The field of oncology is in a state of constant and dynamic evolution, where traditional, morphology-based approaches are increasingly giving way to precise and personalized medicine. It was this fundamental medical transformation that took center stage at GIMPHA 2026, the conference organized by the Georgian International Medical and Public Health Association, which drew significant attention from the medical community. During a session dedicated to current controversies and topical issues in oncology, a presentation by Ketevan Kankava, Pathologist and Head of the Immunohistochemistry and Molecular Pathology Unit at the medical laboratory Megalab, generated particular interest. Her presentation, entitled «Endometrial Cancer: Universal Molecular Classification vs Traditional Histopathology,» clearly demonstrated the revolutionary breakthrough underway in the management of this specific disease. The report highlighted the fact that evaluating the microscopic image alone is no longer sufficient to select an optimal and safe therapeutic strategy for patients.
For decades, the classical approach to endometrial carcinoma relied on criteria such as histopathological type, degree of differentiation (grade), stage of the disease, and lymphovascular space invasion (LVSI). Traditionally, endometrial adenocarcinoma is divided into several main morphological types, among which endometrioid carcinoma is the most common. This is followed by more aggressively behaving serous, clear cell, undifferentiated, dedifferentiated, and mixed carcinomas, as well as carcinosarcoma, which is always characterized by a high grade of malignancy. However, as clinical practice and numerous studies have shown, this classical morphological approach possesses serious limitations, frequently resulting in clinical errors and suboptimal patient management.
One of the primary problems is poor reproducibility and high interobserver variability among pathologists when assessing the tumor type, histologic grade, or the presence of lymphovascular space invasion within the same biopsy material. Furthermore, there is a frequent biologic mismatch, where morphologically identical tumors exhibit radically different clinical courses and outcomes in different patients. Clinicians also frequently encounter discordance between the biopsy material and the subsequent full histological evaluation of the surgically removed uterus, which complicates proper treatment planning at the initial stage.
In classical morphology, one of the most controversial and problematic issues is the assessment of lymphovascular space invasion, which refers to the presence of tumor cells within endothelium-lined vascular or lymphatic spaces. This factor exerts a major impact on the prognosis of practically all histological types, yet the criteria for its quantitative assessment remain inconsistent across leading organizations today. For instance, the European Society of Gynaecological Oncology (ESGO) considers four or more foci to indicate extensive invasion, the World Health Organization (WHO) sets this threshold at five or more foci, while the International Journal of Gynecological Pathology (IJGP) recommends that even three foci are sufficient to confirm substantial involvement. Such methodological discrepancies further exacerbate the uncertainty present in clinical practice.
In response to these challenges, a true breakthrough in medicine was achieved by a large-scale study published in the journal Nature in 2013, which laid the foundation for The Cancer Genome Atlas (TCGA) project. This genomic analysis divided endometrial cancer into four entirely distinct molecular clusters. The first three clusters predominantly comprise endometrioid carcinomas, a portion of which is characterized by a low frequency of somatic copy-number alterations, while the fourth cluster unites serous and mixed tumors characterized by prominent somatic copy-number alterations, p53 mutations, and amplification of genes such as MYC, HER2, CCNE1, FGFR3, and SOX17.
Today, this approach is officially integrated into the standards of the International Collaboration on Cancer Reporting (ICCR). The contemporary universal molecular classification divides tumors into four prognostic groups, identified through a combination of specific molecular and immunohistochemical markers. The first group is represented by tumors with pathogenic mutations in the exonuclease domain of polymerase epsilon (POLE). This enzyme is responsible for proofreading during DNA replication, and its defect leads to an ultramutated phenotype. Although these tumors often exhibit a high histological grade and marked atypia, they carry an excellent clinical prognosis, providing a unique opportunity for therapy de-escalation.
The second molecular group includes tumors with a mismatch repair deficiency (MMRd) system, which manifests as microsatellite instability (MSI). This defect can be hereditary, such as in Lynch syndrome, which accounts for approximately ten percent of cases, or acquired as a result of somatic mutations or epigenetic changes. Statistically, MLH1 gene promoter methylation is the most common finding in this group for endometrial cancer, detected in about seventy-two percent of cases, while somatic mutations in MSH2 and MSH6 genes are found in the remaining cases. Tumors in this group are characterized by an intermediate prognosis and high sensitivity to modern immunotherapy.
The third and most unfavorable group consists of carcinomas with abnormal p53 expression or TP53 gene mutations (p53abn). These tumors are distinguished by an extremely aggressive clinical course, early metastasis, and a high level of resistance to chemotherapy, demanding the most aggressive clinical intervention possible, including a combination of radiotherapy and chemotherapy. The fourth group comprises tumors with no specific molecular profile (NSMP), which exhibit normal, wild-type p53 protein expression and occupy an intermediate position regarding clinical outcomes.
In her presentation, Ketevan Kankava discussed in detail the numerous controversies and dilemmas that accompany the practical implementation of this molecular classification. First and foremost, there is serious concern within the medical community regarding potential tactical treatment errors. Specifically, there is a risk of overtreatment if abnormal p53 status is overemphasized, and conversely, a risk of undertreatment if therapy is de-escalated solely based on the presence of a POLE mutation before mature data from ongoing large-scale prospective clinical trials, such as PORTEC-4a, become fully available.
Another major challenge is presented by tumors with so-called double or multiple classifiers, which are very rare and occur in only about three and a half percent of cases. In these unusual combinations, abnormalities of several markers are recorded simultaneously within the tumor cells, such as a mismatch repair deficiency combined with a p53 mutation, a POLE mutation in combination with a p53 alteration, or the simultaneous presence of all three marker pathologies. Studies have shown that the prognosis in such situations is significantly better than in cases of isolated p53 mutation, as the POLE mutation retains a dominant role; however, the optimal treatment regimen for these groups is still being refined.
Special attention was dedicated to the review of rare and atypical histological variants, where molecular groups frequently completely redefine the perception of tumor aggressiveness. For example, endometrial giant cell carcinoma and pilomatrix-like high-grade endometrioid carcinoma belong to the NSMP group and are often characterized by an aggressive course. Conversely, corded and hyalinized endometrioid carcinoma, which also falls into the same group, is characterized by a fairly favorable clinical outcome. Rare tumors within the p53-abnormal group, such as endometrial carcinoma with histiocyte-like tumor cells, the variant with melanocytic differentiation, and AFP-producing endometrial carcinoma, exhibit an extremely aggressive nature, though predicting their exact biological behavior is impossible without molecular classification.
At the conclusion of the presentation, the speaker raised the critical issue of equity and access to medical services. Identifying POLE mutations requires high-tech and expensive next-generation genetic sequencing, which creates a significant disparity since only well-resourced and highly developed medical centers can benefit from these innovations. There is also notable tension between international guidelines, where some actively support molecular approaches, while certain recommendations still mandate the maintenance of standard, traditional treatments. This presentation delivered at GIMPHA 2026 reconfirmed that leading centers in Georgia, such as Megalab, possess the ambition and the actual technological capability to keep pace with the contemporary standards of world medicine and offer patients the latest personalized diagnostics based at the molecular level.
