Thymoma is one of the most common primary tumors of the anterior mediastinum and is a group of diseases with unique clinicopathological features and multiple paraneoplastic symptoms that originate from different thymic epithelial cells. Ninety percent of thymic tumors are thymomas, and the rest are thymic carcinomas, lymphomas and carcinoid tumors. Thymoma accounts for less than 1% of all adult malignancies and approximately 30% of adult anterior mediastinal tumors. According to the National Cancer Institute, the incidence rate of thymoma in the United States is 0.15/100,000, and there is no relevant data reported in China. The age of prevalence of thymoma is 50-60 years old, with a median age of 56 years old, and the incidence is higher in men than in women, but rare in children. The etiology of thymoma is not clear, but some scholars have confirmed that some patients have previous history of radiation therapy and EBV infection.
I. Clinical manifestations
The majority of thymomas are located in the thymus of the anterosuperior mediastinum, while a very small number may occur ectopically in the posterior mediastinum, lower neck, around the hilum, pleura or lung parenchyma. Smaller thymomas may be asymptomatic; when the tumor grows to a certain size, it may produce symptoms of compression and irritation of surrounding tissues, such as chest pain, chest tightness, cough and anterior chest discomfort. Clinically, 1/3 of patients with thymic malignancy present with asymptomatic anterior mediastinal masses, which are mostly detected during imaging examinations; 1/3 present with local symptoms, such as cough, dyspnea, chest pain, hemoptysis, dysphagia, hoarseness, superior vena cava compression syndrome, phrenic nerve palsy, etc.; another 1/3 present with paraneoplastic syndrome, the most common one is myasthenia gravis, about 30%-50% of patients with thymoma have myasthenia gravis. Patients with myasthenia gravis, and simple erythrocyte aplasia, hypoglobulinemia, nephritis nephrotic syndrome, rheumatoid arthritis, dermatomyositis, lupus erythematosus, megalophagia, etc., of which myasthenia gravis is the most common (about 30% of patients with myasthenia gravis combined with thymoma).
Imaging examination
Nearly 80% of patients with thymoma show abnormal mediastinal contours or masses on orthopantomogram. MRI is more advantageous for evaluating whether the lesion invades blood vessels.
Clinical staging and histological staging
The most widely used staging method for thymoma was developed by Masaoka in 1981, and modified in 1994, the Masaoka staging definition of thymoma is: Stage I: tumor is confined to the thymus without pericardial infiltration both visually and microscopically; Stage II: Stage IIa: pericardial infiltration microscopically, Stage IIb: infiltration of surrounding fatty tissue is visible visually, but confined to the mediastinal pleura; Stage III Stage IV: Stage IVa: pleural cavity dissemination (pleural or pericardial metastasis); Stage IVb: lymphatic or hematogenous metastasis, extrathoracic dissemination (bone metastasis is the most common); Stage I is non-invasive thymoma; Stage II and above are invasive thymoma.
Histologic staging is mostly based on WHO (1999) thymoma staging.
Type A thymoma: i.e., medullary or spindle cell thymoma.
AB thymoma: i.e., mixed thymoma.
Type B thymoma: classified into 3 subtypes.
Type B1 thymoma: i.e., lymphocyte-rich thymoma, lymphocytic thymoma, cortical-dominant thymoma, or organoid thymoma.
Type B2 thymoma: i.e., cortical thymoma.
Type B3 thymoma: i.e., epithelial, atypical, squamous epithelioid thymoma or well-differentiated thymic carcinoma.
Type C thymoma: i.e. thymic carcinoma. Histologically this type has more malignant features than other types of thymoma.
IV. Treatment
Surgery, radiotherapy and chemotherapy are the three main treatments for thymoma, and the treatment of thymic carcinoma is similar to thymoma.
1. Surgery
Surgery is the most effective treatment for thymoma, and all cases that can be resected should be carefully evaluated by a professional team: the surgical resection rate for stage I patients is 95-100%, and the resection rate for stage II disease is also easier, with a complete resection rate of 85%-100%, with a high recurrence rate for patients classified as type B2, type B3 and thymic carcinoma. 65-80% of stage III patients are completely resected. Even with postoperative radiotherapy, nearly 50% of patients will recur within 5 years, with recurrence mostly within the pleura or lung and rarely spreading outside the chest cavity. Surgery alone is not the most effective treatment for stage IVa thymoma patients, with complete resection rates of only 30-40%. In recent years, expanded surgical treatment and multidisciplinary treatment modalities have significantly improved the survival rate of stage IVa patients, and current data show that the 5-year survival rate of stage IVa patients is 40-78%.
2.Radiotherapy
Thymoma cells are sensitive to radiotherapy, and radiotherapy plays an important role in the treatment of thymoma, including postoperative adjuvant therapy and radiotherapy for patients with advanced, unresectable and recurrent disease. Tumor stage is the main basis for deciding whether or not to administer radiotherapy after surgery, but the WHO type of tumor should also be considered.
The recurrence rate after complete resection of stage I thymoma is extremely low (0.9%), and radiotherapy is not required after surgery. stage II thymoma with sarcoid envelope, peri-mediastinal fat invasion, or pleural adhesions has an increased risk of recurrence after surgery, and the 5-year survival rate of stage II is 98%, and the recurrence rate is 4%. There has been controversy over whether to administer conventional radiotherapy to stage II patients, and to date, a growing number of studies have confirmed that patients with completely resected stage II thymomas do not benefit from radiotherapy. In contrast, stage III and IV thymomas and thymic carcinomas have a high recurrence rate (28% and 34%) and should be treated with postoperative radiotherapy to control local recurrence.
Radiotherapy is not recommended for stage I thymomas with sufficiently large surgical margins, but should be administered if they are type B3. For stage II patients, the recurrence rate is higher in type B patients than in type A. Type B2, B3 and thymic carcinoma would benefit from adjuvant radiotherapy even without microscopic invasion of the pleura, and the mediastinal recurrence rates in these patients with and without radiotherapy are 0% and 36.4%, respectively. utsumi et al. analyzed the prognosis of 324 patients with completely resected thymoma, and patients with type A, AB, and B1 after surgical resection alone did not require radiotherapy, and the optimal treatment strategy for patients with types B2 and B3 remains to be explored. If the lesion is immediately adjacent to an organ, radiotherapy is recommended to reduce the risk of local recurrence. Postoperative radiotherapy should be performed for stage II and III patients with incomplete resection to control the lesions and reduce the recurrence rate.
In general, the recommended dose of postoperative radiotherapy for thymoma is 45 Gy-55 Gy; for postoperative residual lesions, the dose can be up to 60 Gy. Currently, the recommended radiotherapy methods are three-dimensional conformal radiotherapy or intensity-modulated radiotherapy with clinical target areas including the entire thymic volume, tumor site, anterior, superior, and middle mediastinum (with field reduction at 50 Gy-55 Gy), and prophylactic supraclavicular lymph node radiotherapy is not recommended. There is no unanimous conclusion on the dose of radiotherapy for thymic carcinoma; radiotherapy doses of 40 Gy-70 Gy at 1.8 Gy/dose – 2.0 Gy/dose are mostly used. The side effects of radiotherapy for thymoma include acute pericarditis and pneumonia, and late side effects include coronary artery disease and pulmonary fibrosis, and the incidence of toxic side effects of radiotherapy of degree 3/4 is 5-10%.
3.Chemotherapy
Chemotherapy can be used for the palliative treatment of advanced thymoma, neoadjuvant chemotherapy and treatment of recurrent disease. When combined with radiotherapy, the sequence is sequential radiotherapy to avoid increasing the toxic side effects of treatment. Thymoma is relatively sensitive to chemotherapy. The current standard regimen for thymoma is a combination regimen based on cisplatin and anthracyclines, including PAC, ADOC, PE and VIP, but which chemotherapy regimen is the best has not been clarified.
4.Treatment of thymoma with myasthenia gravis
One third of thymoma patients show paraneoplastic syndrome, and the most common one is myasthenia gravis. About 30%-50% of thymoma patients have myasthenia gravis, and about 30% of myasthenia gravis patients have thymoma in combination. Myasthenia gravis (MG) is an acquired autoimmune disease mediated by antibodies to acetylcholine receptors, cellular immune-dependent, complement-involved, and primarily involving acetylcholine receptors in the postsynaptic membrane of the neuromuscular junction. Initial clinical manifestations: ptosis (73%), diplopia, strabismus, or limb weakness; late manifestations: dysphagia and dyspnea. Overexertion, viral infections and inappropriate use of drugs can aggravate the disease and even induce myasthenia gravis crisis, in which respiratory muscle weakness resulting in respiratory distress can cause death by asphyxiation within a short period of time. The cause of myasthenia gravis may be related to genetic factors: not only with the major histocompatibility antigen complex (MHC) gene but also with non-MHC genes, such as T receptors, immunoglobulins, cytokines, apoptosis and other genes; clinical studies show that thymic hypertrophy, thymoma and myasthenia gravis are related: about 30% of myasthenia gravis patients have thymoma in combination, 40%-60% have thymoma in combination with myasthenia gravis. More than 75% of patients have central hyperplasia of thymus tissue.
Clinical treatment of myasthenia gravis.
(1) Cholinesterase inhibitors.
Cholinesterase inhibitors are the first-line drugs for the treatment of all types of MG and are used to improve clinical symptoms. The dose of their use should be individualized and should generally be combined with other immunosuppressive drugs, of which pyridostigmine bromide is the most commonly used cholinesterase inhibitor. Adverse effects: nausea, diarrhea, gastrointestinal cramps, bradycardia and increased respiratory secretions. The maximum clinical application dose is 480 mg/d in China.
(2) Glucocorticoids.
Glucocorticosteroids are the first-line drugs for the treatment of MG, which can significantly improve the symptoms of 70% – 80% of MG patients. During the use of glucocorticosteroids, the condition must be closely observed, 40% – 50% of MG patients with muscle weakness symptoms in 4 – 10 d transient aggravation and may promote muscle weakness crisis, at the same time should pay attention to steroid myopathy, supplementation of calcium, vitamin D and (3) Intravenous propecia should be used to prevent osteoporosis, and antacids should be used to prevent gastrointestinal complications.
(3) Intravenous gammaglobulin.
Gammaglobulin is mainly used for MG patients with acute progressive disease and pre-surgical preparation, and can be used in combination with immunosuppressive drugs with slow onset of action or high-dose glucocorticoids that may induce myasthenia gravis crisis, mostly taking effect about 5 – 10 d after use, and the effect can last for about 2 months. Repeated use in stable patients with moderate to severe MG does not increase the efficacy or decrease the amount of glucocorticoids used. Adverse effects include headache, aseptic meningitis, flu-like symptoms and renal impairment.
(4) Other.
Respiratory muscle training and strength exercise in patients with mild MG may improve muscle strength (Class C, Class III evidence). Patients are advised to control body weight, limit daily activities appropriately, and get seasonal influenza vaccine.
V. Summary
Although thymoma develops relatively slowly, it is still an aggressive disease. stage I and II thymoma should be surgically resected, and some stage II patients may benefit from postoperative radiotherapy. Comprehensive multidisciplinary treatment plays an important role in stage III and IVa thymomas. Most of the existing multiple chemotherapy regimens include cisplatin and anthracyclines. Future multicenter prospective clinical studies and targeted therapy studies should be conducted for thymoma to explore more effective therapeutic approaches.