Uterine (Endometrial) Cancer

Endometrial Cancer

What every physician needs to know:

Endometrial carcinoma is the most common gynecological malignancy of the female reproductive tract. In 2010 it is estimated that 43,000 women will be diagnosed with endometrial cancer, while 8000 will die from the disease. The median age at diagnosis is 61 years.

Two clinico-pathological types of endometrial cancer have been described in the literature.

Type I: Estrogen-dependent endometroid carcinomas

• Associated with obesity, polycystic ovarian syndrome, diabetes mellitus, unopposed estrogen replacement therapy and the use of tamoxifen.

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• Often associated with endometrial atypical hyperplasia.

• Tend to be well differentiated and often express hormone receptors.

• Can be associated with hereditary nonpolyposis colorectal syndrome.

• Associated with mutations in the PI3 kinase- PTEN- AKT- mTOr pathway, defects in DNA mismatch repair genes, microsatellite instability, and mutations of the Kras pathway.

Type II: Estrogen-independent cancers (serous and clear cell carcinomas of the uterus)

• Display a higher biological aggressiveness and an overall poor prognosis despite diagnosis at an early stage.

• Typically arise in atrophic endometrium.

• Associated with p53 mutations, p16 gene inactivation and, in a minority of cases, Her2 Neu overexpression.

The majority of endometrial malignancies arise in endometrial glands and are designated endometrial carcinomas. Specific histological subtypes of endometrial carcinoma include:

• endometroid

• papillary

• adenocarcinoma with squamous differentiation

• serous or papillary serous

• mucinous

• clear cell

• squamous

• undifferentiated

The remaining endometrial malignancies are mesenchymal tumors and consistent of endometrial stromal sarcomas, leiomyosarcomas, and adenosarcomas.

Carcinosarcoma of the uterus is a rare malignant uterine neoplasm that contains both carcinomatous and sarcomatous elements. These neoplasms are regarded as rare aggressive malignancies with a high potential to develop distant metastases and are associated with an overall poor survival. Although the histogenesis of this neoplasm has been debated, evidence has begun to accumulate that this neoplasm may be more closely linked to carcinoma than to sarcoma.

Are you sure your patient has endometrial cancer? What should you expect to find?

The vast majority of patients with endometrial cancer present with abnormal vaginal bleeding. At times, patients present with a watery blood-tinged discharge. Other symptoms include dyspareunia, dysuria, pelvic pain, abdominal bloating, and constipation.

Asymptomatic women with endometrial carcinoma are identified during cervical cancer screening when atypical endometrial cells are noted.

Beware of other conditions that can mimic endometrial cancer

Vaginal bleeding in post-menopausal women is a cardinal symptom of uterine cancer. As such, other conditions that mimic endometrial cancer are those that present with abnormal vaginal bleeding.

It is important to note that vaginal bleeding is often attributed to a uterine source, but may arise from disease at any anatomic site in the lower genital tract (vulva, vagina, and cervix) or upper genital tract (uterine corpus, fallopian tubes, ovaries) or urethra, bladder, or bowel.

Other states that present with abnormal bleeding and can mimic endometrial cancer include:

• menorrhagia

• anovulation (in a pre-menopausal or a peri-menopausal patient)

• polycystic ovarian syndrome

• endocrinopathies that affect ovulation (such as hypothyroidism/hyperthyroidism, hyperprolactinemia and Cushing syndrome).

Additional anatomical causes of vaginal bleeding that can mimic endometrial cancer include:

• uterine polyps

• fibroids or leiomyomas

• arteriovenous malformations

• endometritis

• pelvic inflammatory disease.

Other disorders that can often masquerade as an endometrial malignancy include:

• cervicitis

• cervical polyps

• endometriosis

• vasculitis

• vaginitis

• vaginal and/or vulvar malignancies

• vaginal trauma

• fistulas (such as vescicovaginal or rectovaginal fistulas)

• disease of the urethra

• systemic diseases (such as Crohn’s disease).

Which individuals are most at risk for developing endometrial cancer:

Uterine cancer is the most common gynecologic malignancy in the United States with a median age of diagnosis of 61. Women have a 2.5% lifetime risk of developing endometrial cancer, which accounts for 6% of all cancers in women.

Fortunately, most cases are diagnosed at an early stage when surgery alone may be adequate for cure. Incidence rates are higher in white women rather than in black, Hispanic or Asian/Pacific Islander women. However, mortality is almost two-fold higher in black population (7.1 versus 3.9 per 100,000 women) likely due in part to the higher incidence of aggressive cancer subtypes.

The risk factors associated with Type I adenocarcinoma of the uterus include states related to excess estrogen stimulation. Excess estrogen stimulation can be derived from either an endogenous and exogenous source. Endogenous sources of estrogen excess include obesity, while exogenous sources relate to unopposed estrogen replacement therapy or tamoxifen.

Women with diabetes mellitus and hypertension are at increased risk for endometrial cancer. Advancing age is also a risk factor. Endometrial cancer usually occurs in post-menopausal women. However, it is important to note that 25% of cases are diagnosed in pre-menopausal women.

Lynch syndrome (hereditary nonpolyposis colorectal cancer) is also a risk factor for endometrial cancer. The lifetime risk of endometrial cancer is 27-71% compared with 3% in the general population. The mean age at endometrial cancer diagnosis in women with Lynch syndrome is 46-54 years, compared with a mean age of 60 years in other women.

Although there are no commonly described risk factors for type II endometrial cancers, there is some speculation that patients with BRCA1/2 mutations may be at risk for uterine papillary serous cancer.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

Endometrial biopsy (EMB)

EMB helps establish a tissue diagnosis of endometrial cancer.

Surgical staging

Surgical staging is critical for determining prognosis and in navigating treatment in endometrial cancer. A standard surgical approach includes a total abdominal hysterectomy, bilateral salpingo-opherectomy with or without lymph node dissection, and peritoneal washings.

The staging algorithm has launched several debates regarding the importance in determining lymph node status. In the UK, Medical Research Council ASTEC trial, 1408 patients were randomized to standard practice with and without lymph node dissection. There was no difference in 5-year disease-free survival and overall survival. However, in patients who underwent lymph node resection there was a higher incidence of complications such as the development of an ileus, thrombotic events and wound healing. As such, the relevance of determining lymph node status in all patients remains a controversial topic.

Minimal risk procedures are currently being investigated in the surgical management of patients with endometrial cancer. Laparoscopy has been evaluated as an alternative to the traditional procedure. Preliminary studies have reported fewer complications and shorter hospital stays with laparoscopic procedures. Robotic-assisted surgery is also a minimally invasive surgery for endometrial cancer and is gaining popularity in many tertiary care centers.

Regardless of method, surgical staging of endometrial cancer defines the stage, grade, depth of invasive disease and the histological subtype. Endometrial carcinoma is staged according to the International Federation of Gynecology and Obstetrics (FIGO) system.

Basic laboratory tests

Complete blood count with differential and chemistry profile including serum creatinine, electrolytes and liver function tests should be obtained. Anemia is not uncommon in patients with endometrial cancer. A Ca125 is not commonly utilized in type I uterine cancers. In papillary serous carcinoma of the uterus this marker may have utility.

Imaging studies

Computerized tomography (CT), magnetic resonance imaging (MRI) and Positron–emitting tomography (PET) have been evaluated in the staging of endometrial carcinoma. Imaging studies help to differentiate between organ-confined or locally advanced disease.

Cross-sectional imaging studies may underestimate the true extent of pelvic regional lymph node metastases; however, visceral (e.g. liver, adrenal glands) or skeletal metastases may be identified. A study examining the role of PET/CT in staging patients with endometrial cancer was reported to have a specificity of 95% in detecting disease outside of the uterus.

It is important to note that no imaging studies are a substitute for surgical staging.

Staging

Table I. TNM and FIGO staging of endometrial carcinoma.

Table II. TNM and FIGO staging of endometrial sarcoma.

What therapies should you initiate immediately i.e., emergently?

Management of patients with vaginal bleeding

A thorough history and physical examination should be obtained. Presence of hereditary or acquired coagulopathies should be recognized. A careful review of current medications is key. Use of anticoagulant, antiplatelet, and non steroidal anti-inflammatory medications should be recognized.

Careful monitoring of vital signs and evaluation of the patient’s hemodynamic status is fundamental. Initial laboratory tests include a complete blood count (CBC) plus differential, chemistry profile, coagulation profile including PT/INR, PTT, thrombin time, serum D-dimers, and fibrinogen level.

Blood type and cross-match should be obtained for patients who require urgent or emergent transfusion of leukocyte depleted packed red blood cells. A gynecological surgical consultation is of paramount importance.

Several therapeutic options exist for uterine bleeding not attributable to malignancy. These include:

1. Intrauterine tamponade – Intrauterine tamponade can be achieved using either an intrauterine balloon or gauze packing.

2. Uterine curettage — Uterine curettage is the treatment of choice for profuse uterine bleeding in women who are hemodynamically unstable.

3. High dose intravenous estrogen (IV) — High dose IV estrogen is beneficial in combination with other measures in hemodynamically unstable women with acute uterine bleeding. Of note, pulmonary embolism and thrombosis at other sites are potential complications of high dose estrogen therapy. Care must be individualized.

4. Uterine artery embolization — Uterine artery embolization as a first-line therapy is reserved for women in whom the etiology of bleeding is a uterine arteriovenous malformation, since it is the most effective treatment for this condition.

5. High dose oral estrogen — First-line therapy for hemodynamically stable women is high dose oral estrogen.

6. High dose oral contraceptives — High doses of oral contraceptives (OCs) (e.g. an OC containing 35mcg ethinyl estradiol taken two to four times daily) will cause bleeding to subside in most women within 48 hours.

7. High dose progestins — Profuse or prolonged uterine hemorrhage related to anovulation can also be treated with high dose progestins alone.

8. Tranexamic acid — Another medical therapy option is tranexamic acid (1 to 1.5g orally, three to four times daily), which acts within two to three hours of administration.

9. Endometrial ablation is an effective treatment for acute or prolonged uterine bleeding and is used in stable women in whom medical therapy is contraindicated or unsuccessful.

Options must be individualized as hormonal therapy can have significant consequences.

What should the initial definitive therapy for the cancer be?

Surgery, radiation therapy, hormone therapy and chemotherapy are used either alone or sequentially to treat endometrial carcinoma depending on disease stage and histological grade. Currently, patients are most commonly staged by the 2009 FIGO staging system (see Table I).

Initial management of uterine cancer

Surgery

The surgical approach to endometrial cancer is described in “Surgical Staging” above. In contrast to many other solid tumors, for endometrial cancer surgery often has a role even in locally advanced or distant disease.

Radiation Therapy

Radiation therapy consists of external beam radiation therapy (EBRT) and intravaginal irradiation. The dose of radiation for adjuvant therapy is 45 to 60 Gy. The total dose is typically fractionated or spread out over time. Standard EBRT is delivered in once daily fractions, typically 1.8 to 2 Gy, five days a week, for a period of weeks. Fractionation decreases the amount of toxicity to healthy tissues by exploiting their innate capacity for sublethal damage repair and repopulation compared to malignant tissues.

Brachytherapy represents an important part in the treatment of endometrial carcinoma but must be individualized. Brachytherapy can be delivered with either a low dose rate (LDR) or high dose rate (HDR) system. For vaginal brachytherapy, the dose should be prescribed to the vaginal surface or at a depth of 0.5cm from the vaginal surface; the dose depends on the use of EBRT.

For HDR brachytherapy, when used as a boost to EBRT, doses of 4-6 Gy X 2-3 fractions prescribed to the vaginal mucosa are commonly used. For HDR vaginal brachytherapy alone, extended field, the target for vaginal brachytherapy after hysterectomy should be limited to the upper vagina. Commonly used regimens include 7 Gy X 3 prescribed at a depth of 0.5cm from the vaginal surface or 6 Gy X 5 fractions prescribed to the vaginal surface.

The role of adjuvant radiation in early stage endometrial cancer has been evaluated in several major trials. Table IV highlights the various trials that reference the loco regional benefit derived from radiation therapy.

Table IV.

Data derived from four randomized trials (NORWEGIAN, PORTEC-1, GOG-99 and ASTEC/EN.5) evaluated the role of adjuvant pelvic EBRT in patients with early-stage endometrial cancer. Despite the differences in eligibility criteria, these studies established the significant benefit of adjuvant EBRT in preventing isolated locoregional recurrence, but failed to demonstrate any improvement in overall or disease-specific survival.

Recently published were the results of the PORTEC-2 trial, that randomly assigned 427 patients with stage I or IIA endometrial carcinoma of high-intermediate risk features (age = 60 years and stage IC grade 1 or 2 disease or IB grade 3 disease; any age and stage IIA with grade 1 or 2 disease or grade 3 and <50% myometrial invasion) to adjuvant vaginal brachytherapy or pelvic EBRT.

Both treatment modalities were found equivalently effective in preventing vaginal (5-year rate 1.8% vs. 1.6%, P=0.74), locoregional (5-year rate 5.1% vs. 2.1%, P=0.17) and distal (5-year rate 8.3% vs. 5.7%, P=0.46) recurrence with no substantial differences in overall survival (84.8% vs. 79.6%, P=0.57). Vaginal brachytherapy was recommended as treatment of choice for high-intermediate risk patients with early stage disease as of providing an excellent local control with less morbidity.

Chemotherapy

Based on data from several important clinical trials listed in Table III, there is now frequent use of chemotherapy in conjunction with radiation therapy for first-line treatment of women with advanced disease (Stage III) after initial surgery. In patients that have distant or visceral disease chemotherapy alone is often used.

Table III.

When chemotherapy and radiation therapy is deemed appropriate (Stage III A, B and C), potential options include:

• Upfront radiation therapy with cisplatin (50mg/m²; on days 1 and 28) as a radiosensitizer followed in sequence with 4 cycles of a platinum and a taxane (RTOG 9708).

• A “sandwich approach”: namely three cycles of carboplatin (AUC 5-6) and paclitaxel (175mg/m²😉 every three weeks followed in sequence with radiation therapy (external beam radiation therapy/vaginal brachytherapy) followed in sequence with three additional cycles of carboplatin and paclitaxel. Caution must be entertained post radiation therapy as patients may encounter profound myelosuppression. At times paclitaxel is dosed reduced to 135mg/m²;. The use of neulasta or neupogen is encouraged in the appropriate population, i.e. elderly.

For historical purposes, Table IV and Table V highlight the available studies to date. The most commonly and best tolerated regimen is carboplatin (AUC 5-6) with paclitaxel (175 mg/m²;). Doses may need modification if chemotherapy is given post-radiation therapy.