Thymomas are epithelial tumors which may or may not be extensively infiltrated by lymphocytes. A histologic classification has been proposed that divides thymomas into three major subtypes: cortical, medullary, and mixed. These histologic subtypes have been shown to correlate with the degree of local invasion and most studies suggest that histologic type correlates with prognosis.1,2
Cortical and predominantly cortical thymomas are associated with greater risk of invasion than other thymomas.1,3
Other thymic tumors that need to be differentiated from thymoma include thymic carcinomas, germ cell tumors, lymphomas, carcinoids, and T-cell leukemias.4,5
Because no reliable histologic features of malignancy exist, determination of the malignant nature of a thymoma is difficult. Malignancy can only be demonstrated by the finding of invasion of the tumor capsule or surrounding organs, or by the presence of a metastasis. About 30% to 40% of all thymomas are invasive.4,5 References:

Although there is no standardized staging system, the one proposed by Masaoka in 1981 is commonly employed and is shown below. Application of this staging system to a series of 85 surgically-treated patients confirmed its value in determining prognosis.

I Totally encapsulated
II Capsular invasion and/or invasion into surrounding fat or pleura
III Invasion into organs (pericardium, lung, great vessels)
IVa Pleural or pericardial implants
IVb Hematogenous metastases

Noninvasive

In noninvasive (stage I) disease, the tumor is limited to the thymus gland and has not involved other tissues. All of the tumor cells remain within a fibrous capsule that surrounds the tumor.

Invasive

In locally invasive (stage II) disease, the tumor has broken through the capsule and invaded the fat or pleura.
In extensively invasive (stage III and IVa) disease, the tumor has spread contiguously from the thymus gland to involve other organs in the chest.
Spread to organs in the abdomen or metastatic embolic spread (stage IVb) is unusual at the time of presentation. Computed tomography may be useful in the diagnosis and clinical staging of thymoma, especially for noninvasive tumors. It is usually accurate in predicting tumor size, location, and invasion into vessels, pericardium and lung. However, it cannot predict microscopic invasion or resectability with accuracy.1
For the purposes of the discussion of treatment in this summary, the disease is categorized as either noninvasive or invasive. References:

Most thymomas are diagnosed and staged at the time of surgical intervention. Surgical resection is the preferred treatment of patients who can tolerate surgery and have a mediastinal mass that is suspected of being a thymoma.
A total thymectomy with complete resection of all tumor can be achieved in nearly all stage I and II patients and in 27% to 44% of stage III patients.
Postoperative radiation therapy is generally employed for stage II and III patients.
Patients with stage IVa disease can only rarely be resected completely and are usually offered debulking surgery and postoperative radiation therapy, with or without chemotherapy. The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations. NONINVASIVE MALIGNANT THYMOMA Back Up

Standard treatment options:
1. Surgical resection: Complete resection of a well-encapsulated, noninvasive thymoma is usually curative, with a risk of local recurrence of less than 2%.1 In patients with myasthenia gravis, operative mortality can now be minimized with close attention to respiratory support when planning surgical treatment.
2. Radiation therapy is not indicated following complete resection of a well-encapsulated thymoma. However, radiation therapy should be considered in rare cases when a noninvasive thymoma is incompletely resected, and when the patient is a poor surgical risk.1 References:

Standard treatment options:
Operable:
1. En bloc surgical resection if possible: In patients with myasthenia gravis, operative mortality can now be minimized with close attention to respiratory support when planning surgical treatment.
2. Following surgical resection, radiation therapy is generally recommended whether or not the surgical resection has been complete, especially for stage III and IVa patients. Retrospective clinical studies show improved local control and survival with the addition of postoperative radiation therapy.1-3 Inoperable (stages III and IV with vena caval obstruction, pleural involvement, pericardial implants, etc.): Radiation therapy: In patients who have residual macroscopic tumor following biopsy or attempted resection, radiation therapy has been reported to achieve local control in 60% to 90%. Because of an increased risk of radiation-induced injury, doses greater than 60 Gy should be avoided. Overall 5-year survival rates of approximately 50% are reported for patients with unresectable stage III tumors.4-6 It is uncertain whether patients who undergo tumor debulking have an improved prognosis compared with those who undergo biopsy only.4,6

Treatment options under clinical evaluation:
1. Chemotherapy:
Only a few phase II clinical studies have evaluated the role of chemotherapy in adequate numbers of patients. However, combination chemotherapy has been reported to produce both complete and partial remissions; some of the complete remissions have been pathologically confirmed at subsequent surgery.
In a series of 30 patients with stage IV or locally progressive recurrent tumor following radiation therapy, the PAC regimen (cisplatin, doxorubicin, cyclophosphamide) achieved a 50% response rate, including 3 complete responses. The median duration of response was 12 months and 5-year survival was 32%.7
The ADOC regimen (doxorubicin, cisplatin, vincristine, cyclophosphamide) produced a 92% response rate (34 of 37 patients), including complete responses in 43%.8 One trial of combined chemotherapy with cisplatin and etoposide produced responses in 9 out of 16 patients treated, with a median response duration of 3.4 years and a median survival of 4.3 years.9
It remains uncertain whether combination chemotherapy regimens are more effective than single agents; no prospective comparisons have been conducted. Transient partial responses have been reported with doxorubicin, maytansine, cisplatin, ifosfamide, and corticosteroids. Retrospective analysis of 17 patients treated with cisplatin alone or combined with prednisone revealed an overall response rate of 64%.10
However, a phase II trial of cisplatin (50 milligrams per square meter every 21 days) was associated with a partial response rate of only 10% (2 of 20 patients).11
A phase II trial of ifosfamide reported 7 complete and 1 partial response in 13 patients with advanced thymoma.12
Other combination chemotherapy regimens remain under study.13

2. Neoadjuvant chemotherapy followed by resection:
A few studies have reported on the use of chemotherapy followed by surgery with or without radiation therapy for patients with clinically advanced disease.14,15
One series of 16 patients with stages III or IVa disease were treated with initial ADOC chemotherapy. All patients achieved a clinical response to chemotherapy. Eleven patients had residual histologic tumor and received postoperative radiation therapy. The median survival of the entire group was 66 months.14
Additional clinical trials are needed to confirm its value before preoperative chemotherapy can be recommended for routine use in this disease.

3. Combined chemotherapy and radiation therapy for unresectable tumors.
An intergroup trial of patients with unresectable disease who received cisplatin, doxorubicin, and cyclophosphamide followed by thoracic radiation reported a 5- year survival rate of 52%.16[Level of evidence: 3iii]

4. Other clinical trials. References:

Standard treatment options (in order of decreasing effectiveness):

1. Repeat surgical resection, particularly for local recurrences and, in some cases, pleural and pericardial implants. Postoperative radiation therapy has a role for patients with incomplete resections and has been employed in selected patients following complete resection of recurrent thymoma.1

2. Radiation therapy (when possible, based on previous treatment).

3. Corticosteroids in unresectable tumors that have not responded to radiation therapy. Treatment options under clinical evaluation:
1. Chemotherapy: Only a few phase II clinical studies have evaluated the role of chemotherapy in adequate numbers of patients. However, combination chemotherapy has been reported to produce complete and partial remissions; some of the complete remissions have been pathologically confirmed at subsequent surgery. In a series of 30 patients with stage IV or locally progressive recurrent tumor following radiation therapy, the PAC regimen (cisplatin, doxorubicin, cyclophosphamide) achieved a 50% response rate, including 3 complete responses. The median duration of response was 12 months and 5-year survival was 32%.2
The ADOC regimen (doxorubicin, cisplatin, vincristine, cyclophosphamide) produced a 92% response rate (34 of 37 patients), including complete responses in 43%.3
One trial of combined chemotherapy with cisplatin and etoposide produced responses in 9 out of 16 patients treated, with a median response duration of 3.4 years and a median survival of 4.3 years.4
It remains uncertain whether combination chemotherapy regimens are more effective than single agents; no randomized comparisons have been conducted. Transient partial responses to corticosteroids have been noted. One phase II trial of cisplatin (50 milligrams per square meter every 21 days) was associated with a partial response rate of only 10% (2 of 20 patients).5
A retrospective analysis of 17 patients treated with cisplatin with or without prednisone over a ten-year period revealed an overall response rate of 64%.6
A phase II trial of ifosfamide reported 7 complete and 1 partial response in 13 patients with advanced thymoma.7

2. Other clinical trials. References: