Sanaz Memarzadeh and Jonathan S. Berek
GENERAL ASPECTS
I. EPIDEMIOLOGY. Malignancies of the genital tract constitute about 20% of visceral cancers in women. The incidence and mortality rates according to primary site are shown in Table 11.1.
Table 11.1 Yearly Rates for Cancers of the Female Genital Tract in the United Statesa
aExtracted from Siegel R, Ward E, Brawley O, Jemal A. CA Cancer J Clin 2011 Jul-Aug;61(4):212–36.
II. DIAGNOSTIC STUDIES
A. Staging evaluation is necessary regardless of the site of the primary lesion after cancer of the female genital tract is proved histologically. Potentially valuable studies include the following:
1. Pelvic and rectal examinations (to determine whether the adnexa, vagina, or pelvic wall is involved)
2. CBC, serum electrolytes, creatinine, and LFTs
3. Chest radiograph: plain chest x-ray or CT as indicated (for pulmonary metastases)
4. Abdominal-pelvic ultrasonography, CT or positron emission tomography (PET) with CT scans, including evaluation of the ureters, or MRI (to delineate abnormal areas)
5. Sigmoidoscopy with biopsy of abnormal areas is optional, as indicated (for mucosal involvement or mass lesions)
6. Cystoscopy with biopsy of abnormal areas for cancers of the vulva, vagina, cervix, or endometrium is optional as indicated (to look for bladder mucosal involvement)
7. Cytologic evaluation of effusions
B. Immunohistochemical tumor markers Immunohistochemical pertaining to gynecologic cancers are shown in Appendix C.
III. LOCALLY ADVANCED CANCER IN THE PELVIS
A. Pathogenesis. Massive pelvic metastases commonly develop in the course of gynecologic and urologic cancers, rectal carcinomas, and some sarcomas. Locally advanced cancers in the pelvis produce progressive pelvic and perineal pain, ureteral obstruction with uremia, and lymphatic and venous obstruction with pedal and genital edema. Invasion of the rectum or bladder can lead to erosion with bleeding, sloughing of tumor into the urine or bowel, and bladder or bowel outlet obstruction.
B. Management
1. Drug therapy is preferred initially in some tumors, depending on the primary site.
2. Radiation therapy (RT) frequently relieves symptoms and is useful when the tumor does not respond to chemotherapy.
3. Surgery. A bowel resection, colostomy, or suprapubic cystostomy may relieve bowel or urethral obstruction. Ureteral bypass can be accomplished by placement of ureteral stent catheters or by nephrostomy.
4. No therapy. Patients with progressive pelvic disease unresponsive to irradiation or chemotherapy usually die from uremia. Uremia is usually the least painful death possible. Urinary stream bypass techniques are not recommended for patients with progressive, unresponsive pelvic pain syndromes or relentlessly eroding tumors.
IV. ADVERSE EFFECTS OF RADIATION TO THE PELVIS
A. Radiation cystitis
1. Acute transient cystitis may occur during RT to the pelvis. The possibility of urinary tract infection should be investigated. Urinary tract analgesics and antispasmodics may be helpful for pain (see Chapter 5, Section V).
2. Late radiation cystitis occurs when high-dose curative RT to the urinary bladder has been preceded by extensive fulgurations. The bladder becomes contracted, fibrotic, and subject to mucosal ulcerations and infections. Urinary frequency and episodes of pyelonephritis or cystitis (often hemorrhagic) are the clinical findings. If symptomatic management is not successful, cystectomy may be required.
B. Radiation vulvitis of a moist and desquamative type usually begins at about 2,500 cGy and may require temporary discontinuation of treatment for 1 to 2 weeks in up to half of patients.
C. Radiation proctitis. See Chapter 30, Section VI.E.
D. Vaginal stenosis. See “General Aspects,” Section V.B.1.c.
E. Effects on gonads. See Chapter 26.
V. MANAGING TREATMENT-RELATED SEXUAL DYSFUNCTION
Patients treated for cancers of the female genital tract often have difficulty performing sexual intercourse.
A. Broaching the subject
1. Address changes in sexual function directly, preferably before therapy is undertaken; the patient’s sexual partner should also be included.
2. Inquire about current sexual activities and about fears the patient or sexual partner might have about the cancer or therapy. Patients should be specifically reassured that the cancer is not contagious, that a small amount of bleeding after intercourse is not hazardous, and that a reasonably normal sex life is expected and desirable for most patients after therapy. See Chapter 26 for discussion of these issues.
B. Specific sexual problems
1. After radiation therapy(RT)
a. External-beam RT. Patients receiving external-beam RT should be advised to continue their normal sexual activity; continued intercourse may help prevent vaginal stenosis. Should vaginal dryness develop, the patient should be advised to use water-soluble lubricants. Estrogen is also useful for treating vaginal dryness in patients with cervical cancer.
b. Radiation implants. Patients with radiation implants should be advised against intercourse until several weeks after treatment. Implants are usually removed before discharge from the hospital. Manual foreplay to the point of orgasm is advised as a temporary substitute for intercourse.
c. Vaginal stenosis secondary to RT may make penile penetration difficult. This complication is often preventable by using dilation and lubrication during the course of irradiation. Manual foreplay, anogenital sex, and orogenital sex are alternatives. Surgical reconstruction by excision of scar tissue and placement of a split-thickness skin graft may yield good results.
2. After radical hysterectomy, the vaginal cuff may be foreshortened, resulting in dyspareunia. Vaginal reconstruction usually has good results. Alternatively, the woman can place her hips on a pillow to provide a better angle for penetration. The man can approach from the rear, which may be more comfortable. If these measures are unsatisfactory, lubricated hands placed at the base of the penis may give the sensation of a longer vagina.
3. After radical vulvectomy, vulvar sensation may be diminished. The patient and her partner should be counseled.
4. After pelvic exenteration, the physician should emphasize the need to allow adequate time for healing of the wound and adjustment to the ostomies. Thereafter, sexual management is as recommended for the stenotic vagina (see Section V.B.1.c). Patients can be advised that vaginal reconstruction can be accomplished during exenteration.
5. After vaginectomy. Reconstruction is performed at the time of primary surgery. Both sexual and reproductive function can often be preserved after treatment of vaginal cancer. The gynecologist determines when intercourse can be resumed.
CANCER OF THE UTERINE CERVIX
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence (Table 11.1). The mortality rate of cervical cancer has declined by 50% since the 1950s, largely as a result of early detection and treatment.
B. Relationship to sexual history. The common denominator for increased risk for cervical cancer is early age at first sexual intercourse. The incidence is also higher in patients with an early first pregnancy, multiple sexual partners, and venereal disease, especially human papillomavirus (HPV) infection.
C. Relationship to HPV. A large body of evidence supports the relationship among HPV, cervical intraepithelial neoplasia (dysplasia), and invasive carcinoma. DNA transcripts of HPV have been identified by Southern blot analysis in >60% of cervical carcinomas. The viral DNA is typically integrated into the human genome rather than remaining in an intact viral capsid. More than 100 HPV subtypes have been identified and 40 of them are associated with cervical, vulvar, and vaginal pathology. Types 6 and 11 are usually associated with benign condyloma acuminata, whereas types 16, 18, 31, and 33 are more likely to be associated with malignant transformation. HPV 16 and 18 are the causative agents for 70% of all cervical malignancies.
D. Relationship to smoking. There is evidence that a personal history of smoking significantly increases the risk for cervical cancer.
II. PATHOLOGY AND NATURAL HISTORY
A. Histology. About 80% of cervical carcinomas are squamous cancers, and 20% are adenocarcinomas. Sarcomas are rare. The disease is believed to start at the squamocolumnar junction. A continuum from cervical intraepithelial neoplasia (CIN) to invasive squamous cell carcinoma is apparent. The average age of women with CIN is 15 years younger than that of women with invasive carcinoma, suggesting a potentially slow progression. The natural history of HPV infection is in part influenced by the host immune system; that all stages of CIN may regress spontaneously, remain unchanged, or progress to invasive carcinoma reflects this fact. A small percentage of lesions appear to bypass this progression and may evolve over a substantially shorter period of time.
B. Metastases. After invasive cancer is established, the tumor spreads primarily by local extension into other pelvic structures and sequentially along lymph node chains. Uncommonly, patients with locally advanced tumors may have evidence of blood-borne metastases, most often to the lung, liver, or bone.
III. PREVENTION AND EARLY DETECTION OF CERVICAL CANCER
A. Vaccination. Bivalent (HPV 16/18) and quadrivalent HPV 6/11/16/18 vaccines have shown efficacy by demonstrating protection against CIN, persistent HPV, and external genital warts in double-blind, randomized, placebo-controlled trials. The vaccines are well tolerated, and the American College of Obstetricians and Gynecologists (ACOG), in conjunction with the Advisory Committee on Immunization Practices (ACIP), recommends administration of approved vaccines from ages 9 to 26. The exact duration of immunity offered by this vaccine is unknown, but is demonstrated to be up to 8.5 years following vaccination against HPV 16. The HPV vaccine does not eliminate the need for cervical cytology screening.
B. Screening with Pap testing
Most patients with cervical cancer do not have symptoms, and cases are detected by routine Pap test screening.
1. Frequency. For >50 years, the Papanicolaou, or Pap, test has been used as the main screening tool for cervical diseases. Early detection has greatly reduced the morbidity and mortality of cervical cancer. The conventional Pap smear has been shown to have a sensitivity of approximately 50%. Overall, it is estimated that about two-thirds of the false-negative rates are due to sampling error, and the remaining one-third are due to laboratory detection error. The American Cancer Society’s recommendations for Pap testing are as follows:
a. Women should have yearly Pap smears starting at age 21 or 3 years after the onset of sexual activity,
b. Women older than 30 and at low risk for cervical cancer who have never had a significant abnormality may have the test less often, for example, every 2 to 3 years, if she has had three normal tests in a row.
c. Women who have had their uterus removed for benign indications do not need to have regular Pap tests. In postmenopausal patients who are ≥70 years of age, screening may be stopped in the presence of three consecutively normal and satisfactory Pap smears and in the absence of an abnormal Pap test over the last 10 years.
2. Technique. There are many problems that contribute to the low sensitivity of Pap tests. Some of these include sample adequacy, slide preparation, and slide interpretation. The new technologies are aimed at improving the quality of the samples but they do not improve the detection of cervical cancer. The squamocolumnar junction, where cervical cancer arises, recedes upward and inward with advancing age. This process decreases the usefulness of scrapings alone to make the diagnosis.
a. Conventional Pap smears. When performing the conventional Pap smear, the cytobrush, used together with an extended tip spatula, is the most effective combination for cell collection. The specimens are smeared on clean glass slides and fixed immediately.
b. Liquid-based Pap smears. This technique involves thin-layer, liquid-based systems. The cervical sample is taken and suspended in an alcohol-based preservative solution. In this liquid, the blood, mucus, and inflammatory cells are filtered out. In the laboratory, a representative sample of cells is then deposited by an automatic device on the slide. The slide is then stained and screened in the usual manner. This specimen can be used for detection of HPV, and “reflex” HPV testing can be performed if cytology reveals evidence of atypical squamous cells of undetermined significance (ASC-US). ThinPrep and SurePath are the two liquid-based cytology systems that are approved by the Federal Drug Administration (FDA).
3. Pap smears are graded using the 2001 Bethesda system as follows:
Negative for Intraepithelial Lesion or Malignancy
Epithelial Cell Abnormalities
Squamous Cell
Atypical squamous cells (ASC)
Of undetermined significance (ASC-US)
Cannot exclude HSIL (ASC-H)
Low-grade squamous intraepithelial lesion (LSIL)
Encompassing: human papillomavirus (HPV)/mild dysplasia/cervical intraepithelial neoplasia type 1 (CIN 1)
High-grade squamous intraepithelial lesion (HSIL)
Encompassing: moderate and severe dysplasia, carcinoma in situ (CIS)/CIN 2 and CIN 3
With features suspicious for invasion
Squamous cell carcinoma
Glandular Cell
Atypical
Endocervical cells (not otherwise specified, NOS)
Endometrial cells (NOS)
Glandular cells (NOS)
Atypical
Endocervical cells, favor neoplastic
Glandular cells, favor neoplastic
Endocervical adenocarcinoma in situ
Adenocarcinoma
Endocervical
Endometrial
Extrauterine
Not otherwise specified (NOS)
Other Malignant Neoplasms
IV. DIAGNOSIS
A. Symptoms and signs
1. Symptoms of early stage invasive cervical cancer include vaginal discharge, bleeding, and particularly postcoital spotting. More advanced stages often present with a malodorous vaginal discharge, weight loss, or obstructive uropathy.
2. Signs. Findings on pelvic examination include the appearance of obvious masses on the cervix; gray, discolored areas; and bleeding or evidence of cervicitis. If a tumor is present, the extent should be noted; involvement of the vagina or parametria is an important prognostic factor.
B. Biopsy. Biopsy specimens should be taken of all visibly abnormal areas, regardless of the findings on the Pap smear. Diagnostic conization may be required if the biopsy shows microinvasive carcinoma, if endocervical curettage shows high-grade dysplasia, or if adenocarcinoma in situ is suspected from cytology.
C. Patients with a positive Pap smear and no visible lesion generally undergo colposcopy, which can detect 90% of dysplastic lesions. The purpose of colposcopy is the examination of the uterine cervix and lower genital tract epithelium under magnification, identification of potentially dysplastic or cancerous areas, and performance of directed biopsies of abnormal areas to provide a histologic diagnosis.
D. Endocervical curettage (ECC) is required when the Pap smear shows a high-grade lesion but colposcopy does not reveal a lesion, when the entire squamocolumnar junction cannot be visualized, when atypical endocervical cells are present on the Pap smear, or when women previously treated for CIN develop new high-grade findings on cytology. If the ECC reveals a high-grade squamous intraepithelial lesion, patients should undergo cervical conization with a knife or a loop electrosurgical excision procedure (LEEP).
E. Further diagnostic studies in patients whose biopsy reports show cancer depend on the depth of invasion.
1. For early CIS, other studies are not necessary.
2. If blood or lymphatic vessels are invaded, or if the tumor penetrates >3 mm below the basement membrane, pretherapy staging studies are required (see “General Aspects,” Section II.A).
V. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. The staging system is clinical as outlined in Table 11.2.
B. Prognostic factors in each stage include size of primary tumor, presence of lymph node metastasis, tumor grade, and histologic cell type.
Table 11.2 Staging System for Cervical Cancer
VI. MANAGEMENT
A. Dysplasia/cervical intraepithelial neoplasia (CIN) 1–3. Treatment modalities include superficial ablative therapies, LEEP, cone biopsy, and hysterectomy (Fig. 11.1).
1. CIN 1 lesions may be observed if the patient has good follow-up because of the high rate of spontaneous regression of these lesions, or lesions may be treated with ablative therapy. In young patients, especially adolescents, CIN 2 may be followed expectantly.
2. Patients with high-grade (CIN 2 and 3) squamous lesions are suitable for ablative or resection therapies, provided the entire transformation zone is visible on colposcopy, the histology of the biopsies is consistent with the Pap smear, the ECC is negative, and there is no suspicion of occult invasion.
3. For high-grade lesions, we recommend LEEP, which involves the use of wire loop electrodes with radiofrequency alternating current to excise the transformation zone under local anesthesia. This has become the preferred treatment for high-grade CIN that can be adequately assessed by colposcopy. Ablative techniques include cryosurgery, carbon dioxide laser therapy, and electrocoagulation diathermy, which are now less frequently employed.
4. Cone biopsy with a scalpel is preferred for lesions that cannot be assessed colposcopically or when adenocarcinoma in situ is suspected.
5. If the patient has other gynecologic indications for hysterectomy, a vaginal or an extrafascial (type I) abdominal hysterectomy may be performed.
B. Invasive cervical cancer: Stage I disease (Table 11.3). The management of patients with early carcinoma of the cervix is diagrammed in Figure 11.1 and summarized in Table 11.3.
1. Stage Ia1 disease with <3-mm invasion may be treated with excisional conization, provided the lesion has a diameter of <7 mm and no lymph or vascular space invasion. A vaginal or extrafascial hysterectomy is also appropriate if further childbearing is not desired.
2. Stage Ia2 disease. For patients with stage Ia2 disease and 3 to 5 mm of stromal invasion the risk for nodal metastases is 5% to 10%. Bilateral pelvic lymphadenectomy should be performed in conjunction with a modified radical (type II) hysterectomy. If future childbearing is desired, in selected cases with well-differentiated tumors, radical trachelectomy with pelvic lymphadenectomy may be considered.
3. Stage Ib disease carries a 15% to 25% risk for positive pelvic lymph nodes and should be treated with a type II or radical (type III) hysterectomy, bilateral pelvic lymphadenectomy, and para-aortic lymph node evaluation. In patients who are poor surgical candidates or in whom the tumor is large (generally >4 cm), RT in conjunction with cisplatin chemosensitization is preferred. In patients with high-risk features (e.g., lymph node metastasis), postoperative RT with concurrent chemotherapy (CCT) with cisplatin as a radiation sensitizer should be given. Fertility preservation with a radical trachelectomy and pelvic lymphadenectomy may be considered if tumors are <2 cm and well differentiated with no evidence of lymph-vascular space invasion.
Figure 11.1. Management of patients with positive Pap smear cytology and early carcinoma of the uterine cervix. (CIN, cervical intraepithelial neoplasia; CIS, carcinoma in situ; ECC, endocervical curettage. *If invasion is not found on conization, patients are followed with Pap smears, biopsies, or repeat conization, depending on the patient and patient’s age.)
Table 11.3 Treatment of Stage I Cervical Carcinoma
C. Concurrent chemotherapy (CCT) with RT reduces recurrence by 30% to 50% and improves 3-year survival rates by 10% to 15% over adjuvant treatment with RT alone.
1. CCT is indicated in the following circumstances:
a. High-risk stages I to IIa (e.g., with lymph node involvement or positive margins)
b. Stages IIb, III, and IVa
2. Point A and point B are common terms used in the management of cervical cancer. Point A is 2 cm proximal and 2 cm lateral to the cervical os. Point B is 3 cm lateral to point A.
3. Regimens. Several combination chemotherapy regimens involving cisplatin and 5-fluorouracil (5-FU) have been effective. Representative regimens are as follows:
a. Cisplatin, 40 mg/m2 weekly for 6 weeks (with or without 5-FU infusions)
b. Cisplatin, 50 mg/m2 on days 1 and 29, and 5-FU, 1,000 mg/m2 per day by continuous IV infusion for 4 days beginning on days 1 and 29. Extension of treatment to four courses is being investigated.
D. Stage II disease. Stage IIa disease is treated in the same manner as stage Ib disease. When the tumor extends to parametrium (IIb), patients should be treated with RT and CCT involving cisplatin (see Section VI.C).
E. Stage IIb and III disease. When the parametrium (IIb), the distal vagina (IIIa), or the pelvic sidewall (IIIb) is involved, clear surgical margins are not possible to achieve, and patients should be treated with maximum-dose (8,500 cGy) RT delivered both externally and by brachytherapy. CCT with cisplatin as radiation sensitizers improves survival rates when compared with RT alone (see Section VI.C).
F. Recurrent and stage IV disease. Advanced cancer in the pelvis is discussed in “General Aspects,” Section III, and obstructive uropathy is discussed in Chapter 31.
1. Lower vaginal recurrence can occasionally be cured by RT or exenteration.
2. Pelvic exenteration. A pelvic exenteration may also be considered for central pelvic recurrent disease after primary RT when spread is confined to the bladder or rectum. Exenteration carries a higher morbidity rate. Metastatic cancer outside the pelvis and poor medical condition of the patient are contraindications to exenteration. Ureteral obstruction, leg edema, and sciatic pain usually suggest sidewall disease. Surgery should be abandoned if there is more extensive cancer than was clinically suspected.
3. RT alone or with chemotherapeutic sensitizers can occasionally cure stage IVA disease. External-beam RT is combined with intracavitary or interstitial radiation to a total dose of about 8,500 cGy. If disease persists after chemoradiation, pelvic exenteration can be performed.
4. Chemotherapy for metastatic disease is not curative. Distant metastases or incurable local disease should be treated as for any advanced malignancy. A number of chemotherapeutic drugs (e.g., cisplatin, carboplatin, paclitaxel, topotecan) produce short-term responses in 10% to 30% of patients.
G. Complications of surgery or RT
1. LEEP. Bleeding occurs in 1% to 8% of cases, cervical stenosis occurs in 1%, and pelvic cellulitis or adnexal abscess occurs rarely.
2. Conization. Hemorrhage, sepsis, infertility, stenosis, and cervical incompetence occur rarely.
3. Radical hysterectomy. Acute complications include blood loss (average, 800 mL), urinary tract fistulas (1% to 3%), pulmonary embolus (1% to 2%), small bowel obstruction (1%), and febrile morbidity (25% to 50%). Subacute complications include transient bladder dysfunction (30%) and lymphocyst formation (<5%). Chronic complications include bladder hypotonia or atonia (3%) and, rarely, ureteral strictures.
4. Pelvic exenteration. The surgical mortality rate is <1%. The postoperative recuperative period may be as long as 3 months, and the massive fluid shifts and hemodynamic status that sometimes occur may require monitoring. Most postoperative morbidity and mortality result from sepsis, pulmonary embolism, wound dehiscence, and intestinal complications, including small bowel obstruction and fistula formation. A reduction in gastrointestinal complications can be achieved by using unirradiated segments of bowel and closing pelvic floor defects with omentum. The 5-year survival rate for patients undergoing total pelvic exenteration is 30% to 50%.
5. Pelvic irradiation. Radiation proctitis and enteritis with intractable diarrhea or obstruction, cystitis, sexual dysfunction because of vaginal stenosis and loss of secretions, loss of ovarian function, fistula formation, and 0.5% mortality either from intractable small bowel injury or from pelvic sepsis (see “General Aspects,” Section IV).
VII. SPECIAL CLINICAL PROBLEMS
A. Chance finding of cancer at hysterectomy. Cancer found in hysterectomy specimens removed for other reasons carries a poor prognosis unless treated with additional surgery or postoperative RT soon after surgery.
B. Uncertainty of recurrent cancer. Recurrent cancer is usually manifested by pelvic pain, particularly in the sciatic nerve distribution; vaginal bleeding; malodorous discharge; or leg edema. Recurrence must be demonstrated by biopsy specimen because these symptoms and even physical findings are similar to radiation changes. If no tumor is found using noninvasive measures, a surgeon experienced in pelvic cancer should perform exploratory laparotomy.
C. Postirradiation dysplasia. Abnormal Pap smears on follow-up examinations may represent postirradiation dysplastic changes or a new primary cancer. Suspected areas should undergo biopsy. If the biopsy findings show cancer, surgical removal may be necessary.
CANCER OF THE UTERINE BODY
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence (Table 11.1). Endometrial cancer is the most common malignancy of the female genital tract in the United States. The peak incidence is in the sixth and seventh decades of life; 80% of patients are postmenopausal. Most premenopausal women with endometrial carcinoma have the Stein-Leventhal syndrome. <5% of all cases are diagnosed before the age of 40 years.
B. Risk factors
1. Estrogen exposure that is unopposed by progesterone increases the risk for endometrial carcinoma by four- to eightfold. Tamoxifen acts as a weak estrogen. Data suggest that the use of tamoxifen is associated with a twofold increased risk for endometrial cancer.
2. Medical conditions producing increased exposure to unopposed estrogens and associated with increased risk of endometrial carcinoma are
a. Polycystic ovarian disease (anovulatory menstrual cycles with or without hirsutism and other endocrine abnormalities)
b. Anovulatory menstrual cycles
c. Obesity
d. Granulosa cell tumor of the ovary, or any other estrogen-secreting tumor
e. Advanced liver disease
3. Other medical conditions associated with increased risk for endometrial carcinoma
a. Infertility, nulliparity, irregular menses
b. Diabetes mellitus
c. Hypertension
d. History of multiple cancers in the family
e. Patient history of breast or rectal cancer
4. Hereditary factors resulting from germ line mutations in DNA mismatch repair (MMR) genes. Mutations in MMR genes (MSH2, MLH1, or MSH6) can result in Lynch syndrome II (hereditary nonpolyposis colorectal cancer). By age 70, up to 40% of these individuals may be diagnosed with endometrial cancer.
II. PATHOLOGY AND NATURAL HISTORY
A. Histology. About 95% of uterine cancers arise from the endometrium, and the most common histologic subtype is endometrioid adenocarcinoma. Clear cell, papillary serous, and squamous cell carcinoma account for the other 10% of endometrial cancers.
B. Role of estrogens. Classically, unopposed estrogens cause a continuum of endometrial changes from mild hyperplasia to invasive carcinoma. Progestin therapy is very effective in reversing endometrial hyperplasia without atypia, but less effective for endometrial hyperplasia with atypia. The most reliable method for reversing hyperplasia is continuous progestin therapy (megestrol acetate).
C. Mode of spread. Tumors are confined to the body of the uterus (stage I) in 75% of cases. Endometrial cancer most commonly spreads by direct extension. Deep myometrial invasion and involvement of the uterine cervix are associated with a high risk for pelvic lymph node metastases. It is rare to find positive para-aortic nodes in the absence of positive pelvic nodes. The presence of cells in peritoneal washes suggests retrograde flow of exfoliated cells along the fallopian tubes. Hematogenous spread is an uncommon late finding in adenocarcinoma but occurs early in sarcoma. The lungs are the most frequent site of distant metastatic involvement.
III. DIAGNOSIS
A. Symptoms and signs
1. Abnormal vaginal bleeding is the most common symptom (97%).
a. Premenopausal women with prolonged menses, excessive menstrual bleeding, or intermenstrual bleeding must be evaluated for endometrial cancer, particularly if they have a history of irregular menses, diabetes mellitus, hypertension, obesity, or infertility.
b. All postmenopausal women with vaginal bleeding >1 year after the last menstrual period are considered to have endometrial cancer unless proved otherwise. Even women who have been on estrogens to control postmenopausal symptoms must have histologic proof that withdrawal bleeding is not the result of an unrelated endometrial cancer.
2. Patients without symptoms and with atypical endometrial cells on Pap smears should undergo endometrial sampling.
3. Women with AGC (atypical glandular cells) on Pap smears who are >35 years, as well as younger women with AGC who have unexplained vaginal bleeding, must undergo an endometrial biopsy in addition to colposcopy.
4. Locally extensive tumors may be palpable on pelvic examination.
5. Advanced disease is the original manifestation of cancer in 5% of cases. Presenting problems include ascites, jaundice, bowel obstruction, or respiratory distress from lung metastases.
B. Endocervical curettage and office endometrial biopsy should be performed in all patients suspected of having endometrial carcinoma. The preferred technique is to use a small flexible plastic catheter (e.g., Pipelle). An endometrial biopsy should be made for optimal interpretation. The accuracy of endometrial sampling is 95% to 98%. All patients with symptoms and a negative biopsy must undergo dilation and curettage.
C. Fractional curettage is the diagnostic method of choice for endometrial cancer. The technique involves scraping the endocervical canal and then, in a set sequence, the walls of the uterus. If cancer is found by histologic evaluation, the fractional scrapings help to locate the tumor site. The gross appearance of the scrapings often suggests cancerous tissue, which is gray, necrotic, and friable.
D. Pap smears. Conventional Pap smears from endocervical aspiration or brushing have a much lower yield than fractional curettage or jet washout. Pap smears alone should not be used to exclude suspected endometrial cancer. Only half of patients with endometrial cancer have abnormal cells on Pap smear.
E. Transvaginal ultrasound with and without color-flow imaging is under investigation. Early data suggest a strong association between thickness of the endometrial stripe and endometrial disease. Normal endometrium is usually <5 mm thick, and false-positive results based on this criterion alone may be excessively high.
F. Staging evaluation. See “General Aspects,” Section II.A.
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. The staging system is surgical as shown in Table 11.4. Staging for endometrial cancer involves total abdominal hysterectomy, bilateral salpingo-oophorectomy, peritoneal cytology, pelvic and para-aortic lymphadenectomy, and sampling of any suspicious peritoneal implants.
Table 11.4 Surgical Staging System for Endometrial Cancer
Adapted from Creaseman WT, et al. Carcinoma of the corpus uteri: FIGO annual report. Int J Gynaecol Obstet 2003;83:79; and Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 2009;105:103.
B. Prognostic factors
1. Histologic grade and myometrial invasion. Increasing tumor grade and myometrial penetration are associated with increasing risk for pelvic and para-aortic lymph node metastases, positive peritoneal cytology, adnexal metastases, local vault recurrence, and hematogenous spread and thus have great prognostic value.
2. Tumor histology. Histologic types ranked from best to worst prognosis are adenocanthoma, adenocarcinomas, adenosquamous carcinomas, clear cell carcinomas, papillary serous carcinomas, and small cell carcinomas.
3. Vascular space invasion. Vascular space invasion is an independent prognostic factor for recurrence and death from endometrial carcinoma of all histologic types.
4. Hormone receptor status. The average estrogen receptor (ER) and progesterone receptor (PgR) levels are, in general, inversely proportional to the histologic grade. However, ER and PgR levels have also been shown to be independent prognostic indicators, with higher levels corresponding to longer survival.
5. Nuclear grade. Criteria for nuclear atypia vary, and intraobserver and interobserver reproducibility is poor. Despite these difficulties, a number of researchers have shown that nuclear grade is a more accurate prognosticator than histologic grade.
6. Tumor size. The larger the tumor, the larger the risk for lymph node metastases, and, therefore, the worse the prognosis.
7. DNA ploidy. Aneuploid tumors constitute a fairly small percentage (25%) of endometrial carcinomas as compared with ovarian and cervical cancers. Aneuploidy is, however, associated with increased risk for early recurrence and death.
V. PREVENTION AND EARLY DETECTION
A. Prevention. Unopposed exogenous estrogen administration should be avoided in postmenopausal women, and women who are anovulatory or who have endometrial hyperplasia should be treated with cyclic progestins.
B. Early detection. Patients in whom evaluation for endometrial carcinoma is necessary include postmenopausal women who have abnormal bleeding on exogenous estrogens; obese postmenopausal women, particularly with a strong family history of endometrial, breast, bowel, or ovarian cancer; and premenopausal women with chronic anovulatory cycles (i.e., polycystic ovarian disease). Women in whom endometrial carcinoma must be excluded include all postmenopausal women with significant bleeding or with pyometra; perimenopausal women with severe intermenstrual or increasingly heavy periods; and premenopausal women with unexplained abnormal uterine bleeding, especially if chronically anovulatory.
VI. MANAGEMENT
A. Early disease
1. Surgery. Total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAH/BSO), pelvic and para-aortic lymphadenectomy is the treatment for patients with early stage endometrial cancer. Patients with an expanded (enlarged) cervix may be treated with a type II (modified radical) hysterectomy; those with microscopic involvement of the cervix may be treated with an extrafascial hysterectomy. Minimally invasive surgery via standard laparoscopy or robotic assisted surgery is an alternative and safe approach to open abdominal surgery in treating patients with endometrial cancer. Optimal tumor debulking is recommended for patients with metastatic extrauterine disease. Any enlarged pelvic or para-aortic lymph nodes are resected. Any peritoneal fluid should be sent for cytology; if no fluid is found, a peritoneal wash with 50 mL normal saline should be performed.
a. If the lymph nodes are negative and the patient has stage Ia or Ib disease with grade 1 or 2 histology and the tumor measures <2 cm, no further treatment is necessary.
b. Patients with persistent atypical hyperplasia after adequate progestin treatment are adequately treated with TAH/BSO in the absence of endometrial cancer. Notably, 40% of these patients will have coexisting endometrial cancer, and complete surgical staging is essential in this population.
c. In young women who have well-differentiated lesions, the use of high-dose progestin hormones can be curative. We recommend medroxyprogesterone (Megace), 80 to 320 mg/d for 3 to 9 months with endometrial sampling every 3 months to assess response. An alternative well-tolerated option is placement of a Mirena IUD resulting in local release of progesterone in the uterine cavity. After the disease is gone, the patient must undergo cyclic hormonal therapy to avoid anovulatory hyperplasia. Hysterectomy is recommended in this group of patients after completion of childbearing.
2. RT
a. RT alone is used only for patients at high risk for surgical mortality because of concomitant medical conditions. The survival rate of patients with stage I or II disease treated with RT alone is significantly inferior to the rates associated with surgery alone or surgery combined with RT.
b. Postoperative RT. To facilitate accurate risk stratification and selection for RT, surgical staging and the histopathologic finding in the uterine specimen and the status of lymph nodes is essential. Based on the relative risk of recurrent disease, patients are categorized into three groups.
(1) Low-risk disease is defined as well-differentiated tumors (grade 1 or 2) with minimal or less than one-half myometrial invasion or grade 3 tumors with no myometrial invasion, with negative lymph nodes and absence of lymph vascular space invasion in the primary tumor. These patients do not require any further treatment.
(2) Intermediate-risk disease includes patients with grade 1 or 2 tumors invading greater than one-half of the myometrium, or patients with grade 1, stage II disease (cervical involvement). This group precludes any disease in the lymph nodes or involvement of the lymph vascular spaces. We recommend adjuvant RT in the form of brachytherapy in this subset of patients. If this group of patients has not undergone a thorough lymphadenectomy, external pelvic irradiation (about 5,000 cGy) should be considered.
(3) High-risk disease is defined by grade 3 tumor with any evidence of invasion, extrauterine disease, evidence of lymph vascular space invasion in the primary tumor, and grade 2 and beyond stage II disease. These groups of patients are at high risk of recurrence and must receive adjuvant treatment in the form of radiation, chemotherapy, or a combination of these two modalities.
3. Chemotherapy has a role in the management of early endometrial cancers. Randomized studies comparing platinum-based chemotherapy (platinum, taxane, and/or anthracycline) to pelvic radiation in intermediate- and high-risk low-stage endometrial cancer suggest that chemotherapy may be an effective adjuvant in endometrial cancer, and perhaps as effective as radiation. It is unclear whether the sequence of chemotherapy followed by radiation is more effective than chemotherapy alone. In patients with papillary serous or clear cell carcinomas, we prefer the use of carboplatin and paclitaxel (see “Ovarian Cancer,” Section VI.E.2 for regimen dosages).
B. Advanced disease
1 Stage III or IV disease is treated best with optimal cytoreduction. Surgery should be followed with systemic multiagent chemotherapy. Efficacious regimens in this setting include combination of doxorubicin and cisplatin or carboplatin and paclitaxel.
a. Removed tumor should be assayed for ER and PgR levels, because hormonal treatments with progestins, tamoxifen, or aromatase inhibitors can also be utilized in an adjuvant setting.
b. Pelvic exenteration may be considered for the occasional patients with recurrent disease extension limited to the bladder or rectum.
2. Drug therapy. Patients with widespread metastases or with previously irradiated, recurrent local disease are treated with hormones and cytotoxic agents.
a. Hormonal therapy. Response to progestins occurs in 20% to 40% of patients. The average duration of response is 1 year, and expected survival in responding patients is twice that of nonresponders. A few patients survive in excess of 10 years. Hormone receptor studies are of some predictive value. The following drugs are most frequently used:
(1) Repository form of medroxyprogesterone acetate (Depo-Provera), 1.0 g IM weekly for 6 weeks and monthly thereafter
(2) Megestrol acetate (Megace), 40 mg PO four times daily
(3) Tamoxifen, 20 mg PO twice daily for 3 weeks alternating with megestrol acetate 80 mg PO twice daily for 3 weeks.
b. Chemotherapy. Drug regimens containing platinum and doxorubicin can be effective; response may be produced in up to 40% of patients, which improves their expected survival by several months. We prefer carboplatin and paclitaxel, and the patients should be treated as if they have advanced ovarian carcinoma (see “Ovarian Cancer,” Section VI.E.2 for regimen dosages).
VII. SPECIAL CLINICAL PROBLEMS
Daily estrogen replacement therapy for younger patients with stage I disease is important to protect against osteoporosis and to improve quality of life. This treatment has not been associated with deleterious effects; however, it should be individualized for each patient considering all their preexisting medical conditions. Other complications are discussed in “General Aspects.”
VAGINAL CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Primary carcinoma of the vagina constitutes 1% to 2% of cancers of the female genital tract. Dysplastic changes of the vaginal mucosa appear to be precursors of VAIN (vaginal intraepithelial neoplasia). The likelihood of vaginal carcinoma is increased in women with a history of cervical carcinoma. About 80% to 90% of cases of vaginal cancer are metastatic in origin and are treated according to the primary lesion.
B. HPV. HPV is associated with VAIN. The exact potential of VAIN to progress to frankly invasive carcinoma is unknown but appears to be in the range of 3% to 5% when the dysplasia is treated with various methods.
C. Estrogens
1. The 2 million daughters of women treated with diethylstilbestrol (DES) during the first 18 weeks of gestation are at risk for developing vaginal clear cell adenocarcinomas. As of February 1992, 580 cases of clear cell vaginal and cervical carcinomas had been reported by the Registry for Research on Hormonal Transplacental Carcinogenesis. DES exposure accounted for two-thirds of the reported cases. The actual risk for clear cell adenocarcinoma in DES-exposed women is estimated to be 1 in 1,000, with the highest risk in women exposed before 12 weeks’ gestation.
2. Vaginal adenosis is present in nearly 45% of women exposed to DES, and 25% have structural abnormalities of the uterus, cervix, or vagina. Almost all women with vaginal clear cell carcinoma also have vaginal adenosis.
3. This tumor is decreasing in incidence owing to the discontinuation of DES circa 1970.
II. PATHOLOGY AND NATURAL HISTORY
A. Histology. About 85% of vaginal carcinomas are squamous carcinomas, and the remainder are adenocarcinomas, melanomas, and sarcomas.
B. Location. Primary vaginal cancers most commonly arise on the posterior wall of the upper one-third of the vagina. If the cervix is involved, the disease is defined as cervical rather than vaginal cancer. If the vulva is involved, the disease is defined as vulvar cancer.
C. Mode of spread
1. Direct extension to adjacent soft tissues and bony structures, including paracolpos and parametria, bladder, urethra, rectum, and bony pelvis, usually occurs when the tumor is large.
2. Lymphatic dissemination occurs to pelvic and then para-aortic nodes from the upper vagina, whereas the posterior wall is drained by inferior gluteal, sacral, and deep pelvic nodes. The anterior wall drains into lymphatics of the lateral pelvic walls, and the distal one-third of the vagina drains into the inguinal and femoral nodes.
3. Hematogenous spread occurs late and is most often to lung, liver, bone, and supraclavicular lymph nodes.
III. DIAGNOSIS
A. Symptoms and signs. The most frequent presenting symptoms are vaginal discharge and bleeding. Vaginal adenosis is usually asymptomatic but may produce a chronic watery discharge. Bladder pain and urinary frequency may occur early on. Advanced posterior tumors may cause tenesmus or constipation.
B. Diagnostic studies
1. Diagnosis of vaginal carcinoma is often missed on initial examination, especially when the tumor is located in the distal two-thirds of the vagina, where the blades of the speculum may obscure the lesion. The speculum should always be rotated as it is withdrawn and the vaginal mucosa inspected carefully.
2. Vaginal Pap smears and biopsy of abnormal areas on pelvic examination are the mainstays of diagnosis. If no lesion is detected with an abnormal Pap smear, application of Lugol iodine and inspection with a colposcope may be helpful in identifying lesions.
3. Staging procedures are discussed in “General Aspects,” Section II.A.
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. Staging system. Several staging systems are used. Despite their clear influence on prognosis, however, tumor bulk and location of the primary lesion in the vagina are not included. Because expected survival depends on clinical stage, variable survival rates have been reported. A representative staging system and approximate survival rates are shown in Table 11.5.
B. Prognostic factors. Generally, the greater the tumor size, the worse the prognosis. Cancers located in the upper vagina, however, have a better prognosis than those located in the lower vagina (upper posterior tumors can become large before invading the muscularis and changing the stage of disease).
Table 11.5 Staging System for Vaginal Cancer
V. PREVENTION AND EARLY DETECTION
A. Cytology and routine examination are the basis of screening the general population. Up to 30% of patients with vaginal cancer have a history of in situ or invasive cervical cancer; these patients should be screened with annual Pap smears.
B. Females with a history of in utero exposure to DES should have a pelvic examination and Pap smear yearly from the time of menarche. Younger girls who have been exposed to DES should be examined at the first sign of bleeding or discharge because clear cell carcinomas can occur in childhood. All suspected areas should undergo biopsy, and careful palpation of all mucosal surfaces is extremely important.
VI. MANAGEMENT
A. Early disease
1. Surgery. The close proximity of bladder, urethra, and rectum restricts the surgical margins that can be obtained without an exenterative procedure. In addition, attempts to maintain a functional vagina and the associated psychosocial issues play an important role in treatment planning.
a. Vaginal mucosa stripping has been used for CIS.
b. Stage I disease involving the upper posterior vagina may be managed with radical hysterectomy, partial vaginectomy, and bilateral pelvic lymphadenectomy. In a patient with prior hysterectomy, radical upper vaginectomy with bilateral pelvic lymphadenectomies can be used.
c. Pretreatment exploratory laparotomy in patients requiring radiation allows for the following:
(1) More precise determination of disease involvement
(2) Resection of bulky involved lymph nodes
(3) Ovariopexy (ovarian transposition) to minimize the chance of radiation-induced infertility
d. Vaginal reconstruction may be performed using split-thickness skin grafts from the thighs or with myocutaneous flaps, usually with gracilis muscle.
2. RT is an alternative treatment for patients with stage I disease; there are no controlled studies to prove that RT is as effective as surgery. Radiation is the treatment of choice for all higher stages, usually using combined external-beam and intravaginal RT. When the distal vagina is involved, the inguinal nodes are also treated.
3. Chemotherapy. Topical fluorouracil, applied twice daily, has been used for VAIN. Intense vaginal burning results. The long-range benefits of topical fluorouracil are not yet proved; this modality cannot be recommended as standard practice.
4. Immune therapy with 5% imiquimod cream —two to three times per week with close clinical observation and careful colposcopic exams to assess response is an alternative treatment for CIS.
5. Laser therapy is useful for stage 0.
B. Advanced disease is managed as for cancer of the cervix (see “Cancer of the Uterine Cervix,” Section VI). In otherwise healthy patients with stage IV disease or central recurrence after previous RT, an exenterative procedure may be performed.
VII. SPECIAL CLINICAL PROBLEMS
Loss of genitalia and vaginal stenosis are discussed in “General Aspects,” Section V.
VULVAR CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Carcinomas of the vulva constitute 3% to 4% of malignant lesions of the female genital tract. The disease is most common in women >50 years of age, with a mean age at diagnosis of 65 years.
B. Etiology
1. HPV viruses play a role in the development of vulvar cancer. High risk subtypes of HPV (16, 18, 31, 33, and 45) have been isolated from invasive vulvar cancer.
2. Intraepithelial neoplasia of the vulva (VIN) and CIN increase a woman’s risk for carcinoma of the vulva. Vaccination with the quadrivalent HPV virus will provide protection against VIN, commonly a precursor lesion to invasive vulvar cancer.
3. Medical history associated with increased risk of vulvar cancer includes obesity, hypertension, diabetes mellitus, arteriosclerosis, menopause at an early age, and nulliparity.
II. PATHOLOGY AND NATURAL HISTORY
A. Histology. Malignant tumors of the vulva are squamous cell carcinoma in >90% of cases and melanoma in 5% to 10%. Adenocarcinoma, sarcoma, basal cell carcinoma, and other tumors constitute the remainder.
B. Location. The sites of tumor in order of decreasing frequency are labia majora, labia minora, clitoris, and perineum.
C. Natural history
1. Squamous cell carcinomas in the vulva have not been shown to develop as a continuum from vulvar intraepithelial neoplasia to CIS to invasive carcinoma. Most studies report that only about 2% to 4% of vulvar intraepithelial neoplasia lesions become invasive cancer. These cancers tend to grow locally, spread to superficial and deep groin lymph nodes, and then spread to pelvic and distant nodes. Hematogenous spread usually occurs after lymph node involvement, and death usually results from cachexia or respiratory failure secondary to pulmonary metastases.
2. Malignant melanoma of the vulva accounts for 5% of all melanoma cases, despite the comparatively small surface area involved and the paucity of nevi at this site (see Chapter 16, “Malignant Melanoma”). Therefore, all pigmented vulvar lesions should be removed.
3. Paget disease of the vulva is a preinvasive lesion with thickened epithelium infiltrated with mucin-rich Paget cells, which are derived from the stratum germinativum of the epidermis. Approximately 10% to 12% of patients have invasive vulvar Paget disease, and 4% to 8% have an underlying adenocarcinoma. Underlying adenocarcinomas are usually clinically apparent. The natural course of this disease is characterized by local recurrence over many years, and recurrences are almost always in situ. These patients are also predisposed to developing extragenital glandular cancers and need careful clinical evaluation and follow-up.
4. Bartholin gland adenocarcinoma is extremely rare and is usually seen in older women. Inflammation of this gland is uncommon in women >50 years of age and is virtually nonexistent in postmenopausal women; gland swelling in women in these age groups should arouse suspicion for the presence of cancer.
5. Basal cell carcinomas and sarcomas of the vulva have natural histories similar to that of primary tumors located elsewhere.
III. DIAGNOSIS
A. Signs and symptoms
1. Squamous cell carcinomas most often present with a vulvar lump or mass, often with a history of chronic vulvar pruritus. The tumors often ulcerate or become fungating. Bleeding, superinfection, and pain can develop with continued growth.
2. Paget disease has a characteristic lesion that is velvety red, with raised, irregular margins. Lesions are pruritic, with secondary excoriation and bleeding.
3. Basal cell carcinomas and melanomas are discussed in Chapter 16.
4. Lymph node enlargement may be palpable in the inguinal or femoral regions or in the pelvis.
B. Indications for vulvar biopsy
1. Patches of skin that appear red, dark brown, or white
2. Areas that are firm to palpation
3. Pruritic or bleeding lesions
4. Any nevus in the genital region
5. Enlargement or thickening in the region of Bartholin glands, particularly in patients >50 years of age
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS FOR SQUAMOUS CELL CARCINOMA
A. Staging system. FIGO (the International Federation of Gynecology and Obstetrics) has adopted a surgically based TNM (tumor, nodes, metastases) staging system to avoid the problems associated with clinical assessment of lymph nodes (see Table 11.6.).
B. Prognostic factors and survival. Survival is determined by stage, structures invaded, and tumor location.
1. Lymph node involvement is exceedingly important. Metastases to pelvic or periaortic nodes are rare in the absence of inguinal or femoral lymph node metastases.
2. The 5-year survival rate in patients with negative or one microscopically positive lymph node is 95%. In contrast, the 5-year survival rate for patients with two positive nodes is 80%, and that for patients with three or more positive nodes is 25%. Note that the risk for hematogenous spread with three or more positive nodes is 66%, in contrast to the risk with two or fewer nodes, which is only 4%.
Table 11.6 Staging System for Vulvar Squamous Cell Carcinoma
Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 2009; 105:103.
V. PREVENTION AND EARLY DETECTION. The routine history and physical examination of all postmenopausal women should include specific questioning regarding vulvar soreness and pruritus followed by careful inspection and palpation of the vulva and palpation for firm or fixed groin nodes. All suspicious lesions should undergo biopsy.
VI. MANAGEMENT
A. Surgery is the treatment of choice for early stage lesions.
1. Vulvar intraepithelial neoplasia. Wide local excision for small lesions. Carbon dioxide laser of the warty variety is acceptable. Alternative treatments include topical administration of 5-fluorouracil, resulting in a chemical sloughing of the skin, or imiquimod (Aldara), leading to a local inflammatory reaction. Before the use of either agent, the existence of invasive disease has to be ruled out.
2. Paget disease. As the Paget cells may invade the underlying dermis, this dermal layer should also be removed during surgical excision. Recurrent lesions may be treated with local excision in the absence of adenocarcinoma. If invasive adenocarcinoma is present, it should be treated in the same manner as an invasive squamous cell vulvar cancer.
3. Invasive carcinoma with <1 mm invasion. Radical wide local excision
4. Stage I disease with >1 mm invasion. Radical local excision with ipsilateral groin lymphadenectomy for lateralized lesions and bilateral lymphadenectomy for centralized lesions
5. Stage II lesions may be treated with bilateral groin lymphadenectomy and radical local excision (or modified radical vulvectomy) provided that at least 1 cm of clear margins in all directions can be achieved while preserving critical midline structures.
6. Complications of modified radical vulvectomy include wound breakdown, local infection, sepsis, thromboembolism, and chronic edema of the lower extremities. Using separate incisions for the groin lymphadenectomies reduces the incidence of wound breakdown and leg edema.
7. Stage III or IV disease. These lesions should be treated with RT and chemosensitization (with cisplatin or 5-FU). Selected cases can be treated with radical vulvectomy. Rare cases of persistent or recurrent disease can be salvaged with exenterative surgery.
B. RT
1. RT may be used to shrink stage III and IV tumors that involve the anus, rectum, rectovaginal septum, or proximal urethra preoperatively to improve resectability.
2. RT has been shown to improve survival and decrease groin recurrence when there is evidence of ≥3 micrometastases or macrometastasis (≥10 mm) in the groin nodes.
3. Postoperative RT to the vulva may be used to reduce local recurrence when tumors exceed 4 cm or there are positive surgical margins.
4. External-beam RT to 5,000 cGy with follow-up biopsy should be considered for small anterior tumors involving the clitoris, especially in young women, to prevent the psychosocial issues involved with surgery.
5. Patients who have medical conditions precluding surgery may be treated with RT alone.
C. Chemotherapy
1. 5-FU or cisplatin chemotherapy can be used as a radiation sensitizer.
2. Systemic treatment with agents active against cervical squamous cell carcinomas, such as cisplatin, carboplatin, paclitaxel, and topotecan, may be used for metastatic disease, but partial response rates are low (10% to 15%) and usually last only a few months.
OVARIAN CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence (Table 11.1). About 21,880 American women will be diagnosed with ovarian cancer this year, and 13,850 deaths will be expected due to this disease. It is the leading cause of death among all gynecologic cancers, the fifth most common female cancer in the United States, with a lifetime risk of 1.4% to 1.8%. Despite the advances in surgical and chemotherapeutic management of this disease, the 5-year survival rate for women with stage III/IV epithelial ovarian cancer has remained as low as 18 to 30% over the past 30 years.
B. Predisposing factors are listed below.
1. Geographical. The highest rates of ovarian cancer are recorded in industrialized countries.
2. Genetic. Germ line mutations in DNA repair genes (BRCA1, BRCA2, MLH-1, MSH-2, PMS1, and PMS2) account for 10% to 15% of ovarian cancer cases. Identification of this group of women by genetic testing is essential as prophylactic risk reduction surgery with a bilateral salpingo-oophorectomy can decrease the risk of gynecologic cancers by 96%. Patients with the following family pedigrees and family history should be considered for genetic testing:
a. Two or more women with ovarian or breast cancer or both, especially if diagnosed premenopausally
b. Women who have separate diagnoses of breast and ovarian cancer
c. Women who have had breast cancer in both breasts
d. Male relatives who have had breast cancer in both breasts
e. Women of Ashkenazi Jewish ancestry with ovarian cancer at any age
3. Personal history of breast or endometrial cancer results in an increased risk for ovarian cancer.
4. Reproductive history such as nulliparity with “incessant ovulation” is a risk factor. Endometriosis in now found to be an independent risk factor for ovarian cancer. The use of oral contraceptives reduces the risk of ovarian cancer, and postmenopausal estrogens may increase the risk.
5. Environmental. Intraperitoneal exposure to talc has been associated with a slight increase in the risk of ovarian cancer. Cigarette smoking may increase the risk of certain subtypes of ovarian cancer.
II. PATHOLOGY AND NATURAL HISTORY
A. Histology. The World Health Organization (WHO) classification of neoplasms of the ovary is shown in Table 11.7.
B. Histologic grade. The percentage of undifferentiated cells present in tissue determines the grade of the tumors.
C. Biologic behavior
1. Borderline tumors, also called “tumors of low malignant potential,” tend to occur in premenopausal women and remain confined to the ovary for long periods of time. Metastatic implants may occur, and some may be progressive, leading to bowel obstruction and death.
2. Other histologic subtypes behave similarly when grade and stage are considered. Even in early stages, careful exploration frequently reveals subdiaphragmatic and omental implants. Organ invasion and distant metastases are less likely than is spread over serosal surfaces. The lethal potential of ovarian cancer is most frequently related to encasement of intra-abdominal organs. Death usually results from intestinal obstruction and inanition.
D. Associated paraneoplastic syndromes
1. Neurologic syndromes are common. Peripheral neuropathies, organic dementia, amyotrophic lateral sclerosis–like syndrome, and cerebellar ataxia are the most frequent occurrences.
2. Peculiar antibodies that cause difficulties in cross-matching blood can be corrected with prednisone.
3. Cushing syndrome
4. Hypercalcemia
5. Thrombophlebitis
Table 11.7 Histology of Ovarian Neoplasms
III. DIAGNOSIS
A. Symptoms and signs. Early ovarian carcinoma is typically asymptomatic. The majority of patients with advanced ovarian cancer present with vague symptoms of abdominal discomfort, such as bloating, constipation, gas, irregular menses if premenopausal, urinary frequency, or abnormal vaginal bleeding. Physical findings include ascites and abdominal masses. Any pelvic mass in a woman who is more than 1-year postmenopausal is suspicious for ovarian cancer.
B. Tissue diagnosis. Diagnosis requires biopsy of ovarian or other suspected abdominal masses.
1. Masses that are smaller than 8 cm in premenopausal women are most commonly benign cysts. Patients should undergo ultrasound to confirm the cystic nature of the mass and receive suppression with oral contraceptives for 2 months. Benign lesions should regress.
2. Surgical evaluation is necessary for masses with the following characteristics:
a. Less than 8 cm in diameter and cystic but still present after 2 months of observation in premenopausal women
b. Smaller than 8 cm in premenopausal women and solid on ultrasound
c. Larger than 8 cm in premenopausal women
d. Present in any postmenopausal patient
C. Serum tumor markers. CA-125 is useful to monitor the response to therapy in epithelial ovarian tumors. β-human chorionic gonadotropin (βhCG), α-feto-protein (α-FP), and LDH are useful in germ cell malignancies. None of these markers is useful for screening purposes.
D. Staging evaluation (see “General Aspects,” Section II.A)
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS. Staging for ovarian cancer is surgical.
A. Staging system and 5-year survival rate for epithelial tumors are shown in Table 11.8.
B. Prognostic factors. Extent, stage, and grade of disease are more important than specific histologic types. The extent to which the disease can be surgically debulked also affects prognosis.
Table 11.8 Staging System for Ovarian Epithelial Tumors
V. PREVENTION AND EARLY DETECTION
Women with strong family histories of epithelial ovarian cancer are at a twofold increased risk for epithelial ovarian cancer compared with other women, and women with family histories of breast or ovarian cancer or a personal history of breast cancer also are at a twofold increased risk. The risk for developing ovarian cancer by age 70 is 20% to 60% for women with a mutation in BRCA1 and 10% to 35% for women with BRCA2mutations. Mutations in the MMR genes responsible for the Lynch Type II syndrome (see Chapter 9, Table 9.3) portend a lifetime risk of 9% to 12% for ovarian cancer.
All of these groups should undergo proper genetic counseling and consider prophylactic oophorectomy when childbearing has been completed. Women should be advised that prophylactic oophorectomy does not offer absolute protection because peritoneal carcinomas occasionally occur after bilateral oophorectomy. The value of CA-125 for screening and transvaginal ultrasound in these women has not been clearly established.
VI. MANAGEMENT OF EPITHELIAL OVARIAN CANCERS (see part A in Table 11.7 for subtypes of epithelial ovarian cancers)
A. Surgical staging evaluation
1. The ovarian tumor should be removed intact, if possible, and sent for frozen section. If the tumor is confined to the pelvis, a thorough surgical evaluation should be carried out.
2. Any free fluid, especially in the pelvic cul-de-sac, should be sent for cytologic evaluation. If no free fluid is found, peritoneal washings should be obtained with 50 to 100 mL normal saline from the cul-de-sac, from each paracolic gutter, and from beneath each hemidiaphragm.
3. Systematic exploration of all peritoneal surfaces and viscera is performed. Any suspicious areas or adhesions of peritoneal surfaces should undergo biopsy.
4. The diaphragm should be sampled by biopsy or by scraping and preparation of a cytologic smear.
5. The omentum should be resected from the transverse colon (an infracolic omentectomy).
6. The retroperitoneal surfaces are then explored to evaluate the pelvic and para-aortic lymph nodes. Any enlarged lymph nodes are submitted for frozen section. If frozen section is negative, a formal pelvic and para-aortic lymphadenectomy is performed.
B. Borderline tumors. Treatment is surgical resection of the primary tumor. There is no evidence that subsequent chemotherapy or radiation improves survival. Even in most patients who have multifocal disease, adjuvant therapy probably has no role. Chemotherapy can be used for patients with invasive implants.
C. Stage Ia and Ib, grade 1
1. Premenopausal patients in this category may, after staging laparotomy is completed, undergo unilateral oophorectomy to preserve fertility. Follow-up should include regular pelvic examinations and determinations of CA-125 levels. Generally, the other ovary and uterus are removed when childbearing is completed.
2. Postmenopausal patients and women in whom childbearing is not an issue should undergo TAH/BSO and staging.
D. Stage Ia and Ib (grades 2 and 3) and stage Ic are treated with TAH/BSO and staging followed by chemotherapy. Carboplatin plus paclitaxel for three to six cycles is recommended for most patients (see Section VI.E.4for regimen dosages). It may be preferable to give older patients a course of single-agent chemotherapy with carboplatin for four to six cycles.
E. Stages II, III, and IV
1. Surgery with exploration and removal of as much disease as possible should be carried out. Removal of the primary tumor and as much metastatic disease as possible is referred to as cytoreductive surgery or debulking. “Optimal debulking” is defined as having residual tumor diameters <1 cm in diameter.
2. Chemotherapy. Platinum-based combination regimens have been the mainstay of treatment for advanced ovarian cancer. Combination of a platinum agent (carboplatin or cisplatin) with paclitaxel is the standard treatment for epithelial ovarian cancer. This regimen can be administered intravenously or intraperitoneally (in selected patients).
a. The intravenous regimen is given to patients every 3 weeks for six to eight cycles as follows:
Paclitaxel (Taxol), 135 to 175 mg/m2 (given before carboplatin or cisplatin)
Carboplatin, AUC 5 to 6
b. The intraperitoneal (IP) regimen is an option in patients with microscopic residual disease after cytoreductive surgery. In this subset of patients, a significant improvement in progression-free and overall survival was noted compared with intravenous therapy. Due to increased side effects, such as abdominal pain, gastrointestinal discomfort, fatigue, hematologic toxicities, and neuropathy, many patients are not able to tolerate the full six courses of IP therapy. This regimen is administered in six cycles every 21 days as tolerated:
Day 1 IV Paclitaxel 135 mg/m2 over 24 hours
Day 2 IP Cisplatin 100 mg/m2
Day 8 IP Paclitaxel 60 mg/m2
c. Relative toxicities. Carboplatin has fewer gastrointestinal, neurologic, and renal side effects than cisplatin but more hematotoxicity. When paclitaxel is infused over 3 hours, it is associated with more neurologic toxicity and less hematologic toxicity than when it is infused over 24 hours.
d. Maintenance therapy with paclitaxel every 28 days for a 12-month period may improve progression-free survival, but the overall survival is not affected. Therefore, maintenance chemotherapy in patients with advanced ovarian cancer who have achieved complete remission with standard induction chemotherapy is not the standard of care.
e. Antiangiogenic agents. Using bevacizumab (Avastin) as adjuvant and maintenance therapy has been recently investigated in a randomized prospective trial treating patients with advanced ovarian cancer. Data analysis thus far reveals no improvement in overall survival of patients receiving bevacizumab in an adjuvant or consolidation setting.
3. Serial CA-125 determinations should be followed. Rising CA-125 levels to a level >20 to 35 U/mL are associated with persistent or recurrent disease.
F. Second-line therapy
1. Cytotoxic drugs. If disease relapses later than 12 months or more after completion of primary therapy, the original drugs may be retried. If disease progresses on first-line therapy or relapses a short time after completion of primary therapy, other drugs should be used.
a. Chemotherapeutic agents that may be helpful after failure of first-line therapy include liposomal doxorubicin, topotecan, gemcitabine and carboplatin, oral etoposide (100 mg/d for 14 days of each 21-day cycle), and hexamethylmelamine. In most cases, single-agent therapy appears to be as effective as combinations. Response rates are about 15% to 25%.
b. Hormonal treatment with tamoxifen has demonstrated 10% to 20% efficacy in this setting.
c. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been used alone or in combination with cytotoxic agents in the treatment of recurrent epithelial ovarian cancer.
d. Poly-ADP ribose polymerase (PARP) inhibitors target DNA repair mechanisms. Tumor cells that are deficient in BRCA1/2 as a result of germ line or somatic mutations in these pathways are more sensitive to this therapy. PARP inhibitors are administered orally and are well tolerated. Results of phase II trials using these agents are promising and further trials are ongoing both in sporadic and hereditary epithelial ovarian cancer.
2. High-dose chemotherapy with autologous stem cell support has been disappointing for the treatment of ovarian cancer. More dose-intense approaches have not yielded better results than standard intravenous schedules.
3. Second-look laparotomy. A second-look operation is one performed to determine the response to therapy on a patient who has no clinical evidence of disease after a prescribed course of chemotherapy. Second-look laparotomy has not been shown to influence patient survival, although the information obtained at second look is highly prognostic. The operation should only be performed in a research setting, such as in patients receiving therapy in a setting where second-line therapies are undergoing clinical trial.
4. Secondary cytoreductive surgery
a. May be beneficial for patients who have isolated residual disease at relapse, such as a persistent pelvic mass. This benefit depends on the ability to completely resect the residual disease.
b. Is not beneficial for patients with disease that is unresponsive to chemotherapy
5. Palliative surgery may be considered in patients who develop bowel obstruction and resistance to chemotherapy but have a reasonably good performance status; this is usually a difficult recommendation to make for all concerned. The goal is to allow the patient sufficient oral intake to maintain hydration or some nutrition at home. If successful, the procedure may allow 3 to 6 months of relief. Unfortunately, the complication and mortality rates from surgery are high, and the success rate is low. The patient and her family must clearly understand these limitations when decisions are made.
G. Patient follow-up after disease-free second-look operations is clinical because there are no reliable means of surveillance. CA-125 levels should be followed, but CT and ultrasound have proved too insensitive to detect early recurrent disease. CT may be used to follow known masses.
VII. PERITONEAL TUMORS OF MÜLLERIAN HISTOLOGY (PRIMARY PERITONEAL CANCERS)
The histology of peritoneal mesothelium is identical to that of germinal epithelium. The peritoneum may transform into malignant müllerian epithelial patterns that resemble advanced epithelial ovarian carcinoma and present as implants throughout the peritoneal cavity (including ovarian surfaces). Management is the same as for stage III epithelial ovarian carcinoma.
VIII. GERM CELL TUMORS (see part B in Table 11.7 for subtypes)
A. General aspects of germ cell tumors
1. Epidemiology. Germ cell tumors make up 20% to 25% of all ovarian neoplasms, but only 3% of these tumors are malignant. These malignancies constitute <5% of all ovarian cancers in Western countries and up to 15% in Asian and African populations. Germ cell tumors constitute >70% of ovarian neoplasms in the first two decades of life, and in this age range, one-third are malignant.
2. Signs and symptoms. These tumors grow rapidly and often present with subacute pelvic pain and pressure and menstrual irregularity. Acute symptoms related to torsion or adnexal ruptures are often confused with acute appendicitis. Adnexal masses >2 cm in premenarchal girls and in premenopausal women are suspicious; they usually require surgical investigation.
3. Diagnosis
a. Young patients should be tested for serum LDH, β-hCG, and α-FP titers along with other routine blood work.
b. A karyotype should be obtained because of the propensity of these tumors to arise from dysgenetic gonads.
c. A chest radiograph is essential because germ cell tumors may metastasize to lungs or mediastinum.
B. Dysgerminoma
1. Natural history. Dysgerminomas are the most common germ cell malignancy and represent up to 10% of ovarian cancers in patients <20 years of age. Three-fourths of dysgerminomas occur between the ages of 10 and 30 years. About 5% are found in dysgenic gonads. Three-fourths of cases are stage I, and 10% to 15% are bilateral. Unlike other ovarian malignancies, dysgerminomas often spread earlier through the lymphatics than to peritoneal surfaces. These tumors secrete LDH.
2. Treatment is primarily surgical; the minimal operation is unilateral oophorectomy with complete surgical staging. The chance of recurrence in the other ovary during the next 2 years is 5% to 10%, but these lesions are sensitive to chemotherapy. When fertility is an issue, the uterus and contralateral ovary should be preserved even in the presence of metastatic disease. If fertility is not an issue, TAH/BSO should be performed. If a Y chromosome is found by karyotyping, both ovaries should be removed, but the uterus may be left in place.
a. Chemotherapy is the adjuvant treatment of choice for metastatic disease.
A combination of bleomycin, etoposide, and cisplatin (BEP regimen) is most often used. BEP dosages are as follows:
Bleomycin, 15 U/m2 per week for 5 weeks; then on day 1 of the fourth course
Etoposide, 100 mg/m2 per day for 5 days every 3 weeks
Cisplatin, 20 mg/m2 per day for 5 days, or 100 mg/m2 on 1 day, every 3 weeks
b. RT. If fertility is not an issue, metastatic disease may be treated with radiation because these tumors are extremely radiosensitive.
3. Prognosis. The 5-year survival rate for patients with stage Ia disease is >95% when the disease is treated with unilateral oophorectomy alone. Recurrence is most likely in patients with lesions >10 to 15 cm in diameter, who are younger than 20 years of age, and who have an anaplastic histology. Patients with advanced disease that is treated with surgery followed by BEP chemotherapy have a 5-year survival rate of 85% to 90%.
C. Immature teratoma
1. Natural history. Pure immature teratomas account for <1% of all ovarian cancers but are the second most common germ cell malignancy. They constitute 10% to 20% of ovarian malignancies in patients younger than 20 years of age and account for 30% of ovarian cancer deaths in this group. Serum tumor markers (β-hCG, α-FP) are not found unless the tumor is of mixed type. The most common site of spread is the peritoneum; hematogenous spread is uncommon and occurs late.
2. Treatment. In premenopausal women in whom the lesion is confined to one ovary, a unilateral oophorectomy with surgical staging is warranted. In postmenopausal women, TAH/BSO is performed.
a. For patients with stage Ia, grade 1 tumors, no adjuvant therapy is required.
For stage Ia, grade 2 or 3, or for higher stages with gross residual disease, adjuvant chemotherapy with BEP should be used. Chemotherapy is also indicated for patients with ascites, regardless of grade.
b. RT is reserved for patients with localized disease after chemotherapy.
c. Second-look laparotomy is best reserved for patients at high risk for treatment failure (i.e., patients with macroscopic disease at the start of chemotherapy) because there are no reliable tumor markers for this disease.
3. Prognosis. The most important prognostic feature of immature teratomas is their histologic grade. The 5-year survival rate is 80% to 100%. Patients whose lesions cannot be completely resected before chemotherapy have a 5-year survival rate of only 50%, as compared with 94% for completely resected disease.
D. Endodermal sinus tumors (yolk sac carcinomas) are rare. The median age at diagnosis is 18 years. Pelvic or abdominal pain is the most common presenting symptom. Most of these lesions secrete a-FP, and serum levels are useful in monitoring response to treatment.
1. Treatment consists of surgical staging, unilateral oophorectomy, and frozen section for diagnosis.
2. All patients are given adjuvant or therapeutic chemotherapy. BEP appears to be most effective. Other cisplatin-containing regimens include POMB-ACE (cisplatin, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide, etoposide), which may be used for high-risk cases with extensive metastatic disease, such as for those with lung or liver metastasis.
E. Embryonal carcinoma is an extremely rare tumor that occurs in young women and girls, with a median age of 14 years. These tumors may secrete estrogens, producing symptoms of precocious pseudopuberty or irregular bleeding. Two-thirds are confined to one ovary at presentation, and they frequently secrete a-FP and b-hCG, which are useful to follow response to therapy. Treatment is unilateral or bilateral oophorectomy followed by chemotherapy with BEP.
F. Choriocarcinoma of the ovary is extremely rare; most patients are younger than 20 years of age. b-hCG is often a useful tumor marker. Half of premenarchal patients present with isosexual precocity. The prognosis is usually poor, but complete responses have been reported with combination methotrexate, actinomycin D, and cyclophosphamide (Cytotoxan) (MAC III regimen; see “Gestational Trophoblastic Neoplasia,” Section VI.B.3.b).
G. Mixed germ cell tumors most commonly have a dysgerminoma or endodermal sinus component. Secretion of a-FP or b-hCG depends on component parts. Lesions should be managed with unilateral oophorectomy and chemotherapy with BEP. A second-look laparotomy may be indicated when macroscopic disease is present at the start of chemotherapy to determine response to therapy in components that do not produce tumor markers.
IX. SEX CORD STROMAL TUMORS (see part C in Table 11.7 for subtypes) account for 5% to 8% of all ovarian cancers. Most tumors are a combination of cell types derived from the sex cords and ov arian stroma or mesenchyme.
A. Granulosa–stromal cell tumors include granulosa cell tumors, thecomas, and fibromas. Thecomas and fibromas are rarely malignant and are then called fibrosarcomas. Granulosa cell tumors are low-grade, estrogen-secreting malignancies that are seen in women of all ages. Endometrial cancer occurs with granulosa cell tumors in 5% of cases, and 25% to 50% are associated with endometrial hyper-plasia. Inhibin, which may be secreted by some granulosa cell tumors, may be a useful tumor marker. Surgery alone is usually sufficient therapy; RT and chemotherapy are reserved for women with recurrent or metastatic disease. Granulosa cell tumors have a 10-year survival rate of about 90%. DNA ploidy correlates with survival.
B. Sertoli-Leydig tumors have a peak incidence between the third and fourth decades. These rare lesions are usually low-grade malignancies. Most produce androgens, and virilization is seen in 70% to 85% of patients. Usual treatment is unilateral salpingo-oophorectomy with evaluation of the contralateral ovary. TAH/BSO is appropriate for older patients. The utility of radiation or chemotherapy is yet to be proved.
X. OTHER TUMORS (see part D in Table 11.7)
A. Lipoid cell tumors are extremely rare, with only slightly more than 100 cases reported. They are thought to arise from adrenal cortical rests near the ovary. Most are virilizing and are benign or low-grade malignancies. Treatment is surgical extirpation.
B. Ovarian sarcomas are also extremely rare, and most occur in postmenopausal women. They are aggressive lesions with no effective treatment. Most patients die within 2 years.
C. Lymphoma can involve the ovaries, usually bilaterally, especially with Burkitt lymphoma. A hematologist-oncologist should be consulted intraoperatively when lymphoma is found to determine the need for special studies; plans for cytoreductive surgery should be abandoned. Treatment is as for lymphomas elsewhere in the body.
XI. SPECIAL CLINICAL PROBLEMS
A. Pseudomyxoma peritonei occurs in the setting of mucinous cystadenocarcinoma or “benign” mucinous adenomas. The peritoneum becomes filled with jellylike material that compresses the bowel and produces painful abdominal distention. Chemotherapy may impede cellular production of the mucoid material but usually has little direct effect on the tumor. Periodic surgical debulking may be the only way to provide relief of abdominal symptoms. It is now believed that these lesions are typically associated with mucinous adenocarcinomas of the appendix.
B. Fallopian tube cancers account for 0.3% of all cancers of the female genital tract. They are seen most frequently in the fifth and sixth decades of life. The classic triad of symptoms is a prominent watery vaginal discharge, pelvic pain, and pelvic mass; however, this triad is seen in <15% of patients. The histologic features, evaluation, and treatment are similar to those of ovarian cancer.
C. Pregnancy with ovarian cancer (see Chapter 26). Pregnancy is rarely complicated by the development of ovarian cancer. All pregnant patients have luteal cysts, which should be <5 to 6 cm in diameter. Masses that are larger or continue to enlarge over several weeks should be examined by laparoscopy at 16 weeks of gestation. Management of pregnant patients with ovarian cancer is the same as for nonpregnant patients who desire childbearing.
D. Obstructive complications. Intestinal obstruction is discussed in Chapter 30, Section II. Rectal or urinary tract obstruction or dyspareunia in patients with advanced pelvic cancers may respond to either systemic chemotherapy or local irradiation (see “General Aspects,” Section III).
GESTATIONAL TROPHOBLASTIC NEOPLASIA
I. EPIDEMIOLOGY AND ETIOLOGY. Gestational choriocarcinoma accounts for <1% of malignancies in women. The etiology is unknown, but certain risk factors and the relationship with hydatidiform mole are well recognized.
A. Hydatidiform mole develops in about 1 in 1,500 to 2,000 pregnancies in North America and Europe. The incidence is 5 to 10 times greater in Asia, Latin America, and other countries.
B. Other factors that are associated with the occurrence of hydatidiform mole include the following:
1. Patients who have had a prior molar pregnancy
2. Extremes of reproductive age
3. Presence of twin pregnancy
II. PATHOLOGY AND NATURAL HISTORY
A. Classification. Molar pregnancies are classified as partial or complete based on morphology, histopathology, and karyotype. Complete moles have diploid karyotype, tend to have grapelike structures with diffuse hydropic villi, and can be accompanied with paraneoplastic sequelae. Partial moles have triploid karyotype, can resemble hydropic abortion with recognizable fetal tissue, and have focal trophoblastic hyperplasia.
B. Malignant transformation. Persistent gestational trophoblastic disease (GTD) is diagnosed when there is clinical, hormonal, pathologic, and/or radiologic evidence of gestational trophoblastic tissue. About 20% of patients with complete molar pregnancy will develop persistence; 15% will have localized uterine disease, whereas 4% have evidence of metastatic disease. In contrast, partial moles develop nonmetastatic persistence in 2% to 4% of cases. Choriocarcinoma results from the malignant transformation of the trophoblast and is characterized by the absence of villi. The clinical course determines whether the growth is benign or malignant. Occasionally, malignant growth may not become clinically evident until years after the last gestation.
C. Dissemination. Persistent GTD disseminates locally to the vagina and pelvic organs. Choriocarcinoma disseminates rapidly and widely through the bloodstream. The lungs are the most common site of metastases, followed by the vaginal metastases. Hepatic and cerebral metastases are seen less commonly.
III. DIAGNOSIS
A. Symptoms of molar pregnancy or malignant trophoblastic disease include the following:
1. Vaginal bleeding during pregnancy (nearly all cases of molar pregnancy or malignant trophoblastic disease cause bleeding)
2. Hyperemesis gravidarum
3. Passage of grapelike villi from the uterus
4. Sweating, tachycardia, weight loss, and nervousness resulting from paraneoplastic hyperthyroidism (see Section VII.A)
5. Pulmonary symptoms as a consequence of lung metastases
6. Right upper quadrant pain or jaundice as a consequence of liver metastases
7. Any neurologic abnormality resulting from brain metastases
8. Abdominal (uterine) pain early in pregnancy
B. Physical findings
1. The uterus is usually, but not always, larger than expected for the duration of pregnancy.
2. Fetal heart tones are absent (the coexistence of a viable fetus and a partial hydatidiform mole is uncommon).
3. The patient develops signs of toxemia of pregnancy (hypertension, retinal sheen, sudden weight gain, proteinuria, or peripheral edema). If signs occur in the first or second trimester, a molar pregnancy is strongly suspected.
C. Preliminary laboratory studies
1. CBC, platelet count, alkaline phosphatase level, LFTs
2. β-hCG production is maximal in early pregnancy and decreases thereafter. Normal hCG values for pregnancy depend on the assay method used by the laboratory. hCG is elevated in all patients with choriocarcinoma; the serum concentration directly reflects the tumor volume. The serum half-life of hCG is 18 to 24 hours.
D. Special diagnostic studies
1. Ultrasonography of the uterus and Doppler examination reveal no evidence of fetal parts or heartbeat in trophoblastic disease. If these examinations show no fetus, plain radiographs of the pelvic organs are obtained for confirmation.
2. A chest radiograph should be obtained in patients with molar pregnancy.
3. Radionuclide and CT scans are used to detect brain, liver, or other abdominal metastases. Scans and films of the abdomen and pelvis must be avoided until the absence of a fetus is proved.
4. Thyroid studies (serum thyroxine concentration and tri-iodothyronine-resin uptake) are obtained in patients with clinical evidence of hyperthyroidism.
IV. STAGING SYSTEMS AND PROGNOSTIC FACTORS
A. The FIGO staging system for GTD is shown in Table 11.9.
B. The World Health Organization (WHO) scoring system for GTD is summarized in Table 11.10. High-risk patients are those with a score of ≥7 and low-risk patients are those with score of ≤6. In addition, another scoring system can be assigned by determining the risk of resistance to single-agent chemotherapy.
Table 11.9 FIGO Staging System for Gestational Trophoblastic Disease
FIGO, International Federation of Gynecology and Obstetrics.
Table 11.10 WHO Prognostic Scoring System for Gestational Trophoblastic Disease
WHO, World Health Organization.
V. PREVENTION AND EARLY DETECTION
Early detection depends on careful attention to the signs and symptoms of trophoblastic disease in pregnant and postpartum patients.
VI. MANAGEMENT
All forms of gestational trophoblastic neoplasia, from hydatidiform mole to choriocarcinoma, are almost invariably lethal if not treated.
A. Early disease signifies a molar pregnancy without evidence of distant metastases by history, physical examination, LFTs, chest radiograph, or scans.
1. Surgery. Molar tissue is removed by suction curettage while oxytocin is being administered, and then by sharp curettement. Hysterectomy is recommended for women >40 years of age. Disappearance of hCG is achieved within 8 weeks in 80% of patients treated by surgery; virtually all of these patients are cured. The patient is followed with weekly blood assays for hCG.
2. RT has no role in early disease.
3. Chemotherapy. After surgical treatment of a molar pregnancy with no suggestion of metastatic disease, weekly serum hCG titers are obtained. Chemotherapy is started for histologic diagnosis of choriocarcinoma, rising hCG titer (for 2 weeks), plateau of hCG titer (for 3 weeks), documentation of metastatic disease, or return of titers with no other explanation after achieving a zero titer. So long as titers continue to decrease, treatment is usually not started; in the past, treatment was started after a predetermined number of weeks.
a. Methotrexate is the drug of choice in early gestational trophoblastic neoplasia. It can be administered in the following three ways:
(1) Pulse methotrexate, 40 mg/m2 IM weekly
(2) 5-day methotrexate, 0.4 mg/m2 IV or IM daily for 5 days; with response, re-treat at same dose every 2 weeks
(3) Methotrexate, 100 mg/m2 IV in 250 mL of normal saline over 30 minutes or 200 mg/m2 IV in 500 mL normal saline over 12 hours; leucovorin (15 mg PO or IM every 12 hours for 4 doses) is given 24 hours after starting methotrexate.
b. Actinomycin D is used instead of methotrexate in patients with renal function impairment or when there is resistance to methotrexate. This drug can be administered every 2 weeks either as 12 mcg/kg IV push daily for 5 days or as a pulse of 1.25 mg/m2 IV.
B. Advanced disease
1. Surgery is used to evacuate or excise the uterus for the same indications outlined in early disease (see Section VI.A.1).
2. RT, in combination with chemotherapy, is clearly indicated for the primary management of patients with liver or brain metastases.
3. Chemotherapy is the mainstay of management for metastatic trophoblastic disease. All patients undergo the restaging evaluation described in Section III.
a. Low-risk patients are treated with methotrexate or actinomycin D, as for early disease patients. Patients not responding to one of these agents are switched to the alternative drug.
b. High-risk patients are treated with combination chemotherapy regimens, such as EMA-CO or EMA-CE (described subsequently). RT is given if the liver or brain is involved by metastases. Chemotherapy dosage schedules are as follows (cycle intervals should not be extended without good cause):
(1) EMA-CO is given in 14-day cycles:
Etoposide, 100 mg/m2 IV on days 1 and 2
Methotrexate, 100 mg/m2 IV push, followed by 200 mg/m2 by continuous IV infusion over 12 hours on day 1; leucovorin, 15 mg PO or IM, every 12 hours for four doses beginning 24 hours after the start of methotrexate
Actinomycin D, 0.5 mg (not per m2) IV push on days 1 and 2
Cyclophosphamide, 600 mg/m2 IV on day 8
Vincristine (Oncovin), 1.0 mg/m2 IV push on day 8 (maximum 2 mg)
(2) EMA-CE is given in 14-day cycles:
Etoposide, 100 mg/m2 IV on days 1 and 2
Methotrexate, 100 mg/m2 IV push, followed by 1,000 mg/m2 by continuous IV infusion over 12 hours on day 1; leucovorin, 30 mg PO or IM, every 12 hours for six doses beginning 32 hours after starting methotrexate
Actinomycin D, 0.5 mg (not per m2) IV push on days 1 and 2
Cisplatin, 60 mg/m2 IV on day 8 with prehydration
Etoposide, 100 mg/m2 IV on day 8
c. Duration of treatment. Chemotherapy should be continued until no hCG is demonstrable in the serum for three consecutive weekly assays. If the hCG titer rises or plateaus between any two measurements, the chemotherapy regimen must be changed.
C. Patient follow-up
1. The hCG level is the single most important tumor marker in trophoblastic neoplasia. For stage I, II, and III disease weekly hCG levels are recommended until normal for 3 consecutive weeks. Then, monitor hCG levels monthly until they are normal for 12 consecutive months. The duration is increased to 24 months for stage IV disease. Effective contraception during the entire interval of hormonal follow-up is essential.
2. Other studies that demonstrated disease at the start of therapy should be repeated monthly until complete remission is documented.
VII. SPECIAL CLINICAL PROBLEMS
A. Thyrotoxicosis and even “thyroid storm” may result from the thyroid-stimulating hormone–like effect of high concentrations of hCG. Clinical evidence of hyperthyroidism in choriocarcinoma occurs in the presence of widespread metastases and is associated with a poor prognosis. Laboratory confirmation requires a serum thyroxine concentration and tri-iodothyronine-resin uptake levels compatible with hyperthyroidism. If the symptoms are mild, propylthiouracil or methimazole can be used. In severe cases, patients must be given propranolol and Lugol solution.
B. Development of choriocarcinoma can occur long after the last pregnancy or even hysterectomy. This development serves to emphasize that histologic diagnosis is necessary in metastatic cancer when the primary tumor is not evident. The diagnosis of choriocarcinoma can lead to lifesaving therapy.
C. Subsequent pregnancies. Patients should be reassured that they can anticipate normal subsequent pregnancy outcomes. They are, however, at increased risk for repeat molar pregnancy. This risk is 1% after one molar pregnancy and 20% after two molar pregnancies.
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