Peripheral neuropathy and
myelosuppression may occur; IV hydration decreases risk of
nephrotoxicity; selective serotonin antagonists and steroids can be
used for prophylaxis against nausea/vomiting |
Drug Name
|
5-Fluorouracil (Efudex, Adrucil,
Fluoroplex) -- Pyrimidine antagonist. Several mechanisms of action
have been proposed, including inhibition of thymidylate synthase and
inhibition of RNA synthesis. Also is a potent radiosensitizer.
|
| Adult Dose |
225 mg/m2/d continuous
IV for 5 wk
|
| Pediatric Dose |
Not established
|
| Contraindications |
Documented hypersensitivity;
myelosuppression; acute active infection
|
| Interactions |
May increase effects of
anticoagulants, immunosuppressives, NSAIDs, platelet inhibitors, and
thrombolytics
|
| Pregnancy |
D - Unsafe in pregnancy
|
| Precautions |
Inflammatory reactions may occur
with occlusive dressings; porous gauze dressing may be applied for
cosmetic reasons, without increase in reaction |
Drug Name
|
Ifosfamide (Ifex) -- Forms DNA
interstrand and intrastrand bonds that interfere with protein
synthesis.
|
| Adult Dose |
5 g/m2 IV over 24 h q3wk
|
| Pediatric Dose |
Not established
|
| Contraindications |
Documented hypersensitivity;
renal/hepatic failure; bone marrow suppression
|
| Interactions |
Phenobarbital, phenytoin, chloral
hydrate, and other drugs that interfere with cytochrome P-450
activity may alter effects
|
| Pregnancy |
D - Unsafe in pregnancy
|
| Precautions |
May cause hemorrhagic cystitis and
severe myelosuppression; caution in renal function impairment or
compromised bone marrow reserve |
Drug Name
|
Paclitaxel (Taxol) -- Mechanisms of
action are tubulin polymerization and microtubule stabilization.
|
| Adult Dose |
175 mg/m2 IV over 3 h
q3wk; alternatively, 135 mg/m2 IV over 24 h q3wk
|
| Pediatric Dose |
Not established
|
| Contraindications |
Documented hypersensitivity to
paclitaxel or polyoxyethylated castor oil; peripheral neuropathy;
bone marrow suppression; liver failure; severe cardiac disease
|
| Interactions |
Coadministration with cisplatin may
further increase myelosuppression
|
| Pregnancy |
D - Unsafe in pregnancy
|
| Precautions |
Premedicate with steroids, H1
blockers, and H2 blockers to decrease risk of hypersensitivity
reactions; myelosuppression, alopecia, arthralgia/myalgias, and
cardiac arrhythmia may occur |
Deterrence/Prevention:
- Screening of cervical cancer
- Retrospective data have shown that screening with a Pap smear
reduces the incidence rate of cervical cancer by 60-90% and the death
rate by 90%.
- Since 1988, the American Cancer Society and the NCI have
recommended that a Pap smear and pelvic examination be performed
annually after the onset of sexual activity or in women aged 18 years
and older. After 3 consecutive negative results, the screening
interval may be prolonged at the discretion of the physician and
patient. Women older than 60 years 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 or HPV infection,
cervical dysplasia, and multiple sexual partners have annual Pap smear
screening.
- The false-negative rate of a Pap smear is 20%, which mostly
results from sampling error. Physicians can reduce sampling error by
ensuring adequate material is taken from both the endocervical canal
and the ectocervix. Smears without endocervical or metaplastic cells
must be repeated. Suspicious or grossly abnormal cervical lesions upon
physical examination should undergo biopsy regardless of cytologic
findings.
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
often are affected.
- Acute adverse gastrointestinal effects include diarrhea, abdominal
cramping, rectal discomfort, or bleeding. Diarrhea usually is
controlled by either loperamide (Imodium) or atropine sulfate
(Lomotil). Small, steroid-containing enemas are prescribed to
alleviate symptoms from proctitis.
- Cystourethritis also can occur, which leads to dysuria, frequency,
and nocturia. Antispasmodics often are 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 should be used in case erythema or desquamation
occurs.
- Late sequelae of radiation usually appear 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 higher than 90%, for
stage II is 60-80%, for stage III is approximately 50%, and for stage IV
disease is less than 30%.
Patient Education:
- Cervical cancer is over-represented among underserved and minority
groups in the United States. It is imperative to increase awareness
about the benefits of Pap smear screening in these groups.
REFERNECES
|