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Home > Health Library > Thymoma and Thymic Carcinoma Treatment (Adult) (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Thymoma and thymic carcinoma (collectively termed thymic epithelial tumors [TETs]) are relatively rare tumors arising from the thymus. Although infrequent, TETs are the most common tumors of the anterior mediastinum in adults. TETs, particularly thymomas, have unique biological properties and are associated with autoimmune paraneoplastic diseases. TETs have the lowest tumor mutational burden of all solid tumors in adults. All TETs have malignant potential and the ability to metastasize. The clinical behavior of TETs can vary from relatively indolent to aggressive, resulting in a range of clinical outcomes.
Surgery is the main treatment, especially for early-stage disease. Multimodality therapy, including chemotherapy and radiation therapy, is used to treat locally advanced disease, and systemic therapy alone is indicated for metastatic TETs.
Incidence and Mortality
TETs are relatively rare tumors representing about 0.2% to 1.5% of all malignancies. The overall incidence of thymoma is 0.13 cases per 100,000 person years, based on data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program. Thymic carcinomas account for approximately 20% of all TETs. Five-year survival for inoperable, locally advanced carcinoma is 36%; for metastatic thymoma and thymic carcinoma, the 5-year survival is 24%.
Autoimmune Paraneoplastic Diseases Associated With Thymoma and Thymic Carcinomas
Autoimmune paraneoplastic diseases are associated with thymoma and are rarely associated with thymic carcinomas.[6,7,8,9]
The occurrence of autoimmune paraneoplastic diseases in patients with thymoma is related to defective negative selection of autoreactive T cells. Decreased expression of AIRE, the autoimmune regulator gene, contributes to this process. Thymoma-associated autoimmune paraneoplastic disease also involves an alteration in circulating T-cell subsets.[11,12] The primary T-cell abnormality appears to be related to the acquisition of the CD45RA+ phenotype on naive CD4+ T cells during terminal intratumorous thymopoiesis, followed by the export of these activated CD4+ T cells into the circulation.
In addition to T-cell defects, B-cell lymphopenia and the presence of anticytokine antibodies have been observed in patients with thymoma-related immunodeficiency, resulting in an increased risk of developing opportunistic infection.[6,14,15]
The most common autoimmune paraneoplastic diseases associated with thymoma are myasthenia gravis, hypogammaglobulinemia, and autoimmune pure red cell aplasia.
A variety of other autoimmune paraneoplastic diseases can be associated with TETs and include virtually any organ system.[7,9]
Thymoma patients with myasthenia gravis or other autoimmune paraneoplastic diseases are typically diagnosed with early-stage disease and are more likely to undergo complete surgical resection than are those who do not have myasthenia gravis or other autoimmune paraneoplastic diseases.[9,20] Thymectomy may not significantly improve the course of thymoma-associated autoimmune paraneoplastic disease in all cases.[21,22] The presence of autoimmune paraneoplastic disease also does not appear to be an independent prognostic factor in patients with TETs.
At the time of diagnosis, most patients with thymoma or thymic carcinoma are asymptomatic. About one-third of patients present with symptoms that arise either from the underlying tumor or from the presence of associated autoimmune paraneoplastic diseases. Typical clinical signs and symptoms include cough, dyspnea, chest pain, hoarseness of voice, phrenic nerve palsy, or signs suggestive of superior vena cava syndrome.
Diagnostic and Staging Evaluation
TETs are differentiated from a number of nonthymic neoplasms that can present with mediastinal masses, including the following:[25,26]
Nonneoplastic thymic conditions that can present with mediastinal masses include thymic hyperplasia and thymic cysts.
The following tests and procedures may be used in the diagnosis and staging of thymoma and thymic carcinoma:
The appearance of the tumor on CT may indicate the histologic tumor type. In a retrospective study involving 53 patients who underwent thymectomy for TETs, CT indicated that smooth contours with a round shape were most suggestive of type A thymomas, and irregular contours were most suggestive of thymic carcinomas. Calcification was suggestive of type B thymomas. In this study, however, CT was found to be of limited value differentiating type AB, B1, B2, and B3 thymomas.
Thymic carcinoma can metastasize to regional lymph nodes, bone, liver, or lungs. An evaluation for sites of metastases may be warranted.
Prognostic Factors and Prognosis
The World Health Organization (WHO) pathologic classification of tumors of the thymus and stage correlate with prognosis. The degree of invasion or tumor stage is generally thought to be a more important indicator of overall survival (OS).[27,35,36]
Histologic classification of thymoma is not sufficient to distinguish biologically indolent thymomas from thymomas that exhibit aggressive clinical behavior. Although some thymoma histologic types are more likely to be clinically aggressive, treatment outcome and the likelihood of recurrence appear to correlate more closely with the invasive/metastasizing properties of the tumor cells.[25,35] Therefore, some thymomas that appear to be relatively benign by histologic criteria may behave very aggressively. Independent evaluations of both tumor invasiveness (using staging criteria) and tumor histology may be combined to predict the clinical behavior of a thymoma.
Both histologic classification of thymomas and stage may have independent prognostic significance.[35,36] A few series have reported the prognostic value of the WHO classifications. Two large retrospective analyses, one with 100 thymoma cases and the other with 178 thymoma cases, showed that disease-free survival at 10 years varied (refer to Table 1).[37,38] In these series, stage and complete resection were significant independent prognostic factors. Another analysis reported on 273 thymoma patients who were treated over a 44-year period. Refer to Table 1 for the 20-year survival rates.
Thymic carcinomas are usually advanced when diagnosed.[39,40] Thymic carcinomas have a greater propensity for capsular invasion, metastases, and recurrence than thymomas. Patients with thymic carcinoma have a worse survival compared with thymoma (5-year survival rate, 30%–50%). In a retrospective study of 40 patients with thymic carcinoma, the OS rates were 38% for 5 years and 28% for 10 years. In another retrospective study evaluating 43 cases of thymic carcinoma, prognosis was found to be dependent solely on tumor invasion of the brachiocephalic artery.
Follow-up After Treatment of Thymoma
Thymoma has been associated with an increased risk of second malignancies. Because of this risk and because thymoma can recur after a long interval, lifelong surveillance should be considered. The measurement of interferon-alpha and interleukin-2 antibodies is helpful in identifying patients with a thymoma recurrence.
In a study of 849 cases between 1973 and 1998, there was an excess risk of subsequent non-Hodgkin lymphoma and soft tissue sarcomas following thymoma. Risk of second malignancy does not appear to be related to thymectomy, radiation therapy, or a clinical history of myasthenia gravis.[22,43,44]
Refer to the following PDQ summary for additional information related to thymoma:
The histological classification of thymic epithelial tumors (TETs) has evolved and is largely based on the third edition of the World Health Organization (WHO) classification of tumors of the lung, pleura, thymus, and heart that was published in 2004. The fourth edition of the WHO classification, published in 2015, contains refined histological and immunohistochemical diagnostic criteria and is the most widely accepted cellular classification of TETs.[1,2] Thymomas arise from the thymic epithelium and consist of epithelial cells mixed with varying proportions of immature T cells. Thymic carcinomas are epithelial tumors with overt cytological atypia and without organotypic (i.e., thymus-like) features.
The epithelial component of thymomas exhibit no or minimal overt atypia and retain histologic features specific to the normal thymus. Immature nonneoplastic lymphocytes are present in variable numbers depending on the histologic type of thymoma.
Table 2, Table 3, Table 4, Table 5, and Table 6 describe morphologic, molecular, and clinical characteristics of various subtypes of thymoma.
Thymic carcinoma is a TET that exhibits a definite cytologic atypia and a set of histologic features no longer specific to the thymus but similar to histologic features observed in carcinomas of other organs. Unlike type A and B thymomas, thymic carcinomas lack immature lymphocytes. Any lymphocytes that are present are mature and usually admixed with plasma cells.
The characteristics of thymic carcinoma subtypes are described in Table 7.
Molecular Characteristics of Thymoma and Thymic Carcinomas
TETs have the lowest mutational burden of all adult cancers. Multiplatform analyses have revealed four molecular subtypes that are associated with survival and WHO histological subtypes. Mutations in HRAS, NRAS, TP53, and GTF2I have been observed. Targetable mutations are uncommon. Tumor overexpression of muscle autoantigens and increased aneuploidy have also been identified and provide a molecular link between thymoma and myasthenia gravis.
Evaluating the invasiveness of a thymoma involves the use of staging criteria that indicate the presence and degree of contiguous invasion, the presence of tumor implants, and lymph node or distant metastases regardless of histologic type. The staging system, proposed by Masaoka in 1981 and modified by Koga in 1994, is most commonly used, with the modified system being recommended for use by the International Thymic Malignancies Interest Group (ITMIG) (refer to Table 8).[1,2] To establish consistency in the staging of thymic epithelial tumors (TETs), the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) adopted a new TNM (tumor, node, metastasis) classification system developed by the International Association for the Study of Lung Cancer (IASLC) and ITMIG.[3,4,5]
AJCC Stage Groupings and TNM Definitions
When the Masaoka staging system was applied to a series of 85 surgically treated thymoma patients, its value in determining prognosis was confirmed, with 5-year survival rates of 96% for stage I disease, 86% for stage II disease, 69% for stage III disease, and 50% for stage IV disease. In a large, retrospective study involving 273 patients with thymoma, 20-year survival rates (as defined by freedom from tumor death) according to the Masaoka staging system were reported to be 89% for stage I disease, 91% for stage II disease, 49% for stage III disease, and 0% for stage IV disease.
The TNM staging system, applicable to thymoma and thymic carcinoma, is based on a large, global database of more than 10,000 subjects, as opposed to smaller series of fewer than 100 patients that were used to develop older staging systems. The TNM system also benefits from rigorous statistical analysis of a large pool of data and input from a multidisciplinary panel of experts. The rate of disease recurrence was 5% in patients with stage I disease, 18% for stage II disease, 32% for stage III disease, 59% for stage IVA disease, and 49% for stage IVB disease. The death rate was 7% in patients with stage I disease, 16% for stage II disease, 18% for stage III disease, 30% for stage IVA disease, and 33% for stage IVB disease.
Standard primary treatment for patients with thymoma or thymic carcinoma is surgical resection with en bloc resection for invasive tumors, if possible.[1,2,3] Depending on tumor stage, multimodality treatment options—which include the use of radiation therapy and chemotherapy with or without surgery—may be used.[4,5] The optimal strategy for induction therapy, which minimizes operative morbidity and mortality and optimizes resectability rates and ultimately survival, remains unknown. A review of the management of thymic epithelial tumors has been published.
For patients presenting with a mediastinal mass that is highly suspicious for an early-stage thymic epithelial tumor (TET) and is potentially completely resectable, surgical resection is the preferred initial treatment. Under these circumstances, surgical resection serves as a diagnostic and therapeutic procedure. Complete resection of the tumor can be achieved in nearly all patients with stage I and stage II TETs.
Postoperative radiation therapy (PORT) is associated with survival benefit and is generally recommended for patients with stage II or stage III disease. Patients with stage IVA disease are usually offered multimodality therapy consisting of induction chemotherapy followed by surgery (if the disease is considered resectable) and PORT.[3,4,5,6] Patients with stage IVB disease are treated with definitive chemotherapy.[7,8,9,9,10] Surgery and radiation therapy usually do not have a role as primary treatment modalities for advanced disease.
Stage I and Stage II Thymoma
Standard treatment options for stages I and II thymoma
Standard treatment options for stage I and stage II thymoma (operable disease) include the following:
Surgery (stage I)
Excellent long-term survival can be obtained after complete surgical excision for a pathologic stage I thymoma. There appears to be no benefit to adjuvant radiation therapy after complete resection of encapsulated noninvasive tumors.[1,11]
Surgery with or without radiation therapy (PORT) (stage II)
For patients with stage II thymomas with pathologically demonstrated capsular invasion, adjuvant radiation therapy after complete surgical excision has been considered a standard of care despite the lack of prospective clinical trials.[12,13] Most studies use 40 Gy to 70 Gy with a standard fractionation scheme (1.8–2.0 Gy per fraction).
The role and risks of adjuvant radiation therapy for patients with completely resected stage II thymomas need further study. To avoid the potential morbidity and costs associated with thoracic radiation, PORT may be reserved for stage II patients when adjacent organs are within a few millimeters or involve the surgical margin (close or positive surgical margins) as determined by both pathological and intraoperative findings.
Evidence (surgery followed by PORT):
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Stage III and Stage IV Thymoma
Treatment options for operable or potentially operable stages III and IV thymoma
Advances in imaging techniques have resulted in more accurate staging of TETs. However, on occasion, stage III thymoma may be difficult to identify before surgery, and invasion of adjacent mediastinal structures may be identified only at the time of surgery.
Surgical resection with curative intent should be considered for all patients deemed to have resectable stage III thymoma after the initial work-up. PORT is offered to all patients regardless of surgical margin status because it is associated with longer overall survival (OS).
Combined-modality treatment consisting of induction chemotherapy followed by surgery and radiation therapy should be considered for all patients with unresectable stage III thymoma. The optimal strategy for induction therapy, which optimizes resectability rates and ultimately survival, is not defined. However, commonly used induction chemotherapy regimens include combinations of cisplatin, doxorubicin, and cyclophosphamide, or cisplatin and etoposide. Rates of response to induction chemotherapy ranged from 79% to 100%, with subsequent resectability rates of 36% to 69%.[3,4,5,6,7,22,23,24,25]
Treatment options for operable or potentially operable stage III and stage IV thymoma include the following:
Evidence (treatment of stage III and IV operable or potentially operable thymoma):
Treatment options for inoperable stages III and IV thymoma
Treatment options for patients with inoperable stage III and stage IV thymoma include the following:
The role of surgical debulking for patients with either stage III or stage IVA disease is controversial. Phase II data suggest that prolonged survival can be accomplished with chemotherapy and radiation therapy alone in many patients who present with locally advanced or even metastatic thymoma. The value of surgery may be questioned if complete or, at the very least, near-complete extirpation cannot be accomplished.
Evidence (treatment of stage III and IV inoperable thymoma):
The optimal treatment of thymic carcinoma remains undefined because of its rarity. For patients with clearly resectable well-defined disease, surgical resection is often the initial therapeutic intervention. For patients with clinically borderline or frankly unresectable lesions, neoadjuvant (preoperative) chemotherapy, thoracic radiation therapy, or both, have been given. Patients presenting with locally advanced disease are carefully evaluated and undergo multimodality therapy. Patients with poor performance status and high associated operative risks are generally not considered for these types of aggressive treatments. Patients with metastatic disease may respond to combination chemotherapy.
Standard Treatment Options for Thymic Carcinoma
Standard treatment options for patients with operable thymic carcinoma include the following:
Standard treatment options for patients with inoperable thymic carcinoma (stage III and stage IV with vena caval obstruction, pleural involvement, pericardial implants, etc.) include the following:
In most published studies, surgery has been followed by adjuvant radiation therapy.[3,4] A prescriptive dose range has yet to be identified. Most studies use 40 Gy to 70 Gy with a standard fractionation scheme (1.8–2.0 Gy per fraction).
Evidence (surgery followed by PORT with or without postoperative chemotherapy):
The results from these studies call into question conventional thinking regarding the efficacy of an aggressive multimodality approach including debulking, radiation therapy, and cisplatin-based chemotherapy.[6,7,8] While other studies support the addition of adjuvant radiation therapy and chemotherapy, optimum treatment regimens are undetermined.
Chemotherapy is the primary treatment modality for patients with inoperable thymic carcinoma. Most regimens used are similar to those used to treat thymoma and include a platinum compound with or without an anthracycline (PAC [cisplatin, doxorubicin, cyclophosphamide], VIP [etoposide, ifosfamide, and cisplatin], ADOC [doxorubicin, cisplatin, vincristine, cyclophosphamide], cisplatin/etoposide, carboplatin/paclitaxel).[1,9,10,11,12,13,14]
Standard Treatment Options for Recurrent Thymoma and Thymic Carcinoma
Standard treatment options for recurrent thymoma and thymic carcinoma include the following:
A number of studies have demonstrated that certain chemotherapy drugs can induce tumor responses as single-agent or combination therapy. These drugs include pemetrexed, gemcitabine, taxanes, capecitabine, or 5-fluorouracil and etoposide. In general, higher response rates have been reported with combinations, however, no randomized trials have been conducted. In most cases of inoperable disease recurrence, single-agent systemic therapy is preferred. Combination chemotherapy can be considered in selected cases where patients have demonstrated a good response previously, have had a long recurrence-free interval and good performance status, and in the case of anthracycline-containing regimen, have not received high cumulative doses previously, which can jeopardize safety, especially in relation to cardiac toxicity.
Evidence (single-agent chemotherapy):
Evidence (combination chemotherapy):
Octreotide with or without prednisone may induce responses in patients with octreotide scan–positive thymoma. Objective responses have also been observed with sunitinib and everolimus in patients with recurrent TETs.
Octreotide with or without prednisone
Evidence (octreotide with or without prednisone):
Surgical resection may be repeated, particularly for local recurrences and, in some cases, pleural and pericardial implants. Patients with recurrent thymomas who undergo repeat resection of recurrent disease may have prolonged survival when complete resection is attained. However, only a minority of patients may be candidates for resection.
Of note, patients in these series may have received chemotherapy and/or radiation therapy in addition to surgery.
Postoperative radiation therapy has been used for patients with incomplete resections and has been employed in selected patients after complete resections of recurrent thymomas. Radiation therapy is also indicated for palliation of symptoms such as pain due to chest wall invasion, and superior vena cava syndrome.
Treatment Options Under Clinical Evaluation for Recurrent Thymoma and Thymic Carcinoma
Pembrolizumab (anti-programmed death ligand 1 antibody) has been evaluated in patients with recurrent TETs.
Immune checkpoint inhibitor therapy is under clinical evaluation and should be used in the context of a clinical trial.
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Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult thymoma and thymic carcinoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
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Levels of Evidence
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PDQ® Adult Treatment Editorial Board. PDQ Thymoma and Thymic Carcinoma Treatment (Adult). Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/thymoma/hp/thymoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389476]
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Last Revised: 2020-05-14
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