Endometrial cancers constitute more than half of all gynecologic cancer diagnoses in the United States.1 Pathologic evaluation is an important element of disease management. As management approaches continue to evolve in response to reported data from clinicopathologic and molecular genetic studies, pathology will continue to play a central role in diagnosis, prognostic assessment, and treatment planning.
Evolution of Surgical-Pathologic Staging
Most patients with endometrial cancer present with abnormal bleeding and undergo initial evaluation with pelvic ultrasonography and endometrial biopsy/curettage. Histopathologic evaluation of the biopsy/curettage specimen is performed to confirm the diagnosis.2,3 Early staging schemes were essentially based on clinical findings, but since 1988, a more accurate surgical-pathologic staging approach has been used (Table 1).4
Comprehensive Surgical Staging
Preoperatively, staging is performed to estimate recurrence risk, and is based on the imaging evaluation of myometrial invasion, cervical involvement, and lymph node metastasis. MRI and transvaginal ultrasonography are effective modalities for assessing myometrial and cervical invasion, but imaging is poor at detecting lymph
Evolution of FIGO Endometrial Cancer Staging Classification
Traditional and historical surgical staging of endometrial cancer involves removing the uterus, cervix, adnexa, and pelvic and para-aortic lymph nodes, and obtaining pelvic washings, followed by pathologic examination. This allows for an accurate diagnosis, identification of disease extent, prognostic assessment, and selection of patients for adjuvant therapy. The advantage of surgical-pathologic staging over clinical staging was reported in the GOG 33 trial, which showed that 9% of patients with clinical stage I disease had pelvic nodal involvement, 6% had para-aortic lymphadenopathy, 5% had adnexal involvement, and 6% had other extrauterine metastases.8 Comprehensive surgical staging also identifies patients with advanced-stage disease who require radiation therapy and/or chemotherapy; those with low-stage disease with high-risk features (high-grade tumors, deep myometrial invasion, lymphovascular space involvement) who should receive adjuvant treatment; and those without high-risk features who may safely be spared adjuvant chemoradiation and its attendant morbidity.8,9
Despite the benefits of a surgical-pathologic staging system, the 2009 International Federation of Gynecology and Obstetrics (FIGO) staging system has its limitations, particularly in the setting of corpus-confined carcinoma. Because the current staging scheme applies uniformly to all cases, irrespective of staging adequacy or tumor type, clinical outcomes are highly variable. For example, using the Memorial Sloan Kettering Cancer Center Endometrial Cancer Nomogram,10 a 65-year-old woman with FIGO grade 1 endometrioid carcinoma, middle-third myometrial invasion, and a benign lymphadenectomy would have an estimated 5-year overall survival (OS) rate of 92%, whereas a 65-year-old woman with serous carcinoma, middle-third myometrial invasion, and no lymph node evaluation would have an estimated 5-year OS rate of only 64%. This observation prompted a proposal to amend the current FIGO staging scheme.11
Another controversy related to surgical staging in endometrial cancer is the role of para-aortic lymph node dissection. It has been shown that the rate of isolated para-aortic lymph node involvement in the absence of pelvic lymph node involvement is very low (<2%).12 Patients with high-risk disease have a higher frequency of para-aortic lymph node involvement, suggesting that para-aortic lymphadenectomy should be performed as part of surgical staging in these patients.13 However, a classification and regression tree analysis found that OS was predicted by FIGO stage and grade (a binary system of low- vs high-grade) but not by para-aortic lymph node status,14 advocating for an approach with less extensive lymph node dissection.
Sentinel Lymph Node Mapping
Approximately 6% to 23% of women with endometrial cancer who undergo pelvic lymphadenectomy develop long-term morbidity, such as lymphedema.15,16 However, this is likely an underestimation, given that patient surveys have indicated leg lymphedema rates as high as 20% to 40%.16 To reduce this morbidity and improve the detection of lymph node metastases, a sentinel lymph node (SLN) mapping approach to the management of endometrial cancer was introduced and has been incorporated as an option in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Uterine Neoplasms since 2014.17 The goal of SLN mapping is to initially target and assess the lymph nodes most likely to be involved by metastatic cancer (ie, the sentinel, or first, nodes in the path of lymphatic flow away from the tumor), thereby limiting the extent of surgery and morbidity associated with extensive lymphadenectomy. This technique identifies SLNs in approximately 85% of patients, of whom 12% have positive SLNs.18 Detailed pathologic examination of SLNs (ultrastaging), which includes the assessment of multiple sections using routine stains, as well as immunohistochemistry, for epithelial markers,19 allows for the detection of low-volume metastases that can be missed with standard techniques.18,19 SLN assessment also can refine surgical-pathologic stage; for example, in one study, SLN biopsy results upstaged 10% of patients with low-risk and 15% of those with intermediate-risk endometrial cancer,20 with implications for adjuvant treatment planning.
Challenges in the Pathologic Evaluation of Critical Prognostic Factors
Assignment of histotype is straightforward in most endometrial cancers, but can be exceedingly difficult in some high-grade tumors exhibiting morphologic ambiguity.21,22 There are several risk-group stratification systems based on surgical-pathologic staging of endometrial cancer7,9,13,23–27; however, the poor reproducibility of histotype and grade classification21,22,28–30 presents challenges for accurate prognostic assessment,27 selecting optimal treatment, determining eligibility for clinical trials, and comparison of treatment interventions between studies. Integrating pathologic parameters with findings of molecular genetic analyses (described herein) may provide a more accurate and prognostically relevant classification of these tumors.31–34
Tumor grade and histotype designation in preoperative biopsy and curettage specimens may be incorrect.35 For example, in one study, 1% of preoperative grade 1 endometrioid adenocarcinomas were upgraded to grade 2/3 cancers, and a further 1% harbored a high-risk histotype (serous or clear cell carcinoma) in the hysterectomy specimens.36 Similarly, the undifferentiated component of a dedifferentiated carcinoma, which often lies deep to the well-differentiated component, may not be sampled in a biopsy or curettage specimen.37,38 These sampling errors are more likely to occur with small-volume samples. In these cases, there is a potential for surgical under-staging due to the failure to detect high-risk features (high-grade tumor component) in the preoperative specimens.
Although SLN biopsy offers the advantages of accurate staging and reduced morbidity from avoidance of an unnecessary lymphadenectomy, its long-term survival benefits, if any, are unknown.3 Furthermore, the clinical significance of small tumor volumes (eg, isolated tumor cells) in SLNs is unknown, and further studies with long-term follow-up are ongoing.
Evolving Diagnostic Paradigms in Endometrial Cancer and Clinical Implications
Molecular Genetic Findings and Integrated Pathologic-Genetic Classification
The Cancer Genome Atlas (TCGA) study of endometrioid and serous carcinomas found mutations in several genes (eg, TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, CTNNB1, KRAS, and POLE) and, more importantly, identified 4 major genomically defined classes of tumor (POLE-ultramutated, microsatellite instability–hypermutated [MSI-H], copy-number-low, and copy-number-high). These groups were clinically significant, because they correlated with progression-free survival; patients with POLE-mutated tumors had an excellent prognosis and those with copy-number-high tumors had poor outcomes, whereas the MSI-H and copy-number-low groups had intermediate prognoses.34 Recently, DNA ploidy was shown to differ between TCGA groups and was highest in the p53-aberrant group. Abnormal DNA ploidy was associated with higher grade, nonendometrioid histotype, and poorer survival (particularly in mismatch repair [MMR]–deficient tumors).39 A recent study of endometrial clear cell carcinomas identified similar genomic classes, which were also associated with prognosis.40 Uterine carcinosarcomas also frequently harbor mutations in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous carcinomas.41
It is also apparent that genomic classes of endometrial carcinoma are associated with phenotypes. Copy-number-high tumors, which are characterized by TP53 mutations and alterations associated with cell cycle deregulation, constitute some high-grade endometrioid adenocarcinomas and clear cell carcinomas, and all serous cancers.34,40 Copy-number-low tumors are predominantly low-grade endometrioid adenocarcinomas.34 POLE-mutated endometrial carcinomas are typically characterized by high grade; tumor-infiltrating lymphocytes (TILs) and/or peritumoral lymphocytes; morphologic heterogeneity/ambiguity; and bizarre/giant tumor cell nuclei.42,43 Endometrioid histotype is the most frequent, although POLE mutations have also been reported in clear cell carcinomas,40 undifferentiated carcinomas,44 and carcinosarcomas.45 MSI-H endometrial cancers, which may be associated with germline alterations (Lynch syndrome) or sporadic aberrations, are associated with lower uterine segment location, endometrioid histology, mucinous differentiation, TILs, and peritumoral lymphocytes.46–49
Molecular classification of endometrial cancer has been shown to be reproducible and associated with clinical outcomes.31–34 However, these algorithms do have some limitations. p53 immunohistochemistry does not correlate perfectly with TP53 copy number changes,39,40 and its use in these algorithms may therefore misclassify some copy-number-high tumors. The algorithms do not address how to categorize tumors harboring more than one classifying genomic aberration (POLE mutations, MMR deficiency, or TP53 mutations) when the algorithmic components are performed in parallel rather than sequentially. The algorithms do not allow for the exploration of the significant heterogeneity seen within the copy-number-low group.50,51 Finally, in the ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) algorithm, DNA MMR immunohistochemistry is performed before POLE sequencing, which may result in failure to detect MMR-deficient tumors with POLE mutations, as well as incorrectly classify these tumors as MMR-deficient rather than as POLE-mutated tumors; as a result, our approach differs slightly in performing POLE sequencing before DNA MMR immunohistochemistry (Figure 1).
Despite these limitations, an integrated genomic-pathologic classification scheme incorporating genomic-based classifications with traditional clinicopathologic prognostic parameters (Figure 1) represents the best available method for stratifying patients into prognostically distinct groups that may benefit from tailored treatment approaches.52
Molecular Genetic Findings in Synchronous Endometrial and Ovarian Carcinomas
The staging of patients with synchronous endometrial and ovarian carcinomas traditionally has been
Diagnostic algorithm for integrated genomic-pathologic classification of endometrial carcinomas (blue represents histotype; red represents TCGA genomic class).
Abbreviations: MMR, mismatch repair; MSI-H, microsatellite instability–hypermutated; TCGA, The Cancer Genome Atlas.
aMay also apply to clear cell carcinomas.
bThis algorithm does not distinguish between histotypes of TP53-mutated copy-number-high tumors (ie, high-grade endometrioid carcinoma, serous carcinoma, and clear cell carcinoma).
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 2; 10.6004/jnccn.2017.7066
Recently Recognized Types and Variants of Endometrial Carcinoma
There are several recently described phenotypic variants of endometrial carcinoma, which may be associated with specific clinical phenotypes and genotype. A few examples are briefly presented.
Undifferentiated and Dedifferentiated Carcinoma: Undifferentiated and dedifferentiated endometrial carcinomas are uncommon, highly aggressive tumors.38,58 Undifferentiated carcinoma is a monomorphic tumor composed of small- to intermediate-sized cells arranged in sheets without any obvious epithelial differentiation, which mimics lymphoma, plasmacytoma, high-grade endometrial stromal sarcoma, or small cell carcinoma.38,58 Approximately 40% of undifferentiated carcinomas are associated with a component of low-grade endometrioid adenocarcinoma; these cases are termed dedifferentiated carcinomas.37
Most undifferentiated carcinomas display immunohistochemical evidence of epithelial differentiation in the form of intense but focal epithelial membrane antigen and cytokeratin 18 expression, along with vimentin and CD138 expression.59,60 Loss of expression of proteins involved in chromatin remodeling through SWI/SNF (SWItch/Sucrose Non-Fermentable) complexes, such as BRG-1 (the protein product of SMARCA4), INI-1 (protein product of SMARCB1), or BAF250a (protein product of ARID1A), may be seen.61,62 DNA MMR deficiency and loss of expression of MLH1 and PMS2, mostly due to hMLH1 promoter methylation, is seen in 50% to 60% of tumors.63 Genomically, these tumors harbor mutations in POLE, SMARCA4, ARID1B, CTNNB1, PPP2R1A, or TP53.64
Corded and Hyalinized Endometrioid Carcinomas: A subset of endometrioid adenocarcinomas (termed corded and hyalinized endometrioid carcinomas [CHECs]) show unusual morphologic features, including cords of epithelioid cells, spindle cells, and a hyalinized stroma that sometimes form osteoid.65 These tumors present mainly at a low stage and have a good prognosis. Identifying these tumors and distinguishing them from endometrial carcinosarcomas, which are usually seen in older patients and are highly aggressive malignancies, is important.41 Awareness of CHEC allows for the ready morphologic distinction from carcinosarcoma, because the spindle cell component of CHEC lacks conspicuous atypia, in contrast to the high-grade appearance of the sarcomatous component of carcinosarcomas.
Mesonephric-Like Carcinomas: Mesonephric carcinomas have long been recognized in the uterine cervix. Recent studies have identified tumors involving the uterine corpus that show morphologic and immunohistochemical similarities to the cervical tumors. These uterine tumors are termed mesonephric-like carcinomas,66,67 and display a uniform appearance, with tubular, solid and papillary architectural patterns, and are composed of cells with atypical, angulated and overlapping, vesicular nuclei. The tubular structures are small and may contain dense luminal eosinophilic material.66,67 Immunohistochemically, the tumors express thyroid transcription factor 1 (TTF-1), as well as CD10, calretinin, and GATA-binding protein 3 (GATA3), whereas estrogen (ER) and progesterone receptors are negative.67 Mutations in KRAS, NRAS, and chromatin remodeling genes (ARID1A, ARID1B, SMARCA4) have been reported in mesonephric carcinomas.68
Biomarkers for Classification and Prognostic Assessment
Identification of Molecular-Prognostic Subgroups: MSI-H endometrial carcinomas can be effectively identified by assessing morphologic features (described earlier) and DNA MMR deficiencies in histologic material using immunohistochemistry with antibodies directed against MLH1, PMS2, MSH2, and MSH6.69,70 There is a high level of concordance between the results of immunohistochemistry and PCR-based MSI analysis.71 Immunohistochemical expression of p53 (classified as aberrant if absent or diffusely overexpressed) is associated with a poor prognosis in endometrial cancer72,73 and correlates with TP53 mutation status.74 Identification of a POLE mutation in patients with endometrial cancer (based on morphologic features of the tumor and POLE sequencing) may help these patients avoid overtreatment given their excellent prognosis.34 POLE-mutated and MSI-H tumors are also amenable to immunotherapy (as discussed later).
Simplified diagnostic algorithms for the molecular classification of endometrial cancers into TCGA classes were recently proposed.50,75 The ProMisE algorithm involves immunohistochemistry for DNA MMR proteins, sequencing of MMR-proficient tumors for POLE mutations, and immunohistochemistry for p53 in POLE wild-type tumors. This algorithm accurately classifies endometrial cancers as MMR-deficient (MSI-H), POLE-mutated, TP53 wild-type (copy-number-low), or TP53-aberrant (copy-number-high),75 and has potential as a prognostic and risk stratification assay for clinical use.
High-Grade Endometrial Cancers: The copy-number-high group of endometrial carcinomas identified in the TCGA study includes high-grade endometrioid adenocarcinomas and serous carcinomas. The histopathologic and immunohistochemical features of these tumors may overlap considerably, leading to poor interobserver reproducibility in the histotyping of high-grade endometrial carcinomas.22,30 This poor reproducibility doubtless contributes to variability in the reported prognosis of patients with high-grade endometrioid adenocarcinoma compared with those with serous carcinoma.76–80
However, a recent study of copy-number-high endometrial carcinomas showed significant differences between high-grade endometrioid adenocarcinomas and serous carcinomas with respect to their stage distributions and sites of recurrence.81 If these differences also correlate with other differences in clinical behavior, it is important to attempt to distinguish high-grade endometrioid adenocarcinomas from serous carcinomas using available biomarkers to supplement histopathologic interpretation. No single marker is absolutely diagnostic of either histotype, and therefore a panel of markers, including at least p53 and p16 with either ER or PTEN is recommended. Tumors that are p16-negative/PTEN-negative and/or ARID1A-negative/p16-negative/p53 wild-type are most likely endometrioid, whereas serous carcinomas are more likely to be p53-aberrant/p16-positive/ER-negative.82 Tumors with discordant findings may be subjected to an expanded immunohistochemical panel that includes DNA MMR proteins (MLH1, PMS2, MSH2, MSH6), and loss of expression of at least one of these would support the diagnosis of endometrioid adenocarcinoma.
CTNNB1-Mutated Endometrial Carcinomas: Patients with low-stage endometrial cancer without high-risk features, as described earlier, generally have excellent outcomes; however, a small proportion of these patients do poorly. A recent study exploring factors associated with poor outcomes in women with low-grade, early-stage endometrial carcinomas found that in patients with endometrioid adenocarcinomas, CTNNB1 mutations were found to be independent predictors of poorer recurrence-free survival.83 In this study, 84% of tumors with CTNNB1 mutations showed nuclear expression of beta catenin (the protein product of CTNNB1) by immunohistochemistry.83
Pathology and Precision Medicine in Endometrial Cancer
Pathologists play an important role in the development and implementation of novel therapies targeting molecular/genomic alterations in endometrial cancer. Roles of pathology in the present era of precision oncology include identification of homogenous subsets of tumors, which are critical to obtain meaningful results from exploratory molecular/genomic studies seeking to identify novel targets; evaluation of molecular biomarker expression and their localization at the tissue level, which can assist in treatment decisions; phenotype-genotype correlations that help identify tumors likely to harbor specific molecular targets or likely to be amenable to specific therapy; and selection of suitable patients, based on their phenotypes and biomarker profiles, for entry into clinical trials of novel therapies.
Identification of Candidates for Immunotherapy: POLE-mutated and MMR-deficient tumors exhibit TILs, high levels of neoantigens, and expression of immune checkpoint regulators, such as programmed death receptor-1 (PD-1)84,85 or its ligand, PD-L1,86 which are thought to promote escape from immune surveillance. Immune checkpoint blockade with the anti-PD1 antibody pembrolizumab has shown responses in patients with POLE-mutated85 and MMR-deficient endometrial cancer,87 and pembrolizumab has been FDA-approved for metastatic cancers exhibiting MMR deficiency. PD-L1 expression can be directly examined in tissues using immunohistochemistry, but the optimal methods and antibodies have yet to be standardized.88
Identification of Candidates for MAPK Pathway Inhibition: KRAS mutations are common in endometrial cancer34 and are associated with mucinous differentiation.89 ERBB2 amplifications are also identified in endometrial serous carcinomas.90 KRAS is not a direct molecular therapeutic target, but the identification of tumors with MAPK pathway activation might be susceptible to therapy directed against other components of the MAPK/ERK pathway, such as members of the epidermal growth factor receptor family.
Conclusions
During the past 2 decades, numerous ex vivo, genomic, translational, pathologic, and clinical studies have significantly expanded the understanding of endometrial cancer. This improved understanding has led to refinements in the approach to the diagnosis and treatment of women with these tumors. As an integral part of any multidisciplinary team, pathology continues to play an important role in diagnosis and prognostic assessment, risk stratification and therapeutic decision-making, and the development and implementation of novel therapeutic agents and strategies for women with these cancers.
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