Chpt 43 Endometrial Hyperplasia and Carcinoma

What histologic findings would be expected if atypical endometrial cells are identified on a routine PAP smear?

Adenocarcinoma 20%. Hyperplasia 11%. Polyps 11%. Thus, more than 40% of women with atypical endometrial cells identified on a PAP smear will have abnormal histology on an endometrial biopsy.

What factors influence the treatment of endometrial hyperplasia?

Age. Amount and duration of vaginal bleeding. Associated anemia. Desire for future childbearing. The presence or absence of cytologic atypia. The degree of cytologic atypia.

What surgical options are currently available for the treatment of endometrial hyperplasia?

Curettage for acute bleeding. Hysteroscopy to exclude polyps and carcinoma. Hysterectomy, particularly if cytologic atypia is present.

What are the earliest signs of cytologic atypia?

Enlarged, round nuclei. Fine and evenly dispersed chromatin

What other common risk factors have been correlated to the development of endometrial hyperplasia?

Polycystic ovary syndrome. Obesity. Diabetes mellitus. Late menopause (after age 55). Nulliparity

In what clinical circumstances are pelvic and abdominal computed tomography (CT) scans helpful in evaluating patients with endometrial cancer on biopsy?

1. Abnormal liver function tests. 2. Clinical hepatomegaly. 3. Palpable upper abdominal mass. 4. Palpable extrauterine pelvic disease. 5. Clinical ascites.

In whom should a diagnosis of endometrial cancer be excluded?

1. All patients with postmenopausal bleeding. 2. Postmenopausal women with a pyometra. 3. Asymptomatic postmenopausal women with endometrial cells on a Papanicolaou smear. 4. Perimenopausal women with intermenstrual bleeding or increasingly heavy menses. 5. Premenopausal women with abnormal uterine bleeding, particularly if they are anovulatory.

A woman has a diagnosis of well-differentiated adenocarcinoma (histologic grade 1) from a curettage specimen. If surgical staging is performed within one month, how often will the histologic grade be higher? Will there be deep myometrial invasion?

1. Approximately one-third of neoplasms will be grade 2 or 3 (13%-50%). 2. Approximately 25% of uteri will have deep myometrial invasion.

How does endometrial carcinoma spread?

1. Direct extension to adjacent structures. 2. Transtubal passage of exfoliated cells. 3. Lymphatic dissemination. 4. Hematogenous dissemination.

What are the most common presenting symptoms of endometrial hyperplasia in a woman of reproductive age?

1. Metrorrhagia. 2. Menometrorrhagia

The World Health Organization classifies endometrial hyperplasia based on what two factors?

1. Simple or complex glandular/stromal architecture. 2. The presence or absence of cytologic atypia.

Name four medical conditions that increase the risk for developing endometrial cancer because of excess endogenous estrogen?

1. Women with chronic anovulation (PCO). 2. Women with estrogen secreting ovarian neoplasms, most commonly granulosa cell and theca cell tumors. 3. Obese postmenopausal women. 4. Women with severe liver disease.

What is the average time from diagnosis to recurrence in endometrial carcinoma?

2.2yrs

What is the local and distant recurrence for typical endometrial adenocarcinoma?

20% to 30% recur in the pelvis, 55% to 65% recur at distant sites, and 5% to 10% recur in both sites.

What percentage of endometrial carcinomas will shed abnormal cells that can be seen on a cervico-vaginal cytology?

25% to 35%.

What percentage of complex atypical hyperplasia will progress to endometrial cancer?

29%.

When endometrial carcinoma recurs, what percentage of recurrence is detected within the first and second years?

34% and 70%, respectively.

Women who are at risk of HNPCC have what percent risk of developing endometrial and ovarian cancers?

40% to 60% risk for developing endometrial cancer and 12% risk of ovarian cancer.

What percentage of women who develop uterine malignancies have a history of prior pelvic radiation therapy?

5% to 7% and typically develops 10 or more years after radiation therapy.

What percent of women with endometrial cancer are diagnosed while in stage I?

72%.

What percentage of perimenopausal and postmenopausal women will have endometrial hyperplasia on an endometrial biopsy performed for abnormal or postmenopausal bleeding?

8% to 9%. In women younger than 40 years, only 1% to 2% will have endometrial hyperplasia diagnosed on endometrial biopsy.

What characterizes the endometrial hyperplasia that is most likely to progress to endometrial carcinoma?

A complex architectural pattern and a moderate degree of cytologic atypia.

What is hereditary nonpolyposis colorectal cancer (HNPCC) Lynch syndrome type II?

A hereditary predisposition to the development of colon, breast, ovarian, and endometrial cancer. In approximately one-half of cases of affected women, endometrial and ovarian cancers precede colon cancer.

What is the effect of race on the prognosis of endometrial carcinoma?

African-American women tend to have tumors of higher grade and higher stage. They have a poorer survival than C

After which day of the menstrual cycle is the presence of endometrial cells a cause for concern?

After day 14. Some authors would use day 10. During menses and immediately thereafter, the presence of endometrial cells in a PAP smear is normal.

In the absence of cytologic atypia, what percentage of endometrial hyperplasia will progress to endometrial carcinoma?

Approximately 1% to 3%.

In 2007, approximately how many new cases and deaths from endometrial cancer occurred?

Approximately 39,000 new cases and 7,400 deaths.

What is the incidence of pelvic and para-aortic node involvement when the neoplasm appears grossly confined to the endometrium?

Approximately 6% to 7% of patients will have pelvic node metastases and 2% to 3% will have para-aortic node metastases.

What is the estimated prevalence of endometrial cancer in asymptomatic postmenopausal women?

Approximately 7 per 100,000 for Caucasian women and 5.4 per 100,000 for other races.

Why is endometrial hyperplasia more common at the extremes of reproductive life, near puberty, and the perimenopause?

At both extremes, anovulatory cycles are more common.

What is the most common cause of postmenopausal bleeding?

Atrophy

What is the effect of cigarette smoking on the endometrium?

Cigarette smoking significantly reduces the incidence of endometrial cancer. Endometrial atrophy, even in women on estrogen replacement therapy, is common in smokers, particularly if they are thin.

What nonmedical, nonsurgical life style changes are important in counseling the woman with endometrial hyperplasia?

Dietary counseling and weight loss, screening for diabetes mellitus, discontinuing exogenous unopposed estrogen.

What is the significance of estrogen and progesterone receptor status in the prognosis of women with a diagnosis of endometrial carcinoma?

ER status does not correlate well with prognosis. The absence of progesterone receptors is associated with a poor prognosis.

What is the most common gynecological malignancy in the United States?

Endometrial cancer, of which 80% are the endometrioid adenocarcinoma type. Endometrial cancer accounts for 6% of all cancers in women.

The background endometrium in a uterus with typical endometrioid endometrial adenocarcinoma histologically represents what process?

Endometrial hyperplasia of varying types (asynchronous proliferative pattern).

Which ovarian steroid hormone promotes growth of the endometrium?

Estrogen. ❍

In the postmenopausal woman, what is the main circulating estrogen and what is its source?

Estrone. It arises from the peripheral conversion of adrenal and ovarian androstenedione. In a slender woman, this amounts to 40 μg/day. In an obese woman, it may exceed 200 μg/day.

Describe the gross appearance of deeply invasive endometrial cancer?

Finger-like or broad based extensions beneath an exophytic endometrial growth. These extensions are firm, well demarcated, and lighter in color than adjacent myometrium.

A neoplasm that histologically has less than 5% solid area and invades approximately one-third of the myometrial thickness is what grade and stage? There is no other evidence of gross or microscopic disease.

Grade 1, stage IB. Grade 1 has less than 5% solid area. Stage I disease is limited to the uterine corpus, and stage IB can have invasion of up to 50% of the myometrium.

A neoplasm that histologically has more than 50% solid area and invades approximately three-fourths of the myometrial thickness is what grade and stage? There is no other evidence of gross or microscopic disease.

Grade 3, stage IC. Grade 3 has more than 50% solid area. Stage I disease is limited to the uterine corpus, and stage IC has invasion of greater than 50% of the myometrial thickness.

A neoplasm that histologically has more than 50% solid areas and invades for approximately three-fourths of the myometrial thickness is what grade and stage if the para-aortic nodes are positive for disease?

Grade 3, stage IIIC. Grade 3 has more than 50% solid areas. Disease extension beyond the uterus is stage III. Involvement of the pelvic or para-aortic lymph nodes is stage IIIC. Stage II denotes cervical involvement.

What type of ovarian neoplasm is most commonly associated with endometrial hyperplasia?

Granulosa cell tumor, because it secretes estradiol.

What is the 5-year survival rate for women with a diagnosis of endometrial carcinoma confined to the uterus at the time of surgical staging?

Greater than 80%.

What is the effect of gross cervical involvement in the prognosis of endometrial cancer?

Gross cervical involvement is associated with a poor prognosis. When treated with intracavitary application of cesium followed by extrafascial hysterectomy, the mean survival time in women without gross cervical disease was 94.2 months, compared to 29.1 months for women with gross cervical disease.

What are the two best prognostic indicators for endometrioid endometrial adenocarcinoma?

Histologic grade and depth of myometrial invasion.

What is the recommended follow-up for a woman with a histologic diagnosis of simple or complex hyperplasia without cytologic atypia?

In addition to medical therapy, follow-up endometrial sampling is recommended in 6 months

What is the recommended follow-up for a woman with a histologic diagnosis of atypical hyperplasia treated conservatively?

In addition to medical treatment, repeat endometrial sampling in 3 months; however, more recent evidence suggests that intervals up to 6 months may be necessary to establish hormonal conversion.

What is the incidence of complex atypical hyperplasia in postmenopausal women treated with unopposed estrogen?

In the PEPI study, the incidence of complex hyperplasia with atypia was 14 of 170 women (8%).

What is the incidence of simple and complex endometrial hyperplasia without atypia in postmenopausal women treated with unopposed estrogen?

In the PEPI study, the incidence of hyperplasia without atypia was 27 of 170 women (16%).

What is the significance of squamous morules in the diagnosis and prognosis of endometrial hyperplasia?

It is of no value. Squamous morules may be present in normal, hyperplastic, or neoplastic endometrium

What are common side effects of GnRH analog therapy for endometrial hyperplasia?

Menopausal symptoms—hot flushes, vaginal dryness, changes in the serum lipid profile, effects on the coronary arteries, and bone loss.

Can endometrial hyperplasia be accurately diagnosed by transvaginal ultrasonography?

No, endometrial hyperplasia is a histologic diagnosis. An endometrial sample is necessary to exclude adenocarcinoma. A thickened endometrial stripe in excess of 10 mm in a woman with abnormal uterine bleeding may suggest endometrial hyperplasia but is not diagnostic.

Is there any difference between the biologic behavior of simple and complex hyperplasia?

No, neither has cytologic atypia and both have a low incidence of progression to cancer.

What are the risk factors associated with the development of endometrial carcinoma?

Obesity, nulliparity, early menarche, and late menopause. Women weighing 21 to 50 pounds more than ideal body weight increase their risk of developing endometrial carcinomas threefold. Women in excess of 50 pounds more than ideal body weight increase their chance of developing endometrial carcinoma tenfold.

What medical therapeutic options exist for the women who desire pregnancy at this time?

Ovulation induction, typically with clomiphene citrate.

What are the estrogen receptor status and the progesterone receptor status in papillary serous endometrial adenocarcinoma and clear cell endometrial adenocarcinoma?

Papillary serous and clear cell endometrial carcinomas are usually negative for both estrogen and progesterone receptors.

Describe the indicated office evaluation of a woman whose history is suspicious for endometrial cancer?

Pelvic examination, PAP smear, biopsy of any abnormal cervical or vaginal lesion, and endometrial biopsy.

What is the most common presenting complaint of a woman with endometrial cancer?

Postmenopausal bleeding (or abnormal uterine bleeding in the premenopausal woman).

What is the most common presenting complaint in a postmenopausal woman with endometrial hyperplasia?

Postmenopausal vaginal bleeding.

Which ovarian steroid hormone promotes differentiation of the endometrium?

Progesterone

What medical therapeutic options exist for treating endometrial hyperplasia in women who do not desire pregnancy at this time?

Progesterone. Oral contraceptive pills. Gonadotropin-releasing hormone analogs. A progesterone-containing IUD.

How does significant nuclear (cytologic) atypia affect the grading of an architectural grade 1 endometrial adenocarcinoma?

Significant nuclear atypia, otherwise inappropriate for the architectural grade, increases the tumor grade by 1. This commonly occurs in papillary serous and clear cell endometrial carcinomas.

What are the common side effects of depo-medroxyprogesterone therapy for endometrial hyperplasia?

Spotting, breast soreness, weight gain, fluid retention, nervousness, irritability, bloating.

How does the presence of squamous change influence the prognosis of endometrial adenocarcinoma?

Squamous change is typically nonmalignant and occurs in as many as 25% of endometrial adenocarcinomas. The overall prognosis is unchanged for those tumors known as adenocanthomas. The histologic grade is assigned based on the glandular element within the neoplasm.

How is endometrial cancer staged?

Surgically, and includes TAH/BSO, selective pelvic and para-aortic node sampling, and pelvic washings for cytology.

In a postmenopausal woman, what sign on pelvic examination should suggest an elevated endogenous estrogen level?

The absence of vaginal atrophy. The presence of a vagina with multiple rugal folds suggests an estrogen effect.

Is the quantity of estrogen receptor (ER) and progesterone receptor (PR) higher or lower in endometrial carcinoma as compared to normal cycling endometrium?

The concentration varies, but with adenocarcinoma the concentration is usually less than normal cycling endometrium.

What is the gland-stromal ratio in simple hyperplasia?

The gland-stromal ratio in simple hyperplasia favors the glands. In a normal proliferative endometrium, the gland-stromal ratio favors the stroma.

What is the estrogen and progesterone receptor status in obese women with endometrial cancer?

The majority of endometrial adenocarcinomas in obese women are ER+ and PR+.

What differentiates complex atypical hyperplasia from well-differentiated adenocarcinoma?

The presence of stromal invasion defined as a desmoplastic stromal response or a complex proliferation exceeding 1/2 a low power microscopic field, approximately 2.1 mm.

What is the best predictor that endometrial hyperplasia will progress to endometrial carcinoma?

The presence or absence of cytologic atypia.

Describe the screening test for endometrial cancer?

There is no screening test for endometrial cancer; however, the American Cancer Society recommends annual endometrial biopsy starting at age 35 for all women at risk of HNPCC (hereditary nonpolyposis colorectal cancer).

In what type of hyperplasia is there back-to-back glandular crowding without cytologic atypia?

This is the definition of complex hyperplasia.

What is the intent of the pathologist when he or she makes a diagnosis of endometrial hyperplasia?

To communicate to the clinician his or her impression of the biologic potential of the endometrial proliferation to become cancer.

Epidemiologically, how many types of endometrial cancer are there?

Two: 1. Type I is estrogen related and occurs on a background of endometrial hyperplasia. This type occurs in younger women and has a good prognosis. 2. Type II occurs predominantly in older women, appears to arise de novo, and is unassociated with estrogen excess. The histologic grade is high and histopathologic types associated with aggressive behavior (clear cell, papillary serous) are common. The prognosis is poor.

What are the differences in frequency and 5-year survival between surgical stage I typical endometrioid adenocarcinoma and papillary serous carcinoma of the endometrium?

Typical endometrioid adenocarcinoma accounts for approximately 80% of endometrial adenocarcinoma. Papillary serous carcinoma accounts for approximately 8% of all endometrial adenocarcinomas. The 5-year survival for stage I typical endometrioid adenocarcinoma is 88% and that of stage I papillary serous carcinoma is 63%.

What is the endocrinologic milieu for the development of endometrial hyperplasia?

Unopposed estrogen.

What percentage of women with atypical hyperplasia have coexistent endometrial cancer at the time of hysterectomy?

Up to 43%.

What is the correlation between visual inspection of the sectioned uterus for myometrial invasion and histologic measurement of myometrial invasion?

Visual inspection of the uterus accurately determines the depth of invasion in 85% of cases.

What effect does the prior use of oral contraceptive agents have on the development of endometrial cancer?

Women who use combination oral contraceptive pills (OCP) for at least 12 months have a relative risk of endometrial cancer of 0.6. This protective effect persists for at least 15 years after cessation of OCP use.

Are postmenopausal women taking tamoxifen at higher risk of developing endometrial cancer than age-matched controls?

Yes. The increased relative risk of developing endometrial cancer for postmenopausal women taking tamoxifen is two to three times higher than that of age-matched controls.

Why do younger women have a better prognosis when they have endometrial carcinoma as compared to older women?

Young women tend to have low-grade tumors with less myometrial invasion.

What is the failure rate of medical therapy for simple and complex hyperplasia?

approx 20%

What percentage of women with endometrial carcinoma clinically confined to the uterus will develop recurrent disease?

approximately 16%

What is the value of mitotic activity in the diagnosis and prognosis of endometrial hyperplasia?

none

What percentage of women with endometrial cancer will have an abnormal Papanicolaou smear?

up to 50%