Prognostic significance of tumor budding in endometrial cancer: clinicopathological insights

Ashi Dubey; Sana Ahuja; Sufian Zaheer

doi:10.14216/kjco.24306

ABSTRACT

Purpose

Endometrial cancer is one of the most common gynecological cancers worldwide, with rising incidence rates. Despite therapeutic advances, it remains a significant cause of cancer-related deaths. Tumor budding (TB), characterized by single cells or small clusters at the invasive tumor front, is a recognized prognostic marker in several cancers but is less studied in endometrial cancer.

Methods

This prospective cohort study included 30 patients with endometrial cancer who underwent surgical resection from January 2022 to June 2023. Formalin-fixed, paraffin-embedded tissue blocks were reviewed by two blinded pathologists. TB at the invasive front was assessed using hematoxylin and eosin staining. Clinical and pathological parameters, including age, histological type, grade, stage, myometrial invasion, lymphovascular space invasion, and nodal involvement, were recorded. Fisher’s exact and chi-square tests were used for statistical analyses.

Results

Most patients (60%) were aged 51–60 years, with 93.3% diagnosed with endometrioid adenocarcinoma. Tumors were graded as 40% grade 1, 43.3% grade 2, and 16.7% grade 3. Staging showed 36.7% FIGO IA, 36.7% IB, 16.7% II, and 10% III. TB was classified as low (70%), intermediate (23.3%), and high (6.7%). Higher TB levels were significantly associated with higher tumor grade (P=0.03), advanced stage (P=0.02), and nodal involvement (P=0.01).

Conclusion

TB correlates with adverse features in endometrial cancer, including higher grade, advanced stage, and nodal involvement. These findings underscore TB’s potential as a prognostic marker, warranting validation in larger studies and exploration of its molecular basis to guide personalized treatments.

Keywords: Endometrial neoplasms, Adenocarcinoma, Endometrioid

INTRODUCTION

Endometrial cancer is among the most frequently diagnosed gynecological cancers, with its incidence rising globally. According to GLOBOCAN data (global cancer statistics), around 417,367 new cases of endometrial cancer were recorded in 2020, along with 97,370 deaths attributed to the disease. That year, endometrial cancer was identified as the second most common gynecological cancer and the third leading cause of gynecological cancer-related deaths in women worldwide [1]. despite advances in treatment, the prognosis for advanced stages remains poor, necessitating the identification of novel prognostic markers. Tumor budding (TB), defined as the presence of isolated single cells or small clusters of up to four cells at the invasive front of carcinomas, has emerged as a significant prognostic factor in various malignancies, including colorectal, breast, oral squamous cell carcinoma and pancreatic cancers [2–5]. However, its role in endometrial cancer has not been extensively explored [6–10].

TB is hypothesized to represent an epithelial-mesenchymal transition, a process where epithelial cells acquire mesenchymal, migratory characteristics, contributing to tumor aggressiveness and metastasis [1]. As such, investigating the presence and extent of TB in endometrial cancer could provide valuable insights into its prognostic implications and association with clinicopathological parameters such as tumor grade, stage, lymphovascular invasion and nodal status. This study aims to evaluate TB in endometrial cancer and its association with various clinicopathological parameters.

METHODS

Study design and patient selection

This prospective cohort study included patients diagnosed with endometrial cancer who underwent surgical resection between January 2022 and June 2023. Patients who received neoadjuvant chemotherapy or radiotherapy were excluded. The study was done in accordance with the Helsinki Declaration. The study was approved by the Institutional Ethics Committee of Safdarjung Hospital (IEC/VMMC/SJH/Cert./02-2024/242). Written informed consent was taken from all patients included in the study.

Histopathological evaluation

Formalin-fixed, paraffin-embedded tissue blocks from surgical specimens were retrieved from the pathology archives. Hematoxylin and eosin-stained slides were reviewed by two independent pathologists (SA and SZ) blinded to clinical outcomes. TB was assessed at the invasive front of the tumor using a standardized protocol.

TB was defined as isolated single tumor cells or small clusters of up to four cells at the invasive front. The number of buds was counted in 10 high-power fields using a ×40 objective lens. Based on the budding count, tumors were classified into three categories: low budding (0–4 buds), intermediate budding (5–9 buds), and high budding (≥10 buds).

To resolve discrepancies between the two pathologists’ assessments, the final count of TB was determined through a consensus discussion. In cases where the pathologists disagreed on the number of buds, they re-evaluated the specific areas of contention together. After joint review and discussion, a consensus number was agreed upon. A third senior pathologist was consulted to provide an independent assessment if a consensus could not be reached. The final budding count was based on this three-pathologist consensus.

Clinicopathological parameters

The following clinicopathological parameters were recorded: age at diagnosis, histological type (endometrioid, serous), tumor grade (International Federation of Gynecology and Obstetrics [FIGO] grade 1–3), stage (FIGO I–IV), depth of myometrial invasion, lymphovascular space invasion, presence of lymph node metastasis.

Statistical analysis

Statistical analyses were performed using version 25.0 (IBM Corp.). Descriptive statistics were used to summarize patient demographics and clinicopathological features. The Fisher exact test and chi-square test were utilized to assess the association of clinicopathological variables with TB. A P-value of less than 0.05 was considered statistically significant.

RESULTS

Demographics and patient characteristics

The study cohort consisted of 30 patients with endometrial cancer. The majority of patients (n=18, 60%) were in the age group of 51–60 years, followed by 41–50 years (n=8, 26.7%) and above 60 years (n=4, 13.3%). The mean age of the patients was 54.2±7.1 years. Histologically, there were 28 cases (93.3%) of endometrioid adenocarcinoma while there were two cases (6.7%) of serous carcinoma. Among these, 12 patients (40.0%) had grade 1 tumors, 13 patients (43.3%) had grade 2 tumors, and five patients (16.7%) had grade 3 tumors. The distribution of tumor stages was as follows: 11 patients (36.7%) were FIGO IA, 11 patients (36.7%) were IB, five patients (16.7%) were II, and three patients (10.0%) were III. Nodal involvement was observed in five patients (16.7%).

TB and clinicopathological parameters

TB was categorized as low, intermediate, and high. In this cohort, 21 cases (70.0%) exhibited low budding, seven cases (23.3%) showed intermediate budding, and two cases (6.7%) displayed high budding (Fig. 1).

Tumor grade

Grade 1: Among the 12 grade 1 tumors, 11 (91.7%) had low budding, one (8.3%) had intermediate budding, and none (0%) had high budding.
Grade 2: Of the 13 grade 2 tumors, eight (61.5%) had low budding, four (30.8%) had intermediate budding, and one (7.7%) had high budding.
Grade 3: In the five grade 3 tumors, two (40.0%) had low budding, two (40.0%) had intermediate budding, and one (20.0%) had high budding.

Tumor stage

IA: Among the 11 FIGO IA cases, 10 (90.9%) had low budding, one (9.1%) had intermediate budding, and none (0%) had high budding.
IB: Of the 11 stage IB cases, eight (72.7%) had low budding, two (18.2%) had intermediate budding, and one (9.1%) had high budding.
II: In the five stage II cases, two (40.0%) had low budding, two (40.0%) had intermediate budding, and one (20.0%) had high budding.
pT3: Among the three pT3 cases, one (33.3%) had low budding, two (66.7%) had intermediate budding, and none (0%) had high budding.

Nodal involvement

With nodal involvement: Of the five cases with nodal involvement, one (20.0%) had low budding, three (60.0%) had intermediate budding, and one (20.0%) had high budding.
Without nodal involvement: Among the 25 cases without nodal involvement, 20 (80.0%) had low budding, four (16.0%) had intermediate budding, and one (4.0%) had high budding.

Depth of myometrial invasion

Superficial invasion (<50% of myometrium): Out of 11 cases, 10 (90.9%) had low budding, one (9.1%) had intermediate budding, and none (0%) had high budding.
Deep invasion (≥50% of myometrium): Of the 19 cases, 11 (57.9%) had low budding, six (31.6%) had intermediate budding, and two (10.5%) had high budding.

There was a significant association between intermediate to high budding and higher tumor grade (P=0.03), advanced tumor stage (II and III) (P=0.02) and nodal involvement (P=0.01). No association was seen with age, histological subtype, depth of myometrial invasion and lymphovascular invasion (Table 1).

DISCUSSION

This study highlights a significant association between TB and adverse clinicopathological parameters in endometrial cancer. Intermediate to high TB was notably associated with higher tumor grade, advanced tumor stage and nodal involvement. These findings are consistent with reports from Ocal and Guzelis [6], Okcu et al. [7], Park et al. [8], Koyuncuoglu et al. [9], and Rau et al. [10], who similarly identified TB as a predictor of aggressive tumor behavior.

The present study did not find associations with age, histological subtype, depth of myometrial invasion or lymphovascular invasion. Rau et al. [10] reported strong correlations (P<0.001) between TB and these parameters. Ocal and Guzelis [6] and Okcu et al. [7] also highlighted TB’s associations with larger tumor size, nonendometrioid histology.

Ailia et al. [11] in a systematic review on TB in gynecologic cancer concluded that high TB was significantly associated with clinicopathological parameters such as, age, stage (III and IV), depth of invasion (more than half), N stage (N1, N2, N3), M stage, grade (G3), lymphovascular invasion, and perineural invasion.

The distribution of TB among different grades revealed that higher grade tumors (grade 2 and grade 3) were more likely to exhibit intermediate to high budding. This aligns with the concept that TB reflects an aggressive phenotype, possibly due to enhanced epithelial-mesenchymal transition processes that facilitate tumor progression and metastasis.

The significant association of intermediate to high budding with advanced tumor stages (pT2 and pT3) underscores its role in local and regional tumor spread. Nodal involvement, a critical determinant of prognosis, was significantly more common in tumors with intermediate to high budding. This finding emphasizes the potential of TB as a marker for metastatic potential, thereby aiding in the identification of patients who may benefit from more aggressive treatment and vigilant follow-up.

In summary, the assessment of TB in endometrial cancer provides valuable prognostic information. Incorporating TB into routine histopathological evaluation could enhance risk stratification and inform therapeutic decisions. Future studies should aim to validate these findings in larger, prospective cohorts and explore the underlying molecular mechanisms driving TB in endometrial cancer.