Introduction

Premalignant endometrial lesions are a characteristic sequence of endometrial hyperplasia (EH) that progress to endometrial carcinoma (EC). Two types of precursor lesions can lead to the two types of endometrial carcinoma.[1] Atypical hyperplasia/endometrioid intraepithelial neoplasia (AH/EIN) is the premalignant phase for endometrioid adenocarcinoma or type 1 endometrial carcinoma. Over 90% of endometrioid carcinomas are thought to develop from preexisting AH/EIN lesions. Type 1 endometrial carcinoma is typically seen in pre and peri-menopausal women. The etiologic factors include the predominance of estrogen combined with progesterone insufficiency. Rarely, atypical hyperplasia is associated with a secretory or mucinous cell type. Endometrial intraepithelial carcinoma (EIC) is thought to be the precursor lesion for the type 2 or serous carcinoma and a few of the endometrial clear cell carcinomas. Type 2 serous carcinoma is seen in post-menopausal women and is associated with atrophy of the endometrium.[2]

Type 1 endometrial carcinoma accounts for nearly 80 to 85% of all endometrial malignancies. AH shows many of the mutations that are seen in invasive endometrioid carcinoma.[3][4] P53 inactivation is the driving mutation for serous carcinoma.[2][5] Type 2 serous carcinoma is about 3 to 10% of all newly diagnosed cases, and clear cell carcinoma and other rare endometrial carcinomas together account for the rest.

Etiology

Endometrial carcinoma incidence is increasing worldwide as a direct result of an aging population and the rising incidence of obesity. There is a consensus that premalignant lesions develop several years before invasive endometrial carcinoma develops.[1] Atypical EH precedes invasive endometrioid carcinoma (type 1) and that the two share common predisposing factors as follows.[6] Among the non-modifiable risk factors are:

1. The age of the patient (>35 years)
2. Caucasian race

Other predisposing factors may also include a family history of endometrial hyperplasia or carcinoma, features of early menarche, prolonged perimenopause, or late menopause and postmenopausal status. Associated comorbidities that may play a role in predisposing to EH are obesity, diabetes mellitus type 2, and earlier or present diagnosis of granulosa cell tumor of ovary or HNPCC (hereditary non-polyposis colorectal cancer). In addition to this, exposure to tamoxifen therapy, hormone replacement therapy (especially estrogen-only), and any form of exogenous hormonal exposure also increase the risk of developing EH. Environmental factors like smoking and certain genetic mutations may also predispose to the development of EH.

On the other hand, endometrial intraepithelial carcinoma (EIC), the precursor lesion of type 2 ECs, tends to be estrogen-independent and progresses to the clinically aggressive ‘serous’ and ‘clear cell’ histological subtypes. Type 2 ECs are more often associated with endometrial atrophy in the postmenopausal woman as compared to endometrial hyperplasia (EH) seen in type 1 EC.[6]

The tumor progression model suggests that loss of PTEN occurs in sporadic glands in the normal endometrium, but this loss is insufficient to drive atypical glandular proliferation and progression. The PTEN negative glands need to acquire additional molecular ‘hits’ which contribute to the formation of AH/EIN.[7] The loss of PTEN function causes the PI3K/AKT pathway to become overactive. There is evidence that PI3K/AKT signaling enhances or turns on estrogen receptor-targeted gene expression. Therefore, loss of PTEN function may stimulate estrogen-dependent gene expression, leading to the overgrowth of cell types that depend on estrogen for trophic signals, such as endometrial and mammary epithelial cells.[8]

Longstanding molecular observations implicate PTEN inactivation, and it is seen in over 70% of the lesions. Thus, PTEN appears to be an early driver of atypical endometrial hyperplasia.[7] The systematic sequencing of endometrioid carcinomas has identified over 200 protein-encoding genes as pathogenic driver genes for type 1 EC.[3] Overall, there is dysregulation of the PI3K–PTEN–AKT–mTOR, RAS–MEK–ERK, and WNT–β-catenin pathways; microsatellite instability (MSI), mismatch repair (MMR) defects; and a relatively high occurrence of POLE mutations associated with a rare ultra-mutated phenotype.[5] The mutation of the ARID1A tumor suppressor gene may also be seen.[7]

TP53 inactivation as a major driver of most serous carcinomas (type 2), some high-grade endometrioid carcinomas (type 1), and many uterine carcinosarcomas; and inactivation of either gene as drivers of some clear cell carcinomas.[5][6] Mutation or inactivation of TP53 is an early event in the pathogenesis of serous tumors and is seen in nearly 75% of EICs, which precede serous carcinomas.[2] Other molecular events implicated in the pathogenesis of serous carcinoma include somatic mutations in PPP2R1A, FBXW7, SPOP, CHD4, and TAF1; amplification and/or overexpression of ERBB2, MYC, and CCNE1 (cyclin-E); and overexpression of p16 and synuclein-γ.[2][5] The altered PI3K pathway is also detected in serous carcinomas, mainly due to mutations in PIK3CA (in 17–43% of tumors), with some showing PTEN and PIK3R1 mutation.[3][5]

Epidemiology

The incidence of endometrial cancer has been shown to vary by race and ethnicity, with the highest rates among non-Hispanic White (NHW) women, and the lowest rates among Asian women with the worst survival rates among black women.[9] However, comparable data for premalignant lesions of the endometrium is not available.

Endometrial cancer is the most common gynecological malignancy in the Western world, and endometrial hyperplasia is its precursor.  Although historically considered a disease of postmenopausal women, the incidence of EC is rising, with alarming increases described in the 40–44-year-old age group. In the USA, EC is the fourth most common malignancy in women, with 1 in 37 women getting EC. According to the American Cancer Society (ACS), a diagnosis of about 65,620 uterine cancer cases will be made in 2020 in the US.[10] 

The incidence of endometrial hyperplasia is estimated to be at least three times higher than endometrial cancer, and if left untreated, it can progress to cancer.[11] Based on epidemiological registry data, it is estimated that in developed countries, there are about 200,000 new cases of EH per annum.[12] This is thought to be an underestimation.

A nested case-control study of EH progression, using extensive histopathology reports, concluded that AH was 14 times more likely to progress to endometrial carcinoma as compared to the women that presented with disordered proliferative endometrium without hyperplasia. Endometrial hyperplasia without atypia was unlikely to develop into endometrial carcinoma.[13]

Pathophysiology

There is a general consensus that accurate diagnosis of premalignant endometrial lesions and mitigation of risk factors can prevent progression to invasive carcinoma. During the cyclical hormonal endometrial remodeling, the endometrium responds to the estrogenic stimulation in a uniform programmed manner. The proliferative response is regulated by progestogenic effects. However, unopposed estrogenic stimulation of the endometrium can lead to the hyperproliferative glandular epithelium. This may lead to glandular remodeling and crowding of glands impinging on stromal spaces. Additionally, metaplastic changes may occur in glandular epithelium. If sporadic mutations accumulate in these hyperproliferative glands, prolonged or unopposed estrogen exposures act as a selection factor. The positively selected hyperproliferative clones then crowd out the normal glands.[14] 

Thus, two biologically distinct types of lesions, those that represent hormonal field effects i.e., AH and true precancerous lesions i.e., EIN, may be seen. They may either present independently or coexist in the same patient. Biologically, they have differing cancer risks and must be matched with appropriate intervention to avoid under- or over-treatment.[15]

Histopathology

EH is characterized by an increase in the gland-to-stroma ratio as compared to normal proliferative endometrium. Premalignant endometrial lesions, such as AH/EIN and EIC are clonal neoplasms that arise focally and can be diagnosed using specific criteria.

The precursor lesion of type 1 EC is AH. The WHO classification of endometrial hyperplasia includes two major categories, hyperplasia and atypical hyperplasia/endometrial intraepithelial neoplasia (AH/EIN).[16] While simple hyperplasia has a wide range of appearances, including an increased gland-to-stroma ratio and dilated glands; these lesions rarely progress to EC (1% to 3%). They are caused by persistent estrogen stimulation and may evolve into cystic atrophy when estrogen is withdrawn. AH/EIN shows proliferating glands with nuclear atypia.

The glands are crowded together and have complex branching patterns. Individual cells are rounded and haphazardly arranged on the basement membrane, having lost the perpendicular orientation seen in proliferative endometrial glands. The nuclei have prominent nucleoli and open or vesicular chromatin. It may not be possible to differentiate AH from well-differentiated endometrioid adenocarcinoma on biopsy. Up to 50% of women diagnosed with AH may have the final diagnosis of invasive EC when the uterus is examined after hysterectomy.[17]

The precursor lesion of type 2 serous carcinoma is EIC (serous endometrial intraepithelial carcinoma). It arises in the small atrophic uterus; and consists of malignant cells identical to those of serous carcinoma that is confined to the epithelial surface. The cells show marked cytologic atypia, including high nuclear-to-cytoplasmic ratio, atypical mitotic figures, hyperchromasia, and prominent nucleoli. Immunohistochemistry may be helpful in the differential diagnosis of AH and EIC. Atypical hyperplasia/EIN frequently shows PTEN and/or Pax-2 negativity and low Ki-67 and differs from EIC, which shows strong diffuse p53 staining and high Ki-67 staining index.[1][18]

History and Physical

Patients with endometrial hyperplasia mostly present with abnormal uterine bleeding. Women in the reproductive age group present in the form of menorrhagia and metrorrhagia, while postmenopausal bleeding is the presentation in the post-reproductive period. Occasionally patients may present with vaginal discharge. Some patients may be detected due to abnormal glandular or endometrial cells in the Pap smear.[19]

A detailed history and physical examination are required to determine and rule out other sources and causes of the presenting complaints or bleeding. A thorough and focused examination of the lower genital tract for pathologies and lesions of the lower genital tract, e.g., vulva, vagina, cervix, along with uterus and ovaries, should be done. This should include a pelvic examination. In obese patients where the pelvic examination may be difficult to interpret radiological investigations such as pelvic ultrasonography may be used. Pelvic ultrasonography is helpful in ruling out ovarian and other pathologies like uterine fibroids etc.[20]

Evaluation

Imaging the endometrium for diagnostic purposes is done on days 5-10 of the patient’s cycle. Endometrial hyperplasia can be reliably excluded if the endometrium measures less than 6 mm in thickness in pre-menopausal women and less than 5 mm thick in post-menopausal women.[20][21] The endometrium may appear smooth or more often will show an irregular surface with asymmetric/focal thickening. Cystic changes may be present. However, it is not possible to reliably differentiate EH from EC by ultrasonography;[20] unless frank myometrium invasion is seen.

In pre-menopausal patients who present with abnormal bleeding, a pregnancy test should always be done to exclude pregnancy. In all patients (pre- and post-menopausal) with abnormal vaginal bleeding, assessment of the coagulation profile with total platelet counts, prothrombin time, and partial thromboplastin time should be done to exclude coagulation and platelet disorders. A complete blood count should be ordered to assess anemia resulting from excessive blood loss (both chronic and acute).[22]

The final diagnosis of endometrial hyperplasia is usually made by hysteroscopy and direct biopsy sampling of the endometrium. Obtaining tissue via biopsy ideally needs to be done when the patient is not taking progestin-based hormones. If a patient is currently on hormonal therapy, a biopsy should be obtained 2 to 4 weeks after stopping therapy. Assessment of premalignant etiology may include molecular analysis (see etiology section).[23]

Differential Diagnosis

Although the criteria for AH/EIN are well defined, several conditions may mimic the cytological picture. Many of these lesions are interpreted by the pathologist as 'gland crowding.' Localized groups of altered and crowded endometrial glands may be misdiagnosed as premalignant or malignant lesions. In one study, follow-up outcomes of "gland-crowding" reports show 77% benign lesions (proliferative endometrium, secretory endometrium, endometrial polyp, etc.), 19% premalignant lesions, and 4% EC.[28] 

Other benign lesions that may mimic premalignant and malignant lesions when biopsies are examined may include mucinous metaplasia, papillary mucinous metaplasia, and endometrial polyps. If the history of pregnancy is not available, then the Arias-Stella reaction may be misinterpreted as the premalignant lesion. Endometrial hyperplasia with secretory changes may occasionally be difficult to distinguish from the "cork-screw" shaped extensive and proliferative glands of a late secretory endometrium.[28][29]

Prognosis

AH has been reported to progress to endometrial carcinoma in 29% of cases, with a mean duration of the progression being 4.1 years.[11] Additionally, AH may carry a higher risk of coexistent invasive carcinoma.[17] Recent studies report that up to 50% of women with atypia are found to have EC in subsequent hysterectomy specimens.[17][15] On the other hand, EC with concomitant hyperplasia tends to be of a lower grade and stage and higher 5-year survival rates.[30]

Complications

Complications of atypical hyperplasia may include severe uterine hemorrhage, requiring emergency medical or surgical management. Acute hemorrhage may be severe enough to require a blood transfusion.

Deterrence and Patient Education

EC until recently was thought of as a predominantly postmenopausal disease. However, due to the increase in rates of obesity in the US, we are starting to see signs of a shift towards a rising incidence of EH/EIN and cancer amongst pre- and peri-menopausal women as well. Diagnosis and management of EH, therefore, cause a challenge for the treating physician.[6] Early physician intervention and patient education discussing modifiable risk factors such as smoking, diet, and sedentary lifestyle could potentially stem effects on disease development.

Enhancing Healthcare Team Outcomes

Enhancing our understanding of the premalignant stages of EC development will allow us to pursue earlier diagnosis and facilitate appropriate stratification of women at risk of developing EC, permitting timely and appropriate therapeutic interventions. This involves an interprofessional team approach. Patients will often present to their primary care provider with abnormal vaginal bleeding. These physicians, physician assistants, and nurse practitioners in obstetrics/gynecology and family medicine will be the first-line providers to assess the patient. To assist with the diagnosis, these providers will rely on pathologists to review and diagnose endometrial tissue samples.

For radiological evaluation, radiology technicians conduct ultrasound exams on the patients, while radiologists interpret the images. The lab and imaging results communicated to the primary care provider allows the diagnostic picture to come together. If surgery is the chosen treatment, the obstetrician/gynecologist and the surgical team manage the patient. Nurses care for the patients in the outpatient environment, as well as the pre- and post-operative settings. Medical management involves pharmacists who dispense the hormone therapies to the patient and answer any drug-related questions.

Involving and recognizing the interprofessional team’s involvement in the process will help with better care and outcomes. The correct diagnosis, if made early enough in the course of the disease, can lower the risk of advancement to malignancy.[24]