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Management of Premalignant Lesions of the Endometrium

Obstetrics and Gynecology
Oncology

Authors

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Marika Osterbur Badhey MD, PhD
Author
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Michelle Davis, MD
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Parisa Fallah, MD
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Introduction

Endometrial cancer is the most common gynecologic cancer in the U.S., with 66,750 new cases and 12,940 deaths annually.[1] It also represents the 6th most common cancer amongst women globally, with a lifetime risk of 2.5% for average risk patients. Endometrial cancer rates are increasing worldwide by a rate of 0.58% per year, with rates predicted to increase by >50% by 2040.[2] The incidence of endometrial cancer rose from 0.6 per 100,000 in 2001 to 1.2 per 100,000 in 2017 in young women aged 20-29 years old and increased from 4.6 per 100,000 in 2001 to 7.5 per 100,000 in 2017 among women aged 30-39 years old.[3] It is felt that this is partially correlated with trends in increasing prevalence of obesity among women aged 18-34 years old.[4,5] Most cases of endometrial cancer are diagnosed early and the majority can be treated with surgery alone. While the incidence of endometrial cancer is highest in developed countries, mortality remains highest in low-income countries. Recent data has also shown significant disparities in endometrial cancer related outcomes based on race.[6,7]
There are two distinct types of endometrial cancer.
Type 1 endometrial cancer represents approximately 65% of cases. Type 1 cancers are hormonally mediated, are often associated with a precursor lesion, endometrial intraepithelial neoplasia, and typically result from excess estrogen effect on the endometrial lining, and generally carry a good prognosis.
Type 2 endometrial cancer represents 35% of cases and portends a worse prognosis. The exact risk factors for Type 2 cancers remain unknown and no clear precursor lesion has been identified for Type 2 histologic subtypes including high-grade endometrioid, serous, clear cell, and carcinosarcoma.
In Type 1 endometrial cancer, premalignant lesions identifiable on pathology sampling are present prior to, or concomitantly with endometrial cancer.[8] These lesions have previously been classified according to the WHO schema. This has been used to characterize endometrial pathology based on glandular complexity and nuclear atypia.[9] This schema categorizes lesions as simple versus complex hyperplasia and whether atypical cells are present. The most concerning lesion in this schema is an endometrial lesion displaying complex hyperplasia with atypia, which carries an underlying risk of malignancy of approximately 25%.[10]
The WHO nomenclature is used widely around the world, but presents challenges in treatment as there is subjectivity in interpretation with poor interobserver reproducibility.[11] A newer classification schema called Endometrial Intraepithelial Neoplasia, or EIN, was first described by Mutter et al, with the goal of better identifying patients with high risk of developing malignancy.[12,13] Studies have shown that the EIN schema has higher intra-observer reproducibility and increased identification of precancerous lesions.[14,15]
The risk factors for EIN correlate with the risk factors seen in Type 1 endometrial cancer. This includes obesity, diabetes, polycystic ovarian syndrome (PCOS) / anovulatory cycles, and other excess estrogen states.[12,16] Obesity serves as one of the most significant risk factors for EIN and Type 1 endometrial cancer, which is mediated through expression of aromatase in adipocytes, leading to increased peripheral conversion of androgens to estrogen. It is estimated that with a 5 kg/m2 increase in body mass index (BMI), there is a 60% higher lifetime risk of endometrial cancer, such that women with a BMI >40 kg/m2 are seven times more likely to develop endometrial cancer than non-obese women.[17] Risk for endometrial cancer of all types also increases with age, with a median age of 60 years old at diagnosis and higher rates of cancer amongst post-menopausal patients.[16] However, the age of diagnosis for both EIN and endometrial cancer is decreasing such that a higher index of suspicion for precancer or malignancy is warranted in younger, obese patients with abnormal uterine bleeding.

Clinical Presentation

Endometrial cancer and premalignant lesions such as EIN typically present with abnormal uterine bleeding (AUB) in reproductive age women or with post-menopausal bleeding in women who have gone through menopause, which is defined as absence of menses for greater than one year. For reproductive age and perimenopausal women, this can present as heavier menses, intermenstrual bleeding or irregular menstrual bleeding.[8,18]
Given the trend for younger age at diagnosis of both EIN and malignancy, providers should consider evaluation for any obese woman with abnormal bleeding without a clear identifiable cause.

Diagnostic Work-up

In patients in whom there is suspicion for endometrial cancer or premalignant endometrial lesions, endometrial sampling should be obtained with an endometrial biopsy. Initial work up can include a pelvic ultrasound to evaluate the endometrial lining and for any other potential structural cause contributing to abnormal bleeding. In reproductive age women who present for evaluation abnormal uterine bleeding, age and risk factors should be considered. In patients who are over the age of 45, endometrial sampling is recommended. In patients under the age of 45, risk factors for endometrial cancer should be evaluated. If the patient has any risk factor for unopposed estrogen, including obesity or anovulatory disorders such as PCOS, endometrial sampling should be performed.[8,18]
In post-menopausal patients, a pelvic ultrasound can be informative regarding the risk of endometrial cancer. If the endometrial stripe on a transvaginal ultrasound is <4mm, the negative predictive value of this test is >99% to rule out endometrial cancer.[19] However, high grade or Type 2 endometrial cancers can present with thin endometrial linings and thus any recurrent episodes of bleeding should be evaluated with endometrial biopsy.
Endometrial biopsy may be performed either as an office biopsy with an endometrial pipelle or in the operating room with a dilation and curettage. While dilation and curettage is considered the gold standard, an office biopsy is appropriate for most patients.[8] Office endometrial biopsy has a sensitivity of ~83%. In a systematic review, office endometrial biopsy missed lesions when <5% of the endometrium was malignant or if the malignancy or premalignant lesion was located in a structural lesion such as a polyp.[20]
If there are persistent symptoms of abnormal bleeding with a negative office endometrial biopsy, the patient should undergo hysteroscopic evaluation with dilation and curettage in the operating room, as this carries a higher sensitivity for diagnosis of endometrial cancer.[21,22] It is important to highlight that in 40% of patients with EIN, there was concomitant endometrial cancer identified on pathologic investigation of the uterus after hysterectomy.[8]

Management – Surgical

Surgery serves as the first line therapy for EIN and early-stage endometrial cancers. Surgical management of EIN includes a total hysterectomy (removal of both the uterus and cervix) and bilateral salpingectomy with or without a bilateral oophorectomy.[8] Counseling regarding oophorectomy is dependent on the patient’s age as well as the risks and benefits of removal as it relates to the sequelae of oophorectomy. If the patient is over the age of 50 years old oophorectomy is typically recommended.[23]
For patients with EIN who are under the age of 50 years old, retaining the ovaries can be considered. This is supported by data demonstrating increased mortality in women who undergo oophorectomy for benign indications prior to age 50.[24] In endometrial cancer, bilateral oophorectomy is part of surgical staging with a reported risk of ovarian metastasis of 5-8% in the literature.
However, these are based on small studies and national retrospective cohort studies have shown no difference in endometrial cancer survival among young women with and without oophorectomy and thus may be considered on a case-by-case basis with thoughtful counseling.[25]
There are multiple surgical approaches that are appropriate for treatment of EIN. Whenever possible, a minimally invasive approach is preferred, including laparoscopic, robotic, and/or vaginal surgery. Multiple studies demonstrate the safety of minimally invasive surgery in endometrial cancer. The GOG-LAP2 trial showed equivalent outcomes in risk of recurrence and death between open and minimally invasive approaches; however, laparoscopy showed superior short-term safety and decreased length of stay.[26,27]
The LACE trial randomized patients to abdominal versus laparoscopic hysterectomy and demonstrated no difference in risk of recurrence or death.[28] A Danish National Registry Study showed that overall survival and mortality was actually improved amongst patients with early-stage endometrial cancer who underwent minimally-invasive surgery as opposed to laparotomy, even after adjusting for histopathological risk groups.[29]
Total abdominal hysterectomy is reserved for cases when the uterus is enlarged, because morcellation or other forms of contained tissue extraction should generally be avoided in cases of EIN or endometrial cancer. Methods of contained tissue extraction can impede pathologic evaluation, which dictates grade, stage, and the potential need for adjuvant therapy. However, an abdominal approach does come with increased morbidity and length of hospital stay for patients. Vaginal hysterectomy is a reasonable approach for management of EIN, though it is limited in the ability to evaluate the abdominal cavity, potential risk for retention of the ovaries and inability to evaluate the pelvic lymph nodes.
Endometrial cancer staging includes evaluation of the local lymph nodes that drain the uterus as well as the potential for additional biopsies of the omentum for high grade histologies.  Nodal evaluation has evolved over time, initially with complete pelvic and para-aortic lymphadenectomies, to selected lymphadenectomy based on uterine risk factors (also known as the Mayo criteria), to sentinel lymph node biopsy.[30]
The Mayo criteria state that in patients with grade 1 or 2 endometrioid type cancer, less than 2cm in size, and with <50% myometrial invasion, it is safe to defer pelvic lymph node analysis.[31] Multiple studies have demonstrated a low false negative rate with sentinel lymph node biopsy such that this is an appropriate approach for endometrial cancer patients while minimizing the morbidity of a full pelvic lymph node dissections.[32]
Studies have generally shown sentinel lymph node detection rates of 85-95% with sensitivities greater than 90%, equivalent to breast cancer.[33] Nodal evaluation plays a critical role in staging and determines the need for adjuvant therapies. Since EIN carries a risk for an underlying endometrial cancer of up to 40% the optimal evaluation and role for staging for EIN remains undefined. While hysterectomy is standard surgical management, the role for staging surgery with lymphadenectomy remains controversial and will be discussed in the subsequent section.

Management – Medical

As stated above, the standard of care for EIN is surgical management with hysterectomy. This is considered definitive treatment, ruling out a concurrent cancer diagnosis and preventing future progression to endometrial cancer.[8] However, there may be patients who either strongly desire non-surgical management or are not appropriate surgical candidates in which medical management may be appropriate.[8] The two populations that typically undergo medical therapy and close monitoring for an EIN diagnosis are those patients who have not completed their desired childbearing and patients with medical comorbidities who carry an increased surgical risk and are not appropriate surgical candidates.
The goals for medical management of EIN in patients who desire future fertility are: clearance of disease, reversion to normal endometrium, and prevention of progression to endometrial cancer to allow for future pregnancies prior to definitive hysterectomy. The goal for patients who are poor surgical candidates include optimization and management of their comorbidities, disease stabilization, reduction of risk of conversion to endometrial cancer, and reduction in symptoms such as vaginal bleeding.[8]
The mainstay of medical management of EIN is progesterone therapy. Progesterone offsets the mitogenic effects of estrogen and causes secretory differentiation of the endometrium.[34] Currently, medroxyprogesterone acetate (Provera) and megestrol acetate (Megace) are the most common medical therapies used in women desiring future fertility. Dosing includes high dose therapy with 100mg  medroxyprogesterone daily or 80 mg twice daily megestrol acetate. Alternative methods such as IM injections of depot medroxyprogesterone (1000mg per week) and insertion of a levonorgestrel (Mirena) intrauterine device (52mg over 5 years) have also been used and shown to be effective.[35] 
A systematic review looking at all types of progesterone therapy showed that 65.8% of women with hyperplasia had complete resolution of their pathology with medical treatment.[36] A recent retrospective case series demonstrated an 80% regression in patients with complex atypical hyperplasia at 6 months after insertion of a levonorgestrel IUD.[37] A prospective phase II trial looking at the role of the IUD in complex atypical hyperplasia and early endometrial cancer demonstrated a 90.6% response rate in patients with complex atypical hyperplasia at 12 months.[38]
There are no randomized trials identifying an optimal dose or route of progesterone therapy and data are limited by small sample sizes. Thus, there is no preferred or standard route of progesterone therapy for medical management; however, the use of a levonorgestrel IUD has gained favor due to its ease of use and minimal toxicity profile.
For patients who desire fertility preservation, repeat endometrial sampling by office endometrial biopsy or D&C every 3-6 months is recommended. Pending a complete pathologic response, pathologists recommend 2-3 normal endometrial biopsies to confirm a sustained response prior to pregnancy. Patients often will require consultation with maternal fetal medicine and reproductive endocrinology and infertility physicians based on their medical comorbidities, and at the completion of childbearing, completion hysterectomy is recommended. Based on the above data, most patients will have a complete pathologic response within 9-12 months of treatment; however, retrospective studies have shown responses beyond that time frame. As long as no progression is identified, it is reasonable to continue medical management beyond 12 months with appropriate counseling, though hysterectomy should be considered for persistent disease refractory to progesterone therapy. [8]
Given that obesity is associated with an increased risk for endometrial cancer, weight loss options including lifestyle adjustments, and medical interventions such as bariatric surgery should be discussed. One study suggests that greater than 10% total body weight loss has been associated with higher response rates to progesterone therapy and should be consider in young, obese patients considering medical management of EIN.[39]

Controversies / Limitations

In cases of EIN, there is a 30-40% risk of identifying endometrial cancer found at the time of hysterectomy.[8] There is no consensus on the preferred approach to and role for staging surgery in EIN. For example, the need for surgery by a gynecologic oncologist, the use of frozen section evaluation, and the role of sentinel lymph node biopsy in EIN all remain controversial. The use of frozen section with intraoperative pathologic evaluation aids the surgeon in determining the need for lymphadenectomy and reduces the risk for a second operation or overtreatment with adjuvant therapy. Sentinel lymph node mapping may also be considered for patients with EIN, though one must weigh the risks of surgical complications, additional operative time, and surgical morbidity against the risk of an underlying malignancy.
Pre-operative factors have been evaluated to help identify the risk of endometrial cancer at the time of hysterectomy to better triage patients with EIN. In a retrospective study, an endometrial stripe on pelvic ultrasound greater than or equal to 2cm was associated with four-fold odds of concurrent endometrial cancer. Furthermore, approximately 44% of patients with an endometrial stripe greater than or equal to 2cm who were found to have cancer at the time of hysterectomy met Mayo criteria for lymph node evaluation, suggesting a potential patient population who may benefit most from triage to a gynecologic oncologist and staging lymphadenectomy.[40]
Finally, limitations exist regarding medical management, as detailed above. While data has become more robust to support this practice, with response rates ranging from 70-90%, there is no level one evidence to determine the optimal route or duration of progesterone therapy. Reliable and frequent pathologic evaluation is required, in addition to long term compliance by the patient, and thus thorough pre-treatment counseling is necessary to ensure safe practices. Ongoing data is required to guide best practices regarding medical management in the future.

Summary

In summary, Endometrial Intraepithelial Neoplasia (EIN) is a precursor lesion to Type 1 endometrioid type endometrial cancer. There are two pathologic schemas to define precancerous changes of the endometrium, the WHO schema and EIN. The latter shows a higher interobserver reproducibility and improved diagnostics, serving as the preferred pathologic schema when available. The first signs of disease include abnormal uterine bleeding or post-menopausal bleeding, and should be evaluated with a pelvic ultrasound and endometrial biopsy.
Given the underlying risk of endometrial cancer ranging from 30-40%, referral to a gynecologic oncologist should be considered. For patients who have completed childbearing, standard management is with hysterectomy, which should be performed in a minimally invasive fashion without morcellation when feasible.
The role for staging in EIN remains controversial; however, given the high risk for an underlying cancer on final pathology, frozen section evaluation with staging based on tumor characteristics (Mayo criteria) or sentinel lymph node evaluation should be considered. An increased endometrial stripe >2cm may be predictive of an underlying cancer as well as higher risk tumor characteristics necessitating additional staging. For young women, fertility sparing treatment with medical management can be considered. The optimal route of progesterone therapy is not defined; however, progesterone containing intrauterine devices allow for effective treatment with minimal toxicity, with response rates ranging from 70-90%.
Finally, obesity remains one of the single greatest risk factors for EIN and endometrial cancer. With rising cases world-wide, weight loss interventions should be considered as part of the treatment strategy.

References

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