Abnormal p53 expression is associated with poor outcomes in grade I or II, stage I, endometrioid carcinoma: a retrospective single-institute study

Endometrial cancer (EC) is the most common type of gynecological cancer. In 2020, approximately 417,000 new cases of EC were identified worldwide [1, 2]. The most common type of EC is endometrioid carcinoma (EEC), which constitutes approximately 80% of cases of EC. EEC is often diagnosed in perimenopausal women and has a better prognosis [3]. Surgical pathological examination is the primary method for staging EC, and surgery is the primary method for treating EC. Due to noticeable clinical symptoms, EC is usually identified at an early stage, resulting in a 5-year survival rate of more than 90% for stage I EC [4].

Adjuvant therapy after surgical treatment of stage I EEC depends on various patient factors, such as age, tumor grade, myometrium invasion, and lymphovascular space invasion [5, 6]. These clinicopathologic factors may also influence the choice of adjuvant therapy [7]. Traditional pathological immunohistochemical (IHC) stain have been used to identify genetic alterations in EC, but the Cancer Genome Atlas has also been employed for this purpose and has provided insights into a new framework for subclassifying EC on the basis of four molecular subtypes: ultramutated (POLE-mutant), hypermutated (mismatch repair deficient [MMRd]), copy-number low (no specific molecular profile), and copy-number high (p53-abnormal) [8, 9]. The copy-number high subtype is mainly associated with type-II EC and is uncommon in type-I EEC (only 2%–15% of cases) [10]. Specifically, p53-mutated EEC is extremely rare among grade 1 and 2 tumors, and the effect of p53 mutation on prognosis is controversial.

We conducted a retrospective study to investigate the effect of p53 mutation on patient outcomes in clinicopathologic stage I, grade 1 or 2 EEC.

From January 2019 to December 2022, 537 patients with EC were registered in the cancer registry of our institute. We reviewed these patients’ charts to identify eligible patients. In total, 115 patients were eligible for analysis (Fig. 1). Of these, 89 were categorized into the normal_p53 group and 26 were categorized into the abnormal_p53 group. Patient characteristics are shown in Table 1 and did not differ between the groups. No significant differences in deep myometrium invasion, surgical approach, lymphovascular space invasion, MMR status, or adjuvant therapy were discovered. The normal_p53 group was significantly younger than the abnormal_p53 group (54 vs. 63 years, p=0.047).

Fig. 1
Participant recruitment process.
EEC, endometrioid carcinoma; MMH, MacKay Memorial Hospital.

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Table 1
Patient characteristics

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In the abnormal_p53 group, five patients (19.2%) had recurrent disease. Specifically, two patients had local regional recurrence, and three patients had distant recurrence. Of these five patients with recurrent disease, two died due to disease progression. By contrast, no patients in the normal_p53 group experienced recurrent disease or died due to disease progression. Significant intergroup differences were found in recurrent disease status (19.4% vs. 0%, p<0.001) and mortality (7.7% vs. 0%, p<0.001). Additionally, significant difference was determined in PFS (p=0.0003; Fig. 2) and powerful worse trend was revealed in OS (p=0.055; Fig. 3), as revealed by survival analysis performed using Kaplan–Meier analysis and the log-rank test.

Fig. 2
Progression-free survival.
Abnormal = abnormal_p53 group; wild-type = normal_p53 group.

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Fig. 3
Overall survival.
Abnormal = abnormal_p53 group; wild-type = normal_p53 group.

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Cox regression analysis and proportional-hazards models were used to assess recurrence and mortality and to identify potential clinical contributors, such as FIGO stage, grade, surgical approach, lymphovascular space invasion, and MMR status. However, hazards ratios could not be calculated because no recurrent disease or mortality occurred in the normal_p53 group.

Recurrence was encountered in 5 (19.2%) patients in p53 abnormal expression group. The detail information of these patients is shown in Table 2. All patients were absence of lymphatic vascular space invasion. Two of them had abnormal IHC of MMR protein(s). Two patients had over half myometrial invasion and received adjuvant vaginal brachytherapy only according to current treatment guideline. However, they both developed lung metastases and one died because of failure of salvage systemic therapies. The remaining 3 cases were observed without adjuvant therapy due to their low pathological risks. One of them developed lung metastasis and died even aggressive radiation and chemotherapy. The remaining two cases developed pelvic recurrence. After surgical debulking and salvage systemic therapies, currently, they are still alive with disease.

Table 2
Patient characteristics in recurrent cases (n=5)

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EC is the most common gynecological malignancy in developed countries. Poor diet, obesity, diabetes mellitus, and genetic factors, such as MMRd status, are potential risk factors for EC [13, 14, 15]. Surgical pathological examination is the primary method for staging EC and determining the appropriate adjuvant treatment. A new staging system was announced by FIGO in 2023; however, most current guidelines follow the 2009 recommendations and apply adjuvant management on the basis of morphological factors [7, 16]. EC is typically classified on the basis of the molecular characteristics of the cancerous tissue. A flowchart was developed for this purpose by the Cancer Genome Atlas study in 2013 [10]. According to the flowchart, EC is classified as POLE mutation, MMRd, copy-number low (MMRp), or copy-number high (abnormal p53) by using next generation gene sequencing for POLE and IHC staining for MMR proteins (MLH-1, MSH-2, MSH-6, and PMS-2) and p53 expression. However, these molecular classifications are not currently taken into account when determining the choice of adjuvant management despite the fact that they may be important prognostic factors.

Most patients with low-grade EEC have normal pattern or wild-type p53 expression. By contrast, patients with type-II EC or high-grade EEC commonly have aberrant or mutated p53 expression, namely the overexpression, complete absence, or cytoplasmic pattern [17]. According to Stelloo et al., p53 mutations may be indicators of a poor prognosis in EEC. They analyzed data from the PORTEC 1 and 2 studies, using both univariate and multivariate regression models, and discovered associations between p53 mutations and locoregional, distant recurrence and OS. They recommended escalating adjuvant therapy if IHC staining revealed abnormal p53 in addition to considering traditional morphological risk factors [18].

Abnormal mutant-type p53 staining is rare in low-grade EEC. This presents a paradoxical scenario in which a morphologically low-grade pattern in EEC exhibits molecular alterations associated with aggressive clinical behavior, such as p53 mutation [9]. This situation is estimated to occur in 10% to 15% of instances. Currently, adjuvant therapies for these cases are the same as those for cases involving wild-type p53 because of the practical guidelines. This is because p53 status is not considered a decisive factor in the treatment of EC [19]. However, Kurnit et al. showed that p53 mutation status could be integrated into risk stratification systems for early-stage, low-grade EEC because TP53 mutation is associated with significantly poorer PFS (hazard ratio [HR]=2.49; 95% confidence interval [CI]=1.05–5.90; p=0.04) [20]. Yano et al. [21] suggested that low-grade EEC with TP53-aberrant expression should be reclassified as high-grade (i.e., grade 3 disease) because of poor PFS (HR=2.91; p<0.001) and OS (HR=3.62; p<0.001) compared with low-grade EEC with TP53-normal expression. In addition, subgroup analysis of both early-stage (FIGO stage I/II) and advanced-stage (FIGO stage III/IV) EEC obtained similar results [21]. These studies have provided strong evidence of the possibility of p53 mutations being associated with poor prognosis in EEC. Our study specifically focused on patients with abnormal p53 and stage I, low-grade EEC to indicate their poor prognosis and to highlight the need for escalation of adjuvant therapies beyond what is recommended by current guidelines.

The TP53 gene is a type of tumor suppressor gene located on the short arm of chromosome 17p13.1 [22]. The normal p53 protein acts as a transcription factor and plays a crucial role in regulating various cellular processes, such as the cell cycle, apoptosis, genomic stability, and carcinogenesis [23, 24]. Mutations in the TP53 gene are frequently observed in high-grade serous ovarian cancer, fallopian tube cancer, peritoneal cancer, and EC [25]. In clinical practice, p53 IHC is used to predict TP53 mutation status due to its accessibility and affordability [17]. However, interpreting p53 IHC results can be technically challenging. This can be due to factors such as delayed fixation, inadequate presence of normal cells, or stronger staining of tumor cells [26]. Proper training in interpretation techniques and adherence to laboratory protocols are essential for obtaining reliable results from p53 IHC analysis.

Another challenging aspect is the heterogenous expression of p53 and subclonal TP53 mutations. Currently, this group is associated with certain mutator phenotypes, such as POLE ultramutation and MMRd/MMRp IHC, but cannot be classified into a single molecular subtype [27]. A universally accepted definition for subclonal abnormal p53 expression has not been established. We conducted subgroup analysis on heterogenous p53 expression; however, the results did not reveal better outcomes compared with those of the homogenous p53 abnormal group (not shown in the results and tables), inconsistent with the findings of several studies. This discrepancy may be attributable to statistical power limitations due to an insufficient number of cases in our study. Multicenter collaborative trials with more cases are warranted.

Our study has several limitations. First, this was a retrospective study with a limited number of cases from a single institute. Although we initially identified more than 500 patients, we had to omit most of them due to a lack of p53 IHC data. In our institute, we began routine p53 IHC staining for EC after mid-2021. Additional funding is required to obtain the missing p53 IHC data in these excluded cases. Second, most of the p53 IHC data were incomplete or ambiguous due to differences in p53 IHC nomenclature between nongynecological specialist pathologists in our department. Third, ultramutated (POLE-mutant) EEC could not be identified in our study due to a lack of facilities.

Finally, this study simply indicated an association between abnormal p53 and a poorer prognosis in low-grade EEC. On the basis of our findings, we recommend that patients receive aggressive therapies beyond what is recommended by current guidelines. This is because the risks of recurrence, mortality, and poor outcomes may be higher than current guidelines estimate. In the future, we may compare outcomes between aggressive adjuvant therapies and traditional adjuvant modalities recommended by current guidelines in cases of low-grade EEC with abnormal p53 IHC.