Endometrial cancer: Pathology and classification

INTRODUCTION — Endometrial carcinomas (EC) comprise a variety of neoplasms with variable patient outcomes/prognosis. Traditionally, EC has been classified by histomorphologic features and stratified into the more common, lower-risk, estrogen-driven type 1 cancers and the less common, more aggressive, nonestrogen-driven type 2 cancers. However, this approach does not adequately capture the complexity of these neoplasms. Subsequently, novel classification systems that incorporate molecular features have been developed to provide objective reproducible categorization and prognostic information.

The 5^th edition of the World Health Organization (WHO) Classification of Tumours of the Female Genital Tract, published in 2020, highlights the proposed new molecular classification system for ECs and how it relates to the traditional histomorphologic classification [1]. As this molecular classification has been integrated into key guidelines [2,3], it is important that clinicians are aware of this new system, familiar with how to interpret molecular results provided in pathology reports, and aware of the implications these features have on clinical care [4]. The relationship between type 1/2 EC histomorphologic and molecular classification is shown in the figure (figure 1) and will be discussed in this topic. Other important issues related to EC are reviewed separately.

●(See "Overview of endometrial carcinoma".)

●(See "Endometrial carcinoma: Epidemiology, risk factors, and prevention".)

●(See "Endometrial carcinoma: Clinical features, diagnosis, prognosis, and screening".)

●(See "Endometrial carcinoma: Staging and surgical treatment".)

CLASSIFICATION

Traditional histomorphologic classification systems — In 1983, Bokhman described two clinicopathogenetic types of EC based on endocrine and metabolic influences, pathologic features, and prognosis:

●Type 1 ECs comprise approximately 65 percent of ECs. They are estrogen driven, mostly endometrioid histology, lower grade, and typically have less myometrial invasion than type 2 ECs, and patients have a favorable prognosis (>85 percent five-year survival rate).

●By contrast, type 2 ECs comprise a diverse mix of high-grade, clinically aggressive histologies (eg, serous, clear cell). They have a poor response rate to progestogens, and patients tend to have poor outcomes [5,6].

This classification system, although helpful in providing a conceptual framework for understanding EC, did not capture the biological diversity or diversity of clinical outcomes of some histotypes (eg, grade 3 endometrioid cancers, mixed ECs) which do not fit neatly into one of the two categories (figure 1).

Distinguishing between patients who may be cured by surgery alone and those at significant risk of both local and distant recurrence, and therefore in need of adjuvant therapy, remains a tremendous challenge for clinicians caring for patients with EC. For advanced-stage disease, identifying a need for additional therapy is more straightforward, but for early-stage disease, identifying whether a patient is "low," "intermediate," or "high risk" of recurrence and needing adjuvant therapy depends on multiple pathologic features, some of which are poorly reproducible. A further challenge is that grade assigned from diagnostic biopsies has also been shown to differ from that assigned based on the hysterectomy specimen, with 15 to 30 percent of ECs upgraded on final pathology [7-11]. Histologic subtype assignment has only a moderate levels of interobserver agreement (kappa value approximately 0.50 to 0.65) with no diagnostic consensus or major disagreement in histotype assignment in over one third of cases [12-15].

Multiple risk stratification systems for EC have been developed [16-21], driven by landmark clinical trials [22-28] or based on individual institutional preferences [29]. Assessment and comparison of the most commonly utilized risk stratification systems have shown that none reliably predict the risk of lymph node involvement or disease recurrence in early-stage ECs [30,31], presumably due to the challenges noted previously.

Emerging molecular classification systems — Given increasing understanding of the molecular pathogenesis of EC, incorporating the molecular subtype of EC may offer more consistent categorization and both predictive and prognostic information. In 2013, The Cancer Genome Atlas (TCGA) used genomic, transcriptomic, and proteomic analyses to characterize over 370 ECs, identifying four molecular subtypes based on tumor cell genomic architecture with distinct prognostic outcomes [32] and clinicopathologic features, as shown in the table (table 1). These four molecular subtypes provide insight into the pathogenesis of ECs and a framework for subclassification of ECs for interpretation of research endeavors [33-43] and clinical trials [19,22,25,44-47]. Subsequently, a clinically applicable molecular classification system that can be performed on standard formalin-fixed, paraffin-embedded material and serve as a surrogate for diagnosis of the four TCGA molecular subtypes was developed [14,27,32,48,49]. This algorithm arose independently from two research teams, and subsequently through international collaboration has clarified several critical features: (1) consensus on the nomenclature and color designations for the four molecular subtypes, evolving through multiple different iterations with the final terminology reflected in the World Health Organization (WHO) 2020 publication on the classification of Female Genital Tumors and as shown in the figure (figure 2) [1]; and (2) characterization of "multiple classifier" endometrial carcinomas that harbor more than one key classification feature (eg, a tumor with both a POLE mutation and p53 abnormality and/or mismatch repair deficiency). The order of segregation shown in the figure (figure 2) reflects the now agreed upon categorization of these rare tumors (approximately 3 percent of ECs have more than one molecular feature) and their clinical behavior/outcomes [42].

Molecular subtype assignment is highly reproducible and can be done on diagnostic endometrial biopsies or curettings, showing high concordance with classification performed on the subsequent hysterectomy specimen [40,50-52]. The prognostic value of molecular classification has consistently been demonstrated, with predictive value emerging with respect to response to radiotherapy [53], chemotherapy [22,23,46,47], and targeted treatment [22,44,54-58].

The four molecular subtypes of EC are as follows, with WHO nomenclature given [59]:

●DNA polymerase epsilon (POLE) mutated subtype (POLEmut; TCGA "POLE [ultramutated]," previously "POLE," or "POLE EDM") – These are copy number (CN) stable ECs with recurrent mutations in the exonuclease domain of POLE, a gene involved in DNA replication and repair [60-63]. In-depth characterization of ECs with POLE mutations, both within and outside the exonuclease domain, has generated a structured scoring system that limits the assignment of POLEmut to a list of 11 pathogenic mutations [43]. These tumors have one of the highest somatic mutation frequencies of any solid tumors, frequently exceeding 100 mutations per megabase (Mb). Often, but not exclusively, of endometrioid histologic type, POLEmut ECs have prominent tumor-infiltrating lymphocytes (TILs).

Patients with POLEmut ECs tend to be younger and thinner, and despite often having seemingly aggressive pathologic features (eg, high-grade, lymphovascular space invasion), they have highly favorable outcomes (>96 percent five-year survival) confirmed across multiple studies [64-68].

In an individual patient data meta-analysis of all POLEmut ECs, adjuvant therapy was not associated with improved outcomes for women with pathogenic POLE mutations, supporting de-escalation of therapy in clinical trials [68]. Two prospective studies assessing the possibility of de-escalation of therapy are ongoing: (1) PORTEC-4a is a multicenter randomized phase III trial in patients with high-intermediate risk EC [69-71], and (2) Tailored Adjuvant Therapy in POLE-mutated and p53-wildtype/no specific molecular profile (NSMP) Early Stage Endometrial Cancer (TAPER) is a prospective cohort study in early-stage EC [68,71].

Immunotherapy may be an option in the rare scenario of recurrent POLEmut EC given the high observed TIL [72-74].

●Mismatch repair deficient subtype (MMRd; TCGA "MSI [hypermutated]" previously MMR-D) – These tumors have low levels of somatic CN alterations but a very high mutational burden and high TIL secondary to dysfunctional mismatch repair (MMR) proteins (mutL homolog 1 [MLH1], postmeiotic segregation 2 [PMS2], mutS homolog 2 [MSH2], or mutS homolog 6 [MSH6]) [75]. Epigenetic silencing of MLH1 is responsible for the majority of this subtype, but it also includes both somatic and germline mutations (Lynch syndrome (see "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and prevention of endometrial and ovarian cancer")) in any of the MMR genes. This molecular subtype is associated with a high tumor mutational frequency (>10 mutations/Mb).

The receptor tyrosine kinase (RTK)/RAS/beta-catenin pathways and phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K) signaling pathways are commonly involved in "microsatellite instability" (MSI) ECs (69.5 and >90 percent of cases, respectively) [32,76]. Studies on MSI status and clinical outcomes in EC have had discordant results, but retrospective data suggest an increased sensitivity to radiation treatment in MMRd ECs and may explain somewhat more favorable outcomes than would be anticipated in patients with advanced-stage disease [53]. The US Food and Drug Administration has approved the use of immune checkpoint inhibitors for metastatic or recurrent MSI ECs with promising response rates observed even with heavily pretreated disease [74,77,78].

●No specific molecular profile (NSMP; TCGA copy-number low [endometrioid], previously also termed p53 wild-type ["p53wt"] and "NSMP/p53wt") – This third molecular subtype is genomically stable, MMR proficient, with moderate mutational load ECs (frequently involving PI3K/Akt and Wnt/catenin beta 1 [CTNNB1] signaling pathways) and has intermediate to favorable outcomes. NSMP ECs have normal p53 IHC expression and are POLE wildtype. This group encompasses mostly endometrioid neoplasms with estrogen and progesterone receptor (ER, PR) positivity and high response rates to hormonal therapy.

●p53 abnormal (p53abn; TCGA copy number high [serous-like]) – The fourth molecular subtype has high somatic CN alterations and mutational profiles, similar to high-grade serous ovarian and basal-like breast carcinomas. TP53 mutations are characteristic for this group. The p53abn cases are associated with a poor prognosis and responsible for 50 to 70 percent of endometrial cancer mortality. Human epidermal growth factor receptor 2 (HER2) amplification was reported in approximately 20 to 25 percent of CN high ECs, and >40 percent of CN high ECs have homologous recombination deficiency (HRD) based on RAD51 foci formation, with a lower percentage showing HRD based on mutational signatures [54,79,80]. Antiangiogenic agents, alone or in combination, may also add value in advanced or recurrent p53abn EC [56,81,82].

The proportion of p53abn ECs for each histologic type are as follows: serous carcinoma (93 percent), carcinosarcoma (85 percent), clear cell carcinoma (38 percent), type II EC (grade 3; 22 percent), and type I EC (grade 1 or 2; 5 percent) [83]. Data from patients enrolled in the PORTEC-3 trial suggest that ECs with p53 abnormalities are associated with superior outcomes when treated with chemotherapy in addition to radiation as compared with radiation alone [47]. Attempts to capitalize on other molecular features within this molecular subclass (eg, HER2 amplification, HRD) are ongoing [54,55,84].

Breast cancer susceptibility genes (BRCA1/2) mutation carriers are at increased risk for p53abn EC, with the highest risk within BRCA1 mutation carriers [85].

The 2020 European Society of Gynaecological Oncology (ESGO), European Society for Radiotherapy and Oncology (ESTRO), and European Society of Pathology (ESP) guidelines integrate molecular features, where available, and assign risk group and direct treatment according to these subtype assignment [2]. Principal changes include grouping all early-stage (stage I/II) POLEmut ECs as "low risk" with no adjuvant therapy recommended, and classifying stage IA p53abn ECs with any myometrial invasion as "high risk," recommending chemotherapy (with or without radiation) for these individuals. In one retrospective study including 594 patients, performing molecular classification and applying the ESGO/ESTRO/ESP guidelines led to a change in risk group assignment in 7 percent of EC cases of whom 44 percent were assigned a lower risk group due to identification of a pathogenic POLE mutation and 56 percent were assigned a higher risk group due to identification of p53 abnormalities [86].

HISTOGENESIS AND PRECURSOR LESIONS — ECs that arise from atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (AEH/EIN) can be associated with any of the four molecular subtypes described above; POLE mutations and loss of mismatch repair (MMR) expression are typically seen in AEH/EIN associated with POLEmut and MMR-deficient (MMRd) EC, respectively, indicating that these alterations are early events in oncogenesis. Serous EC and carcinosarcoma mostly arise from serous endometrial intraepithelial carcinoma (SEIC), but some arise from AEH/EIN (and are associated with mutations in phosphatase and tensin homolog [PTEN]).

●Atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia is characterized by a clonal proliferation of endometrial glands such that glands predominate over stroma. The glandular epithelial cells have mild or moderate cytologic atypia, with nuclear stratification and enlargement, sometimes with prominent nucleoli.

AEH/EIN is associated with unopposed estrogenic stimulation and acquisition of mutations in PTEN, Kirsten rat sarcoma viral oncogene homolog, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3KCA), PI3K/Akt and Wnt/catenin beta 1 (CTNNB1), and/or AT-rich interaction domain 1A. It gives rise to MMRd and POLEmut ECs, some of the p53 mutated ECs, as well as no specific molecular profile (NSMP) ECs. In an individual patient, the mutational/molecular profiles of AEH/EIN and the concurrent EC are highly concordant [50,87,88].

●Serous endometrial intraepithelial carcinoma – In SEIC, the preexisting endometrial glands are lined by markedly atypical glandular epithelial cells. These epithelial cells show nucleomegaly; typically are less polarized; have rounded, more atypical and pleomorphic nuclei and high nucleus-to-cytoplasm (n:c) ratios; and are associated with a high proliferative index.

Tumor protein 53 (TP53) mutations are the defining feature of SEIC, and mutations in protein phosphatase 2, structural/regulatory subunit alpha are common. SEIC is the precursor of many p53abn ECs, but the percentage is not known.

WORLD HEALTH ORGANIZATION CATEGORIZATION OF EC HISTOLOGY — The World Health Organization (WHO) system for histologic categorization of EC is shown in the table (table 2) [1].

Endometrioid carcinoma — Endometrioid EC is the most common EC histology, accounting for 75 to 80 percent of cases. Endometrioid carcinomas can be of all four molecular subtypes, which indicates the genetic heterogeneity within this histologic type. Many grade 3 endometrioid ECs have a genomic profile similar to serous ECs, with high copy number (CN) alterations and tumor protein 53 (TP53) mutations [89-91], and grade 3 endometrioid carcinomas represent a particularly diverse subset of EC [41].

Most endometrioid ECs are low grade (grade 1 or 2), diagnosed at an early stage, and have a good prognosis [92]. Approximately 5 percent of low-grade endometrioid carcinomas are p53abn with worse outcomes [89,93]. Grade 3 p53abn endometrioid ECs behave more aggressively and have a poorer prognosis than other molecular subtypes of grade 3 endometrioid EC [41]. (See "Treatment of low-risk endometrial cancer", section on 'Prognosis'.)

Histology — Endometrioid EC is composed of tall columnar cells lining back-to-back glands without intervening stroma. The glands have a smooth, luminal contour. Cribriform (gland within a gland) patterns are also common. Occasionally, endometrioid ECs have a prominent papillary or villoglandular growth pattern.

Endometrioid ECs are graded using the International Federation of Gynecology and Obstetrics (FIGO) classification system, which assesses the architectural pattern and nuclear grade:

●Grade 1 – Less than 5 percent solid growth patterns (picture 1)

●Grade 2 – 6 to 50 percent solid growth patterns

●Grade 3 – Greater than 50 percent solid growth (picture 2)

Squamous differentiation is common and not included in assessment of solid growth when determining grade. Marked nuclear atypia (nuclear grade 3) raises the grade by one, from 1 to 2 or from 2 to 3.

Several variant types of endometrioid EC are recognized, including carcinomas with squamous differentiation, carcinomas with mucinous differentiation (characterized by prominent intracellular mucin within the neoplastic cells), and carcinomas with prominent cytoplasmic vacuoles (secretory carcinoma).

Myometrial invasion, if present, may have either an infiltrative pattern with reactive stromal fibrosis and inflammatory cells ("desmoplastic reaction") or a more subtle pushing pattern (large nests of neoplastic cells extend into the myometrium without eliciting a stromal reaction). An unusual pattern seen with grade 1 endometrioid ECs, the microcystic elongated and fragmented pattern, is associated with lymphovascular space invasion and nodal metastases [94,95].

Serous endometrial carcinoma — Serous endometrial carcinoma (SEC) is the second most common type of EC but only accounts for approximately 10 percent of cases.

A very large majority of SECs are of the p53abn molecular subtype. Human epidermal growth factor receptor 2 (HER2) is overexpressed/amplified/mutated in a minority of SECs and can be targeted therapeutically [55].

Clinically occult extrauterine disease is often present at diagnosis [96]. SEC often diffusely infiltrates the myometrium and may have extensive lymphovascular space invasion and peritoneal spread, similar to ovarian carcinoma. However, SEC confined to the endometrium (or a polyp) with minimal myometrial invasion and no distant disease after surgical staging has a good prognosis.

Histology — In SEC, the neoplastic cells form papillary structures and glands with serrated outlines. The cells have marked nuclear atypia with prominent nucleoli and numerous mitotic figures (picture 3). Occasionally, an SEC is composed primarily of glands, but the marked nuclear atypia is a key to proper tumor classification. Psammoma bodies may be present.

Clear cell carcinoma — Clear cell EC is an uncommon subtype, comprising <5 percent of EC, and patients are usually older, postmenopausal patients [97,98].

Clear cell ECs can be of any of the four molecular subtypes; POLEmut clear cell carcinomas have the most favorable prognosis while p53abn clear cell carcinomas are associated with aggressive behavior [36,39,99]. The mismatch repair-deficient (MMRd) cases often show mixed morphology, with clear cell and endometrioid components [100].

Clear cell ECs are typically negative for estrogen receptor (ER) protein and positive for Napsin A, which can aid in distinguishing this form of high-grade carcinoma from its mimics: SEC and the secretory variant of endometrioid EC.

The 2020 European Society of Gynaecological Oncology (ESGO), European Society for Radiotherapy and Oncology (ESTRO), and European Society of Pathology (ESP) guidelines do not offer specific recommendations for cases of clear cell EC that have undergone molecular classification, citing insufficient evidence to direct risk group assignment and treatment in these rare cancers [2].

Histology — Clear cell ECs share morphologic features with ovarian clear cell carcinoma and have several different architectural patterns: papillary, glandular, tubulocystic, and diffuse. The neoplasm is often composed of cells with abundant clear cytoplasm (picture 4); however, eosinophilic cytoplasm, hobnail, and flat cells can also be seen. Cytologic atypia is variable, and occasional enlarged irregular nucleoli are seen.

Mixed carcinoma — Mixed carcinomas have at least two distinct histologic components, typically endometrioid and a high-grade nonendometrioid pattern (usually serous, sometimes clear cell). These neoplasms are almost all clonal rather than being a collision between two synchronous but independent primary neoplasms and are usually the same molecular subtypes throughout (ie, they are an example of morphologic variability within a molecular subtype).

Undifferentiated/dedifferentiated carcinoma

Undifferentiated carcinoma — These neoplasms have no glandular or squamous differentiation. Most express epithelial antigens (eg, cytokeratin), but this is typically focal. Dedifferentiated carcinomas are composed of FIGO grade 1 or 2 endometrioid EC adjacent to areas of undifferentiated carcinoma. Undifferentiated/dedifferentiated carcinomas are frequently MMRd, often have mutations in genes encoding proteins of the switch/sucrose nonfermentable (SWI/SNF) complex, and, in most cases, do not have mutations in TP53. This category of neoplasms is the least well understood of the major histologic types of EC as it was only recently described [101-103].

Carcinosarcoma — Carcinosarcoma (previously known as malignant mixed Müllerian tumor) is an uncommon, aggressive, biphasic carcinoma (not sarcoma) that accounts for <5 percent of ECs. (See "Clinical features, diagnosis, staging, and treatment of uterine carcinosarcoma".)

A large majority of carcinosarcomas are of the p53abn molecular subtype (90 percent of carcinosarcomas characterized by The Cancer Genome Atlas [TCGA] had TP53 mutations), but they can also be of the other three molecular subtypes of EC [104,105].

Histology — Carcinosarcoma is a biphasic carcinoma composed of a high-grade sarcoma component juxtaposed with a high-grade carcinoma. The sarcomatous component is composed of cell types intrinsic to the uterus (homologous tumors), such as endometrial stromal sarcoma or leiomyosarcoma, or cell types extrinsic to the uterus (heterologous tumors), such as chondrosarcoma or rhabdomyosarcoma. The carcinomatous component is high grade, frequently difficult to assign to a specific histologic type, and can show features of high-grade endometrioid carcinoma, serous carcinoma, clear cell carcinoma, or undifferentiated carcinoma (picture 5). Metastatic neoplasms are purely carcinomatous or mixed carcinoma and sarcoma in over 90 percent of cases with only a few comprising pure sarcoma [106].

Rare EC subtypes — Mesonephric and mesonephric-like adenocarcinoma of the uterine corpus resemble morphologically their better described counterparts in the uterine cervix. They have a characteristic immunophenotype (GATA-binding protein 3 [GATA3] positive, thyroid transcription factor-1 [TTF1] positive, ER negative) and are associated with aggressive behavior.

Squamous cell carcinomas of the endometrium, in their pure form, are rare and must be distinguished from the much more common endometrioid adenocarcinomas with squamous differentiation, which can be squamous. They can arise in association with chronic inflammation and squamous metaplasia.

PATHOLOGY REPORTING — The International Collaboration on Cancer Reporting determines the core and noncore factors that should be reported for EC resection specimens (table 3) [107].

This list includes factors not included in the College of American Pathologists Protocol for the examination of specimens from patients with carcinoma and carcinosarcoma of the endometrium, but does not include adenomyosis and specimen integrity, which do appear in the College of American Pathologists Protocol. The 2017 list is in the process of being updated based on the World Health Organization (WHO) 2020 classification of female genital tumors [1].

The diagnostic report for EC based on an endometrial biopsy or curetting specimen is very simple and includes neoplasm histology and, for endometrioid carcinomas, grade. We are transitioning toward the use of molecular classification of EC, but it is currently limited by the restricted availability of POLE mutational analysis, which is not funded by most insurance providers (and is unlikely to be funded until the PORTEC-4a clinical trial [69] demonstrates that this information can be used to guide treatment, with reduced treatment given to patients with POLEmut EC).

The following is a pragmatic approach to use of molecular markers at this time, acknowledging that this is an area in evolution.

●Perform mismatch repair (MMR) immunohistochemistry (or microsatellite instability [MSI] assay) in all EC cases. The most cost-effective approach is to screen with mutL homolog 6 (MSH6) and postmeiotic segregation 2 (PMS2) immunohistochemistry alone, with subsequent mutL homolog 2 (MSH2) or mutL homolog 1 (MLH1) immunohistochemistry when needed. The determination of MMR expression is recommended by the Society of Gynecologic Oncology as part of Lynch syndrome screening in EC patients. Additionally, MMR status provides both prognostic and predictive information (table 3).

●Protein 53 (p53) immunostaining should be performed in all high-grade endometrioid and clear cell ECs and in low-grade neoplasms with any unusual features, such as increased nuclear atypia or mitotic activity. The role of p53 immunostaining in "typical" low-grade endometrioid carcinomas is uncertain; most centers do not routinely perform p53 testing of grade 1 or grade 2 EC as relatively few will show abnormal p53 immunostaining. Because patients with p53abn EC, irrespective of histology, will be candidates for adjuvant chemotherapy based on the results data from PORTEC-3 [47], there is a trend towards increased p53 testing in EC, with reflex p53 immunostaining of all EC performed in some centers.

●POLE mutational testing may be performed for qualification in clinical trials and in clinical practice where adjuvant treatment decisions would be altered (eg, stage I/II disease with high-risk features such as lymphovascular space invasion, deep myometrial invasion, and poorly differentiated features). Subclonal abnormal p53abn immunostaining could also be an indication as approximately one-half of ECs with subclonal complete loss or overexpression of p53 are POLEmut and thus associated with a favorable (POLEmut) rather than unfavourable (p53abn) EC molecular subtype. At this time, the role of routine POLE mutational testing for all ECs in clinical practice is still uncertain and will depend on the results of clinical trials that are ongoing. Currently, no surrogate markers are available for POLE mutational testing

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Uterine cancer".)

SUMMARY AND RECOMMENDATIONS

●Historically, endometrial carcinoma (EC) has been classified as type 1 or type 2. Type 1 comprises approximately 65 percent of ECs, is estrogen driven, mostly endometrioid histology, lower grade, and typically has less myometrial invasion than type 2 EC, and patients have a favorable prognosis (>85 percent five-year survival rate). By contrast, type 2 comprises a diverse mix of high-grade, clinically aggressive histologies (eg, serous, clear cell), with a poor response rate to progestogens and a poor outcome. This system is no longer routinely used, nor reflects the biological diversity of ECs. (See 'Traditional histomorphologic classification systems' above.)

●Molecular features are increasingly being integrated into routine pathology reporting. The four molecular subtypes of EC differ with respect to histogenesis/precursor lesions, risk factors, hereditary susceptibility syndromes, molecular abnormalities, response to treatment, and outcomes. In effect, molecular classification identifies different diseases, and clinical practice is moving toward treating them as such. Major guidelines assign risk group and direct treatment according to these molecular subtypes. (See 'Emerging molecular classification systems' above.)

●ECs that arise from atypical endometrial hyperplasia/endometrioid intraepithelial neoplasm (AEH/EIN) can be associated with any of the four molecular subtypes of EC; POLE mutations and loss of mismatch repair (MMR) expression are typically seen in AEH/EIN associated with POLEmut and MMR-deficient (MMRd) EC, respectively, indicating that they are early events in oncogenesis. Serous EC and carcinosarcoma mostly arise from serous endometrial intraepithelial carcinoma, but some arise from AEH/EIN (and are associated with mutations in phosphatase and tensin homolog [PTEN]). (See 'Histogenesis and precursor lesions' above.)

●The World Health Organization (WHO) categorization of the histologic types of EC is shown in the table (table 2). (See 'World Health Organization categorization of EC histology' above.)

●The International Collaboration on Cancer Reporting determines the core and noncore factors that should be reported for EC resection specimens (table 3). (See 'Pathology reporting' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Lesley Lomo, MD; Jonathan Hecht, MD, PhD; and Margaret Steinhoff, MD, who contributed to earlier versions of this topic review.