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Trans Abstract

Introduction

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder in which autoantibodies against the structure of neuromuscular junction induce weakness of ocular, bulbar, limb, and/or respiratory muscles. Approximately 10-20% of patients with MG are known to have thymic neoplasm, most commonly thymoma. Thymomas are neoplasms of thymic epithelial cells. Alteration of thymic microenvironment by the neoplasm may lead to the release of self-reactive T cells to peripheral circulation, causing various paraneoplastic syndrome including MG.1 Individuals with MG and thymoma, a condition known as thymoma-associated MG (TAMG), are known to experience more severe symptoms of MG and likely to have higher levels of acetylcholine receptor antibodies (AChR Abs) than the patients with MG without thymoma.2 Thymectomy is recommended to the patients with TAMG for the management of tumor.

Recurrence of thymoma after the resection of thymoma is not uncommon. The chance of thymoma recurrence after complete resection of the initial thymoma ranges from 5% to 50%.3-5 Recurrence is usually confined to the pleural dissemination or local relapse, while distant metastasis is rare. Pleural recurrence of thymoma is often asymptomatic and is frequently detected incidentally during routine follow-up. When symptomatic, clinical manifestations commonly include pleural effusion, thoracic discomfort, and dyspnea. Interestingly, symptoms of MG can exacerbate along with the recurrence of thymoma. A previous study showed that thymoma recurrences were accompanied by worsening of MG.2 Another study similarly observed that exacerbation of MG can be accompanied by recurrence of thymoma and that many of these recurrences were identified due to the worsening of MG symptoms.6 However, these studies are based on small number of patients and clinical characteristics of MG were not thoroughly evaluated.

In this study, we intended to investigate the potential link between thymoma recurrence and exacerbation of MG in patients with TAMG. Patients with TAMG who experienced the recurrence of thymoma were identified. The proportion of patients with TAMG who experienced the exacerbation of MG during the period one year before and after the recurrence of thymoma was analyzed.

Methods

Results

Patient characteristics

A total of 178 patients with TAMG who were histologically diagnosed with thymoma in Severance Hospital were included. Of these patients, 18 patients (10.1%) experienced recurrence of thymoma and were classified as recurrence group. Mean age at MG onset of the patients in recurrence group was 43.7±9.7 years. Mean age at initial thymectomy and at thymoma recurrence was 44.1±9.4 years and 48.8±9.1 years, respectively. Duration from initial thymectomy to recurrence of thymoma was 56.3±35.3 months. At the point of initial thymectomy, two patients (11.1%) were classified as ocular and 16 patients (88.9%) as generalized MG. Worst MGA classification before initial thymectomy was class I in two patients (11.1%), class II in six (33.3%), class III in six (33.3%), and class V in four patients (22.2%). Median MG ADL score at the point of initial thymectomy was 4.0 (interquartile range [Q1-Q3], 2.3-8.8). The initial World Health Organization (WHO) histology classification was B1 in 16.7%, B2 in 61.1%, and B3 in 22.2%. Masaoka stage II was the most common (44.4%), followed by stage III (22.2%), stage I (16.7%) and stage IV (16.7%). When clinical and histological characteristic were compared between the recurrence and non-recurrence groups (Table 1), no significant differences were observed between groups in the aspect of age of MG onset, age at thymectomy, sex, MGA classification at initial thymectomy, WHO histology classification, and titer of AChR Ab. However, the proportion of patients with invasive thymoma were significantly higher in recurrence group (38.9%) compared to non-recurrence group (5.6%; p<0.01).

Table 1.

Comparison of clinical characteristic between the patients with thymoma-associated with myasthenia gravis who experienced recurrence of thymoma and those who did not

State of MG at the point when recurrence of thymoma was detected

Table 2 presents the clinical and treatment status of the patients with TAMG at the point that thymoma recurrence was radiologically observed. MGA PIS of the patient was complete stable remission in four (22.2%), pharmacologic remission in five (27.8%), minimal manifestation in five (27.8%), improved in two (11.1%), and unchanged in two patients (11.1%). None of the patients were experiencing worsening or exacerbation of MG at this point. In terms of treatment, 10 patients (55.6%) were taking prednisolone and four (22.2%) were on oral immunosuppressants. Five patients (27.8%) were not receiving MG-specific therapy. Median MG ADL score was 0.0 (Q1-Q3, 0.0-1.8). Table 3 presents the detailed clinical characteristics of the 18 patients in recurrence group. In patient 17 and patient 18, recurrence of thymoma was confirmed exclusively on CT imaging without surgical intervention. Of the 14 patients whose serum level of AChR Ab was assessed both before and after the first thymectomy, level of AChR Ab increased in eight patients (57.1%) and decreased in six patients (42.9%).

Table 2.

Clinical status and treatments status of the patients with thymoma-associated myasthenia gravis (MG) at the point of thymoma recurrence

Table 3.

Detailed clinical characteristics of patients with thymoma-associated with MG who experienced thymoma recurrence

Change of MG ADL before and after the thymoma recurrence

Table 4 displays the baseline recurrence rate of MG and changes in MG ADL score before and after thymoma recurrence. Baseline recurrence rate, calculated by dividing the number of total events of worsening by the total follow-up duration, was 0.29 per years. A total of seven events of worsening occurred during the 2-year period around the recurrence of thymoma, with the worsening rate of 0.19 per year. MG ADL scores were recorded at four time points: 1 year prior to thymoma recurrence, at the time when thymoma recurrence was first detected, following secondary thymectomy, and 1 year after thymoma recurrence. Of the 18 patients in recurrence group, 12 patients remained unchanged during the 2-year period around the thymoma recurrence. Three patients experienced worsening of MG during the 1-year period prior to the recurrence date. In detail, symptoms of MG in patient 14 worsened along with pulmonary tuberculosis infection. Patients 15 and 16 experienced worsening of MG after the self-discontinuation of prednisolone treatment. our patients (patients 11, 12, 13, and 14) exhibited worsening of MG symptoms during the 1-year period after the recurrence date. In these four patients, symptoms of MG worsened 2-4 months after second thymectomy.

Table 4.

Change in severity of MG before and after thymoma recurrence

Discussion

Of the patients with TAMG who underwent thymectomy, 10.1% experienced recurrence of thymoma during the mean follow-up duration of 10.8 years. Clinical characteristics of MG were not significantly different between the patients who experienced and did not experience recurrence of thymoma. MG was in stable stats in all patients at the time when the recurrence of thymoma was first detected. Of the 18 patients with thymoma recurrence, three and four patients experienced worsening of MG during the 1-year period before and after the recurrence of thymoma, respectively. Rate of MG worsening was 0.19 per year during the 2-year period around the thymoma recurrence. The rate of recurrence was comparable to the baseline rate of worsening during the period other than peri-recurrence period. Patients who experienced worsening of MG around the point of thymoma recurrence had other possible cause of MG worsening besides thymoma recurrence including infection, discontinuation of MG medication and surgery requiring general anesthesia.

In the present study, the recurrence rate of thymoma among the patients with TAMG was 10.1%. This is consistent with the Japanese Association for Research on Thymus data, where 14.8% of patients with thymoma experienced recurrence.4 In other studies, recurrence rates were similarly reported, including 13.7% in a cohort of 95 patients, 14.2% among 148 patients, and 12.3% in a separate analysis, with a median recurrence-free period of 8.2 years, demonstrating comparable outcomes across various populations.2,8,9 In previous studies, risk of thymoma recurrence was significantly higher in patients with early-onset MG, suggesting a potential correlation between earlier onset of the disease and increased recurrence risk.10 Similarly, although not clinically significant, age of onset was younger in recurrence group compared to those in non-recurrence group. In our study, patients with recurrence had a larger tumor size and higher Masaoka stage, which are the known risk factors associated with the recurrence of thymoma.9,11 Consistent with the results from Liu et al.,9 which found that MG symptoms did not significantly influence thymoma recurrence, there were no significant difference in clinical feature of MG between the recurrence and non-recurrence groups in this study.

The precise mechanisms underlying MG exacerbation after thymoma recurrence remain unclear. A previous studies demonstrated that worsening of MG could be a sign of thymoma recurrences.2,6 Especially, Haniuda et al.6 stated that recurrences of thymoma was noticed by the worsening of MG in patients with TAMG. In general, destruction of thymic microenvironment by thymoma and release of nontolerogenic T cells to peripheral circulation are considered to be the main pathomechanism of TAMG.12 However, further studies are required to elucidate whether the recurrent thymoma can also trigger these pathways and result in worsening of MG, or whether the worsening of MG is an indirect result of thymoma recurrence. In addition, in the present analysis, MG exacerbations were associated with respiratory infections, changes in medication, and surgical interventions, which are the known risk factors for the worsening of MG.13,14 Thus, conventionally recognized risk factors for MG exacerbation including infections, emotional stress, microaspiration, medication adjustments, surgery, or trauma, should also be considered in interpreting the cause of MG worsening around the recurrence of thymoma.

This study has several limitations that should be noted. irst, its retrospective design and relatively small sample size may introduce selection bias, limiting the statistical power and generalizability of the findings. This design also constrains our ability to control for potential confounding factors, which may independently influence patient outcomes. Second, clinical decisions on surgical approaches and MG management were individualized, introducing variability in treatment strategies. Third, the exact time of thymoma recurrence cannot be precisely determined, and the time of thymoma recurrence could only be estimated as the time when thymoma recurrence was first observed on chest CT. Lastly, as this is a single-center study, the findings may not fully represent broader populations. Larger, multicenter prospective studies are needed to confirm these observations.

In conclusion, 16.7% and 22.2% of the patients with thymoma recurrence experienced worsening of MG during the year prior to and after the recurrence of thymoma, respectively. However, the rate of worsening was comparable to the generally known rate of MG worsening. In addition, symptom exacerbation in these cases could be attributable to external factors such as infection, discontinuation of medication, or surgical intervention, rather than the recurrence of thymoma itself. These highlights the need for a careful assessment of other contributing factors when evaluating MG worsening in the context of thymoma recurrence.

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