Uterine Corpus Tumors

CREATED BY :-PATEL SABIRGROUP NO:-601(2010-2016)

Endometrial Cancer

Carcinoma of the epithelial lining (endometrium) of the uterine corpus is the most common female pelvic malignancy, with 52,630 new cases estimated to be diagnosed in 2014 and 8,590 deaths expected. Factors influencing its prominence are the declining incidence of cervical cancer, longer life expectancy, and earlier diagnosis.

Epidemiology

Age Endometrial cancer is primarily a disease of postmenopausal women, although

25% of cases occur in premenopausal patients, with 5% of cases developing in patients younger than 40 years.

Geography The incidence of endometrial cancer is high in Western nations and very low in

Eastern countries. Immigrant populations tend to assume the risks of native populations,

highlighting the importance of environmental factors in the genesis of this disease. Endometrial cancers tend to be more common in urban than in rural residents. In the United States, the incidence of endometrial cancer is twice as high in white women as in black women.

Etiology and Risk Factors

Adenocarcinoma of the endometrium may arise in normal, atrophic, or hyperplastic endometrium. Two mechanisms are generally believed to be involved in the development of endometrial cancer. In approximately 75% of women, there is a history of exposure to unopposed estrogen, either endogenous or exogenous (type I). The tumors in these women begin as endometrial hyperplasia and progress to carcinomas, which usually are better differentiated and have a more favorable prognosis than tumors unrelated to estrogens.

In 25% of women, carcinomas appear spontaneously, are not clearly related to a transition from atypical hyperplasia, and rather arise in a background of atrophic or inert endometrium. These neoplasms tend to be associated with a more undifferentiated cell type and a poorer prognosis (type II).

Unopposed Estrogen

It has been hypothesized that long-term estrogenic stimulation of the endometrium unmodified by progesterone has a role in the development of endometrial carcinoma. This hypothesis derives from observations that women who are infertile or obese or who have dysfunctional bleeding due to anovulation are at high risk for this disease, as are women with estrogen-secreting granulosa theca cell ovarian tumors. Also, the recognition that atypical adenomatous (complex) hyperplasia is a precursor of cancer, and that it is associated with unopposed estrogen use in women, underscores the importance of the association among risk factors, estrogens, and cancer. In the late 1970s and early 1980s, several case-control studies demonstrated that the risk of endometrial cancer is increased 4- to 15-fold in long-term estrogen users, as compared with age-matched controls.

It is well established that past use of oral contraceptives (OCs) protects against endometrial cancer. The use of OCs with either high-potency progestin or low-potency progestin is associated with a decreased risk of endometrial cancer. The potency of the progestin in most OCs appears adequate to provide a protective effect against endometrial cancer. OCs with higher progestin potency may be more protective than OCs with lower progestin potency among women with a larger body habitus.

Sidebar: The Women's Health Initiative enrolled 16,608 postmenopausal women from 40 US clinical centers into a randomized, double-blind, placebo-controlled trial. Women aged 50 to 70 with an intact uterus and normal endometrial histology were assigned to once-daily 0.625-mg conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate or to placebo. After 6 years of the intervention and 7 years of additional follow-up, endometrial cancer was diagnosed in 66 women in the combined-hormone–therapy group and in 95 women in the placebo group, which translated to a 35% reduction in risk (P = .007) (Chlebowski RT, Anderson GL, Sarto G, et al: European Cancer Congress abstract LBA13, 2013).

Diet

The high rate of occurrence of endometrial cancer in Western societies and the very low rate in Eastern countries suggest a possible etiologic role for nutrition, especially the high content of animal fat in Western diets. There may be a relationship between high-fat diets and the higher incidence of endometrial carcinoma in women with conditions of unopposed estrogen. Endogenous estrogens rise in postmenopausal women because of increased production of androstenedione or a greater peripheral conversion of this hormone to estrone. In obese women, the extraglandular aromatization of androstenedione to estrone is increased in fatty tissue.

Obesity Phenotypically, the majority of women who develop endometrial cancer

tend to be obese. Women who are 30 lb over ideal weight have a threefold increased risk of developing endometrial cancer, whereas those 50 lb or more over ideal weight have a 10-fold increased risk.

Parity Nulliparous women are at 2 times greater risk for developing endometrial

cancer, women who undergo menopause after age 52 are at 2.5 times greater risk, and those who experience increased bleeding at the time of menopause are at 4 times greater risk.

- See more at: http://www.cancernetwork.com/cancer-management/uterine-corpus-tumors/page/0/1#sthash.NoaQtR7D.dpuf

ENDOMETRIAL HYPERPLASIA

Excessive proliferation of the endometrial glands & to a lesser extent endometrial stroma

Due to excessive estrogen stimulation Only 25% of Pt with E Ca have Hx of hyperplasiaCLASSIFICATION1-Hyperplasia without atypia (not premalignant) 1-A-Simple Microscopically crowding of the glands in the stroma Glands are cystically dilated & give a “Swiss cheese” appearance Commonly asymptomatic 1% progress to Ca over 15 Y 80% regress

ENDOMETRIAL HYPERPLASIA

1-B-Complex hyperplasia without atypia A complex crowded appearance of the glands with very little stroma Epithelial stratification & mitotic activity 3% progress to Ca over 13 Y 80% regress 85% reversal with progestin Rx

ENDOMETRIAL HYPERPLASIA

2-Hyperplasia with atypia (premalignant) Histologically endometrial glands are lined by enlarged cells with

nuclear : cytoplasmic ratios The nuclei are irregular with coarse chromatin clumping & prominent nucleoli 50-94% regress with progestin therapy A higher rate of relapse after stopping Rx compared to that of lesions

without atypia2-A-Simple Progression to carcinoma occur in 8%2-B- Complex Progression to carcinoma occur in 29%

ENDOMETRIAL HYPERPLASIA

3-CARCINOMA IN SITU

Histologically differentiated from carcinoma by

Presence of intervening stroma between abnormal glands

There is no evidence of invasion

It is difficult to differentiate from Ca

Signs and Symptoms

Postmenopausal women Symptoms of early endometrial carcinoma are few but common. However, 90% of

patients complain of abnormal vaginal discharge, and 80% of these women experience abnormal bleeding, usually after menopause. In the general population, 15% of postmenopausal women presenting with abnormal bleeding will be found to have endometrial carcinoma. Signs and symptoms of more advanced disease include pelvic pressure and other symptoms indicative of uterine enlargement or extrauterine tumor spread.

Premenopausal women The diagnosis of endometrial cancer may be difficult to make in premenopausal

patients. The physician must maintain a high index of suspicion in this group of patients and perform endometrial sampling in any women who complain of prolonged, heavy menstrual periods or intermenstrual spotting.

Screening and Diagnosis

Screening There is no role for screening of average-risk, asymptomatic patients for

endometrial cancer. Outpatient endometrial sampling These procedures, such as endometrial biopsy or aspiration curettage coupled

with endocervical sampling, are definitive if results are positive for cancer. The results of endometrial biopsies correlate well with endometrial curettings, and these biopsy procedures have the advantage of avoiding general anesthesia. However, if sampling techniques fail to provide sufficient diagnostic information or if abnormal bleeding persists, formal dilation and curettage is required.

Screening and Diagnosis

Dilation and curettage This is the gold standard for assessing uterine bleeding and diagnosing endometrial carcinoma. Before

dilating the cervix, the endocervix should be curetted. Next, careful sounding of the uterus is accomplished. Dilation of the cervix is then performed, followed by systematic curetting of the entire endometrial cavity. Cervical and endometrial specimens should be kept separate and forwarded for pathologic interpretation.

The American Cancer Society (ACS) has concluded that there is insufficient evidence to recommend routine screening for endometrial cancer for average-risk women. However, the ACS recommends that at the time of menopause, all women should be informed about the risks and symptoms of endometrial cancer and strongly encouraged to report any unexpected bleeding or spotting to their physicians. Women at elevated risk for endometrial cancer from tamoxifen therapy should be informed about the risk and symptoms of endometrial cancer and strongly encouraged to report any unexpected bleeding or spotting to their physicians.

Women who carry the HNPCC abnormality should be considered for a prophylactic total abdominal hysterectomy bilateral saphingo-oophorectomy, especially after childbearing and when contemplating abdominal surgery for any reason. Additional investigation is needed to determine the appropriate monitoring for endometrial cancer in HNPCC carriers.

PathologyAdenocarcinoma

Endometrioid adenocarcinoma is the most common form of endometrial carcinoma, accounting for 75% to 80% of cases. It varies from well differentiated to undifferentiated. The former demonstrates well-preserved glands in at least 95% of the tumor, whereas in the latter, less than half of the neoplasm shows glandular differentiation. Squamous differentiation can be seen in 30% to 50% of cases.

Adenocarcinoma with benign squamous differentiation has been termed "adenoacanthoma" and generally has a good prognosis.

If the squamous component resembles squamous carcinoma, the tumor is designated an adenosquamous carcinoma. These lesions tend to have a worse prognosis because of their association with a poorly differentiated glandular component.

Serous carcinoma

This is an aggressive form of endometrial cancer that accounts for fewer than 10% of these tumors. Serous cancer of the endometrium closely resembles serous carcinoma of the ovaries and fallopian tubes and is usually found in an advanced stage in older women.

Clear-cell carcinomas

Clear-cell carcinomas of the endometrium closely resemble their counterparts in the cervix, vagina, and ovaries. As with serous cancers, these tumors generally occur in older women and have a poor prognosis because of their propensity for early intraperitoneal spread

Secretory adenocarcinoma

This is an uncommon endometrial cancer that resembles secretory endometrium with its associated progestational changes. These cancers tend to be of low grade and have a good prognosis.

Staging and Prognosis

Two large prospective GOG surgical staging trials reported in 1984 and 1987 helped define the prognostic factors for endometrial carcinoma and the current treatment approaches. In addition to evaluating the predictive value of such factors as age, race, and endocrine status, the studies confirmed that prognosis is directly related to the presence or absence of easily determined uterine and extrauterine risk factors. Uterine prognostic factors include histologic cell type, tumor grade, depth of myometrial invasion, occult extension of disease to the cervix, and vascular space invasion. Extrauterine prognostic factors include adnexal metastases, intraperitoneal spread of disease to other extrauterine structures, positive peritoneal cytology, pelvic lymph node metastases, and aortic node involvement. The revised staging system takes into account the nearly equivalent survival rates among low to intermediate grade IA and IB tumors, the lack of prognostic significance of endocervical gland involvement, and the marked survival differences of pelvic node or para-aortic node involvement. A revised staging system can be seen in Table 1.

Uterine size

The size of the uterus was previously believed to be a risk factor and was part of the older clinical staging system. However, recent information indicates that uterine size is not an independent risk factor but rather relates to cell type, grade, and myometrial invasion

Surgical staging

Cell type and grade can be determined before hysterectomy, although in some series, grade, as determined by dilation and curettage, has an overall inaccuracy rate of 31% compared with grade in the hysterectomy specimen, and grade 3 tumors have an inaccuracy rate of 50%. Recognition of all of the other factors requires an exploratory laparotomy, peritoneal fluid sampling, and hysterectomy with careful pathologic interpretation of all removed tissue. This primary surgical approach led the International Federation of Gynecology and Obstetrics (FIGO) to define endometrial cancer as a surgically staged disease in 1988, incorporating many of the prognostic factors into th

Treatment

Surgery Approximately 90% of patients with a diagnosis of endometrial cancer are

medically able to undergo surgery. Preparation for this surgery should include evaluation of such concurrent medical problems as hypertension and diabetes, which are frequently found in patients with endometrial cancer.

Open surgical procedure.

 The operative procedure is performed through an adequate abdominal incision that allows for thorough intra-abdominal exploration and retroperitoneal lymph node removal if necessary. On entry into the peritoneal cavity, fluid samples are obtained for subsequent cytologic determination (intraperitoneal cell washings). Next, thorough intra-abdominal and pelvic exploration is undertaken, with biopsy or excision of any suspicious lesions. In particular, the uterus should be observed for tumor breakthrough of the serosal surface. The distal ends of the fallopian tubes are clipped or ligated to prevent possible tumor spillage during uterine manipulation.

These procedures should be followed by total extrafascial hysterectomy and bilateral salpingo-oophorectomy. The excised uterus is opened away from the operating table, and the depth of myometrial penetration is determined by clinical observation or microscopic frozen section. The depth of myometrial invasion can be accurately assessed in more than 90% of cases.

Laparoscopic surgery

An alternative method of surgically staging patients with clinical stage I endometrial cancer is gaining in popularity. This approach combines laparoscopically assisted vaginal hysterectomy with laparoscopic lymphadenectomy.

Treatment

Lymph node evaluation Lymphadenectomy Surgical staging Adjuvant radiation therapy Brachytherapy Vaginal irradiation

Uterine Sarcomas

Carcinosarcomas and other uterine sarcomas are uncommon tumors, accounting for less than 4% of all cancers of the uterine corpus. Carcinosarcomas, the most common histologic subtype, demonstrate both epithelial and stromal differentiation. Endometrial stromal sarcomas and leiomyosarcomas are characterized by differentiation toward one or more stromal tissues. Leiomyosarcomas occur at an earlier age than do carcinosarcomas, with a plateau observed in middle age. There is strong epidemiologic evidence that prior exposure to pelvic irradiation may increase the risk for the development of uterine sarcomas. Generally, these tumors are characterized by aggressive growth, with early lymphatic or hematogenous spread. The overall survival rate is poor, with the majority of deaths occurring within 2 years of diagnosis.

Patterns of Spread

Lymphatic metastases are a significant route of spread for carcinosarcoma, with a reported incidence of 40% to 60% occurring with stage I disease. Leiomyosarcoma has a propensity for extra-abdominal spread, often involving the lungs. For carcinosarcoma, the initial site for recurrence after surgical resection is likely to be the pelvis or abdomen, whereas leiomyosarcomas tend to fail to recur distantly. In a prospective surgical staging trial by the GOG, the recurrence rate for early-stage carcinosarcoma was 53% and for leiomyosarcoma, 71%.

Treatment

Surgery Surgery is the mainstay of treatment for uterine sarcomas. For carcinosarcoma,

this usually consists of total abdominal hysterectomy and bilateral salpingo-oophorectomy, with washings to be obtained for peritoneal cytology. The GOG prospective staging study reported a 17% incidence of nodal metastasis for this histologic subtype, so retroperitoneal nodes should be sampled as for poorly differentiated endometrial cancers. For patients with advanced/recurrent disease, aggressive surgical debulking does not appear to improve outcome.

Hysterectomy with oophorectomy is also standard therapy for uterine leiomyosarcoma

Treatment

Adjuvant irradiation Radiotherapy Chemotherapy

Gestational Trophoblastic Diseases Gestational trophoblastic diseases (GTDs) encompass a spectrum of neoplastic

disorders that arise from placental trophoblastic tissue after abnormal fertilization. In the United States, GTDs account for less than 1% of gynecologic malignancies. Forty years ago, women with choriocarcinoma had a 95% mortality rate. Today, with the advent of effective chemotherapy and the development of a reliable tumor marker (β-subunit human chorionic gonadotropin [β-hCG]), the cure rate for choriocarcinoma is 90% to 95%.

Clinical Presentation

Complete mole The classic signs of a molar pregnancy include the absence of fetal heart sounds, physical

evidence of a uterus that is larger than expected for gestational age, and vaginal bleeding. Although an intact fetus may coexist with a partial mole, this occurs in fewer than 1 in 100,000 pregnancies.

The most common presenting symptom of molar pregnancy is vaginal bleeding, reported in up to 97% of patients. Intrauterine clots may undergo oxidation and liquefaction, producing pathognomonic prune juice–like fluid. Prolonged or recurrent bleeding may result in iron deficiency anemia. Symptoms of anemia occur in approximately 50% of patients at the time of diagnosis. Early toxemia (hypertension, proteinuria, and edema) presenting during the first or second trimester is common (20% to 30% of cases) in molar pregnancy.

Hyperthyroidism is seen clinically in approximately 7% of molar pregnancies. An elevation of triiodothyronine and thyroxine (T4) levels is observed more commonly than are the clinical manifestations of tachycardia, sweating, weight loss, and tremor. These hormonal elevations are presumed to be secondary to the structural similarity of hCG to thyroid-stimulating hormone.

Partial mole

Patients with partial mole have clinical features different from those with complete mole. Fewer than 10% of patients with partial mole have uterine enlargement. Patients with partial mole do not have prominent theca-lutein cysts, hyperthyroidism, or respiratory insufficiency. They experience toxemia only rarely. The diagnosis of partial mole is usually made after histologic review of curettage specimens.

Diagnostic studies

Laboratory studies. Thyroid function studies should be performed in all patients with a clinical history or physical examination suggestive of hyperthyroidism. Abnormal thyroid function, manifested as an elevated T4 level, is common in GTD. Metastatic deposits in the kidneys or GI tract may reveal themselves by hematuria or hematochezia.

Tumor markers. A well-characterized glycoprotein hormone secreted by the syncytiotrophoblast, hCG is essential to maintaining normal function of the corpus luteum during pregnancy. Because all trophoblastic tumors secrete β-hCG, this hormone serves as an excellent marker for tumor activity in the nonpregnant patient. Serial β-hCG levels should be monitored during therapy to ensure adequate treatment. The level of β-hCG is roughly proportional to the tumor burden and inversely proportional to the therapeutic outcome.

Treatment

Molar pregnancy. For patients with complete or partial hydatidiform mole, evacuation of the mole by suction and sharp curettage should be performed. Oxytocics also are given to produce uterine involution and to control bleeding. However, these agents should be used judiciously because they may cause hyponatremia and fluid overload. A baseline chest radiograph and β-hCG measurement should be obtained before surgery. After molar evacuation, 80% of patients will need no further intervention

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