Download Cervical Cancer

MINISTRY OF PUBLIC HEALTH OF UKRAINE
KHARKOV NATINAL MEDICAL UNIVERSITY
МИНИСТЕРСТВО ЗДРАВООХРАНЕНИЯ УКРАИНЫ
ХАРЬКОВСКИЙ НАЦИОНАЛЬНЫЙ МЕДИЦИНСКИЙ
УНИВЕРСИТЕТ
Gynecologic malignancies
Онкогинекология
Утверждено
ученым советом ХНМУ
Протокол № 4 от 19.01.2007 г.
Kharov KNMU- 2007
Харьков ХНМУ – 2007
Онкогинекология: Метод. указ. к практ. занятиям для студентов V-VI
курсов медицинских вузов, обучающихся на английском языке / Сост.
В.И. Стариков, А.Н. Белый.– Харьков: ХНМУ, 2007.– 24 с.
Gynecologic malignancies are approved by the Scientific Committee of the
Kharkov state medical university and is recommended for V-th, VI-th year
students of medical faculty / Authors: V.I. Starikov, A.N. Bely.– Kharkov:
KNMU.2007. – 24 p.
Authors: Starikov V.I.
Bely A.N.
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CERVICAL CANCER
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, cervical cancer is relatively uncommon. 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.
Frequency
Internationally, 500,000 new cases are diagnosed each year.
Mortality/Morbidity
The American Cancer Society estimates that 4,070 women will die from cervical cancer in
the United States in 2009.1 This represents 1.3% of all cancer deaths and 6.5% of deaths from
gynecologic cancers.
Race
In the United States, cervical cancer is more common in Hispanic, African American, and
Native American women than in white women.
Age
Cervical cancers usually affect women of middle age or older, but it may be diagnosed in
any reproductive-aged woman.
Clinical
History
 Because women are screened routinely, the most common finding is an abnormal
Papanicolaou test 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.
o Symptoms that can evolve, such as constipation, hematuria, fistula, and ureteral
obstruction with or without hydroureter or hydronephrosis, reflect local organ involvement.
o 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, hepatomegaly may develop.
 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
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potential sexually transmitted carcinogen was unsuccessful until breakthroughs 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 90% of squamous intraepithelial lesions (SILs) and
invasive cervical cancers compared with 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 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.
 Human papillomavirus
o 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.
o 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.
o The HPVs that infect the human cervix fall into 2 broad categories. The low-risk types,
HPV 6b and 11, 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. Although less common, types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 should
also be considered carcinogenic.
o 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
o 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.
o Impaired lymphocyte function has been postulated to enhance latent or subclinical HPV
activity, resulting in a higher rate of persistent infection.
o Whether HIV has a synergistic effect on HPV infection, either by direct molecular
interaction or through an indirect immunologic effect, remains unclear.
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Workup
Laboratory Studies
 If cervical cancer is the suggested diagnosis, a Papanicolaou test should be performed.
 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.
 The use of positron emission tomography (PET) scan is now recommended for patients
with stage IB2 disease or higher.
Other Tests
In the International Federation of Gynecology and Obstetrics (Federation Internationale de
Gynecologie et d’Obstetrique [FIGO]) guidelines for staging, procedures are limited to colposcopy,
biopsy,
conization
of
cervix,
cystoscopy,
and
proctosigmoidoscopy.
In the United States, more complex radiologic imaging, such as CT, MRI, and PET scans as well as
surgical staging, are often done to guide therapeutic options.
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 Papanicolaou test. The
Papanicolaou test classification system has evolved over the years. Standardized Papanicolaou test
reporting emerged from a 1988 workshop sponsored by the National Cancer Institute. Currently,
cervical cytology results are reported according to the 2001 Bethesda System.
General considerations
Complete evaluation should include Papanicolaou test 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.
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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.
Staging
Two staging systems are frequently used in cervical cancer: FIGO, in collaboration with the
World Health Organization (WHO), and TNM system of the International Union Against Cancer
(UICC) and the American Joint Committee on Cancer (AJCC).
Table. Cervical Cancer Staging (primary tumor [T])
Table
TNM Stage
Tx
FIGO Stage
-
Primary tumor cannot be assessed
T0
-
No evidence of primary tumor
Tis
0
Carcinoma in situ
T1
I
Cervical carcinoma confined to uterus (extension to
corpus should be disregarded)
T1a
IA
Invasive carcinoma diagnosed only by microscopy. All
macroscopically visible lesions--even with superficial invasion-are T1b/1B. Stromal invasion with a maximal depth of 5.0 mm
measured from the base of the epithelium and a horizontal spread
of 7.0 mm or less. Vascular space involvement, venous or
lymphatic, does not affect classification.
T1a1
IA1
Measured stromal invasion 3 mm or less in depth and 7
mm or less in lateral spread
T1a2
IA2
Measured stromal invasion more than 3 mm but not more
than 5 mm with a horizontal spread 7 mm or less
T1b
IB
Clinically visible lesion confined to the cervix or
microscopic lesion greater than IA2
T1b1
IB1
Clinically visible lesion 4 cm or less in greatest
dimension
IB2
Clinically visible lesion more than 4 cm
T2
II
Cervical carcinoma invades beyond uterus but not to
pelvic wall or to the lower third of vagina
T2a
IIA
Tumor without parametrial invasion
T2b
IIB
Tumor with parametrial invasion
T3
III
Tumor extends to the pelvic wall and/or involves the
lower third of the vagina and/or causes hydronephrosis or
nonfunctioning kidney
T3a
IIIA
Tumor involves lower third of vagina; no extension to
pelvic wall
T3b
IIIB
Tumor extends to pelvic wall
hydronephrosis or nonfunctioning kidney
-
IV
and/or
causes
Cervical carcinoma has extended beyond the true pelvis
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or has involved (biopsy proven) the bladder mucosa or rectal
mucosa. Bullous edema does not qualify as a criteria for stage IV
disease.
T4
IVA
Spread to adjacent organs (bladder, rectum, or both)
M1
IVB
Distant metastasis
Regional lymph nodes (N), AJCC staging only, include paracervical, parametrial, hypogastric
(obturator), common, internal and external iliac, presacral and sacral.
 NX: Regional lymph nodes cannot be assessed.
 N0: No regional lymph nodes metastasis.
 N1: Regional lymph nodes metastasis.
Treatment
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.
 Stage 0: Treatment options for stage 0 cancer include loop electrosurgical excision
procedure (LEEP), laser therapy, conization, and cryotherapy.
 Stage IA: The treatment of choice for stage IA disease is surgery—total hysterectomy,
radical hysterectomy, and conization are accepted procedures. According to National
Comprehensive Cancer Network guidelines, pelvic radiation therapy is now a category 1
recommendation for women with stage IA disease and negative lymph nodes after surgery who have
high-risk factors, including large primary tumor, deep stromal invasion and/or lymphovascular space
invasion.
 Stage IB or IIA
o 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.
o Radical trachelectomy with pelvic lymph node dissection is appropriate for fertility
preservation in women with stage IA2 disease, and those with stage IB1 disease whose lesions
are £2 cm.
o 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 study showed identical overall and disease-free survival rates.
o Quality-of-life data, particularly in the psychosexual area, is relatively scant.
o Postoperative radiation to the pelvis decreases the risk of local recurrence in patients with
high-risk factors (positive pelvic nodes, positive surgical margins, and residual parametrial disease).
o A 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.
 Stage IIB-IVA
o For locally advanced cervical carcinoma (stages IIB, III, and IVA), radiation therapy was
the treatment of choice for many years. However, the results from large, well-conducted, prospective
randomized clinical trials demonstrated a dramatic improvement in survival with the combined use
of chemotherapy and radiation. Consequently, the use of cisplatin-based chemotherapy in
combination with radiation has become the standard of care for patients with locally advanced
cervical cancer.
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o Radiation therapy 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.
 Stage IVB and recurrent cancer
o These patients are treated with chemotherapy. For many years, single-agent cisplatin
represented the standard of care. Recently, the combined use of cisplatin and topotecan was shown
to significantly improve survival compared with single-agent cisplatin.
o Palliative radiation is often used on an individualized basis to control bleeding, pelvic pain,
or urinary or partial large bowel obstructions from pelvic disease.
o Special effort should be made to ensure comprehensive palliative care, including adequate
pain control for these patients.
Monk and colleagues studied chemotherapy regimens consisting of cisplatin plus 1 other
antineoplastic agent in advanced and recurrent cervical carcinoma. In this study, 513 patients were
randomized to 1 of 4 regimens, and, in each regimen, patients receive cisplatin 50 mg/m2 on 1 day
every 3 weeks. The following drugs were combined with cisplatin for the 4 regimens: (1) paclitaxel
135 mg/m2 over 24 hours (PC, reference arm), (2) vinorelbine 30 mg/m2 on days 1 and 8 (VC), (3)
gemcitabine 1000 mg/m2 on days 1 and 8 (GC), or (4) topotecan 0.75 mg/m2 on days 1, 2, and 3
(TC). The primary end point was survival with 33% improvement relative to the reference arm of
paclitaxel and cisplatin. The authors found the various treatment arms were not superior to PC for
overall survival. Furthermore, the trend for response rates, progression-free survival, and overall
survival favored paclitaxel and cisplatin.
Surgical Care
 Carcinoma in situ (stage 0) is treated with local ablative measures such as cryosurgery,
laser ablation, and loop excision.
o Hysterectomy should be reserved for patients with other gynecologic indications to justify
the procedure.
o After local treatment, these patients require lifelong surveillance.
 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.
 The standard treatment for microinvasive disease (stage IA) is total hysterectomy.
o Lymph node dissection is not required if the depth of invasion is less than 3 mm and no
lymphovascular invasion is noted.
o 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.
o Patients with medical comorbidities who are not surgical candidates can be successfully
treated with radiation.
 Total pelvic exenteration may be considered in patients with an isolated central pelvic
recurrence.
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.
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 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 megestrol (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.
Topotecan, ifosfamide, and paclitaxel also have significant activity in this setting. The combination
of topotecan and cisplatin improves overall survival. However, acute toxicities are also increased.
Follow-up
Deterrence/Prevention
 Screening of cervical cancer
o For many years, the standard method for cervical cancer screening has been the
Papanicolaou test. Retrospective data have shown that screening with a Papanicolaou test reduces
the incidence of cervical cancer by 60-90% and the death rate by 90%.
o The false-negative rate of a Papanicolaou test 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. Upon physical examination, suspicious or grossly abnormal cervical lesions should
undergo biopsy regardless of cytologic findings.
o Recently, new technologies have become available. Limited information is available
regarding their sensitivity and specificity (compared with the conventional Papanicolaou test).
Whether these new methods improve survival, compared with the conventional Papanicolaou test, is
unknown.
o Since its introduction more than 50 years ago, the use of the Papanicolaou test for cervical
screening has reduced mortality by 70%. Nonetheless, the mortality rate in the United States has
remained relatively constant during the last 25 years. One of the factors to explain this has been
described as limitations of the traditional Papanicolaou test method itself.
 The limitations of the conventional Papanicolaou test include limited sensitivity (51%) and
a significant proportion of inadequate specimens. In addition, accurate interpretation of conventional
Papanicolaou tests are often compromised by the presence of artifacts (such as blood, mucus,
obscuring inflammation, scant cellular material, and air-drying artifact).
o ThinPrep test: The ThinPrep test samples are collected the same way as the conventional
Papanicolaou test. However, the specimen is placed in a preservative solution rather than on a slide.
An automated processor prepares the sample and makes a uniform slide for review. Mucus and
blood are removed in the process. The ThinPrep Papanicolaou test was approved in 1996 as an
alternative to the traditional conventional smear.
o HPV testing: The Hybrid Capture II HPV test was approved by the Food and Drug
Administration (FDA) as a new approach for cervical cancer in 2003. This test is indicated for
women aged 30 years and older, in conjunction with the Papanicolaou test. If both tests are negative,
then the next Papanicolaou test can be delayed for 3 years.
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o The HPV test is also useful to interpret equivocal results from a Papanicolaou test. If a
women has an ASCUS Papanicolaou test result and a positive HPV test, then additional workup with
a colposcopy is indicated.
 Screening recommendations are as follows:
o The American Cancer Society (ACS) and the US Preventive Services Task Force
(USPSTF) recommend that all women should begin screening for cervical cancer approximately 3
years after they begin to have vaginal intercourse, but no later than age 21.
o Beginning at age 30, women who have had 3 consecutive normal Papanicolaou test results
may get screening every 2-3 years. Women with high risk factors (DES exposure, HIV infection, or
other immunodeficiencies) should continue yearly screening.
o Another option for women aged 30 years and older is to get screened every 3 years with
the conventional- or liquid-based Papanicolaou test plus HPV DNA test.
o The ACS recommends that women aged 70 years and older with 3 or more normal
consecutive Papanicolaou test results and no abnormal Papanicolaou test results within the last 10
years may choose to stop having cervical cancer screening. The USPSTF recommends against
routinely screening women older than age 65 cancer if they have had adequate recent screening with
normal Pap smears and are not otherwise at high risk for cervical cancer.
o Women who have had a total hysterectomy may stop having cervical cancer screening.
Exceptions are those who had a hysterectomy due to cervical carcinoma (or preinvasive changes)
and women who had a hysterectomy without removal of the cervix.
 Prevention: Several measures are effective to prevent HPV infection and hence prevent
cervical cancer.
o Sexual abstinence
o Barrier protection and/or spermicidal gels during sexual intercourse
o Vaccination: Evidence suggests that HPV vaccines prevent HPV infection. A vaccine for
HPV, Gardasil, is approved by the FDA for girls and women 9 to 26 years of age for prevention of
cervical cancer caused by HPV types 6, 11, 16, and 18.
Complications
 Complications from radiation alone
o During the acute phase of pelvic radiation therapy, the surrounding normal tissues such as
the intestines, the bladder, and the perineum skin often are affected.
o 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.
o Cystourethritis also can occur, which leads to dysuria, frequency, and nocturia.
Antispasmodics often are helpful for symptom relief.
o Urine should be examined for possible infection. If urinary tract infection is diagnosed,
therapy should be instituted without delay.
o Proper skin hygiene should be maintained for the perineum, and topical lotion should be
used if erythema or desquamation occurs.
o 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
o The most frequent complication of radical hysterectomy is urinary dysfunction as a result
of partial denervation of the detrusor muscle.
o 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.
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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%.
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UTERINE CANCER
Invasive neoplasms of the female pelvic organs account for almost 15% of all cancers in
women. The most common of these malignancies is uterine cancer, specifically, endometrial
cancer. Endometrial cancer is the most common gynecologic malignancy in the United States. An
estimated 40,100 cases are diagnosed annually, leading to 7470 deaths. It is the fourth most common
cancer, accounting for 6% of female cancers, following breast, lung, and colorectal
cancer. However, it has a favorable prognosis because the majority of patients present at an early
stage, resulting in only 3% of cancer deaths in women.1
History of the Procedure
Cancer of the uterine corpus is the most common pelvic gynecologic malignancy in the
United States and in most developed countries with access to sufficient health care. Approximately
95% of these malignancies are carcinomas of the endometrium. The most common symptom in 90%
of women is postmenopausal (PMP) bleeding. Most women recognize the need for prompt
evaluation, although only 10-20% of women with postmenopausal vaginal bleeding have a
gynecologic malignancy. Because of this prompt evaluation, 70-75% of women are diagnosed with
surgical stage I disease.
Currently, no screening tests for cancer of the uterus are recommended for asymptomatic
women. No evidence suggests that routine endometrial sampling or transvaginal sonography to
evaluate the endometrial stripe in asymptomatic women has a role in early detection of uterine
cancer, even in women who take tamoxifen after breast cancer. The early detection, presenting
symptoms, and higher survival rate make it unlikely that screening will have a successful impact on
earlier detection and increased survival rate.
Sixty percent of endometrial carcinomas are adenocarcinomas. Other histologic subtypes
include adenosquamous, clear cell, and papillary serous carcinomas. Sarcomas make up about 4% of
uterine corpus malignancies, including carcinosarcomas or mixed homologous müllerian tumors, 4850%; leiomyosarcomas (LMSs), 38-40%; and endometrial stromal sarcomas (EESs), 8-10%. The
remaining sarcomas are made up of heterologous tumors—tumors that contain histologic
components foreign to the uterus, such as rhabdomyosarcomas, osteosarcomas, and
chondrosarcomas. This article discusses endometrial cancer and uterine sarcomas.
Frequency
Approximately 40,100 women were predicted to develop this form of malignancy in 2008 in
the United States. After doubling in the early 1970s, the incidence of uterine cancer has remained
fairly constant. In 2008, 7,470 deaths were predicted.
While endometrial cancer affects reproductive age as well as postmenopausal women, 75%
of endometrial cancers occur in postmenopausal women, with the mean age of diagnosis at 61
years. Premenopausal women are at increased risk if they have certain risk factors. The most
common low-grade endometrioid endometrial cancers have been associated with obesity, nulliparity,
anovulatory menstrual cycles, diabetes, and hypertension. In addition, these younger women are at
higher risk for a synchronous primary ovarian cancer, with a rate up to 19-25%.
Another group of women at increased risk of premenopausal endometrial cancer are those
with Lynch II syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC). This is
an autosomally dominant germline mutation in DNA mismatch repair (MMR) genes (MSH1, MSH2,
MSH6) and accounts for 9% of patients younger than 50 years with endometrial cancer. These
mutations lead to microsatellite instability in 90% of colon cancers and 75% of endometrial
cancers. Besides colon cancer, women affected have a 40-60% risk of endometrial cancer by age 70
years, compared to a baseline population risk of 1.5% at the same age. Fifty-one percent of women
had endometrial or ovarian cancer diagnosed first as the sentinel cancer. These women are also at
increased risk for cancer of the ovary, stomach, small bowel, hepatobiliary system, pancreas, brain,
breast, and ureter or kidney.
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Incidence of endometrial cancer is higher among Caucasians compared with Asian or black
women; however, mortality is higher among blacks. This is thought to be due to poor access to care
and presentation at more advanced stages.
Uterine sarcomas, regardless of the histologic subtype, are more common in black women.
Leiomyosarcoma (LMS) tends to occur more often in women aged 30-50 years compared with
carcinosarcomas and endometrial stromal sarcomas (EES), which have a much higher incidence in
women older than 50 years.
Etiology
Endometrioid adenocarcinoma can be due to excess estrogen from various sources, either
exogenous or endogenous. Exogenous sources have included unopposed estrogen replacement
therapy or tamoxifen use. Tamoxifen increases endometrial cancer risk by its agonist activity on the
estrogen receptors on the endometrial lining. Endogenous estrogen sources include obesity and
polycystic ovary syndrome (PCOS) with anovulatory cycles, or estrogen-secreting tumors such as
granulose cell tumors. Increasing body mass index has been associated with increasing risk of
endometrial cancer. Research has found a relative risk of 3 in women 21-50 lb overweight and
relative risk over 10 in women more than 50 lb overweight. Androstenedione is converted to estrone,
and androgens are aromatized to estradiol in the adipose tissue, leading to higher levels of
unopposed estrogen in obese women.
The other factors associated with increasing one’s risk of endometrial cancer are believed to
be related to the same mechanism of increased levels of unopposed estrogen. Nulliparity and
infertility are likely related to chronic anovulation. Increased alcohol use can elevate estrogen
levels. Late menopause and early menarche can be associated with more anovulatory cycles and thus
more unopposed estrogen.
While there is no evidence that screening for endometrial cancer in high-risk populations,
such as patients on tamoxifen or patients who have HNPCC syndrome, decreases mortality, some
societies advocate screening with endometrial biopsies starting at age 35 years in patients with
HNPCC.
Factors that decrease unopposed estrogen are associated with decreased risk of endometrial
cancers. The use of combination oral contraceptive pills for 12 months decreases the risk of
endometrial cancer by more than 40%. Similarly, postmenopausal women taking the combined
estrogen and progesterone hormone replacement therapy have also been found to decrease their rate
of endometrial cancer.8 Smoking is thought to decrease the risk of endometrial cancer by decreasing
estrogen levels as well as leading to earlier menopause.
The following have been identified as risk factors for the various uterine sarcomas. Risk
factors for uterine LMS may include early menarche, late menopause, and African American
race. Women with a history of pelvic radiation are at greatest risk for carcinosarcomas and, to a
lesser extent, LMS. Nulliparous women may be at greater risk for both types of sarcomas.
Pathophysiology
Endometrial cancers are divided into 2 classes, each with differing pathophysiology and
prognosis.
More than 80% of endometrial carcinomas are type I and are due to unopposed estrogen
stimulation, resulting in a low-grade histology. It is often found in association with atypical
endometrial hyperplasia, which is thought to be a precursor lesion. Type II endometrial cancers are
thought to be estrogen independent, occurring in older women, with high-grade histologies such as
uterine papillary serous or clear cell.
Endometrial cancer may originate in a small area (eg, within an endometrial polyp) or in a
diffuse multifocal pattern. Early tumor growth is characterized by an exophytic and spreading
pattern. As noted in Clinical, this growth is characterized by friability and spontaneous bleeding,
even at early stages. Later tumor growth is characterized by myometrial invasion and growth toward
the cervix. Four routes of spread occur beyond the uterus:
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 Direct/local spread accounts for most local extension beyond the uterus.
 Lymphatic spread accounts for spread to pelvic, para-aortic, and, rarely, inguinal lymph
nodes.
 Hematologic spread is responsible for metastases to the lungs, liver, bone, and brain (rare).
 Peritoneal/transtubal spread results in intraperitoneal implants, particularly with uterine
papillary serous carcinoma (UPSC), similar to the pattern observed in ovarian cancer.
Adenocarcinoma of the endometrium, the most common histology, is usually preceded by
adenomatous hyperplasia with atypia. If left untreated, simple and complex endometrial hyperplasia
with atypia progress to adenocarcinoma in 8% and 29% of cases, respectively. Without atypia,
simple and complex hyperplasia progress to cancer in only 1% and 3% of cases, respectively.
Endometrial adenocarcinoma is histologically characterized by cribriform glands (or
glandular crowding) with little, if any, stromal tissue between the glands. Nuclear atypia, variation in
gland size, and increased mitoses are common in adenocarcinoma. Well-differentiated tumors may
be confused with complex hyperplasia with atypia histologically. Likewise, poorly differentiated
tumors might be confused with sarcomas histologically. All papillary serous and clear cell
histologies are considered grade 3. The differentiation of endometrial cancers is one of the most
important prognostic factors. Grade 1, 2, and 3 tumors make up approximately 45%, 35%, and 20%,
respectively, of adenocarcinomas of the endometrium. The 5-year survival rate of clinical stage I
cancers is 94%, 88%, and 79% for grade 1, 2, and 3 tumors, respectively. The degree of histologic
differentiation of adenocarcinoma of the endometrium as defined by the International Federation of
Gynecology and Obstetrics (FIGO) is as follows:
 FIGO grade 1 - 5% or less of solid/nonglandular areas
 FIGO grade 2 - 6-50% of solid/nonglandular areas
 FIGO grade 3 - More than 50% of solid/nonglandular areas
Less histologic differentiation is associated with a higher incidence of deep (ie, greater than
one half) myometrial invasion and lymph node metastases. Subsequently, the depth of myometrial
invasion and presence of tumor in the lymph nodes is directly related to recurrence rates and 5-year
survival rates.
Histological variants
The most common histologic subtype of endometrial cancer is endometrioid
adenocarcinoma, accounting for about 75-80% of endometrial cancers. Less common histologies
include adenosquamous (2%) and mucinous (2%). When corrected for grade, however, the presence
of squamous components has not been demonstrated to cause a significant difference in prognosis
compared to pure adenocarcinomas. PTEN mutation is thought to be an early event in low-grade
endometrial cancers and is found in 55% of hyperplasia and 85% of cancers, whereas it is not found
in benign endometrium.
Approximately 15-20% of endometrial cancers are type II cancers with papillary serous or
clear cell histologies. Papillary serous histology represents 5-10% and clear cell histology represents
less than 5% of endometrial cancers. They are considered high grade with poor prognosis. They have
a propensity for early nodal or upper abdominal spread even with minimal or no myometrial
invasion. The p53 mutation is more common in high-grade tumors, and ERBB-2 (HER-2/neu)
mutation is common in type II cancers. Even with surgical stage I cancer, the 5-year survival rate is
60%. Histologically, uterine papillary serous carcinoma (UPSC) resembles papillary serous
carcinoma of the ovary. Although adjuvant chemotherapy is helpful, UPSC does not have the same
duration of response to cytotoxic agents (eg, paclitaxel, carboplatin) as its ovarian counterpart.
In regards to uterine sarcomas, specifically LMS, the histopathologic diagnosis can be
unclear until the time of definitive surgery. Diagnosis of LMS is dependent on the number of
mitoses (or mitotic count) and the degree of cellular atypia. The diagnosis of LMS versus
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leiomyoma and leiomyoma with high mitotic activity or uncertain malignant potential is based on
the metastatic potential of the tumor. The mitotic count and cellular atypia correlates to this
metastatic potential.
Although controversy continues to exist regarding the diagnosis of LMS, several studies
support the theory that if the mitotic count is less than 5 per 10 high-powered fields (HPF), the tumor
is a leiomyoma with negligible metastatic potential regardless of the presence of any cellular atypia.
Likewise, the tumor has a high metastatic potential and is considered an LMS, regardless of the
degree of cellular atypia, if the mitotic count is greater than 10 per 10 HPF. Some believe that
mitotic count alone is not a good indicator of metastatic potential.
Carcinosarcomas or homologous mixed müllerian tumors (MMT) typically have an
endometrioid carcinoma, usually a higher grade, and an undifferentiated spindle cell sarcoma. The
sarcomatous portion of the tumor may exhibit an endometrial stromal sarcoma (ESS) pattern, if
differentiated. MMTs are termed heterologous only if identifiable extrauterine histology is
demonstrated. MMTs are characterized by early extrauterine spread and lymph node metastases.
Extrauterine disease and lymph node metastases are directly related to depth of myometrial invasion
and the presence of cervical disease. The presence of heterologous elements does not seem to affect
prognosis in terms of the initial extent of disease. New evidence points to a substantial expression of
c-kit receptors in MMTs.
ESS can be divided into 2 categories: low-grade ESS (LGESS) and high-grade ESS
(HGESS). LGESS is characterized by fewer than 5-10 mitoses per 10 HPF and minimal cellular
atypia. These tumors can have a recurrence rate of up to 50% but demonstrate indolent growth and
late recurrences. HGESS have a greater mitotic count and degree of cellular atypia. Risk of
recurrence in both LGESS and HGESS is determined not only by histological characteristics but also
by surgical stage and extent of disease.
Presentation
More than 90% of patients with endometrial cancer will present with abnormal vaginal
bleeding, whether it is menorrhagia, metrorrhagia, or any amount of postmenopausal
bleeding. Approximately 10% of postmenopausal bleeding will lead to a diagnosis of endometrial
cancer. Advanced cases, especially patients with uterine papillary serous or clear cell histologies
may present with abdominal pain and bloating or other symptoms of metastatic disease. Other
presenting symptoms may include purulent genital discharge, pain, weight loss, and a change in
bladder or bowel habits. Fortunately, most cases of endometrial cancer are diagnosed prior to this
clinical presentation because of the recognition of postmenopausal (PMP) bleeding as a possible
early symptom of cancer. About 5% of women may be asymptomatic and diagnosed after workup of
abnormal Papanicolaou test results.
Uterine sarcomas can present in a similar fashion to endometrial carcinomas.
Leiomyosarcoma (LMS) may present in women early in the sixth decade of life with irregular
menses or PMP bleeding. Other symptoms include pain, pelvic pressure, and a rapidly enlarging
pelvic mass. Unfortunately, the diagnosis is rarely made prior to definitive surgery. Endometrial
stromal sarcoma (ESS) usually presents with PMP bleeding, pelvic pain, and an enlarging mass.
Like mixed müllerian tumors (MMT), ESS typically presents in the seventh decade of life. Irregular
and PMP bleeding are the most common symptoms of MMT also. Weight loss, anorexia, and change
in bowel or bladder habits are signs of advanced disease in all cases of uterine cancer.
Indications
The mainstay of primary treatment in endometrial cancer and uterine sarcomas is surgery.
Radiation has an important role in adjuvant treatment of endometrial cancers and
sarcomas. Chemotherapy plays a role in adjuvant therapy for high-grade uterine sarcomas, in
addition to recurrent or metastatic endometrial cancer. Hormonal therapy also has a role in adjuvant
therapy in receptor-positive endometrial cancers. Details regarding all of these therapies are
discussed later in this article.
15
Most endometrial cancers are diagnosed as stage I tumors. In fact, most endometrial cancer
can be cured with surgery alone, and relatively few patients need adjuvant radiotherapy. In the past,
surgery and radiation therapy were both used as primary therapy. Now, survival rates with surgery
are known to be 15-20% better than with primary radiation therapy. Thus, primary radiation therapy
is reserved only for patients who are poor surgical candidates or for those with unresectable disease.
Like endometrial cancer, primary surgical therapy is the first step in treatment of uterine
sarcomas. In fact, these tumors are often found at the time of surgery for benign indications such as
uterine leiomyomata and dysfunctional uterine bleeding, or they are found postoperatively.
Approximately 1 of every 2000 women older than 40 years who are undergoing a hysterectomy for
uterine leiomyomata have leiomyosarcoma (LMS) on final pathologic diagnosis.
Contraindications
In the rare cases of clinical stage I, grade 1 endometrial adenocarcinoma in young women
who have not completed childbearing, an attempt can be made to preserve fertility with medical
management after careful counseling regarding the potential risks. Full evaluation is needed to rule
out higher stage or grade disease. Pelvic ultrasonography, a pelvic MRI, or both is necessary to
assess approximate depth of invasion and to rule out adnexal pathology. A hysteroscopy D&C is
also necessary to thoroughly sample the endometrial cavity and rule out large volume or highergrade disease. Prospective and retrospective series report initial response rates of 50-75%, but many
will recur. One study reports 25% have achieved pregnancies after conservative management.
Recommendation is for definitive total abdominal hysterectomy (TAH), bilateral salpingooophorectomy (BSO), and possible staging with disease persistence, recurrence, or at completion
ofchildbearing.
Some have suggested ovarian preservation after hysterectomy in young women wishing to
preserve hormonal function and future childbearing through egg retrieval. This should be cautioned
against due to risk of adnexal metastases or synchronous tumors, which occur in up to 25% of young
women.
Women with significant comorbidities who are not surgical candidates and have clinical
stage I endometrial cancer can be managed by primary radiation. Although the survival rate with
primary radiation alone is 15-20% less than with surgery, the morbidity and mortality from surgical
therapy in some patients may outweigh the benefits gained in terms of survival and recurrence.
Many of these women will die due to other comorbid conditions.
Workup
Laboratory Studies
Although no laboratory tests aid in the diagnosis of uterine cancer, CA-125 has been used in
surveillance of advanced endometrial cancer. In those patients who have increased CA-125 values
pretreatment, this test might prove useful in post treatment surveillance. Elevated preoperative levels
of CA-125 may also be useful in predicting who might need comprehensive surgical staging.
Imaging Studies
Because performance of an endometrial biopsy in the office is relatively easy and costeffective, most physicians choose to perform this test in lieu of ultrasonography. Ultrasonography,
nonetheless, helps exclude other pelvic pathology that might contribute to postmenopausal (PMP)
bleeding. Endometrial stripe thickness also helps in determining which women with negative
findings on office endometrial biopsy samples should have a formal curettage.
If cancer is diagnosed, appropriate laboratory and radiologic studies can be obtained based
on individual risk factors. Chest imaging should be obtained in all patients to rule out lung
metastases prior to treatment. Chest radiography is adequate for grade 1, clinically early-stage
cancers. A CT of the chest, abdomen, and pelvis may be helpful for high-grade cancers or when
examination findings or symptoms suggest advanced-stage disease. CT scan and/or MRI are
typically not necessary in the workup of apparent early-stage endometrial cancer or uterine sarcomas
because the first-line therapy for the vast majority of these patients includes exploratory surgery.
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Local extension and metastatic disease, requiring comprehensive staging, can be predicted using
clinical evidence, including obvious cervical disease and high tumor grade on the endometrial
biopsy specimen.
Other Tests
Currently, no screening regimens are recommended for asymptomatic women, including
those who take tamoxifen or have hereditary nonpolyposis colorectal cancer (HNPCC) syndrome.
The early detection, presenting symptoms, and higher survival rate make it unlikely that screening
(eg, endometrial biopsy or transvaginal ultrasonography/endometrial stripe) can have a successful
impact on earlier detection and increased survival rates.
Diagnostic Procedures
A workup should be completed for any postmenopausal vaginal discharge or bleeding and
cancer or hyperplasia ruled out. Additionally, any woman older than 35 years and any woman
younger than 35 years with risk factors for endometrial cancer, as outlined below, should have a
workup for any irregular, heavy, or inter-menstrual bleeding.
The easiest way is to obtain tissue by performing an endometrial biopsy in the office. The
use of office biopsies has proven cost-effective by reducing the number of women who need a
curettage under general anesthesia. If the patient’s cervix is very stenotic, an alternative method of
initial workup can be ultrasonographic assessment of the endometrial stripe. If the stripe is ≤4 mm,
the risk of endometrial pathology is <5.5%. However if the stripe is >4 mm, or bleeding is persistent,
tissue biopsy is still required. Up to 17% of type II endometrial cancers will have a thin stripe as
these cancers develop in a background of atrophy.
The technique of dilatation and curettage (D&C) remains an important option for the
diagnosis of endometrial cancer. If the office biopsy findings are negative, inadequate, or not
possible; if the endometrial thickness by ultrasonography is greater than 4 mm; or if a high degree of
suspicion exists, further thorough investigation with diagnostic hysteroscopy with D&C for sitedirected biopsies is warranted. Concern exists regarding transtubal intraperitoneal expulsion of
cancer cells, which can lead to controversies in treatment and prognosis.
Atypical glandular cells (AGC) reported on Papanicolaou test result is associated with cancer
3-17% of the time. The cancers can be of the cervix, endometrium, ovary, or fallopian
tube. Therefore, along with cervical assessment, endometrial biopsy is crucial for women older than
35 years, as well as younger women at risk for endometrial pathology. Similarly, the presence of any
endometrial cells in a postmenopausal woman’s Papanicolaou test result, any atypical endometrial
cells, or any endometrial cells out of sync with menses in women older than 40 years requires
endometrial biopsy to rule out pathology.
Staging
Knowledge of the surgicopathologic, as well as clinical, staging of cancer of the uterine
corpus is crucial in developing an appropriate management plan for endometrial cancer and uterine
sarcomas.:
Table 2. Staging of Cancer of the Uterine Corpus
Stage
Characteristics
Stage I
IA
(grade 1, 2, or 3) IB
IC
Limited to the endometrium
Invasion of less than one half of the myometrium
Invasion of one half or more than one half of the myometrium
Stage II
IIA
(grade 1, 2, or 3) IIB
Endocervical glandular involvement only
Stage III
Invades serosa and/or adnexa and/or positive peritoneal cytology
IIIA
Cervical stromal invasion
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(grade 1, 2, or 3) IIIB
IIIC
Stage IV
IVA
(grade 1, 2, or 3) IVB
Vaginal metastases
Metastases to pelvic and/or para-aortic lymph nodes
Invasion of bladder and/or bowel mucosa
Distant metastases, including intra-abdominal metastases and/or
inguinal lymph nodes
Medical Therapy
The treatment of endometrial cancer needs to be individualized depending on patient factors
and disease stage. Although surgical therapy and surgicopathologic staging is the mainstay of
therapy for most endometrial cancers and uterine sarcomas, nonsurgical therapies, such as radiation
therapy, chemotherapy, and hormonal therapy, play a role in the treatment of uterine cancers.
However, most of these therapies are used as adjuvant/adjunctive therapy or in the treatment of
recurrences or metastatic disease.
Of these therapies, only radiotherapy has any place in primary therapy for early endometrial
cancer and uterine sarcomas. Primary radiotherapy (total dose to tumor of up to 80 Gy) is the
treatment of choice for those patients who are poor surgical candidates. Although the survival rate
with primary radiation alone is 15-20% less than with surgery, the morbidity and mortality from
surgical therapy in some patients may outweigh the benefits gained in terms of survival and
recurrence.
The other instance in which primary radiation is recommended is with stage III disease based
on vaginal and/or parametrial extension, where complete resection of the tumor with primary
surgery is unlikely. Even in this case, adjuvant hysterectomy and adnexectomy are performed 6
weeks after radiation is completed, when feasible. Treatment of clinical stage IV disease is
individualized based on the disease sites. In addition to surgical therapy to control bleeding,
radiation therapy is usually administered for symptomatic bone and CNS metastases, as well as for
local tumor control if the tumor extends to the bladder or rectum. Primary hormone therapy and
chemotherapy may be indicated with distant disease. Primary radiation for uterine sarcomas is
usually limited to those patients who are medically inoperable.
Surgical Therapy
For most patients, the recommended primary treatment is surgical excision and
staging. Surgical staging involves abdominal exploration, obtaining pelvic washings, total
hysterectomy, bilateral salpingo-oophorectomy, biopsy of any suspicious lesions, and pelvic +/para-aortic lymphadenectomy. If papillary serous or clear cell carcinoma is present, omental biopsy
is also required for full staging. The International Federation of Gynecology and Obstetrics (FIGO)
and AJCC stage classifications are based on surgical-pathological findings.
Clinically early stages
Many gynecologic oncologists use the grade and intraoperative frozen analysis of the uterine
specimen to determine the extent of lymph node staging performed. Some oncologists treat patients
with well-differentiated endometrioid adenocarcinomas of the endometrium without adverse risk
factors (eg, no deep myometrial invasion and tumor size <2 cm) by simple total abdominal
hysterectomy (TAH), and bilateral salpingo-oophorectomy (BSO). However, many will perform a
full bilateral pelvic and para-aortic lymphadenectomy for every endometrial cancer patient. The
rationale for this more aggressive approach is frozen analysis of the grade and depth of endometrial
cancer is notoriously unreliable, with upgrading from grade 1 or less in 61% and upstaging in 28%
of specimens on final pathology. A complete lymph node dissection would prevent the need to return
to the operating room (OR) for lymph node staging or use of unnecessary radiation therapy.
One recent study found that almost 20% of patients with grade 1 disease who underwent
routine staging, avoided whole-pelvic radiation based on pathologic findings. Also, a small
percentage of patients with grade 1 disease required whole-pelvic radiation that they would not have
18
received based on uterine and adnexal pathology. In addition, controversy exists as to whether
lymph node sampling is adequate or if more extensive full lymphadenectomy might offer a survival
advantage.
Laparoscopic or robot-assisted staging is becoming increasingly common. Laparoscopy
offers less intraoperative blood loss, less complications, shorter hospital stay, and faster recovery
with comparable lymph node yield. Significantly longer operative times were reported. Comparable
disease-free and over-all survival is seen thus far. Concerns have been raised regarding seeding of
laparoscopic port sites, tubal spillage of tumor, or vaginal cuff metastases due to uterine
manipulation. No data are available to support an increase in these complications, but care should be
used to decrease possible seeding by decreasing uterine manipulation, fulguration of tubes upon
entry, and removal of large lymph nodes and specimens using endo-pouches.
Morbidity with extended staging when performed by surgeons trained in these techniques is
not dramatically increased. Most gynecologic oncologists suggest performing at least limited staging
for all patients with endometrial cancer because a significant upgrade or deeper microscopic
myoinvasion (15% in some series) may be missed on frozen section and gross examination.
However, some patients, specifically elderly patients or those with significant comorbidities, are
better served by extrafascial hysterectomy and bilateral adnexectomy alone, followed by radiation as
indicated by histologic factors, even in light of adverse risk factors. Vaginal hysterectomy may be
used in the morbidly obese or medically infirm patient who may tolerate the vaginal approach better
than the abdominal or laparoscopic approach. Recent studies demonstrate similar survival rates for
clinical stage I disease.
In cases of gross cervical involvement, the traditional procedure is a Wertheim radical
hysterectomy with BPPLND followed by postoperative radiation (vaginal brachytherapy or wholepelvic radiotherapy based on pathologic results). TAH/BSO and BPPLND followed by whole-pelvic
postoperative radiation based on pathologic results have been suggested to be adequate for clinical
stage II disease.
Advanced stages
The significance and management of positive cytology in the absence of other peritoneal or
retroperitoneal disease is controversial. Some evidence suggests the endometrial cancer cell in the
washings without other high-risk factors, such as high grade, or other extra-uterine disease may not
lead to worse outcome and may not need aggressive intervention. This may be caused by uterine
manipulation or tubal spillage after hysteroscopy. Others found it to be an independent predictor of
worse survival, similar to those patients with positive adnexal or serosal disease.
If bulky disease is found at laparotomy, optimal cytoreduction is recommended to improve
patient outcome. All patients with advanced stages III and IV disease should be offered adjuvant
treatment after surgery.
The role of surgery in stage IVB disease may involve tumor reduction or palliative
chemotherapy or radiation. Tumor reductive surgery is typically followed with adjuvant/adjunctive
chemotherapy, hormonal therapy, and/or radiation therapy.
Surgery with staging is also the primary treatment of choice for uterine sarcomas. Patients
with leiomyosarcoma (LMS), mixed müllerian tumors (MMT), or high-grade endometrial stromal
sarcoma (HGESS) benefit from total abdominal hysterectomy and bilateral salpingo-oophorectomy
through a vertical midline incision, with pelvic washings, omental biopsy, and selective pelvic and
para-aortic lymphadenectomy. Lymphadenectomy for low-grade endometrial stromal sarcoma
(LGESS) is of limited value because the incidence of lymph node metastases is low. The difficulty
with LMS and LGESS is that the diagnosis is usually made intraoperatively or postoperatively.
HGESS and MMT are typically diagnosed preoperatively. Subsequently, surgical therapy for
patients with LMS and LGESS is often incomplete unless surgeons comfortable with extensive
staging are available. The management dilemma is dealt with in the postoperative period.
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Preoperative Details
After diagnosis of endometrial cancer or uterine sarcoma is made, preoperative workup
should include complete blood cell count, electrolytes, CA-125 (if indicated by atypical presentation
or histology), chest radiographs, and any of the above-noted tests, as indicated. Also, the patient
should be in compliance with routine health maintenance screening (ie, mammography,
Papanicolaou test, sigmoidoscopy/colonoscopy as indicated by the patient’s age or symptoms).
If the patient has specific symptoms such as neurologic abnormalities, bone pain, or
respiratory symptoms, a directed metastatic workup should be performed preoperatively (eg, head
CT scan/MRI, bone scan).
Other tests that are occasionally used are CT, MRI, PET/CT, proctosigmoidoscopy, and
cystoscopy. These studies are more important in the patient who is medically inoperable.
Nonsurgical treatment can then be individualized for these patients. An early referral to a
gynecologic oncologist should be made for complete preoperative workup and discussion of
extensive staging and cytoreductive surgery or nonsurgical management options.
Postoperative Details
Risk factors associated with higher recurrence risk include lymph node metastases, high
histologic grade, deep myometrial invasion, lymphovascular space invasion, cervical involvement,
positive cytology, and adnexal or serosal involvement.
With endometrial cancer that is clinically confined to the uterus, 3 separate categories for
recurrence risk exist: low risk, moderate risk, and high risk.
Low risk
Low risk is defined as grade 1 or 2 endometrioid/adenosquamous tumors with only inner one
half myometrial invasion, no cervical extension, no lymphovascular space involvement, and
negative findings on cytology and grade 3 with no myometrial invasion. These patients need no
adjuvant therapy, although some gynecologic oncologists administer adjuvant therapy to all patients
with grade 3 tumors.
Moderate risk
Much controversy and research surrounds postoperative management of intermediate risk for
recurrence in patients with endometrial cancer, which includes low grade (1 or 2) with deep
myometrial invasion or cervical involvement. Guidelines suggest consideration of adjuvant external
beam or vaginal brachytherapy or both. Prospective trials have shown a decrease in local recurrence
but no change in overall survival.
A subset of patients with high intermediate risk has a significant decrease in local recurrence
and would benefit from adjuvant radiation. This category includes patients who have any 2 of the
following 3 risk factors: grade 3 histology, age older than 60 years, or deep invasion to outer one
half of the myometrium. More recent reports suggest vaginal brachytherapy may have similar
efficacy of decreasing local recurrence as external beam radiation with less toxicity.
High risk
High risk for recurrence includes patients with grade 3 disease with any myometrium
invasion, stage IIA or greater, have lymphovascular or low uterine segment involvement, or clear
cell and papillary serous histologies. These patients need adjuvant radiation, chemotherapy, or both.
While some recommend whole-pelvic radiation therapy, others advocate only vaginal brachytherapy
if the tumor is fully staged without evidence of extracorporeal spread. The results of a recent
Gynecologic Oncology Group study demonstrated that, while adjuvant whole-pelvic radiation
therapy for patients with high-risk early-stage disease reduced the risk of pelvic recurrence by 50%,
overall survival was not improved.
There will be a subset of patients who after hysterectomy do not undergo lymph node
staging, either because of falsely reassuring frozen section or because cancer was not diagnosed
preoperatively. Management will need to be individualized depending on grade, histology, and depth
20
of invasion. Management may include close follow-up, returning to the operating room for full
staging, vaginal radiation, or pelvic radiation.
A shift toward the use of more systemic chemotherapy over radiation for the treatment of
extra-uterine metastatic endometrial cancer has occurred. A Gynecologic Oncology Group (GOG)
prospective trial found a survival benefit for patients with stage III or IV disease with the use of
systemic chemotherapy with doxorubicin and cisplatin (AP) when compared to whole-abdominal
pelvic radiation (WART). Another GOG trial found a survival advantage with the addition of
paclitaxel to cisplatin and doxorubicin (TAP), and this is considered by many to be the current
standard for those patients who can tolerate the treatment.
A popular alternative regimen is carboplatin and paclitaxel, which has shown efficacy in
retrospective trials, and is currently compared to TAP in an ongoing GOG trial. Due to a higher
pelvic recurrence rate seen in the subgroups receiving chemotherapy instead of radiation, ongoing
trials are studying the efficacy and tolerability of chemotherapy and radiation together as dual
modality treatment.
After tumor reductive surgery for extrapelvic/advanced disease at the time of laparotomy,
adjuvant/adjunctive therapy is individualized. Localized radiation therapy is administered for CNS
and bone metastases. Otherwise, these patients are treated with chemotherapy and/or progestin or
antiestrogen therapy. Medroxyprogesterone acetate and megestrol therapy is efficacious for those
low-grade tumors that are estrogen and/or progesterone receptor–positive.
Tamoxifen is another alternative when progestin therapy is contraindicated or has failed. A
75-80% objective response occurs with estrogen and/or progesterone receptor–positive tumors
compared to less than 5% in the absence of estrogen and/or progesterone receptor–positive tumors.
Unfortunately, the tumors that tend to have intra-abdominal metastases are high grade and are less
likely to be estrogen and/or progesterone receptor–positive tumors (15-41%). In cases of advanced
disease, sending tissue, specifically from metastatic sites, for receptor analysis is useful. Metastases
are receptor positive in 25% of metastatic tumors compared to 60% of primary tumors.
The major curative treatment of uterine sarcomas is TAH/BSO with surgical staging.
However, a significant number of these tumors are diagnosed intraoperatively and postoperatively.
Subsequently, postoperative therapy usually is necessary, although disagreement generally exists
regarding its efficacy in terms of survival. At times, reoperation for removal of remaining
gynecologic organs with surgical staging may be necessary. In terms of adjuvant therapy, wholepelvic radiation or progestin therapy is recommended for LGESS only with extrauterine disease or
lymphovascular space involvement. Whole-pelvic radiation improves local control for HGESS,
especially stage I disease.
However, if advanced disease is present, progestin therapy and doxorubicin-based
chemotherapy have a role. Because of the increased tendency for LMS to hematogenously spread
and recur at distant/extrapelvic sites, whole-pelvic radiotherapy is relatively ineffective.
Chemotherapy with doxorubicin, ifosfamide, etoposide, and/or cisplatin may be used with LMS.
Recently, gemcitabine and docetaxel (Taxotere) combination therapy has shown promise in
unresectable LMSs of different sites. Patients with MMT that is limited to the pelvis benefit from
whole-pelvic radiation with respect to local control. Those patients with evidence of extrapelvic
disease may respond to additional postoperative therapy with doxorubicin, cisplatin, and/or
ifosfamide. These cytotoxic therapies have demonstrated up to a 20% complete response rate in
patients with advanced or recurrent disease.
In conclusion, radiation therapy provides local tumor control but no consistent improvement
in survival rates. Chemotherapy and hormonal therapy are better suited for evidence of extrapelvic
spread but yield somewhat inconsistent results. For these reasons, postoperative therapy for uterine
sarcomas is variable.
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Follow-up
Routine surveillance intervals are typically every 3-4 months for the first 2 years, since 85%
of recurrences occur in the first 2 years after diagnosis. Intervals are every 6 months for the next 3
years and annually thereafter. Each visit should include a pelvic examination, a Papanicolaou test,
and a lymph node survey. Chest radiographs may be taken annually. CT scan is recommended only
if symptoms arise or examination suggests a new finding. CA-125 levels are helpful if they were
elevated preoperatively in advanced-stage cancers. Most recurrences are discovered during
evaluation of symptomatic patients. Most recurrences in early-stage disease are at the vaginal cuff
and pelvis.
Outcome and Prognosis
Because of the typical early clinical presentation, most cases of endometrial cancer are
endometrioid adenocarcinoma that is well-differentiated and stage I disease. Overall 5-year survival
rates for all grades and histologic subtypes are approximately 85-95%, 75%, 50%, and 20% for
surgical stage I, II, III, and IV disease, respectively. The nuclear grade is an important determinant
of prognosis. For surgical stage I disease, 5-year survival rates for grade 1, 2, and 3 endometrial
carcinoma is 92%, 87%, and 74%, respectively.
Most recurrences of endometrial cancer are diagnosed within 2 years. Recurrences in
patients treated with surgery alone tend to be more localized to the pelvis (40%), particularly at the
vaginal cuff. Most recurrences (70%) are associated with symptoms of vaginal bleeding, pain, or
weight loss. Asymptomatic recurrences are found by physical examination, abdominal/pelvic
imaging, or chest radiography. Rarely is a recurrence found by abnormal vaginal cytology. These
recurrences are usually salvageable with radiation therapy, surgical excision, occasionally pelvic
exenteration, or a combination of surgical excision and radiation. The prognosis for these patients is
better if the original diagnosis was more than 2 years before the recurrence.
Endometrial cancer treated with surgery and radiation that does recur is less often localized
and, as such, is less amenable to localized therapy such as surgical excision and radiation. The most
common extrapelvic sites for recurrences include the lungs, abdomen, para-aortic lymph nodes,
brain, bones, and liver. Distant recurrences also present in the anterior scalene, supraclavicular, and
inguinal lymph nodes. If the tumor is hormone receptor–rich, it may be amenable to progestin or
antiestrogen therapy. Otherwise, the same chemotherapy that is used for advanced endometrial
cancer has been studied for recurrent disease, with the same results.
Recurrence is the rule for uterine sarcomas. Stage I uterine sarcomas recur in up to 50% of
cases. The overall 5-year survival rate for leiomyosarcoma (LMS) is 15-25%. Stage I LMS has a
58% and 70% 5-year survival after surgery without and with radiation therapy, respectively.
Recurrences are rarely localized and tend to reappear in the lungs most often. Stage I low-grade
endometrial stromal sarcomas (LGESS) and high-grade endometrial stromal sarcomas (HGESS)
have 5-year survival rates of 80% and 50%, respectively.
As expected, advanced disease has a much worse prognosis, with a 5-year survival rate of 033% for stages II-IV. Early-stage mixed müllerian tumor (MMT) has a 5-year survival rate of
approximately 50%, whereas stages II-IV have a 5-year survival rate of 5-15%.
Localized disease, pelvic or extrapelvic, may be responsive to surgical excision or radiation
therapy. Although doxorubicin, ifosfamide, and cisplatin have been studied and used in treatment of
distant multifocal recurrent disease, no definitive choice of chemotherapeutic has been
recommended for the treatment of recurrent uterine sarcomas. Evaluation of imatinib mesylate
(Gleevec) in advanced and recurrent MMTs is in progress.
Future and Controversies
Malignant cytology
Debate still continues regarding the management of surgical stage III endometrial cancer as
determined by positive findings on peritoneal cytology with disease otherwise limited to the uterine
corpus. Several multivariate studies have demonstrated that positive findings on peritoneal cytology
22
are an adverse risk factor for recurrence. A recent retrospective study found that patients with stage
IIIA disease identified by cytology alone had survival similar to that of patients with early-stage
disease compared to patients with stage IIIA disease identified by adnexal and uterine spread.
Therapy is very controversial.
Options include observation, progestin therapy, chemotherapy, or whole-abdominal
radiation. However, review the cytopathology carefully before initiating any of these treatments.
Estrogen replacement therapy
The use of estrogen replacement therapy (ERT) in women with a history of endometrial
cancer is controversial in stage I, grade 1 endometrioid adenocarcinoma. The results of the recent
Women's Health Initiative (WHI) have only clouded this issue. Although data are limited, patients
who are in complete remission or who have surgical stage I disease and have undergone optimal
treatment may be candidates for ERT. The Gynecologic Oncology Group study designed to evaluate
ERT in early-stage endometrial cancer patients was closed prematurely because of the fallout from
the WHI results. As a result, it is hard to draw any conclusions from the limited data.
Therapy should be individualized and extensive counseling regarding risks, benefits, and
alternatives must be completed prior to initiating estrogen replacement therapy. An alternative for
relief of vasomotor symptoms is clonidine. Raloxifene is a selective estrogen receptor modulator,
has bone protective benefits without increased risk of endometrial or breast cancer, and may be used
as an alternative. However, vasomotor symptoms may worsen with raloxifene.
23
OVARIAN CANCER
Ovarian cancer is the most common cause of cancer death from gynecologic tumors in the
United States. Early disease causes minimal, nonspecific, or no symptoms. Therefore, most cases are
diagnosed in an advanced stage. Overall, prognosis for these patients remains poor. Standard
treatment involves aggressive debulking surgery followed by chemotherapy. Although many
histologic types of ovarian tumors have been described, more than 90% of ovarian malignancies are
epithelial tumors. Therefore, the remainder of this article focuses on these tumors.
Pathophysiology
Ovarian carcinoma can spread by local extension, lymphatic invasion, intraperitoneal
implantation, hematogenous dissemination, and transdiaphragmatic passage. Intraperitoneal
dissemination is the most common and recognized characteristic of ovarian cancer. Malignant cells
can implant anywhere in the peritoneal cavity but are more likely to implant in sites of stasis along
the peritoneal fluid circulation. As discussed later, these mechanisms of dissemination represent the
rationale to conduct surgical staging, debulking surgery, and intraperitoneal administration of
chemotherapy. In contrast, hematogenous spread is clinically unusual early on in the disease process,
although it is not infrequent in patients with advanced disease.
Frequency
The American Cancer Society estimated that there would be 21,550 new cases of ovarian
cancer in 2009 and 14,600 deaths from the disease. Estimates indicate that 1 in 70 women will
develop ovarian cancer in her lifetime. The ovaries are the ninth most common site of cancer in
women, accounting for approximately 3% of all new cases, but ovarian cancer causes 5% of cancer
deaths—more than any other cancer of the female reproductive system. However, during 2001–
2005, the incidence of ovarian cancer declined at a rate of 2.4% annually, and the death rate from
ovarian cancer has been stable since 1998.
Mortality/Morbidity
 Overall, the prognosis of ovarian cancer remains poor, with a 45% 5-year survival rate.
Approximately 15,280 women die every year in the United States from ovarian cancer.
 The prognosis of ovarian cancer is closely related to the stage at diagnosis.
 Ovarian cancer is staged using the International Federation of Gynecology and Obstetrics
(FIGO) staging system. Approximately 20%, 5%, 58%, and 17% of women present with stage I, II,
III, and IV, respectively. Despite this, the 5-year survival rate for ovarian cancer has improved
significantly in the last 30 years. The overall survival rate in 1975-1977 was 36%, compared to 45%
in 1995-2002.
Sex
 Ovarian cancer affects females.
Age
 The disease is uncommon in patients younger than 40 years, after which incidence
increases.
 Most cases are diagnosed in the seventh decade of life.
Clinical
History
 The signs and symptoms of ovarian cancer are nonspecific. Most patients present with
symptoms of several months' duration.
 Symptoms include the following:
o Abdominal/pelvic pain
o Vaginal bleeding
o Bloating
o Abdominal distention
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o Irregular menses
o Change in bowel habits
 A prospective case-control study of 1,709 women visiting primary care clinics found that
the combination of bloating, increased abdominal size, and urinary symptoms was found in 43% of
those with ovarian cancer but in only 8% of those presenting to primary care clinics.
Physical
 Physical findings are uncommon in patients with early disease.
 Patients with more advanced disease present with the following:
o Ovarian or pelvic mass
o Ascites
o Pleural effusion
o Abdominal mass or bowel obstruction
Causes
Traditionally, ovarian cancer has been suggested to originate from cells in the serosa of the
ovary. However, some authors suggest a different cell of origin. The precise cause of ovarian cancer
is unknown, but several risk and contributing factors have been identified.
 Reproductive factors
o Parity is an important risk factor. Women who have been pregnant have a 50% decreased
risk for developing ovarian cancer compared with nulliparous women. Multiple pregnancies offer an
increasingly protective effect.
o Oral contraceptive use decreases the risk of ovarian cancer.
o These factors support the theory that risk for ovarian cancer is related to ovulation and that
conditions that suppress the ovulatory cycle play a protective role.
o Ovarian cancer may develop from an abnormal repair process of the surface of the ovary,
which is ruptured and repaired during each ovulatory cycle. Therefore, the probability of ovarian
cancer may be related to the number of ovulatory cycles.
 Genetic factors
o Family history plays an important role in the risk of developing ovarian cancer.
o The lifetime risk for developing ovarian cancer is 1.6% in the general population. This
compares with a 4-5% risk when 1 first-degree family member is affected, rising to 7% when 2
relatives are affected.
o A history of breast cancer increases a woman's risk of developing ovarian cancer.
 Hereditary ovarian cancer
o Families in which multiple members have ovarian cancer (alone or associated with other
tumors) are defined as having hereditary ovarian cancer.
o Fewer than 5% of all ovarian cancers have a hereditary predisposition. At least 2
syndromes are clearly identified, as follows:
 Breast/ovarian cancer syndrome: This is associated with early onset of breast or ovarian
cancer. Inheritance follows an autosomal dominant transmission. It can be inherited from either
parent. Most cases are related to the BRCA1 gene mutation. BRCA1 is a tumor suppressor gene that
inhibits cell growth when functioning properly; the inheritance of mutant alleles of BRCA1 leads to a
considerable increase in risk for developing ovarian cancer.
 Lynch II syndrome or hereditary nonpolyposis colorectal cancer: These families are
characterized by a high risk for developing colorectal, endometrial, stomach, small bowel, breast,
pancreas, and ovarian cancers. This syndrome is caused by mutations in the mismatch repair genes.
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Workup
Laboratory Studies
 If ovarian cancer is suspected on the basis of a pelvic or ovarian mass, minimize
preoperative testing and expedite laparotomy for diagnosis and staging.
 Routine preoperative tests include CBC, chemistry panel (including liver function tests),
and a cancer antigen 125 assay (CA-125). Remember that CA-125 may be within normal limits in
50% of women with early ovarian cancer.
Imaging Studies
 Routine imaging is not required in all patients in whom ovarian cancer is highly suggested.
 If diagnostic uncertainty is present, a pelvic ultrasound or CT scan of the abdomen and
pelvis is warranted.
 Chest radiographs are common and considered routine.
 CT scan of the chest is seldom indicated.
 MRI can increase the specificity of imaging evaluation in cases where the ultrasound
appearance of the lesion is indeterminate.3 MRI is not definitive, however. On MRI, endometriotic
cysts with enhanced mural nodules are a hallmark of ovarian cancer, but they may also be a feature
of benign neoplasms and even inflammatory diseases. Large contrast-enhanced nodules on large
endometriotic cysts in an elderly patient are more likely to indicate malignancy.
 When imaging studies demonstrate an adnexal mass, the decision whether to observe the
patient with repeat imaging or to proceed to surgical evaluation must take into account not only the
imaging characteristics but also the patient's medical history, physical examination results, and CA125 level.
Other Tests
 In patients with diffuse carcinomatosis and GI symptoms, a GI tract workup may be
indicated, including one of the following:
o Upper and/or lower endoscopy
o Barium enema
o Upper GI series
Procedures
 Biopsy
o Fine-needle aspiration (FNA) or percutaneous biopsy of an adnexal mass is not routinely
recommended. In most cases, this approach may only serve to delay diagnosis and treatment of
ovarian cancer. Instead, if a clinical suggestion of ovarian cancer is present, the patient should
undergo a laparotomy for diagnosis and staging.
o An FNA or diagnostic paracentesis should be performed in patients with diffuse
carcinomatosis or ascites without an obvious ovarian mass.
Histologic Findings
Epithelial tumors represent the most common histology (90%) of ovarian tumors. Other
histologies include the following:
 Low malignant or borderline ovarian tumors
 Sex cord stromal tumors
 Germ cell tumors
 Primary peritoneal carcinoma
 Metastatic tumors of the ovary.
Staging
FIGO staging for ovarian cancer is as follows:
 Stage I - Growth limited to the ovaries
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o Stage Ia - Growth limited to 1 ovary, no ascites, no tumor on external surface, capsule
intact
o Stage Ib - Growth limited to both ovaries, no ascites, no tumor on external surface, capsule
intact
o Stage Ic - Tumor either stage Ia or Ib but with tumor on surface of one or both ovaries,
ruptured capsule, ascites with malignant cells or positive peritoneal washings
 Stage II - Growth involving one or both ovaries, with pelvic extension
o Stage IIa - Extension and/or metastasis to the uterus or fallopian tubes
o Stage IIb - Extension to other pelvic tissues
o Stage IIc - Stage IIa or IIb but with tumor on surface of one or both ovaries, ruptured
capsule, ascites with malignant cells or positive peritoneal washings
 Stage III - Tumor involving one or both ovaries, with peritoneal implants outside the pelvis
and/or positive retroperitoneal or inguinal nodes; superficial liver metastases constitute stage III
disease
o Stage IIIa - Tumor grossly limited to pelvis, negative lymph nodes but histological proof
of microscopic disease on abdominal peritoneal surfaces
o Stage IIIb - Confirmed implants outside of pelvis in the abdominal peritoneal surface; no
implant exceeds 2 cm in diameter and lymph nodes are negative
o Stage IIIc - Abdominal implants larger than 2 cm in diameter and/or positive lymph nodes
 Stage IV - Distant metastases; pleural effusion must have a positive cytology to be
classified as stage IV; parenchymal liver metastases constitute stage IV disease
Treatment
Medical Care
The standard treatment for ovarian cancer starts with staging and cytoreductive surgery.
Based on the surgical staging, patients are classified as having limited disease (stages I and II) or
advanced disease (stages III and IV).
 Patients with limited disease are classified as having low or high risk for recurrence as
follows:
o Low risk for recurrence is indicated by the following:
 Grade 1 or 2 disease
 No tumor on external surface of the ovary
 Negative peritoneal cytology
 No ascites
 Tumor growth confined to the ovaries
o High risk for recurrence is indicated by the following:
 Grade 3 disease
 Preoperative rupture of the capsule
 Tumor on the external surface of the ovary
 Positive peritoneal cytology
 Ascites
 Tumor growth outside of the ovary
 Clear cell tumors
 Surgical stage II
 Postoperative chemotherapy is indicated in all patients with ovarian cancer except those
who have surgical-pathologic stage I disease with low-risk characteristics.
o A meta-analysis suggests that postoperative platinum-based chemotherapy prolongs both
progression-free survival and overall survival in the majority of patients with early-stage ovarian
27
cancer. However, these authors also noted strong evidence that optimal surgical staging identifies
patients who are at low risk and have little or nothing to gain from adjuvant chemotherapy.
 For female patients with carcinomatosis of an unknown primary tumor, consider the
following:
o In women who present with GI carcinomatosis but without an obvious pelvic mass, an
extensive search often fails to identify a primary tumor. These patients can be presumed to have
ovarian carcinoma or primary peritoneal carcinoma and treated with cytoreductive surgery followed
by platinum-based chemotherapy.
Surgical Care
The standard care for ovarian cancer includes surgical exploration for primary staging and
for cytoreduction or debulking.
 Surgical staging
o If the disease appears to be confined to the pelvis, comprehensive surgical staging is
indicated.
o The staging procedure should include the following:
 Peritoneal cytology
 Multiple peritoneal biopsies
 Omentectomy
 Pelvic and para-aortic lymph node sampling.
 Cytoreductive surgery
o This should be performed by a gynecologic oncologist at the time of initial laparotomy.
o The volume of residual disease at the completion of surgery represents one of the most
powerful prognostic factors.
 Prognosis after cytoreductive surgery: Patients with advanced ovarian cancer are classified
in 3 groups as follows, based on the postoperative residual tumor:
o Good risk - Microscopic disease outside the pelvis (stage IIIa) or macroscopic disease less
than 2 cm outside the pelvis (stage IIIb)
o Intermediate risk - Macroscopic disease less than 2 cm outside the pelvis only after surgery
o Poor risk - Macroscopic disease more than 2 cm after surgery or disease outside the
peritoneal cavity
 Interval debulking
o This can be performed in patients who were not adequately debulked at the time of initial
surgery.
o Patients receive 3 cycles of postoperative chemotherapy. Approximately 60% of patients
are then able to undergo optimal resection. Surgical treatment is followed by 3 more cycles of
chemotherapy.
o A European prospective, randomized, clinical trial demonstrated that this approach
improves the outcome of patients with advanced ovarian cancer.7 However, this was not confirmed
in a study conducted in the United States. A major difference between both studies was the extent of
the initial debulking procedure. In the US study, initial optimal debulking was attempted in all
patients. A meta-analysis found no conclusive evidence regarding the possible survival benefit of
interval debulking but noted apparent benefit only in patients whose primary surgery was not
performed by gynecologic oncologists or was less extensive.
o Interval debulking surgery may also be considered in those patients in whom an initial
debulking surgery was not attempted.
 Secondary surgery
o An assessment by Park et al found that secondary cytoreductive surgery is safe and
effective in patients with platinum-sensitive recurrent ovarian cancer. The surgery was most
28
beneficial in patients who had remained disease free for more than 24 months after primary
treatment and in those who achieved optimal cytoreduction.
Medication
Chemotherapy regimens
Standard postoperative chemotherapy is combination therapy with platinum and paclitaxel.
Cisplatin and paclitaxel or carboplatin and paclitaxel are accepted alternatives. Randomized studies
have proven that both regimens result in equivalent survival rates. However, because of a more
tolerable toxicity profile, the combination of carboplatin and paclitaxel is preferred. If patients are
treated with cisplatin, paclitaxel should be administered as a 24-hour infusion to decrease the risk of
neurotoxicity. Another alternative is to combine carboplatin with docetaxel.
The combination of paclitaxel and carboplatin is customarily given every 3 weeks (day 1 of
a 21-day cycle). Because the addition of other drugs to this regimen has proved disappointing,
Katsumata et al studied the use of a dose-dense regimen, in which paclitaxel is given on days 1, 8,
and 15 and carboplatin is given on day 1. Compared with the conventional regimen, the dose-dense
regimen resulted in longer median progression-free survival (28.0 mo versus 17.2 mo) and higher
overall survival at 3 years (72.1% versus 65.1%). Early discontinuation was more common with the
dose-dense regimen, and these patients were more likely to experience toxicity, especially
neutropenia and anemia.
Intraperitoneal chemotherapy
Results from randomized clinical trials suggest that in patients with optimally debulked
disease, intraperitoneal administration of chemotherapy (cisplatin) is superior to intravenous
administration. Recent meta-analyses confirm that intraperitoneal administration of chemotherapy is
associated with an improvement in survival. However, this approach is also associated with more
toxicity. The National Cancer Institute released a clinical announcement supporting the use of
intraperitoneal chemotherapy in optimally debulked ovarian cancer.
Neoadjuvant chemotherapy
Patients with advanced ovarian cancer who are not candidates for surgical cytoreduction may
be treated initially with 2-3 cycles of conventional chemotherapy and can then be reevaluated for
surgical cytoreduction. However, optimal initial cytoreduction remains the standard of care for most
patients.
Maintenance chemotherapy
Most patients with ovarian cancer achieve a complete clinical response after debulking
surgery and platinum-based chemotherapy. However, 50% experience relapse and ultimately die of
the disease. Therefore, strategies to decrease the risk of recurrence have been investigated. A phase
III randomized trial exploring the impact of 12 monthly cycles of paclitaxel as maintenance
chemotherapy was discontinued by the Data Safety and Monitoring Committee when a prospectively
defined interim analysis revealed a highly statistically significant improvement in progression-free
survival; an ongoing phase III trial is addressing the question of whether this maintenance strategy
has a significant effect on overall survival.
Second-line chemotherapy
Recurrent ovarian cancer is classified into 2 categories, depending on the length of time the
patient remained disease-free after completing chemotherapy: (1) relapse that occurs more than 6
months after initial chemotherapy is considered platinum-sensitive; (2) earlier relapse is considered
platinum-resistant. Patients with platinum-sensitive disease may exhibit a good response if
rechallenged with a platinum-based regimen. The probability of response increases with the duration
of the disease-free interval.
Results from clinical trials suggest that combination chemotherapy offers an improvement in
response rate, progression-free survival, and overall survival. Several chemotherapy agents elicit a
response in patients whose disease is resistant to platinum-based therapies. These include liposomal
doxorubicin, topotecan, oral etoposide, gemcitabine, docetaxel, and vinorelbine. Other agents that
29
may be used are ifosfamide, 5-fluorouracil with leucovorin, and altretamine (Hexalen). Tamoxifen,
an oral antiestrogen, exhibits modest activity but has a favorable toxicity profile.
Follow-up
Deterrence/Prevention
 Pregnancy and the use of oral contraceptives significantly decrease the risk of ovarian
cancer.
 Prophylactic bilateral salpingo-oophorectomy is indicated in high-risk women. The
American College of Obstetricians and Gynecologists recommends offering salpingo-oophorectomy
to women with BRCA1 or BRCA2 mutations by age 40 years or when childbearing is complete (level
A recommendation). Surgical prophylaxis decreases the risk by at least 90%. Not all cases of ovarian
cancer are prevented, as women are still at risk for developing primary peritoneal carcinomas.
 No approved screening method is available for ovarian cancer. The U.S. Preventive
Services Task Force (USPSTF) recommends against screening for ovarian cancer in the general
population. The USPSTF found fair evidence that although screening with serum CA-125 level or
transvaginal ultrasound can detect ovarian cancer at an earlier stage, earlier detection is likely to
have a small effect, at best, on mortality from ovarian cancer. In addition, because of the low
prevalence of ovarian cancer and the invasive nature of diagnostic testing, the USPSTF concluded
that the potential harms outweigh the potential benefits.
 Screening with transvaginal ultrasonography and CA-125 tumor marker measurement is
recommended in high-risk women.
Prognosis
 The 5-year survival rates are as follows:
o Stage I - 73%
o Stage II - 45%
o Stage III - 21%
o Stage IV - Less than 5%
30