| Abstract|| |
Background: Tumor budding (TB) is a morphological finding believed to play an important role in determining the prognosis in many cancers. Aim: Our aim is to evaluate the prognostic importance of TB in endometrial carcinomas. Settings and Design: Two-hundred-eleven endometrial cancers were obtained from 2008 to 2015 that were comprised of those having undergone surgical staging with a hysterectomy and at least 5 years followed up. Material and Methods: All hematoxylin and eosin stained slides were reevaluated for the status of TB. Statistical Analysis: Nonparametric tests, the Kaplan–Meier method, the Log-rank test, and Cox proportional hazard regression were used. Results and Conclusion: TB was found to correlated with larger diameter (P = 0.000), nonendometrioid (P = 0.038), mixed cell types (P = 0.005), higher grade (P = 0.000), deeper invasion of the myometrium (P = 0.000), cervical stromal invasion (P = 0.000), advanced pT (P = 0.011), lymph node involvement (P = 0.000), lymphovascular invasion (P = 0.000), and advanced stage (P = 0.000). The presence of TB worsens the 5-year overall survival (OS) (P = 0.0001). In cases such as grade 1, pT1, or stage 1 endometrial carcinomas, the presence of TB decreases the OS rate (P = 0.00017, P = 0.0016, P < 0.0001). Our result suggested that the presence of TB adversely affects the prognosis. It was concluded that TB could be a valuable prognostic parameter.
Keywords: Early stage, endometrial carcinoma, lymph node involvement, lymphovascular invasion, prognosis, tumor budding
|How to cite this article:|
Ocal I, Guzelis I. Tumor budding is a valuable prognostic parameter in endometrial carcinomas. Indian J Pathol Microbiol 2022;65:851-5
| Introduction|| |
Endometrial carcinoma is the second most common female genital tract cancer after cervical cancer in the world. Besides, it also ranks the third most mortal gynecologic cancer following cervical and ovarian cancer.
As Bokhman proposed, there are two types of endometrial carcinoma which are type I (endometrioid) and type II (nonendometrioid).
According to the Fédération Internationale de Gynécologie et d'Obstétrique (FIGO), depth of myometrial invasion, lymph node status, and other staging parameters are standardized tools for indicating the clinical outcome in endometrial carcinoma. There are also studies investigating the factors that contribute to the prediction of the survival rate such as lymphovascular invasion (LVI), tumor size, and pattern of myometrial invasion.,
Tumor budding (TB) is a morphological finding that is seen in hematoxylin and eosin (H&E) stained sections, which is described as an isolated single cancer cell or nonglandular small cell clusters less than five cells in front of the invasive margin., However, there is no standardized evaluation of TB in endometrial carcinomas.,, TB is shown to play an important role in determining lymph node status, local recurrence, and poor prognosis especially in colorectal, anal, lung, and esophageal carcinomas.,,,, We aimed to reveal the effect of TB on prognosis and its relationship with other prognostic parameters in a large case series.
| Materials and Methods|| |
Patients and specimens
A retrospective review of all cases of endometrial cancer diagnosed at the Izmir Kâtip Celebi University Ataturk Training and Research Hospital from March 2008 through October 2015 was carried out. The patients included in the study were comprised of those having undergone surgical staging with a hysterectomy and at least 5 years followed-up. The patients with preoperative chemotherapy, radiotherapy or hormone therapy, incomplete surgeries, and no documented postoperative 5-year follow-up were excluded. Besides, endometrial carcinomas without myometrial invasion or with adenomyosis like invasion were excluded from the study.
Parameters such as patient demographics, tumor grade, histological type, cervical stromal invasion, lymph node status, and follow-up data were gathered from our medical records. Tumors were classified according to histological typing and surgical staging described in 2020 WHO classification of tumors of the female genital tract (WHO female genital tumors 5th edition). According to FIGO Cancer Report 2018, the patients with the diagnosis of mixed cell type (mixed carcinoma is a carcinoma composed of two or more discrete histological types of endometrial carcinoma, where at least one component is either serous or clear cell) or nonendometrioid type (serous, clear cell, undifferentiated, dedifferentiated, or carcinosarcoma) were accepted as grade 3. Stage I and II were grouped as early stage, while stage III and IV as the advanced stage. Because of the small number of cases with pT2 and pT4, pT1 and pT2 were grouped together as one group, and pT3 and pT4 were grouped together as another group.
Overall survival data were gathered from The Death Notification Service. All patients were followed- up, and the mean follow-up period was 76.9 ± 32.4 months (ranging from 1 to 132 months). The study approval was obtained from the institutional review board at Izmir Kâtip Celebi University medical faculty (2020-GOKAE-0522).
All available H and E stained sections of tumoral tissue (median 14 slides) were collected from the archive. All slides were re-examined by an expert gynecopathologist with 8 years of experience (I.O.) and an assistantpathologist (I. G.), who were blind to the clinical outcomes, in an attempt to evaluate TB. Cases called TB in two observers were considered TB positive.
TB was defined as an isolated single cancer cell or small cell clusters composed of <5 tumor cells found in the invasive margin as mentioned in the International Tumor Budding Consensus Conference 2016. The presence of a five TB focus in a high-power field (HPF) was considered TB positive similarly to previously recorded.,, The number of TB was counted using a ×20 objective lens/HPF (Olympus BX-50) [Figure 1].
|Figure 1: (a, b). Tumor budding areas (arrows indicating tumor buds) visible in an endometrioid type endometrial cancer (a) and the serous component of a mixed cell type endometrial cancer (b) at the leading area of invasion in endometrial cancer (magnification:×20)|
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Statistical analysis was conducted by Jamovi (version 1.2). The comparison of the groups and the relationship between TB and the other parameters were investigated using nonparametric tests, such as the Kruskal–Wallis test, Pearson's Chi-square test, and Mann–Whitney U test. Survival analyses were calculated using the Kaplan–Meier method. The Log-rank test was used for univariate analysis, while Cox proportional hazard regression (HR) models were performed for multivariate analysis. The probability level of 0.05 or less was chosen to represent statistical significance.
| Results|| |
A total of 211 patients with endometrial carcinoma were included in the study. The clinicopathological characteristics of the patients are shown in [Table 1]. The mean age was found to be 60.4 ± 9.57. The mean tumor diameter was measured as 3.27 ± 1.95 centimeters. In our case group consisting of 211 patients, 192 cases (91.0%) were endometrioid type, 3 cases (1.4%) were nonendometrioid type (two of which were undifferentiated and one was a carcinosarcoma), and 16 cases (7.6%) were mixed cell type (10 of which contained a serous component and 6 a clear cell component).
Based on FIGO grading system, 92 patients (43.6%) were evaluated as grade 1, 83 (39.3%) as grade 2, and 36 (17.1%) as grade 3. Myometrial invasion in 92 individuals (43.6%) was more than 50% and in 119 (56.4%) was less than 50%. The cervical stromal invasion was detected in 39 individuals (18.5%). One hundred sixty-eight patients (79.6%) were present with pT1, 29 (13.7%) with pT2, 13 (6.2%) with pT3 and 1 (0.5%) with pT4. Lymph node involvement (LNI) was present in 38 patients (18%), while LVI was present in 49 (23.2%). TB was identified in 70 patients (33.2%). According to FIGO staging system, 151 patients were stage I (71.6%), 19 patients were stage II (9%), 39 patients were stage III (18.5%), and 2 patients were stage IV (0.9%).
Patholocigal features with survival
Mortality risk was higher in patients with grade 2 and grade 3 endometrial carcinomas than patients with grade 1 endometrial carcinoma, respectively, univariate HR 2.62 and 3.50 (P = 0.005, P = 0.000). More than 50% of myometrial invasion, cervical stromal invasion, LNI, and LVI were found to worsen overall survival (OS), respectively (P < 0.0001, P = 0.015, P < 0.001, P < 0.0001). The survival rates were high in pT1 and pT2 (P < 0.0027). Also, the early stage was associated with better OS (P < 0.001). A total of 51 patients (24.17%) died during follow-up, 37 of them within the first 5 years after surgery.
Association of tumor budding with clinicopatholocigal features
The relationship between TB status and clinicopathological features is shown in [Table 2]. TB was found to be statistically insignificant with age (P = 0.274). The diameter of the carcinomas with TB (mean 4 cm) was larger than those without TB (mean 2.80 cm) (P = 0.000). TB has been revealed to be associated with nonendometrioid and mixed cell types (P < 0.005). In endometrioid types, as the grade increased, TB was detected more frequently (P < 0.001). TB was more common in all types of endometrial carcinomas as the grade increased (P < 0.001). The presence of TB was correlated with the invasion of more than 50% of the myometrium (P < 0.001) and cervical stromal invasion (P < 0.001). TB was more frequent as pT advanced (P = 0.001). It was revealed that TB was associated with LNI (P < 0.001) and LVI (P = 0.000). Also, TB was found more frequently as the stage advanced (P = 0.000).
|Table 2: Clinicopathological features associated with the state of tumor budding|
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Association of tumor budding with survival
The 5-year OS rates associated with the state of TB are shown in [Figure 2]. According to the absence or presence of TB, the OS rate was 89.4 and 68.6%, respectively. The presence of TB worsened the OS rate (P < 0.0001). The OS rate declined in grade 1 endometrial carcinomas when TB was present (P = 0.00017). This was more significant in grade 1 endometrial carcinomas compared with LVI and LNI (HR multivariable = 6.77, P = 0.001). The presence of TB was not correlated with the OS in grade 2 and grade 3 endometrial carcinomas (P = 0.51 and P = 0.079). In cases with a myometrium invasion of less than 50%, TB worsened the OS (P = 0.0053). The OS was 92.97 and 78.05%, respectively, in pT1 tumors depending on the absence or presence of TB. In pT1, TB presence worsened the OS (P = 0.00016). All in all, pT1 and pT2 with TB was correlated with unfavorable outcome (P < 0.001). Also, the OS was 94.02 and 73.53%, respectively, in stage 1 tumors depending on the absence or presence of TB. In stage 1 tumors, the presence of TB worsened the OS (P < 0.0001) and posed a more outstanding mortality risk than the presence of LVI (HR multivariable = 3.61, P = 0.002). The OS was 92.97 and 78.05%, respectively, in early stage tumors according to the absence or presence of TB. In the early stage, TB was correlated with unfavorable outcome (P = 0.00038) and was associated with a worsened prognosis more than the presence of LVI (HR multivariate = 3.29, P = 0.002).
|Figure 2: (a–f) Five-year overall survival analyses based on Kaplan–Meier method. (a–f) TB is associated with unfavorable clinical outcome. TB is a significant poor prognostic parameter in general (a), grade 1 (b), pT1 (c), pT1 and T2 (d), stage 1 (e), and early stage (f)|
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| Discussion|| |
A useful parameter in terms of prognosis in many organ cancers, TB can be easily detected in routine H and E staining.,,, There are limited studies about TB in endometrial carcinoma.,, We evaluated the effect of TB on prognosis and its relationship with other prognostic parameters with a large group of cases. In endometrial cancers, TB was found at a rate of 33.2% according to our study, while TB was found 23.2–65.6% in the literature.,, While 16 cases of our cases (7.6%) were mixed cell type (10 of which contained a serous component and 6 a clear cell component), in the study of Rau et al. with mentioning having minor endometrioid component seven cases (4.7%) were serous type and three cases (2.7%) were clear cell type. While in our study, TB was present in all nonendometrioid cancers and nine of the mixed cell types, Rau et al. found TB in two of the serous type and none of the clear cell type and carcinosarcoma cases.
In contrast to Park et al., in our study, the presence of TB worsened the OS, as in the study of Rau et al. In the current study in endometrial carcinomas, as the grade increased, TB was encountered more commonly, similarly to Rau et al. Similar to the previous studies, in endometrioid type, it was found that as grade increased TB was more frequent.,,
Contrary to Park et al., in our study TB was seen to be associated with cervical stromal invasion. The presence of TB was also seen to be correlated with the depth of myometrial invasion similar to the literature.,, In the present study as pT increased, TB was seen more frequently, similarly to Rau et al. In our study, TB was found to be related to LNI, parallel with Park et al. and Rau et al. Similar to some findings in the literature, the presence of TB was found to be associated with LVI in our study, but there were also findings opposite to ours in the literature.,, In the current study as the stage advanced, TB was seen more frequently similarly to Koyuncuoglu et al. In the present study, TB was found to be significant in early stage tumors as in the literature. However, the significance of TB in advanced stage tumors could not be determined due to the low number of advanced stage cases.
In this study, the relationship of TB with the diameter and histological subtypes and also the effect of TB status on the OS in prognostic subgroups such as tumor grade, myometrial invasion depth, pT, and stage were evaluated separately for the first time in the English literature.
As a result, it was revealed that the presence of TB is associated with a larger diameter, cervical stromal invasion, depth of myometrial invasion, LNI, LVI, advanced pT, advanced stage, and worse prognosis. Even, in the presence of low grade, pT1, and early-stage, TB affects the prognosis adversely. Therefore, it was concluded that TB is a valuable prognostic parameter that can be easily evaluated in routine pathology.
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Conflicts of interest
There are no conflicts of interest.
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Atatürk Training and Research Hospital, Gazeteci Hasan Tahsin Street, Basinsitesi, Postal Code: 35360, Izmir
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2]