Postmenopausal Bleeding Case File

Postmenopausal Bleeding Case File

Eugene C. Toy, MD, Patti Jayne Ross, MD, Benton Baker III, MD, John C. Jennings, MD

CASE 57

A 60-year-old nulliparous woman who underwent menopause at age 55 years complains of a 4-week history of vaginal bleeding. Prior to menopause, she had irregular menses for about 20 years. She denies the use of estrogen-replacement therapy. Her medical history is significant for diabetes mellitus controlled with an oral hypoglycemic agent. On examination, she weighs 190 lb, her height is 5 ft 3 in, blood pressure is 150/90 mm Hg, and temperature is 99°F (37.2°C). The heart and lung examinations are normal. The abdomen is obese, and no masses are palpated. The external genitalia appear normal, and the uterus seems to be of normal size without adnexal masses.

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ANSWER TO CASE 57:

Postmenopausal Bleeding                              

Summary: A 66-year-old diabetic, nulliparous woman complains of postmenopausal vaginal bleeding. Prior to menopause, which occurred at age 55, she had irregular menses. She denies the use of estrogen-replacement therapy. Her examination is significant for obesity and hypertension.

• Next step: Perform an endometrial biopsy.
• Concern: Endometrial cancer.

ANALYSIS

Objectives

1. Understand that postmenopausal bleeding requires endometrial sampling or vaginal ultrasound assessment of the endometrial stripe to assess for endometrial cancer.
2. Know the risk factors for endometrial cancer.
3. Know that endometrial cancer is staged surgically.

Considerations

This patient has postmenopausal vaginal bleeding, which should always be investigated, because it can indicate malignant or premalignant conditions. The biggest concern should be endometrial cancer. She also has numerous risk factors for endometrial cancer including obesity, diabetes, hypertension, prior anovulation (irregular menses), late menopause, and nulliparity. The endometrial sampling or biopsy can be performed in the office by placing a thin, flexible catheter through the cervix. Either endometrial biopsy or transvaginal ultrasound is acceptable initial tests to assess for endometrial cancer. This patient is not taking unopposed estrogen-replacement therapy, which would be another risk factor. If endometrial cancer were diagnosed, the patient would need surgical staging. If the endometrial sampling is negative for cancer, another cause for postmenopausal bleeding, such as atrophic endometrium or endometrial polyp, is possible. A blind sampling of the endometrium, such as with the endometrial biopsy device, has 90% to 95% sensitivity for detecting cancer. If this patient, who has so many risk factors for endometrial cancer, were to have a negative endometrial sampling, many practitioners would go to a direct visualization of the endometrial cavity such as hysteroscopy. If the clinician were to elect to observe this patient after the endometrial biopsy, any further bleeding episodes would necessitate further investigation.

APPROACH TO:

Postmenopausal Bleeding and Endometrial Cancer                          

DEFINITIONS

ENDOMETRIAL SAMPLING (BIOPSY): A thin catheter is introduced through the cervix into the uterine cavity to aspirate endometrial cells (see Figure 57– 1).

ENDOMETRIAL POLYPS: A growth of endometrial glands and stroma, which projects into the uterine cavity, usually on a stalk; it can cause postmenopausal bleeding.

Figure 57–1. Endometrial biopsy. Pipelle is a thin flexible catheter and placed through the cervix into the uterus via speculum. The stylet is withdrawn creating a suction, and then the apparatus is gently withdrawn while rotating to get a sampling of the entire endometrium.

ATROPHIC ENDOMETRIUM: The most common cause of postmenopausal bleeding is friable tissue of the endometrium or vagina due to low estrogen levels.

ENDOMETRIAL STRIPE: Transvaginal sonographic assessment of the endometrial thickness; a thickness greater than 4 mm is abnormal in a postmenopausal woman.

TYPE I ENDOMETRIAL CANCER: This is the typical endometrioid cell type which is estrogen dependent, occurring in the perimenopausal or early menopause patient with the classic risk factors of unopposed estrogen. This type of cancer is typically lower grade and not as aggressive.

TYPE II ENDOMETRIAL CANCER: This is usually an aggressive disease with cell types of papillary serous or clear cell, and is estrogen independent (ER negative). These cancers involve late menopausal women, thin patients, or those with regular menses.

CLINICAL APPROACH

Postmenopausal bleeding always needs to be investigated because it can indicate malignant disorders or premalignant conditions, such as endometrial hyperplasia. Notably, complex hyperplasia with atypia is associated with endometrial carcinoma in 30% to 50% of cases.

    The most common etiology of postmenopausal bleeding is atrophic endometritis or vaginitis. Vaginal spotting can occur in a patient taking hormonal therapy. However, since endometrial malignancy can coexist with atrophic changes or in women taking hormone-replacement therapy, endometrial carcinoma must be ruled out in any patient with postmenopausal bleeding. Possible methods for assessment of the endometrium include endometrial sampling, hysteroscopy, or transvaginal sonography.

    Risk factors for endometrial cancer are listed in Table 57– 1. They primarily include conditions of estrogen exposure without progesterone. Although endometrial cancer typically affects older women, a woman in her 30s with a history of chronic anovulation, such as polycystic ovarian syndrome, may be affected. For this reason, women over the age of 40 to 45 with abnormal uterine bleeding should have assessment for endometrial cancer, and those women less than age 40 to 45 with risk factors should also be considered for a diagnostic procedure. Endometrial hyperplasia especially with cellular atypia is strongly associated with the development of endometrial cancer.

    When the endometrial sampling is unrevealing, the patient with persistent postmenopausal bleeding, or with numerous risk factors for endometrial cancer, should undergo further evaluation, such as by hysteroscopy. Direct visualization of the intrauterine cavity can identify small lesions that may be missed by the office endometrial sampling device. Additionally, endometrial polyps can be identified by hysteroscopy. More recently, saline infusion sonohysterography has been used to identify endometrial pathology such as polyps. These polyps still need surgical management since they could be malignant.

Endometrial Cancer

Endometrial carcinoma is the most common female genital tract malignancy. Although endometrial cancer is not the most common cause of postmenopausal bleeding, it is the one that is most concerning. Fortunately, because endometrial cancer is associated with an early symptom, abnormal uterine bleeding, it is usually detected at an early stage. Once diagnosed, endometrial cancer is staged surgically (Table 57– 2). The subset of women who have grade 1 (well differentiated), endometriod carcinoma that is minimally invasive may not necessarily need lymph node sampling. Minimally invasive surgery has advantages particularly in obese patients, but power morcellation should not be used (see also Case 41 for FDA warning).

    Sometimes endometrial cancer may occur in the atypical patient such as a thin patient; these cancers tend to be of the Type II variety (clear cell and papillary serous type) and more aggressive and associated with extrauterine metastases. In fact, clear cell carcinoma only accounts for 10% of uterine cancer but is associated with 40% of deaths. African-American women are more likely to have Type II disease. Also, those patients with uterine cancer with a thin endometrial stripe (<4 mm) postmenopausal bleeding are likely to have Type II cancer.

    Women with Lynch syndrome are at increased risk of developing colon cancer, ovarian cancer, and Type I endometrial cancer. This is an autosomal dominant disorder and associated with mutations of one of the mismatch repair genes. The lifetime risk of developing endometrial cancer varies from 16% to 61% depending on the exact mutation.

Emerging Concepts

Young women with endometrial carcinoma may strongly desire to have a child. Although extensive data are lacking, patients are sometimes given high-dose progestins or less commonly the levonorgestrel intrauterine device (IUD) with frequent periodic endometrial sampling. Strict criteria are used in these settings: grade 1, no myometrial invasion, no extrauterine involvement, and strong desire for fertility sparing procedure. Most experts recommend definitive surgical management immediately after childbearing.

aPapillary serous or clear cell histology is associated with a worse prognosis and more aggressive spread.

CASE CORRELATION See also Case 52 (Polycystic Ovarian Syndrome) which is a risk factor for endometrial cancer.

COMPREHENSION QUESTIONS

57.1 A 60-year-old woman presents to her physician’s office with postmenopausal bleeding. She undergoes endometrial sampling, and is diagnosed with endometrial cancer. Which of the following is a risk factor for endometrial cancer?

A. Multiparity

B. Herpes simplex infection

C. Diabetes mellitus

D. Oral contraceptive use

E. Smoking

57.2 A 48-year-old healthy postmenopausal woman has a Pap smear performed, which reveals atypical glandular cells. She does not have a history of abnormal Pap smears. Which of the following is the best next step?

A. Repeat Pap smear in 3 months

B. Colposcopy, endocervical curettage, endometrial sampling

C. Hormone-replacement therapy

D. Vaginal sampling

57.3 A 57-year-old postmenopausal woman with hypertension, diabetes, and a history of polycystic ovarian syndrome complains of vaginal bleeding for 2 weeks. The endometrial sampling shows a few fragments of atrophic endometrium. Estrogen-replacement therapy is begun. The patient continues to have several episodes of vaginal bleeding 3 months later. Which of the following is the best next step?

A. Continued observation and reassurance

B. Unopposed estrogen-replacement therapy

C. Hysteroscopic examination

D. Endometrial ablation

E. Serum CA-125 testing

57.4 A 52-year-old woman, who has hypertension and diabetes, is diagnosed with endometrial cancer. Her diseases are well controlled. Her physician has diagnosed the condition as tentatively stage I disease (confined to the uterus). Which of the following is the most important therapeutic measure in the treatment of this patient?

A. Radiation therapy

B. Chemotherapy

C. Immunostimulation therapy

D. Progestin therapy

E. Surgical therapy

57.5 A 35-year-old woman is diagnosed with endometrial cancer. Which of the following is most likely to be present?

A. Ascites

B. BRCA-1 mutation

C. Galactorrhea

D. Pelvic irradiation

E. Polycystic ovarian syndrome

ANSWERS

57.1 C. Diabetes mellitus is associated with endometrial cancer. Other risk factors include advanced age, early menarche, late menopause, obesity, chronic anovulation, estrogen-secreting ovarian tumors, hypertension, family history, and, the biggest risk factor, ingestion of unopposed estrogen. Taking a combination oral contraceptive decreases the risk of endometrial cancer due to the progestin component in the pill that prevents the endometrium from becoming hyperprolific. Smoking is associated with a lower estrogenic state, which would, therefore, also decrease a patient’s risk for endometrial cancer. But this poses a major public health risk, since smoking itself is associated with an overall increase in morbidity and mortality. Multiparity decreases the risk of endometrial cancer as well, and herpes simplex infection does not influence a patient’s chance of acquiring endometrial cancer.

57.2 B. Atypical glandular cells on the Pap smear may indicate cervical, endometrial, or ovarian cancer. Therefore, a colposcopic examination of the cervix, curettage of the endocervix, and endometrial sampling are indicated. Because endometrial carcinoma is the most common female genital tract malignancy and is very treatable when detected at an early stage, the benefit of using multiple techniques to further examine the cervix and endometrium at a microscopic level should not be delayed. Delaying further investigation by repeating a Pap smear in 3 months may allow progression of any sort of malignancy the patient might have. An abnormal Pap smear is not very specific, so waiting to repeat the test and again obtaining abnormal results would still not specify whether or not the patient has cancer or another pathologic process. Vaginal sampling would not give us information as to the patient’s likelihood of having an endometrial or cervical malignancy. In addition, vaginal cancer is not nearly as common as endometrial or cervical cancer and vaginal sampling would not be cost-effective if there are no symptoms associated with vaginal carcinoma. Hormone-replacement therapy (estrogen) would either worsen the situation if it were endometrial cancer. Unopposed estrogens increase the proliferation of endometrial cells and the likelihood of developing endometrial hyperplasia and eventually, endometrial carcinoma.

57.3 C. Persistent postmenopausal bleeding, especially in a woman with risk factors for endometrial cancer, must be evaluated. Hysteroscopy would be very cost-effective in this patient, who presents with persistent postmenopausal bleeding with many risk factors. Hysteroscopy is one of the best methods for assessing the uterine cavity since it allows for direct visualization and guided biopsy of the uterine cavity. Continued observation and reassurance would not be indicated since there is a high suspicion that this patient may be presenting with endometrial cancer. Any delay in treatment may allow progression of the cancer, making it more difficult to treat, and reassurance would be misleading. Unopposed estrogen-replacement therapy would not be indicated for this patient who already has so many risk factors and symptoms for endometrial cancer. Endometrial ablation may be beneficial in stopping bleeding in patients with menorrhagia who no longer wish to bear children, but it is not a method for diagnosing or treating endometrial carcinoma. Endometrial ablation in this patient would delay the diagnosis and treatment of endometrial cancer. The serum antigen CA-125 is not a specific cancer marker, and is mostly associated with epithelial tumors of the ovary.

57.4 E. Surgery is a fundamental aspect of the treatment and staging of endometrial carcinoma. Radiotherapy is used as an adjunctive treatment when the surgery performed for staging shows high suspicion of spread. Chemotherapy would be indicated if the surgery revealed metastasis. Progestin therapy is effective in shedding the endometrial lining, but not at inhibiting cellular proliferation or treating endometrial cancer.

57.5 E. Endometrial cancer usually affects postmenopausal women. Less commonly, women who are below 40 are affected, and almost always with a long history of anovulation (unopposed estrogen). Ascites typically is present with ovarian cancer and not as often with endometrial cancer. A BRCA-1 mutation usually presents with breast and ovarian cancer, and not endometrial cancer. Galactorrhea causes hypothalamic dysfunction and a hypoestrogenic state. Pelvic irradiation is associated with uterine sarcomas and not endometrial cancer.

    CLINICAL PEARLS    

» An endometrial assessment (sampling vs ultrasound) should be performed in a woman with postmenopausal bleeding to assess for endometrial carcinoma. » Unopposed estrogen is generally the biggest risk factor for the development of endometrial cancer. » Endometrial cancer is staged surgically, and surgery is a fundamental part of its treatment. » Persistent postmenopausal bleeding warrants further investigation (such as hysteroscopy) even after a normal endometrial sampling. » Endometrial cancer is usually discovered at an early stage due to an early symptom: abnormal uterine bleeding. » Type II endometrial cancer, involving clear cell or papillary serous subtypes, occurs in an atypical patient without a history of anovulation; it tends to be more aggressive. » Women with Lynch syndrome have a high risk of developing endometrial cancer.

REFERENCES

American College of Obstetricians and Gynecologists. Management of abnormal cervical cancer screening test results and cervical cancer precursors. ACOG Practice Bulletin 140. Washington, DC; 2013. 

American College of Obstetricians and Gynecologists. Management of endometrial cancer. ACOG Practice Bulletin 149. Washington, DC; 2015. 

American College of Obstetricians and Gynecologists. The role of transvaginal ultrasonography in the evaluation of postmenopausal bleeding. ACOG Committee Opinion 440. Washington, DC; 2009. (Reaffirmed 2013.) 

Hacker NF. Uterine corpus cancer. In: H acker NF, Moore JG, Gambone JC, eds. Essentials of Obstetrics and Gynecology. 6th ed. Philadelphia, PA: Saunders; 2015:428-434. 

Lu K, Slomovitz BM. Neoplastic diseases of the uterus. In: Katz VL, Lentz GM, Lobo RA, Gersenson DM, eds. Comprehensive Gynecology. 6th ed. St. Louis, MO: Mosby-Year Book; 2012:813-839.

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