p53 Mutation Predicts Recurrence Even in Non-Invasive High-Grade Endometrial Cancer

Endometrial cancer is the most common gynecologic malignancy in developed countries and the second most common worldwide, yet its most confusing corner may be the group of tumors that never invade the muscle of the uterus. Under the FIGO 2023 staging system, all high-grade endometrial cancers without myometrial invasion are lumped together as stage IC, regardless of whether they are grade 3 endometrioid, serous, clear cell, carcinosarcoma, mixed, or undifferentiated tumors. That simplification has created a clinical dilemma: some of these tumors behave indolently, while others relapse aggressively at sites far beyond the pelvis. A new retrospective study from the Brazilian National Cancer Institute (INCA) in Rio de Janeiro suggests that a single molecular feature, the status of the tumor-suppressor protein p53, may be the key to telling these patients apart.

The research, published in Pathology and Oncology Research, followed 59 patients treated between 2010 and 2025, all of whom had high-grade histologies confined to the endometrium or to an endometrial polyp, with no invasion of the myometrium. The investigators performed immunohistochemical analysis of p53 expression on paraffin-embedded surgical specimens and correlated the results with recurrence patterns and survival. Their central finding is striking: among the 56 patients with FIGO stage IC disease, every single recurrence occurred in the subgroup with abnormal p53 expression, while not one patient with wild-type p53 experienced progression during follow-up.

The biology behind this observation traces back to The Cancer Genome Atlas, which used next-generation sequencing to divide endometrial carcinoma into four molecular subtypes: POLE ultra-mutated tumors with a favorable prognosis, microsatellite-instable hypermutated tumors, copy-number-low tumors, and copy-number-high tumors characterized by TP53 mutation and widespread somatic copy-number alterations. The copy-number-high class carries a poor outcome regardless of histologic type or grade. A pragmatic Canadian approach later showed that the same subgroups could be reproduced using immunohistochemistry for p53 and mismatch repair proteins plus POLE sequencing, making molecular classification feasible in routine pathology laboratories around the world.

In the INCA cohort, abnormal p53 expression was far from rare. Forty-six of the 59 patients, or 78 percent, had p53-abnormal tumors, defined by strong diffuse nuclear staining in 80 to 100 percent of tumor cells, complete absence of staining despite a positive internal control, or abnormal cytoplasmic staining. Only 13 patients, 22 percent, showed wild-type patterns. The patients had a mean age of 65 years, and histology split evenly between endometrioid grade 3 and serous carcinoma at 39 percent each, with smaller numbers of clear cell, carcinosarcoma, and mixed tumors. Notably, the study could not perform full molecular classification beyond p53 because of financial constraints, a limitation the authors acknowledge openly.

Surgical management varied considerably, reflecting the uncertainty that surrounds this disease stage. A majority of patients, 59.3 percent, underwent total hysterectomy with or without bilateral salpingo-oophorectomy, while 40.7 percent also received lymphadenectomy with or without omentectomy. Adjuvant therapy was applied inconsistently: only 11.9 percent of patients received chemotherapy, and 25.4 percent received external beam radiotherapy or brachytherapy. Treatment patterns were similar across the p53-abnormal and wild-type groups, meaning that differences in outcome cannot be easily explained by more aggressive treatment of one subgroup. Despite the absence of myometrial invasion in the uterine specimen, three patients already had disease outside the uterus at presentation, a detail that underscores how deceptive these tumors can be.

The recurrence data carry the study’s main message. Among the 56 patients with FIGO stage IC disease, recurrence occurred in 16.1 percent, and the relapses were predominantly extra-pelvic: 33.3 percent were abdominal and 22.2 percent were at distant sites such as lung, liver, bone, or non-pelvic lymph nodes. The estimated five-year recurrence rate was 23.2 percent for p53-abnormal tumors compared with zero percent for wild-type tumors. At last follow-up, seven patients, or 12.5 percent of the stage IC cohort, had died, six of them with p53-abnormal disease. Kaplan-Meier curves showed differences in recurrence-free and overall survival according to p53 status, although the comparisons did not reach statistical significance, likely reflecting the small sample size and short numbers of events.

These findings align with and extend a growing international literature. A retrospective analysis of 40 patients with non-invasive uterine serous carcinoma found extrauterine disease in 45 percent of cases and concluded that surgical staging is an essential step in management. A Turkish study of 33 similar patients reported that 39 percent already had spread outside the uterus, especially to the omentum and adnexa, and that adjuvant treatment conferred no benefit. In contrast, a Dutch observational cohort of pure serous endometrial intraepithelial carcinoma reported no recurrences or disease-related deaths, suggesting that lesions strictly confined to the endometrium may behave more indolently than the traditional WHO classification implies. The picture that emerges is genuinely contradictory, which is precisely why molecular markers matter.

The most influential recent evidence comes from a large multicenter study by Jamieson and colleagues, which showed that the prognostic impact of stage IA p53-abnormal endometrial cancer is driven by p53 status rather than histotype alone. In that cohort, p53-abnormal tumors without myometrial invasion recurred at a rate of 16 percent, mostly at distant sites, and patients with residual endometrial disease fared worse than those with tumors confined to a polyp. Adjuvant chemotherapy, with or without radiation, appeared to reduce recurrence risk, whereas brachytherapy alone offered little protection against distant relapse. The INCA results mirror this pattern: all nine recurrences fell within the p53-abnormal subgroup, most relapses escaped the pelvis, and the wild-type patients enjoyed an essentially perfect record.

The clinical implications are potentially practice-changing, but they come with important caveats. If wild-type p53 tumors confined to the endometrium truly almost never recur, then intensifying surgery or radiation for these patients may constitute overtreatment that can be safely avoided. Conversely, the roughly one-in-four five-year recurrence risk in p53-abnormal tumors suggests that this subgroup, even without myometrial invasion, may warrant comprehensive surgical staging and consideration of systemic therapy, particularly chemotherapy. The authors argue that their results support individualized treatment approaches built on molecular stratification rather than histology or depth of invasion alone, and they call for larger, prospective validation studies before definitive treatment recommendations can be made.

As a retrospective, single-institution analysis, the study has real limitations: potential selection bias, a small number of patients, heterogeneous surgical staging, non-standardized adjuvant therapy over fifteen years, and the absence of uniform molecular testing beyond p53. Yet the signal is coherent with independent data from multiple countries, and it arrives at a moment when the FIGO 2023 staging system has created an urgent need to subdivide stage IC into biologically meaningful groups. For now, the message for clinicians is that a simple, widely available immunohistochemical stain may separate the rare non-invasive high-grade endometrial cancer destined to relapse from the patient who can be reassured after surgery. For researchers, the message is that the next generation of trials in early endometrial cancer should be designed around molecules, not microscopes.

Subject of Research: Impact of p53 molecular status on recurrence patterns and outcomes in non-invasive high-grade endometrial cancer

Article Title: Impact of p53 status on recurrence patterns and oncologic outcomes in non-invasive high-grade endometrial cancer

Article References: Paulino, E., Branco, T., Gomes de Mesquita, G., & Cristina de Melo, A. (2026). Impact of p53 status on recurrence patterns and oncologic outcomes in non-invasive high-grade endometrial cancer. Pathology & Oncology Research, 32, Article 1612543. https://doi.org/10.3389/pore.2026.1612543

Image Credits: AI Generated

DOI: 10.3389/pore.2026.1612543

Keywords: endometrial cancer, p53, FIGO 2023 staging, molecular classification, immunohistochemistry, recurrence, uterine serous carcinoma, TP53 mutation, gynecologic oncology, adjuvant therapy, surgical staging, prognosis