Thymoma Profile at Dr. Moewardi General Hospital: Does Thymoma Size Really Affect Distant Metastasis?

ABSTRACT


INTRODUCTION
Thymic epithelial tumors are classified as thymoma, thymic carcinoma, and thymic neuroendocrine tumors (NETs), with thymoma being the most common. 1,2According to the United States Cancer Statistics and Surveillance, Epidemiology, and End Results databases, thymoma accounts for 66.3% of all thymic tumors, thymic carcinoma for 20.4%, and thymic NETs for 3.5%. 3Thymoma represents only 0.2-1.5% of all malignancies and has an estimated incidence of between 0.13 and 0.32/100,000/year. 4The incidence of thymoma in Indonesia is still unknown.A study by Vianney and Rachmadi in 2021 found 32 cases of thymoma over five years (2014-2018) based on archival data from the Department of Anatomical Pathology, Faculty of Medicine, Universitas Indonesia/Dr.Cipto Mangunkusumo Hospital. 5The epidemiology of thymoma has limited information because the majority of data come from relatively small, retrospective, singlecenter cohort reviews with a small number of population-based studies. 4,6,7espite being slow-growing, about 50% of malignant epithelial tumors in the anterior mediastinum are thymomas. 1,8Approximately 30% of thymoma patients were asymptomatic. 9Thymoma is often detected by incidental findings on chest radiography or computed tomography (CT) scan upon routine physical *Corresponding author: novsiltho@gmail.comD ORIGINAL ARTICLE examination on medical check-ups or when patients present with shortness of breath and chest pain. 8,91][12] Even after a radical thymectomy has been conducted, recurrent thymoma can be found and follow-up should be performed for long enough to find its recurrence. 13hymomas can be locally invade to surrounding structures, including the adjacent pericardium, mediastinal pleura, lungs, and major vessels. 1,14Distant metastasis to regional lymph nodes or extra thoracic sites was uncommon. 14The recognition of thymic metastasis were challenging because of extra thoracic metastasis incidence is around 3-6%. 10,14,15 Tumor size is a predictor factor of patient's prognosis in various type of solid tumors. 167][18][19] Although the tumor size has been widely used in thoracic oncology staging system, this criterion is not applied in thymoma staging. 16,20Hence, this study was conducted to describe thymoma profile of patients treated at Dr. Moewardi General Hospital, Surakarta, and investigate the relationship between the tumor size and distant metastasis in thymoma patients.

METHODS
A cohort retrospective study was conducted using medical record data of patients diagnosed with thoracic oncology at Dr. Moewardi General Hospital, Surakarta.There were 1,430 thoracic oncologic patients from January 2019 to August 2021.Of these, 150 patients (10%) were diagnosed with mediastinal mass, 73 patients (48.6%) with comprising thymoma, 11 patients (7.3%) with thymic carcinoma, 23 patients (15.3%) with Hodgkin/non-Hodgkin lymphoma, one patient with germ cell carcinoma (0.6%), and 42 patients (28%) on diagnostic examination.Patients suffering from thymoma whose baseline information, characteristics of tumor, and follow-up information were recorded in detail were included.Patients with incomplete information were excluded from the study.
Thymoma patients were divided into two groups based on the tumor size with the cut-off point of 8.25 cm (<8.25 cm and ≥8.25 cm).Patients with thymoma size >8.25 cm was categorized as large thymoma.The metastasis was classified into distant and non-distant.In this study, distant metastasis is an extra thoracic organ or lymph node metastasis and is diagnosed by radiographic findings using a CT scan before getting any treatment.To evaluate the significance relationship between thymoma size and the distance of metastasis, univariate and bivariate analyses were performed using the odds ratio analysis and Chi-Square test.The result was significant at p < 0.05 with a 95% confidence interval.

RESULTS
A total of 73 thymoma patients were included in this study.Gender, age, clinical symptoms, occupation, origin, tumors size before getting any treatment, metastasis, treatment, and mortality data were gained from each patient's medical record (Table 1).Thymoma was predominated by males (53.4%) rather than females (46.6%).Most of thymoma patients were less than 40 years old (45.2%), with the mean age was 43 ± 16 years old.At the time of diagnosis, dyspnea was the most common symptom (64.4%), followed by chest pain (20.5%) and cough (15.11%).These patients presented with the tumor size of ≥91 mm (56.2%), 51-90 mm (34.2%), and 0-50 mm (9.6%) with mean tumor size was 9.98 cm (SD ± 4.25).
Metastatic lesions were found in 87.7% of the patient, and the most common metastatic sites were intra thoracic (79.5%), followed by axillary lymph nodes (49.3%), bone (21.9%), liver (20.5%), and brain (1.4%).Most of these patients had chemotherapy (45.2%), followed by combination of chemotherapy and surgery (16.4%), chemotherapy and radiation therapy (12.3%), surgery only (4.1%), and combination of chemotherapy, radiation, and surgery (2.7%).There were 19.2% patients that who did not want to get any treatment.The most common chemotherapy agent administered to thymoma patients was the combination of cyclophosphamide, doxorubicin, platinum-based, and vincristine about 38 patients (52.1%), followed by ten patients (13.7%) received combination cisplatin and etoposide, and six patients (8.2%) received chemotherapy cisplatin and paclitaxel.This study found 5.5% death on the observation.
Of 73 thymoma patients, 53 patients (72.6%) had distant metastasis.The cut-off points of thymoma size evaluated by receiver operating characteristic (ROC) analysis obtained that the size of ≥8.25 cm was considered as a large size of thymoma.Most patients with distant metastasis had the thymoma size of ≥8.25 cm (n = 37; 86.0%).Large tumor had a tendency to spread into various sites (OR = 5.39; 95% CI 1.8-16.6;p < 0.002).This indicated that distant metastasis of thymoma was significantly related to the tumor size (Table 2).

DISCUSSION
This study found that most common thymoma was mediastinal mass (48.6%).The National Comprehensive Cancer Network (NCCN) 2023 and Han's study in 2019 support that thymoma accounts for 20% to 50% malignancies in the anterior mediastinum. 1,8his study also showed that thymoma was predominated by males (53.4%), similar to studies conducted in Indonesia by Singh, et al. (2013) and Nikita, et al. (2021). 21,22Another studies showed that females were dominated in thymoma. 7,16In general, other evidences showed gender has no influence on the development of the disease. 3,4,6Most of the patients in this study were entrepreneur and live in Surakarta with the majority was Javanese ethnic.Incidence of thymoma varied in terms of race, as shown by Engels, et al. (2010) who stated that black people have a higher incidence than white people (0.20/100,000 vs. 0.12/ 100,000). 4NCCN 2023 showed that the incidence of thymomas is higher in African Americans as well as Asians and Pacific Islanders, which indicates that genetics plays a role. 1,3his study could not be compared to other studies because specific ethnic patterns were not reported.
Thymoma patients were mostly aged less than 40 years old (45.2%), with the mean age was 43 ± 16 years old ranging from 16 to 86 years old.Bian, et al. (2018)  reported the mean age of subjects with thymoma was 56 years old (12-90 years old). 16Suryaman, et al. (2022) reported two thymoma cases that showed thymoma occur at 30 years old. 23There were variations in the incidence of thymoma, but usually occurred in adults aged 35 to 70 years old. 1,6,24ost of this study subjects had prior symptoms such as dyspnea, chest pain, and cough.Approximately ⅓ of thymoma patients will not report significant symptoms and an additional ⅓ will report symptoms. 9,24ough, dyspnea, and/or chest pain are usually associated with mass effects including compression and invasion of surrounding structures. 9The size and density of the thymus decrease with age.Hussein, et al. (2022) showed normal thymus size was about 3 cm with homogenous soft tissue in children less than 10 years old. 25It will decrease until 1.5 cm in patients older than 20 years old with fatty infiltration, and after 35 years old, it could not be seen. 25In Indonesia, most patients visit hospital because of their symptoms rather than due to routine examination results. 21Similar with this study, most of these patients presented with the tumor size of more than 9 cm that could be associated with the symptoms caused by mass effect. 9Most presenting symptoms during the diagnosis were associated with malignant lesions. 21etastatic lesions were found in 87.7% of the patients, and the most common metastatic sites were intra thorax (79.5%), followed by axillary lymph nodes (49.3%), bone (21.9%), liver (20.5%), and brain (1.4%).Metastasis was common in thymic carcinomas, followed by high risk thymomas. 10A study by Khandelwal, et al.  (2016) was in line with this study that showed the most common locations for metastasis were pleura, lungs, and thoracic nodes. 10Extra thorax metastasis incidence is rare (3-6%). 10,14,15Some studies showed the most common sites of thymoma metastasis are lymph nodes, liver, bone, brain, spleen, kidneys, pancreas, gastrointestinal tract, ovary, and other soft tissues. 14,15enerally, thymomas are indolent tumors, but malignancy should be considered because of the ability to local invasion, pleural dissemination, and systemic metastasis. 26n this study, the patients presented with the tumor size of ≥91 mm (56.2%) with mean tumor size was 9.98 cm (SD ± 4.25). Tseng, et al. (2022) found that the mean tumor size was 5.7 cm. 7The mean tumor size can vary due to stage of the thymoma.The majority of the population were at an earlier stage, while in this study, most of the patients came with end-stage metastasis.
The size of thymoma has been underestimated and has hindered meaningful comparisons. 16 Yun, et al.  (2021) showed that tumor size has a significant prognostic effect. 17The optimal cut-off value was 5.4 cm for overall survival (OS) and 5.5 cm for recurrence free survival (RFS). 17 Fukui, et al. (2016) suggested that tumors larger than 40 mm showed significantly worse outcomes in survival. 18 Hwang, et al. (2016) showed the node metastasis rate was 17.6% at tumor size larger than 60 mm. 19 Bian, et al. (2018) found that patients with tumor size larger than 90 mm had worse outcomes and increase the rate of metastasis. 16Their studies showed that patients with a tumor larger than 50 mm had an increase metastasis at a rate of 1.958 times and tumor larger than 90 mm had metastasis rate of 3.845 times. 16kumura, et al. (2019) found a significantly higher incidence of recurrence in cases with a thymoma larger than 50 mm in size and of tumor death in cases with a thymoma larger than 80 mm. 11This study found that patients with tumor size larger than 8.25 cm had an increase metastatic rate about 5.39 times higher.These studies support this study that increased thymoma size influenced distant metastatic rate. 16,19ost of the patients in this study had chemotherapy (45.2%) because the population in this study were stage IV and chemotherapy was the primary therapeutic approach in the case of metastasis. 1,15NCCN Guidelines 2023 recommended surgery such as total thymectomy and complete excision of tumor for all resectable thymoma patients who can tolerate the surgery. 1 Surgical resection plays an important role in survival and recurrence rate. 24,27For patients with advanced disease (stage III or IV thymoma), chemotherapy is recommended and is often followed by radiation for patients with incompletely resected disease.For thymoma that is initially considered unresectable, induction chemotherapy followed by surgical resection can result in favorable rates of overall and disease-free survival. 1,24The variation treatment in this study was already based on the newest NCCN recommendation and local guideline consent with patients preference.
Chemotherapy agent administered to thymoma patients was the combination of cyclophosphamide, doxorubicin, platinum-based, and vincristine for 38 patients (52.1%), followed by the combination of cisplatin and etoposide for 10 patients (13.7%), and chemotherapy cisplatin and paclitaxel for six patients (8.2%).There were six first-line recommendation chemotherapy regimens, and all of the patients in this study had been treated according to the NCCN guidelines. 1 The mortality rate in Tseng's (2017) study is relatively similar to that of this study, 5.56% and 5.5%, respectively. 7Factors associated with mortality included increasing patient's age, larger tumor size, and presence of metastasis. 28his study has several limitations.This was a cohort retrospective and single-centered study.Therefore, the sample size was relatively small with a lack of ethnic variation.This study also did not include risk factors and comorbidity of patients which can be investigated further in future studies.Large number of thymoma cases in multiple centers with longer duration will be needed to get the incidence, risk factors, and thymoma size for scientific research conclusions.

CONCLUSION
Thymoma must be taken into account when there are male patients in their forties presented with dyspnea and mediastinal mass.This study could be an additional baseline research to evaluate the relationship of thymoma tumor size and the distance of metastasis.

Table 1 .
Characteristics of thymoma patients