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Endometrial Cancer

Course Authors

Yevgeniya Ioffe, M.D., and Israel Zighelboim, M.D.

Dr. Ioffe is Clinical Fellow, Division of Gynecologic Oncology, and Dr. Zighelboim is Assistant Professor, Division of Gynecologic Oncology, Washington University School of Medicine and Siteman Cancer Center, St. Louis, MO.

Within the past 12 months, Drs. Ioffe and Zighelboim report no commercial conflicts of interest.

Albert Einstein College of Medicine, CCME staff, and interMDnet staff have nothing to disclose.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 
Learning Objectives

Upon completion of this Cyberounds®, you should be able to:

  • Discuss the clinical presentation and disease characteristics of patients with endometrial cancer

  • Apply the epidemiology and risk factors associated with the development of endometrial cancer to their patients

  • Detail surgical and non-surgical treatment options available for the management of patients with endometrial cancer

  • List the most common cancer susceptibility syndromes associated with endometrial cancer

  • Apply information about outcome and prognosis to patients with endometrial cancer

 

Case History

A 45-year-old G2P1 female presents to her primary care physician complaining of worsening menometrorrhagia for the last six months. Five years before presentation, she underwent bilateral tubal ligation. In the last ten years, the patient’s BMI increased from 29 to 37, and she developed type II diabetes mellitus and hypertension.

Upon review of her family history, the physician learns that the patient’s brother was diagnosed with colon cancer at the age of 47, and that the patient’s mother was diagnosed with colon cancer at the age of 44. In addition, the patient’s sister and maternal aunt were diagnosed with ovarian and endometrial cancer at the ages of 55 and 38, respectively.

After an evaluation by an Ob/Gyn, the patient was found to have an enlarged uterus, measuring 13 x 9 x 6 cm, with a dominant fundal fibroid, fluid in the endometrial cavity and an endometrial complex (uterine cavity lining that appears trilaminar on ultrasound evaluation) measuring 25 mm in thickness. An in-office endometrial biopsy revealed endometrioid endometrial adenocarcinoma, International Federation of Gynecology and Obstetrics (FIGO) grade 1.

Endometrial carcinoma is the most common female genital tract neoplasm in the United States.

Epidemiology

Endometrial carcinoma is the most common female genital tract neoplasm in the United States. This malignancy accounts for >95% of uterine cancers which represent approximately 6% of all carcinomas diagnosed among U.S. women in 2010. It is estimated that 46,470 women will be diagnosed with uterine cancer and that 8,120 will die of this disease in 2011. The median age at diagnosis is 63 years.(1)(2)

Patients with endometrial carcinomas have traditionally been classified into two clinicopathologic groups. The largest group is represented by estrogen-dependent or type I tumors. These tumors are classically driven by unopposed estrogen stimulation. Patients with type I tumors tend to be younger at diagnosis and carry an overall better prognosis. Type II tumors account for 10-20% of sporadic endometrial carcinomas. The prognosis for type II tumors tends to be poor.(3)

Risk Factors

Risk factors for type I endometrial cancer include iatrogenic unopposed stimulation of estrogenic receptors in the uterus (estrogens without progestins or selective estrogen receptor modulators such as tamoxifen), chronic anovulation, truncal obesity, diabetes mellitus, hypertension, nulliparity and late menopause, as well as genetic predispositions (see below).

Patients with Type II endometrial carcinomas are on average older at diagnosis and lack evidence of sustained unopposed estrogenic endometrial exposure as their main risk factor. The risk factors for Type II tumors are not as well delineated as that of Type I endometrial carcinomas. Low incidence of Type II tumors makes this endometrial cancer subtype more challenging to study and characterize. Several studies report that Type II cases are more likely to occur in older, normal weight, multiparous, and African American women.(4)(5)

Histopathologic Characteristics

Type I Tumors
Endometrial hyperplasia is thought to be the precursor lesion of these well- to moderately-differentiated endometrioid adenocarcinomas. In a classic study, Kurman et al. followed 170 patients with endometrial hyperplasia who did not undergo a hysterectomy for at least one year. The authors quantified the risk of progression to carcinoma in patients with various pre-cancerous changes.(6)

Cancer precursor lesions were classified as either lacking (hyperplasia) or displaying cytologic atypia (atypical hyperplasia). Hyperplasia and atypical hyperplasia were further subdivided, based on glandular crowding and complexity, as simple vs. complex hyperplasia and simple vs. complex atypical hyperplasia.

Progression to carcinoma occurred in one of 93 (1%) patients with simple hyperplasia; in one of 29 (3%) patients with complex hyperplasia; in one of 13 (8%) patients with simple atypical hyperplasia; and in ten of 35 (29%) patients with complex atypical hyperplasia. The findings of this study highlight the fact that cytologic atypia represents a useful criterion in predicting the likelihood of progression to carcinoma.(6)

Type II Tumors
Tumors in this group tend to be poorly differentiated and include more uncommon and aggressive histologic subtypes such as clear cell, papillary serous carcinoma and carcinosarcoma (malignant mixed mullerian tumor).

These tumors arise in a background of an atrophic endometrium or in association with endometrial intraepithelial carcinoma (thought to represent the precursor lesion of papillary serous carcinomas).(7)

Diagnosis

The main objective of investigations for abnormal uterine bleeding is to exclude intrauterine pathology, particularly endometrial cancer.(8)(9)(10) More than 90% of cases of endometrial carcinomas will initially present with abnormal uterine bleeding. Therefore, the presence of abnormal bleeding in females over the age of 35, as well as in a younger female with a history of chronic anovulation (as suggested by coexistent obesity or additional signs of polycystic ovarian syndrome), should prompt immediate evaluation to rule out the presence of endometrial hyperplasia and malignancy.

The physical exam is usually unremarkable, although slight uterine enlargement may occasionally be present. An in-office endometrial biopsy is accurate (>90% sensitive) and detects most cases of endometrial carcinoma. Several sampling devices are currently available.

A patient about whom there is high clinical suspicion, yet who has a non-diagnostic office biopsy or a negative biopsy, should, nevertheless, be evaluated further with a dilatation and curettage (D&C),(9)(10) ideally with direct visual evaluation of the entire cavity with hysteroscopy.

Transvaginal ultrasonography is a sensitive and noninvasive method to evaluate postmenopausal patients with vaginal bleeding. The goal of the ultrasonographic evaluation in a postmenopausal patient is to differentiate between atrophic bleeding (the main cause of postmenopausal vaginal bleeding) and structural abnormalities that will require further evaluation. Postmenopausal women with an endometrial thickness of less than 4 to 5 mm measured by the transvaginal ultrasound examination have a low risk of endometrial disease.(11)(12) However, even in this group, if bleeding is recurrent or persistent, endometrial sampling must be carried out to rule out endometrial cancer or its precursor lesions.

Initial laboratory evaluation of newly diagnosed endometrial cancer patients is highly individualized and may include investigation of blood counts, liver and renal function and radiologic imaging for suspected advanced disease. At a minimum, a chest radiograph should be done to rule out pulmonary metastases. Lungs are a common site of hematogenous dissemination of metastatic disease in endometrial cancer.(13)

CA-125 is a high molecular weight mucinous glycoprotein (MUC16) that was first identified in 1981. CA-125 tumor marker has been extensively studied in ovarian cancer for its utility in screening and early detection, monitoring of disease status and its role as a prognostic indicator.(14)(15)(16) Elevated CA-125 serum levels can also be indicative of the presence of other malignancies, i.e. endometrial, endocervical and lung epithelial carcinomas.(16) Elevated CA-125 in patients with endometrial cancer may be suggestive of extrauterine disease and assist in evaluating response to treatment.(17)

Biopsy of the endometrium for screening purposes should be reserved for women at high risk.

Screening

Biopsy of the endometrium for screening purposes should be reserved for women at high risk. In this category are patients with proven genetic predisposition for developing endometrial cancer (such as those with Lynch syndrome, see below), postmenopausal women who have been treated with unopposed estrogen replacement therapy, premenopausal women with prolonged untreated chronic anovulation and patients with estrogen-producing tumors. History of tamoxifen use does not represent an indication for endometrial surveillance with ultrasound or biopsy in asymptomatic patients.(18)(19)

Associated Clinical Syndromes

It is estimated that three to five percent of endometrial carcinomas are associated with a site-specific cancer susceptibility syndrome. Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), accounts for the majority of heritable cases of endometrial carcinoma.(20) The average age of diagnosis of endometrial cancer in patients with Lynch syndrome is approximately 46 years. Individuals afflicted with this syndrome are at risk for colon, endometrial, ovarian, gastric, intestinal, hepatobilliary tract, upper urinary tract, brain and skin cancers.

Cowden syndrome was first described in 1963 and named after a last name of a patient.(21) It is a rare inherited disorder with evolving diagnostic criteria. Individuals afflicted with Cowden syndrome have an increased risk of developing several types of cancer, i.e., breast, thyroid, and uterus. A recent review of 211 patients with Cowden syndrome quantified the lifetime risk of endometrial cancer as 19% by age 70.(22)

Cancer Staging and Initial Treatment

The current treatment modalities available for the management of patients with endometrial cancer include surgery, radiation therapy, hormone therapy and chemotherapy. These modalities can either be used alone or in combination.

All patients who are medically fit should undergo surgical exploration and be assigned a disease stage according to the FIGO staging system revised in 2009.(23) After surgical staging is completed, the patient will be stratified into the low, intermediate or high-risk category for recurrence based on features such as stage of disease, age, grade, lymphovascular invasion and depth of myometrial invasion. Decision to proceed with adjuvant chemotherapy and/or radiation is based on the presence of specific intermediate to high-risk features.(24)(25)

Surgical Staging Procedure
The surgical staging procedure includes pelvic washings for cytologic evaluation, exploration of peritoneal surfaces with directed biopsies as indicated, extrafascial hysterectomy with bilateral salpingo-oophorectomy, and pelvic and para-aortic lymph node dissection.(26)

Minimally invasive procedures are becoming increasingly common for the initial surgical staging.

The therapeutic role of lymphadenectomy in patients with suspected early-stage disease remains somewhat controversial. Some suggest that nodal dissection may be omitted in cases of well-differentiated adenocarcinoma that are at low risk for metastatic disease (small-sized and non- to minimally-invasive tumors).(27)(28)

Minimally invasive procedures are becoming increasingly common for the initial surgical staging and treatment of endometrial cancer. A recent Gynecologic Oncology Group (GOG) trial by Walker and colleagues (LAP2) suggested that when laparoscopy was conducted for surgical staging of uterine cancer, patients had fewer moderate to severe postoperative adverse events than laparotomy, but similar rates of intraoperative complications. The operative time was significantly longer in the laparoscopy group. Prolonged post-operative stay (>2 days) was significantly lower in patients who underwent laparoscopic surgical staging.(29)

Radiation Therapy
Since FIGO instituted standard surgical staging for patients with endometrial cancer in 1988, the widespread use of preoperative and postoperative radiotherapy has been closely scrutinized. The role for adjuvant external beam pelvic radiotherapy in patients with early-stage endometrial cancer was evaluated in three major clinical trials.(30)(31)(32) All three trials demonstrated that adjuvant radiation improved local control without significant impact on five-year survival or distant metastasis rates.

The Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) study enrolled patients with endometrial cancer of any histology thought to be confined to the uterus and perceived to be at intermediate risk of recurrence or progression (grade 1 with >50% myoinvasion, all grade 2 and grade 3 with <50% myoinvasion). The results of this trial, published in 1980, demonstrated improved locoregional disease control in the group of patients receiving pelvic radiotherapy (4% vs. 14%), but no improvement in the 5-year overall survival rate.(31)

In 2004, results of the GOG-99 trial became available. In contrast with the PORTEC trial, only patients who underwent pelvic and peri-aortic lymphadenectomy, in addition to total abdominal hysterectomy/bilateral salpingo-oophrectomy, were eligible. Patients with papillary serous and clear cell histologies were not included in GOG-99 analyses. Similar to the PORTEC trial, GOG-99 demonstrated that administration of pelvic radiotherapy was associated with decreased risk of local recurrence at two years post-treatment (3% vs. 12%), but failed to improve overall survival rates.(31)

Upon review of the results of the GOG-99 trial, the authors identified a group of patients who would particularly benefit from receiving pelvic radiation treatment and defined the group as the high-intermediate risk category. The three risk factors considered in the classification were: grade 2 or 3 tumor histology, lympho-vascular invasion and invasion of the outer one-third of the myometrium. The risk factors were further stratified by age categories.(32)

While the PORTEC and GOG-99(31)(32) trials did demonstrate decreased rate of local recurrences with pelvic radiotherapy, this was not without a concurrent increase in treatment-associated gastrointestinal toxicities. The PORTEC-2 trial, designed as a non-inferiority clinical trial, aimed to show that the experimental treatment (vaginal brachytherapy) was not worse than an active control (external beam radiation therapy) for patients with high-intermediate risk endometrial cancer. Of note, pelvic and peri-aortic lymphadenectomy was not a pre-requisite for study entry, and high-intermediate risk category was defined somewhat differently from that proposed by GOG-99.

Results of PORTEC-2 confirmed the non-inferiority of vaginal brachytherapy-only treatment in the high-intermediate risk factor group (1.6% recurrence rate vs. 1.8% with external beam radiotherapy). PORTEC-2 also demonstrated decreased gastrointestinal toxicity in patients treated with vaginal brachytherapy only (13% vs. 54%).(33)

The search for effective cytotoxic agents for the treatment of endometrial carcinoma continues.

Chemotherapy

Multiple trials have evaluated the use of cytotoxic chemotherapeutic agents in patients with endometrial cancer found to be at significant risk for recurrence. Still, the search for effective cytotoxic agents for the treatment of endometrial carcinoma continues. The three compounds with definitive activity are: platinum (cisplatin and carboplatin), taxanes (paclitaxel) and doxorubicin. They are commonly used alone or in combination for the treatment of advanced cases, with response rates ranging from 20% to >40%. Other cytotoxic agents including 5-fluorouracil, vincristine, ifosfamide and ixabepilone may have possible activity.(34)(35)

A GOG study (GOG-184) compared two different chemotherapy regimens in the high-risk adjuvant setting (stage III disease). All women received radiotherapy followed by cisplatin and doxorubin (AP) or cisplatin plus doxorubicin plus paclitaxel (TAP). The percentage of patients alive and recurrence free at 36 months was 62% for AP compared with 64% for TAP. However, in subgroup analysis, TAP was associated with a 50% reduction in the risk of recurrence or death in patients with gross residual disease. The TAP arm did have a higher percentage of patients with hematologic adverse events, as well as neuropathy and myalgias.(36)

A subsequent study, GOG-209, seeks to test the non-inferiority of carboplatin/paclitaxel compared with TAP. The study is evaluating the regimen (carboplatin and paclitaxel) that is already widely used based on promising results in phase II studies with respect to associated convenience (outpatient) and decreased toxicity. GOG-209 included patients with measurable advanced/recurrent disease, patients with non-measurable stage IV disease and those with stage III disease. The study completed accrual in 2009 and the data is currently under analysis.(37)

Hormonal manipulation with high-dose progestins is another treatment option for patients with advanced or recurrent disease. Prior to using hormonal therapy, the tumor specimens are tested for expression of estrogen and progesterone receptors. The response rates approach 20% in the presence of estrogen and progesterone receptors (most commonly well- or moderately-differentiated tumors).(38)(39) The use of progesterone caproate as an adjuvant therapy, with the aim of relapse prevention and survival prolongation, was investigated by Vergote et al. in a large group (n=1148) of post-surgical clinical stage I and II patients.(40) The authors concluded that this is an ineffective strategy in preventing relapse and prolonging survival. However, it should be noted, that patients in this study were not stratified by estrogen/progesterone receptor expression status, and the patients with grade 1 tumors only constituted approximately 40% of the study cohort.

Other investigations, including a GOG study by Whitney et al., have demonstrated that the combination of daily tamoxifen and intermittent weekly medroxyprogesterone acetate may be an effective treatment option for advanced or recurrent endometrial carcinoma. The authors hypothesized that the increase in relative cytosolic concentration of progesterone receptors modulated by tamoxifen may, in part, augment the efficacy of progestation treatment.(41)

Biologics

Over the past several years, there have been several investigations of the utility of biologic noncytotoxic agents such as bevacizumab and tyrosine kinase inhibitors in the treatment of advanced and recurrent endometrial cancer. A phase II trial (GOG-229E) of single-agent bevacizumab administered to patients with recurrent or persistent endometrial cancer demonstrated 13.5% clinical response rate. Also, 40% of patients had a progression free survival interval that lasted six months or longer. All patients enrolled in GOG-229E had measurable disease despite being previously treated with one or two chemotherapy regimens.(42)

Treatment options for recurrent disease are fairly limited.

Recurrent Disease

Treatment options for recurrent disease are fairly limited. Vaginal recurrences can often be salvaged with radiation therapy. A multi-institutional study by Huh et al. demonstrated that the majority of isolated vaginal recurrences in women with stage I endometrial cancer can be successfully salvaged with radiation therapy. All of the patients in the trial were initially treated with surgery alone and did not undergo post-operative radiation therapy.(43)

Single site recurrences may be amenable of surgical resection and/or radiation. Distant failures are typically treated with cytotoxic chemotherapy, biologic or hormonal agents, as previously discussed.

Genetic Predisposition

Understanding of familial clustering of endometrial cancer has been somewhat slow to emerge. The breakthrough in characterizing genetic susceptibility to endometrial cancer occurred in 1913 when Alfred Warthin described an excess of gastric and uterine cancers in the family of his seamstress (family G). The pedigree of Warthin’s “cancer family G” was studied during the next six decades by Warthin and his colleagues, and finally Henry Lynch et al.(44)(45)(46)

Lynch Syndrome
At the molecular level, tumors of patients with Lynch Syndrome exhibit microsatellite instability (MSI), the phenotypic effect of a defective DNA mismatch repair system. A mutation in one of the mismatch repair genes (hMLH1, hMSH2, hMSH6, or hPMS2 genes) causes a microsatellite repeat error to remain uncorrected during the DNA replication process. Most cases result in changes in the lengths of dinucleotide repeats of the cytosine and adenine bases (CACACAC...). The inheritance pattern for the disorder is autosomal dominant.(47)(48)(49)

The estimated risk of developing colon cancer in women affected with Lynch syndrome is 40% to 60%.(44) Additionally, for women with Lynch syndrome, their lifetime endometrial cancer risk equals or exceeds their risk of developing colon cancer(50)(51). For individuals with documented hMLH1 and hMSH2 germline mutations, the lifetime risk of endometrial cancer is estimated to be between 40% to 60%. In a study specifically evaluating cancer risk in women with hMSH6 mutations, the cumulative risk for endometrial cancer was 71% by 70 years of age.(50)(51)(52)(53)

Cowden Syndrome
Cowden syndrome (CS) is another cancer susceptibility condition associated with endometrial cancer. The disorder was first characterized in 1963, in the family of Rachel Cowden. It appears that the disease has high penetrance in both males and females.

Signs and symptoms of Cowden include mucocutaneous lesions, hamartomatous gastrointenstinal polyps, macrocephaly, thyroid disease, benign breast disease, breast cancer and endometrial cancer. The overwhelming majority of patients will manifest clinical signs (mucocutaneous lesions) by age 29.

Cowden incidence is approximately 1 per 200,000. Similar to Lynch syndrome, CS also exhibits autosomal dominant transmission. PTEN [phosphatase and tensin homolog deleted on chromosome 10 (locus 10q23)] tumor suppressor gene germline mutations are found in approximately 80% of patients with CS. PTEN plays a vital role in regulating the highly oncogenic PI3K/Akt pathway, as well as the mTOR pathway. Both pathways play a role in cell survival and resistance to apoptotic signaling.

The importance of PTEN as a tumor suppressor is further highlighted by the finding of mutations in PTEN in an array of sporadic tumors, i.e., thyroid, endometrium, prostate and brain.(54) Research carried out in a mouse model has demonstrated a high rate of endometrial and breast cancers (findings resembling Cowden syndrome) in PTEN +/- mice.(54)(55)(56)(57) However, most genetic abnormalities present in endometrial cancer are sporadic and rarely associated with increased cancer susceptibility syndromes.

The most common genetic derrangement in endometrioid endometrial carcinomas is inactivation of PTEN.

The most common genetic derrangement in endometrioid endometrial carcinomas is inactivation of PTEN. Other common mutations observed in sporadic endometrial cancers are found in K-ras, and beta-catenin. (58)

Diagnosis and Management for Lynch and Cowden Syndromes

A detailed family history helps to identify individuals and families who may have a genetic cancer predisposition. Tissue testing via immunohistochemistry (IHC) or MSI analysis can serve as a screening tool for women thought to be at risk for having Lynch syndrome. Prophylactic hysterectomy with bilateral salpingo-oophorectomy has been shown to be an effective strategy for preventing endometrial and ovarian cancers in women with Lynch syndrome.(59)

Diagnostic criteria for Cowden syndrome have evolved over the years. The most recent is the Cleveland Clinic scoring system in 2011. For an individual patient, the probability of a relevant gene mutation may be evaluated by the Cleveland Clinic web calculator to derive.(60)

It should be noted that inactivation of the DNA mismatch repair system leading to MSI has been demonstrated in 20% of sporadic (non-hereditary) endometrioid endometrial carcinomas (type I tumors). Such a finding is caused by methylation of the hMLH1 gene promoter -- an epigenetic and non-heritable event.(61)

Outcome/Prognosis

Endometrial cancer patients tend to experience vaginal bleeding and pelvic discomfort early in the disease process which, fortunately, leads to early diagnosis. As a result, 75% of the patients are diagnosed with early-stage carcinomas and will survive their disease.(62) The survival by FIGO stage in endometrial cancer approaches 85% for stage I, 75% for stage II, 45% for stage III and 25% for stage IV disease. However, these figures can vary considerably, as they depend on tumor grade, histologic type and other clinicopathologic variables.

Several factors are associated with prognosis in patients with endometrial cancer. These include histologic type, age at diagnosis, tumor grade and stage, depth of myometrial invasion and presence of lymph-vascular invasion. Patients are triaged to adjuvant therapy according to currently available clinicopathologic risk models.

Conclusion

The risk models, however, are imperfect and some women perceived to be at low risk experience recurrences, while others probably receive unnecessary, costly and toxic treatments. In the future, it is expected that novel biomarkers will allow for better risk stratification and optimization of therapeutic recommendations with improved outcomes for these patients.


Footnotes

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