thymoma is an uncommon neoplasm of the thymus , derived from the thymic epithelial cells . myasthenia gravis ( mg ) is the most common paraneoplastic neurological disorder associated with thymoma . about 3050% of thymoma patients mg with thymoma is particularly associated with autoantibodies against postsynaptic nicotinic acetylcholine receptors ( achr - abs ) . however , mediastinal and pleural recurrence remains a significant clinical problem , especially for patients with advanced and incompletely resected thymoma [ 68 ] . surgical treatment of recurrent thymoma is technically challenging and has been reported to be effective in only one - third of patients . even following radical thymoma resection , patients may still suffer from mg , and continuous follow - up and pharmacological treatments are needed for these patients . a growing number of studies have indicated that these drugs are effective in treatment of the patients with advanced or invasive thymoma [ 1116 ] . in patients with mg - associated thymoma , symptoms of both mg and the tumor have been reported to be improved by steroid therapy , particularly in advanced or metastatic cases . immunosuppressive agents such as azathioprine and methylprednisolone have also been used for treatment of invasive thymoma - associated mg , with improved clinical symptoms and reduced tumor volumes . moreover , combined treatment with steroids and immunosuppressive agents has been suggested to be useful in treatment of invasive thymoma and myasthenic symptoms . myasthenic crisis has been reported in a patient receiving steroid chemotherapy for advanced thymoma with mg . unfortunately , almost all these studies are case reports , making it difficult to assess the therapeutic potential of steroids in these patients . in this study , we retrospectively analyzed a series of mg patients with metastatic thymoma that received steroid pulse therapy in combination with immunosuppressive agent therapy . mg patients with metastatic thymoma were reviewed retrospectively . a total of 12 patients who underwent methylprednisolone pulse therapy during january 2013 to january 2016 were identified . the diagnosis of mg was based on clinical symptoms and confirmed by acetylcholine receptor antibody ( achr - ab ) test , neostigmine test , fatigue test , and electromyography tests . histological diagnosis of thymomas was performed based on the world health organization ( who ) histological classification . as shown in table 1 , 8 mg patients with metastatic thymoma were initially treated according to their clinical conditions , but the symptoms were not improved . methylprednisolone pulse therapy was begun at 1 g / day and reduced by half every 3 days until reaching 60 mg / day . oral methylprednisolone at 52 mg / day was then prescribed and the patients were discharged from the hospital . the dose of methylprednisolone was reduced and then tapered slowly on alternate days cyclophosphamide was given simultaneously at a dose of 100 mg / day and continued for 2 months until the discontinuance of oral methylprednisolone . the clinical outcome of mg at discharge and during the follow - up was assessed based on the clinical absolute and relative scoring system . briefly , the clinical relative score ( crs ) was calculated to evaluate the improvement or deterioration of the mg : ( 1 ) clinical remission ( cr ) : crs 95% ; ( 2 ) basic remission ( br ) : 80% crs < 95% ; ( 3 ) marked improvement ( mi ) : 50% crs < 80% ; ( 4 ) improvement ( i m ) : 25% crs < 50% ; and ( 5 ) ineffectiveness ( ie ) : crs < 25% . the total clinical efficiency was based on the number of patients with crs 25% ( cr , br , mi , and i m ) . a follow - up ct scan was performed to assess the response of the thymoma according to who criteria . complete remission was defined as the disappearance of clinical evidence of active tumors for at least 4 weeks ; partial remission ( pr ) as a minimum 50% reduction in total tumor size for at least 4 weeks ; non - response ( nr ) as less than 50% reduction or more than 25% increase in total tumor size of existing lesions ; and progressive disease ( pd ) as more than 25% increase in any measurable lesions or appearance of new lesion(s ) . all patients were followed up until the date of death or june 2016 , and the activity and progression of the diseases were recorded . mg patients with metastatic thymoma were reviewed retrospectively . a total of 12 patients who underwent methylprednisolone pulse therapy during january 2013 to january 2016 were identified . the diagnosis of mg was based on clinical symptoms and confirmed by acetylcholine receptor antibody ( achr - ab ) test , neostigmine test , fatigue test , and electromyography tests . histological diagnosis of thymomas was performed based on the world health organization ( who ) histological classification . as shown in table 1 , 8 mg patients with metastatic thymoma were initially treated according to their clinical conditions , but the symptoms were not improved . methylprednisolone pulse therapy was begun at 1 g / day and reduced by half every 3 days until reaching 60 mg / day . oral methylprednisolone at 52 mg / day was then prescribed and the patients were discharged from the hospital . the dose of methylprednisolone was reduced and then tapered slowly on alternate days . cyclophosphamide was given simultaneously at a dose of 100 mg / day and continued for 2 months until the discontinuance of oral methylprednisolone . the clinical outcome of mg at discharge and during the follow - up was assessed based on the clinical absolute and relative scoring system . briefly , the clinical relative score ( crs ) was calculated to evaluate the improvement or deterioration of the mg : ( 1 ) clinical remission ( cr ) : crs 95% ; ( 2 ) basic remission ( br ) : 80% crs < 95% ; ( 3 ) marked improvement ( mi ) : 50% crs < 80% ; ( 4 ) improvement ( i m ) : 25% crs < 50% ; and ( 5 ) ineffectiveness ( ie ) : crs < 25% . the total clinical efficiency was based on the number of patients with crs 25% ( cr , br , mi , and i m ) . a follow - up ct scan was performed to assess the response of the thymoma according to who criteria . complete remission was defined as the disappearance of clinical evidence of active tumors for at least 4 weeks ; partial remission ( pr ) as a minimum 50% reduction in total tumor size for at least 4 weeks ; non - response ( nr ) as less than 50% reduction or more than 25% increase in total tumor size of existing lesions ; and progressive disease ( pd ) as more than 25% increase in any measurable lesions or appearance of new lesion(s ) . all patients were followed up until the date of death or june 2016 , and the activity and progression of the diseases were recorded . the medical records of 12 mg patients with metastatic thymoma who underwent methylprednisolone pulse therapy plus methylprednisolone were reviewed . the median age of the patients was 48 years ( range : 2665 years ) . clinical characteristics with regard to thymoma and mg of the patients and prior treatments are summarized in table 1 . anti - acetylcholine receptor ( anti - achr - ab ) test results were positive in all but 1 patient . the histologic types of thymoma were b2 in 4 patients , b3 in 3 patients , b1 in 2 patients , and ab in 1 patient . the clinical type of mg was iib in 8 patients , iv in 3 patients , and i in 1 patient . as shown in table 3 , the most common sites of metastases were the pleura , occurring in 5 out of 12 patients . however , biopsies were not performed in some cases ; therefore , the exact histological types of their thymomas were not available . the mean time from surgery to local metastasis was 42 months ( range : 1865 ) . the patients were initially treated by radiotherapy , docetaxel - based chemotherapy ( docetaxel plus cisplatinum or docetaxel alone ) , and/or immune globulin therapy , without improvement in clinical outcome . methylprednisolone pulse therapy was then prescribed in combination with an immunosuppressive agent ( ctx ) . after methylprednisolone pulse plus ctx therapy for 15 days , chest ct showed marked shrinkage of the thymoma in all patients . as shown in table 4 , 5 patients were in complete remission and the remaining 7 patients were in partial remission . with respect to clinical outcome of mg , the symptoms of all patients were resolved , with a remission rate of 100% ( crs 25% ) . the response to mg was mi in 6 cases , br in 4 cases , cr and i m in 1 case each . during the treatment period , 1 patient developed myasthenic crisis and the symptom infection was the most common one and occurred in 4 patients ( 3 with pulmonary infection and 1 with gastrointestinal fungal infection ) . the patients were followed up for 11.5 months ( range : 435 ) . during the follow - up , 1 patient ( case no . 8) developed pleural metastasis 20 months later and received further methylprednisolone pulse plus ctx therapy . steroids and immunosuppressive agents have both been used for treatment of mg and thymoma . the latter is generally prescribed together with steroids to allow tapering the dose of steroids . however , to the best of our knowledge , their use in treatment of mg and thymoma has been reported as case reports in only a few patients with mg - associated thymoma . therefore , we retrospectively analyzed the therapeutic potential of methylprednisolone pulse plus ctx therapy in a case series of 12 mg patients with metastatic thymoma during january 2013 to january 2016 . our study showed a marked beneficial effect of combined use of high - dose steroid pulse therapy in combination with an immunosuppressive agent in treatment of metastatic thymoma and mg . glucocorticoids are widely used for treatment of thymoma , especially for advanced or recurrent / metastatic ones . the most dramatic response has been reported in cases of subtype b1 thymoma , which contains numerous lymphocytes [ 11,2830 ] . the mechanism has been suggested to be associated with the apoptotic effects of corticosteroids on the lymphocyte component of the tumors . however , it was also reported to act on both neoplastic thymic epithelial cells and lymphocytes . glucocorticoid receptor ( gr ) is expressed in all histological types of thymoma , and no significant difference has been identified among the different subtypes . furthermore , steroid pulse therapy has been reported to induce the apoptosis of both neoplastic thymic epithelial cells and lymphocytes . in mg - associated thymoma , mg was found to be significantly more common in type b thymomas , particularly in subtype b1 . most mg - associated thymomas that have been reported to respond to glucocorticoids ( alone and combined ) were b type . corroborating the results of these studies , in the present study almost all primary thymomas high - dose methylprednisolone pulse therapy plus immunosuppressive agents dramatically reduced the tumor sizes of all patients . our findings show that glucocorticoids pulse therapy plus immunosuppressive agents is helpful for treatment of metastatic thymoma with mg . hayashi et al . suggested that high - dose methylprednisolone with chemotherapy was potentially effective for invasive thymoma , regardless of the histological subtypes of thymoma . however , in view of the few cases reported and the few cases of type a thymoma - associated mg in our study , it is hard for us to determine the therapeutic effect of glucocorticoids in different histological types of thymoma associated with mg . therefore , future studies with a larger number of patients , especially with type a thymoma - associated mg , are needed . both mg and thymoma however , high - dose glucocorticoid pulse therapy has been reported to cause transient exacerbation of mg symptoms , which may lead to use of low - dose steroids among patients and physicians . however , according to a double - blind placebo - controlled study , a single intravenous methylprednisolone pulse caused no severe adverse effects in patients with moderate mg . a comparative study of high - dose intravenous methylprednisone with low - dose oral prednisolone in an open - label , randomized trial showed more rapid improvement and fewer adverse effects in the high - dose intravenous methylprednisone group . in mg - associated thymoma , mg crisis has been reported in a patient when chemotherapy , including high - dose methylprednisolone , was prescribed for advanced thymoma . in other case studies of mg - associated thymoma , however , no adverse effects were reported with use of steroids or their combined therapy with immunosuppressive agents . our results showed some adverse effects of methylprednisolone pulse therapy plus immunosuppressive agents , most commonly infections . these variations seem to be caused by the different regimens of steroids and immunosuppressive agents used in our study . the combined treatment with  steroid - sparing immunosuppressants has been suggested to be helpful for dose - tapering of steroids , which may contribute to the reduced risk of related adverse effects . however , despite these variations , the results of our study show that methylprednisolone pulse therapy plus an immunosuppressive agent was effective and well - tolerated in synchronous treatment of mg and metastatic thymoma , without significant adverse events . primarily , it was a retrospective study without a control group ; therefore , the same diagnostic and therapeutic protocols were not available . in addition , the number of patients recruited was small and it was difficult for us to analyze the risk factors based on this small sample size , and a larger cohort study is needed . despite these limitations , our study shows therapeutic benefit of methylprednisolone pulse therapy plus immunosuppressive agents in treatment of both mg and metastatic thymoma . our study describes a series of mg patients with metastatic thymoma well controlled by methylprednisolone pulse therapy plus immunosuppressive agents ( ctx ) . our findings suggest that steroid pulse therapy in combination with immunosuppressive agents were effective and well - tolerated in treatment of both metastatic thymoma and mg . steroid pulse therapy plus immunosuppressive agents should therefore be considered in mg patients with metastatic thymoma for synchronous treatment of both thymoma and mg .
backgroundour study retrospectively reviewed the therapeutic effect of steroid pulse therapy in combination with an immunosuppressive agent in myasthenia gravis ( mg ) patients with metastatic thymoma.material/methodsmg patients with metastatic thymoma that underwent methylprednisolone pulse therapy plus cyclophosphamide were retrospectively analyzed . 
 patients initially received methylprednisolone pulse therapy followed by oral methylprednisolone . 
 cyclophosphamide was prescribed simultaneously at the beginning of treatment . 
 clinical outcomes , including therapeutic efficacy and adverse effects of mg and thymoma , were assessed.resultstwelve patients were recruited . according to histological classification , 4 cases were type b2 thymoma , 3 were type b3 , 2 were type b1 , and 1 was type ab . 
 after combined treatment for 15 days , both the thymoma and mg responded dramatically to high - dose methylprednisolone plus cyclophosphamide . 
 the symptoms of mg were improved in all patients , with marked improvement in 6 patients and basic remission in 4 . 
 interestingly , complete remission of thymoma was achieved in 5 patients and partial remission in 7 patients . 
 myasthenic crisis was observed in 1 patient and was relieved after intubation and ventilation . 
 adverse reactions were observed in 7 patients ( 58.3% ) , most commonly infections , and all were resolved without discontinuation of therapy . during the follow - up , 
 all patients were stabilized except for 1 with pleural metastasis who received further treatment and another 1 who died from myasthenic crisis.conclusionsthe present study in a series of mg patients with metastatic thymoma indicated that steroid pulse therapy in combination with immunosuppressive agents was an effective and well - tolerated for treatment of both metastatic thymoma and mg . 
 glucocorticoid pulse therapy plus immunosuppressive agents should therefore be considered in mg patients with metastatic thymoma .