Gynecologic Cancers

Sanaz Memarzadeh

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.

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.

Table 11.1 Yearly Rates for Cancers of the Female Genital Tract in the United States^a

Primary Site	New Cases	Percentage (%)	Deaths from Cancer
Cervix	12,710	14	4,290
Uterine corpus	46,470	53	8,120
Ovary	21,990	25	15,460
Vulva	4,340	5	940
Vagina	2,570	3	780
Total	88,080	100%	29,590
^aExtracted from Siegel R, Ward E, Brawley O, Jemal A. CA Cancer J Clin 2011 Jul-Aug;61(4):212-36.

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.

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.

Table 11.2 Staging System for Cervical Cancer

Stage			Extent		5-yr Survival Rate (%)
0			Carcinoma in situ (no stromal invasion)		100
I			Strictly confined to cervix (disregard extension to the corpus)		80
	Ia		Preclinical carcinoma (diagnosed only by microscopy)
		Ia1		Lesions with ≤3 mm depth of stromal invasion and ≤7 mm in horizontal spread
			Ia2		Lesions detected microscopically that can be measured (>3-5 mm in depth of invasion from the originating epithelial base and ≤7 mm in horizontal spread)
	Ib		Lesions with greater dimensions than Ia2, whether seen clinically or not
		Ib1		Lesion ≤4 cm in greatest dimension
		Ib2		Lesion >4 cm in greatest dimension
II			Tumor extends beyond the cervix but not onto the pelvic sidewall or lower aspect of vagina		60
			Parametria is not involved
		IIa1		Lesion ≤4 cm in greatest dimension
		IIa2		Lesion >4 cm in greatest dimension
		IIb	Obvious parametrial involvement
III			Tumor extends to the pelvic sidewall or to the lower one-third of vagina, or causes hydronephrosis or a nonfunctioning kidney		30
IV			Tumor extends beyond true pelvis, or biopsy-proved involvement of bladder or rectal mucosa		5
		IVa		Spread to adjacent organs
		IVb		Distant metastases

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.)

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.

Table 11.3 Treatment of Stage I Cervical Carcinoma

Stage	Typical Treatment Options
Ia1 with ≤ 3 mm invasion but without lymph-vascular space invasion	Therapeutic cone or type I hysterectomy
Ia1 with 1-3 mm invasion and with lymph-vascular space invasion	Type I or II hysterectomy with pelvic lymph node dissection
Ia2 with > 3-5 mm invasion	Type II hysterectomy and bilateral pelvic lymphadenectomy or radiation therapy for inoperable patients
Ib and IIa	Type II or III hysterectomy with bilateral pelvic lymphadenectomy with para-aortic lymph node evaluation or radiation therapy for inoperable patients

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.

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.

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