{"paper_id":"fc016b13-2b1b-4802-ad94-c83a5202501b","body_text":"Medical Studies/Studia Medyczne 2023; 39/3\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0). \nLicense (http://creativecommons.org/licenses/by-nc-sa/4.0/)\nReview paper\nA new approach to endometrial cancer subtyping – a hope for \na milestone in correct patient triaging\nNowe podejście do subtypowania raka endometrium – nadzieja na kamień milowy \nw prawidłowej segregacji pacjentów\nOlga Adamczyk-Gruszka1,2 \n1Department of Gynaecology and Obstetrics, Collegium Medicum, Jan Kochanowski University, Kielce, Poland \n2Department of Gynaecology and Obstetrics, Provincial Integrated Hospital, Kielce, Poland\nMedical Studies/Studia Medyczne 2032; 39 (3): 267–271\nDOI: https://doi.org/10.5114/ms.2023.130882\nKey words: genomics, pathology, oncology, endometrial cancer, stage.\nSłowa kluczowe: genomika, patologia, onkologia, rak endometrium, stadium zaawansowania \nAbstract\nEndometrial cancer is the most common cancer of the female genital organs. For many years the prognosis was based on \nhistopathological grade and type. The pathological identification of endometrial carcinomas included two types. Type I – \nendometrioid (EEC), similar to the endometrium – was characterized by genetic predisposition, obesity, polycystic ovary \nsyndrome, anovulatory cycles, and irregular menstruation resulting from hyperestrogenism, which is the main predispos -\ning factor for the development of type I EC. Type II included serous, clear cell, and undifferentiated carcinomas. Here were \nobserved older patient’s age, higher clinical stage to compare with non-endometrioid histology, and finally poorer progno -\nsis. The Cancer Genome Atlas (TCGA) study found mutations in several endometrioid and serous cancer genes. The TCGA \nhas identified four molecular subclasses based on somatic mutation burden and copy number variations. Recent data show \nthe prognostic value of TCGA subclasses because they correlate with patient survival.\nStreszczenie \nRak endometrium jest najczęściej występującym nowotworem żeńskich narządów płciowych. Przez wiele lat podstawą \nrokowania był stopień dojrzałości histologicznej i typ histopatologiczny. Patologiczna identyfikacja raków endometrium \nobejmowała jego dwa typy. Typ I – endometrioidalny (EEC), podobny do endometrium, charakteryzuje się predyspozycja -\nmi genetycznymi, otyłością, zespołem policystycznych jajników, cyklami bezowulacyjnymi, nieregularnymi miesiączkami \nwynikającymi z hiperestrogenizmu, który jest głównym czynnikiem predysponującym do rozwoju EC typu I. Do typu II \nzaliczono: raki surowicze, jasnokomórkowe i niezróżnicowane. Zaobserwowano tu starszy wiek pacjentek, wyższy stopień \nzaawansowania klinicznego w  porównaniu z  histologią nieendometrioidalną, a  także gorsze rokowanie. Badanie Cancer \nGenome Atlas (TCGA) wykazało mutacje w kilku genach raka endometrioidalnego i surowiczego. TCGA zidentyfikowała \ncztery podklasy molekularne na podstawie obciążenia mutacjami somatycznymi i zmienności liczby kopii. Najnowsze dane \nwskazują na wartość prognostyczną TCGA, ponieważ korelują one z przeżyciem pacjentów.\nIntroduction\nEndometrial cancer accounts for close to half of all \ngynecological malignancies. Pathological examina -\ntion is a  part of  diagnostics which may be the  basis \nfor the  further decision-making process and man -\nagement. Over the  years, the  method of  treatment \nchanged with the introduction of molecular genetics \ninto diagnostics, in addition to clinical and pathologi -\ncal tests. Numerous authors maintain that the impor -\ntance of pathology in diagnosis, predicting outcomes \nand treatment is likely to persist [1, 2]. The FIGO clas -\nsification created between 1961 and 1971 included \nthe clinical basis for the first time. Since 1988, the clas -\nsification has included the surgical-pathological data \nwith tumor grade. The  histological grading system \nbased only on the  proportion of  solid and glandu -\nlar areas is still recommended and used. To improve \nprognostic evaluation the  sentinel node (SLN) map -\nping method has been included in the  National \nComprehensive Cancer Network (NCCN) guidelines \nsince 2014. The  aim was to improve the  identifica -\ntion of lymph node metastases, which are extremely \nuseful in cancer diagnosis, in particular the sentinel \nnodes or initial nodes of the lymphatic pathways dis -\ntal to the tumor. This, in turn, could potentially mini -\nmize the extent of surgery and associated side effects \nfrom extended lymphadenectomy [1, 3].\n\nOlga Adamczyk-Gruszka268\nMedical Studies/Studia Medyczne 2023; 39/3\nHistotyping is simple for most endometrial can -\ncers. For high-grade tumors with morphological \nambiguity, several systems exist based on surgical-\npathological staging. Therefore, incorporating molec -\nular genetics analysis into pathology studies becomes \ncrucial in evaluating the best treatment options. This \napproach facilitates a more precise and prognostically \nsignificant categorization of these cancers [1, 4].\nClinical staging and histotyping in curettage or \npreoperative biopsy samples may vary with post-sur -\ngical specimen examination. An initial curettage di -\nagnosis of endometrioid G1 adenocarcinoma could be \ncorrected to a higher grade of G2 or G3 in the postsur -\ngical specimen. In such cases, there is a risk of under -\nestimation due to non-detection of high-risk tumors. \nTherefore, additional support by the use of molecular \ngenetics and pathological-genetic classification of en -\ndometrial cancer has become important [5].\nThe TCGA classification\nThe  Cancer Genome Atlas (TCGA) study found \nmutations in several endometrioid and serous can -\ncers, e.g., TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, \nCTNNB1, KRAS, and POLE. The  asset of  this study \nwas to create a simple, cheap and available classifica -\ntion helping with correct triaging [6].\nThey identified four molecular subclasses based on \nsomatic mutation burden and copy amount changes \n[7]. The first group includes ultra-mutant endometrial \ncancer with mutations in the DNA exonuclease epsi -\nlon polymerase (POLE) domain. The second group is \nhypermutated endometrial carcinoma with microsat -\nellite instability. The third group presents high-copy \nendometrial cancer with frequent TP53 mutation, and \nfinally the  fourth group comprises low- and high-\ncopy endometrial tumors. The  differences between \nthese groups reached prognostic value and made it \npossible to explain different outcomes of patients with \nsimilar histopathological tumors [8]. \nEndometrial cancers, termed “ultramutated”, are \ndistinguished by pathogenic variants in the  POLE \nexonuclease domain. These mutations in POLE cause \nmisreading during DNA replication, which then leads \nto a high mutation burden in the endometrium. Ap -\nproximately 8–10% of  all endometrial cancers have \none of these POLE mutations. In endometrial cancer \nmolecular classification systems, such cases are re -\nferred to as “POLE mutations”. They usually occur \nin relatively young women with early-stage but high-\ngrade tumors with lymphovascular invasion. Despite \nthe high degree of malignancy, POLE mutated tumors \nare associated with a favorable prognosis and low re -\ncurrence rate, regardless of the adjuvant treatment. It \nis hypothesized that cancer neopeptides caused by an \nultramutation may induce a strong cytotoxic immune \nresponse. In addition, the ultramutation state may im -\npair the function of POLE mutated tumor cells, lead -\ning to a decrease in metastatic potential [9, 10].\nThe  microsatellite unstable group is more com -\nmonly referred to as the  ‘mismatch repair deficient \ngroup’. It comprises approximately 25–30% of all en -\ndometrial cancers and is defined as the loss of nuclear \nexpression targeted oncoprotein in immunohisto -\nchemistry. Moreover, loss of one or more mismatch re-\npair proteins leads to the accumulation of mismatch -\nes, insertions, and deletions. Frequently, it is caused \nby epigenetically driven dysfunction such as hyper -\nmethylation of  the  MLH1 promoter. In a  small per -\ncentage of cases, it is caused by a germline mutation \nin one of the mismatch repair genes known as Lynch \nsyndrome. This type of cancer also elicits a strong im -\nmunogenic response and has an intermediate prog -\nnosis [11].\nThe third molecular subgroup consists of tumors \nwith a high number of somatic copy number changes \nand a relatively low percentage of somatic mutations. \nHowever, mutations in TP53 are regularly observed, \nreaching an incidence of up to 90%. This category in -\ncludes high-grade tumors that generally have a poor \nprognosis due to their aggressive growth patterns and \nearly propagation. This molecular subgroup is domi -\nnated by non-endometrioid histology, most com -\nmonly serous adenocarcinoma and about 50% of clear \ncell carcinomas. Here also are included endometrioid \ncancers with TP53 mutation, which occur in approxi -\nmately 61% of cases. \nThe fourth and the largest subgroup of low copy \nnumber endometrial cancers, defined as ‘endometrial \ncancers without a defined molecular profile,’ is char -\nacterized by a low mutation burden and low somatic \ncopy number variation. The prognosis of these tumors \ndepends on the stage, but it can be considered as inter-\nmediate risk. This group usually includes tumors with \nendometrioid features and expression of estrogen and \nprogesterone receptors. The molecular heterogeneity \nin this group suggests that further refinement in this \ngroup is possible [8, 12, 13].\nThere may be a  worse prognosis in the  presence \nof mutations in exon 3 β-catenin (CTNNB1). They have \nbeen identified in 30–50% of endometrial cancers in \nthis subgroup, and the  prognosis is relatively poor \ncompared to endometrial cancers without a  specific \nmolecular profile without the CTNNB1 mutation [14]. \nMost endometrial cancers can be precisely classi -\nfied into one of four molecular subgroups using sur -\nrogate markers. 3–6% may fall into more than one \nclassification group, e.g. both abnormal p53 staining \nand a pathogenic POLE mutation, and are referred to \nas ‘multiple classification endometrial carcinomas’. \nRecent reports indicate that TP53 mutations may oc -\ncur as a secondary event to the deficiency of ‘mutator’ \nmismatch repair and endometrial carcinoma POLE \nmutated, without affecting the  outcome. Evidence \n\n269A new approach to endometrial cancer subtyping – a hope for a milestone in correct patient triaging\nMedical Studies/Studia Medyczne 2023; 39/3\nsupports the classification of endometrial cancer with \na pathogenic variant of POLE in the exonuclease do -\nmain as POLE endometrial carcinoma, regardless \nof the co-occurrence of a mismatch repair deficiency \nor abnormal mutant-like p53 immunostaining [12, 13].\nRisk factors of endometrial cancer\nIn addition to the TCGA molecular groups, several \nother clinicopathological and molecular risk factors \nhave prognostic significance. These include signifi -\ncant (diffuse or multifocal) lymphovascular infiltra -\ntion, overexpression of  L1 cell adhesion molecules, \nCTNNB1 and 1q32 mutations. L1 cell adhesion mole -\ncule is a membrane glycoprotein playing an important \nrole in tumor cell adhesion and migration, strongly \nassociated with TP53 mutation, non-endometrioid \nhistology, high tumor grade, and lymphovascular \nspace involvement. It is an independent risk factor for \nloco-regional and distant spread. CTNNB1 mutations \nstimulate the  growth of  endometrial tissues, which \nis associated with a higher risk of recurrence and re -\nduced recurrence-free survival [15]. 1q32.1 amplifica -\ntion is associated with a significantly worse prognosis \nin the subgroup without a specific molecular profile. \nOur own experience additionally showed the impact \nof FGFR-2 and also epithelial-mesenchymal transition \non outcome. \nThe  ongoing randomized PORTEC-4a study is \nthe  first clinical trial to prospectively investigate \nthe use of an integrated clinicopathological and mo -\nlecular risk profile for the choice of adjuvant therapy. \nIn the  study, four molecular subgroups were com -\nbined with other prognostic factors (significant lym -\nphovascular space involvement, expression of  L1 \ncell adhesion molecules and CTNNB1 mutation) to \ndetermine a favorable, intermediate and unfavorable \nprofile. The PORTEC-4a study is expected to provide \nimportant evidence for risk-based treatment selection \nin patients with high intermediate risk endometrial \ncancer.\nA study of endometrial clear cell carcinomas iden -\ntified similar genomic classes that were also associated \nwith similar prognosis. Uterine cancer sarcomas also \noften contain mutations in the TP53, PTEN, PIK3CA, \nPPP2R1A, FBXW7, and KRAS genes, similar to endo -\nmetrioid and serous carcinomas [16].\nThe  molecular classification of  endometrial can -\ncer is repeatable and has limitations related to clinical \noutcomes. \nThe correlation between p53 immunohistochem -\nistry and TP53 copy number changes is not flawless. \nAs a result, the use of this method in these algorithms \nmay lead to misclassification of some high copy num -\nber tumors. The algorithms also fail to provide guid -\nance on how to classify tumors with more than one \ngenomic aberration, such as POLE mutations, MMR \ndeficiency, or TP53 mutations, when the components \nof the algorithm are processed simultaneously rather \nthan sequentially. For example, the  ProMisE algo -\nrithm performs MMR DNA immunohistochemistry \nprior to POLE sequencing, which may miss MMR-de -\nficient tumors with POLE mutations and lead to incor-\nrect categorization as MMR-deficient tumors instead \nof  POLE mutations. However, despite these limita -\ntions, an integrated approach to genomic-pathologi -\ncal classification, combining genome-based classifica -\ntions with traditional clinicopathological prognostic \nfactors, remains the most effective method currently \navailable to segregate patients into prognostically dif -\nferent categories that could benefit from personalized \ntreatment options [1, 17, 18].\nUndifferentiated endometrial carcinomas, which \nare rare and highly aggressive neoplasms composed \nof small to medium-sized cells without noticeable epi -\nthelial differentiation, may resemble lymphoma, plas-\nmacytoma, high-grade stromal endometrial sarcoma, \nor small cell carcinoma. About 40% of  these undif -\nferentiated carcinomas are associated with the  low-\ngrade endometrioid adenocarcinoma component. At \nthe  genomic level, these tumors carry mutations in \ngenes such as POLE, SMARCA4, ARID1B, CTNNB1, \nPPP2R1A or TP53. A  unique subset of  endometrioid \nadenocarcinomas, termed “hyalinized-conducted \nendometrioid carcinomas” (CHECs), exhibit distinct \nmorphological features such as strings of  epithelial \ncells, spindle-shaped cells, and a stroma that is hyalin -\nized and sometimes forms an osteoid. These tumors \nare characterized by low malignancy and generally \nfavorable prognosis. Distinguishing them from endo -\nmetrial carcinomas is essential because the latter tend \nto occur in older patients and are aggressive malig -\nnancies [1, 19].\nMSI-H endometrial carcinomas can be identified \nby assessing morphological features, DNA mismatch \nrepair deficiencies in histology by immunohisto -\nchemistry using antibodies directed against MLH1, \nPMS2, MSH2 and MSH6. There is a  strong agree -\nment between the  results of  immunohistochemistry \nand PCR-based analysis of  microsatellite instability. \np53 expression is associated with poor prognosis in \nendometrial cancer. It correlates with the TP53 muta -\ntion status. Identification of POLE mutations in endo -\nmetrial cancer patients based on tumor morphology \nand POLE sequencing may help these patients avoid \nunnecessary treatment given their excellent progno -\nsis. POLE and MSI-H mutation tumors potentially re -\nspond well to immunotherapy [1, 20].\nFor any of  the  endometrial cancer histotypes, \na single marker cannot be a diagnostic tool; therefore \nit is recommended to use a set of markers containing \nat least p53 and p16 with ER or PTEN. p16-negative/\nPTEN-negative and/or ARID1A-negative/p16-nega -\ntive/p53-wild-type tumors are most likely endometri -\noid tumors, while serous carcinomas are more likely \n\nOlga Adamczyk-Gruszka270\nMedical Studies/Studia Medyczne 2023; 39/3\nto be abnormal p53/p16-positive/ER-negative. In an \nextended immunohistochemistry panel including \nDNA mismatch repair proteins (MLH1, PMS2, MSH2, \nMSH6), the loss of expression of at least one of them \nsupports the  diagnosis of  endometrioid adenocarci -\nnoma [1, 21, 22].\nExcellent results are characteristic of  patients \nwith endometrial cancer without high-risk features \nand with low-grade malignancy. CTNNB1 mutations \nturned out to be independent predictors of  worse \nrecurrence-free survival in groups of  patients with \nendometrial adenocarcinoma. Tumors with CTNNB1 \nmutations expressed nuclear beta-catenin (a  protein \nproduct of CTNNB1) [1, 23].\nThe role of pathology\nThe  role of  pathologists in the  development and \nimplementation of  new therapies is extremely im -\nportant. In the age of modern oncology, their role in -\ncludes: identifying homogeneous subsets of  cancers \nthat are necessary to obtain meaningful results from \nmolecular/genomic studies aimed at identifying new \ntargets. Evaluation of the expression of molecular bio -\nmarkers and their localization at the tissue level can \nhelp in making therapeutic decisions. The correlation \nbetween phenotype and genotype helps identify tu -\nmors with specific molecular targets and amenable \nto specific therapy. Appropriate patients are selected, \nbased on their phenotypes and biomarker profiles, for \nparticipation in clinical trials on new therapies [1, 24].\nPatients with the POLE gene mutation have been \nshown to have a good prognosis and do not require \nadjuvant treatment. Immunotherapy may apply to \na very small percentage of patients with advanced or \nrecurrent disease, and additionally with microsatellite \ninstability and dMMR [25]. Mutated and mismatched \nrepair-deficient tumors exhibit tumor-infiltrating \nlymphocytes, high levels of  neoantigens, expression \nof immune checkpoint regulators such as programmed \ndeath receptor 1 (PD-1) or its ligand PDL-1, which \npromote escape from immune surveillance. Immune \ncheckpoint blockade with pembrolizumab, an anti-\nPD1 antibody, has shown a response in patients with \nendometrial cancer with a POLE mutation and endo -\nmetrial cancer unable to repair the mismatch. PDL-1 \nexpression can be directly tested in tissues by immu -\nnohistochemistry, but optimal methods and antibodies \nhave not yet been standardized [26, 27].\nKRAS mutations are common in endometrial can -\ncer and are associated with mucus differentiation. \nERBB2 amplifications are also identified in serous en -\ndometrial carcinomas. KRAS is not a direct molecular \ntherapeutic target, but the  identification of  tumors \nwith activation of  the  MAPK pathway may be ame -\nnable to therapy directed against other components \nof  the  MAPK/ERK pathway, such as EGFR family \nmembers [2, 8].\nConclusions\nNumerous ex vivo, genomic, translational, patho -\nlogical, and clinical studies have been conducted over \nthe past years that have greatly advanced the knowl -\nedge of  endometrial cancer. This has led to refined \napproaches to diagnosing and treating women with \nthese cancers. As an integral part of  any multidisci -\nplinary team, pathology continues to play an impor -\ntant role in diagnosis and prognostic assessment, risk \nstratification and therapeutic decision making, and \nthe  development and implementation of  new thera -\npeutic agents and strategies for women with these \ncancers. 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Daniilidis A, Margioula-Siarkou C, Margioula-Siarkou G, \nPapandreou P , Papanikolaou A, Dinas K, Petousis S. Sen-\ntinel lymph node mapping in endometrial cancer to re-\nduce surgical morbidity: always, sometimes, or never. \nMenopause Rev 2022; 21: 207-213. \n29. Bulsa M, Jankowska-Szabłowska S, Urasińska E. Immu-\nnohistochemical expression of PARP-1 in triple-negative \nendometrial cancer – a comparison of different score sys-\ntems. Pol J Pathol 2022; 73: 330-337. \nAddress for correspondence\nOlga Adamczyk-Gruszka \nDepartment of Gynaecology and Obstetrics\nCollegium Medicum\nJan Kochanowski University\nDepartment of Gynaecology and Obstetrics\nProvincial Integrated Hospital\nKielce, Poland\nPhone: +48 605233038\nE-mail: oadamczyk@ujk.edu.pl","source_license":"CC0","license_restricted":false}