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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of thymoma and thymic carcinoma. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.
Information about the following is included in this summary:
This summary 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.
Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.
This summary is available in a patient version, written in less technical language, and in Spanish.
Note: Information on thymoma in children is available in the PDQ summary on Unusual Cancers of Chilhood.
Thymomas are epithelial tumors of the thymus, which may or may not be extensively infiltrated by nonneoplastic lymphocytes. The term, thymoma, is customarily used to describe neoplasms that show no overt atypia of the epithelial component. A thymic epithelial tumor that exhibits clear-cut cytologic atypia and histologic features no longer specific to the thymus is known as a thymic carcinoma (also known as type C thymoma). [1]
Invasive thymomas and thymic carcinomas are relatively rare tumors, which together represent about 0.2% to 1.5% of all malignancies. [2] Thymic carcinomas are rare and have been reported to account for only 0.06% of all thymic neoplasms. [3] In general, thymomas are indolent tumors with a tendency toward local recurrence rather than metastasis. Thymic carcinomas, however, are typically invasive, with a high risk of relapse and death. [4] [5]
Most patients with thymoma or thymic carcinoma are aged 40 through 60 years. [6] The etiology of these types of tumors is not known. In about 50% of the patients, thymomas/thymic carcinomas are detected by chance with plain-film chest radiography. [6] Ninety percent occur in the anterior mediastinum. [7]
Approximately 30% of the patients with thymoma/thymic carcinoma are asymptomatic at the time of diagnosis. [6] In other cases, the presenting clinical signs of these types of tumors may include coughing, chest pain, and signs of upper airway congestion. Paraneoplastic autoimmune syndromes associated with thymoma include myasthenia gravis, polymyositis, lupus erythematosus, rheumatoid arthritis, thyroiditis, and Sjögren syndrome, among others. [6] [8] [9] Autoimmune pure red cell aplasia and hypogammaglobulinemia affect approximately 5% and 5% to 10%, respectively, of patients with thymoma. [7] Thymoma-associated autoimmune disease involves an alteration in circulating T-cell subsets. [10] [11] 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 export of these activated CD4+ T cells into the circulation. [12] In addition to T-cell defects, B-cell lymphopenia has been observed in thymoma-related immunodeficiency, with hypogammaglobulinemia (Good syndrome) and opportunistic infection. [13] [14] [15] In contrast to thymoma, the association of thymic carcinoma and autoimmune diseases is rare. [8] [16]
In a large retrospective study, approximately 47% of thymoma cases (excluding thymic carcinoma) were found to be associated with myasthenia gravis. [17] Although the oncologic prognosis of thymoma is reported to be more favorable in patients with myasthenia gravis than in patients without myasthenia gravis, [7] treatment with thymectomy may not significantly improve the course of thymoma-associated myasthenia gravis. [18] [19]
Thymoma and thymic carcinoma should be differentiated from a number of nonepithelial thymic neoplasms, including neuroendocrine tumors, germ cell tumors, lymphomas, stromal tumors, tumor-like lesions (such as true thymic hyperplasia), thymic cysts, metastatic tumors, and lung cancer. [1] [20] Standard primary treatment for these types of tumors is surgical with en bloc resection for invasive tumors, if possible. [4] [6] [7] [21] Depending on tumor stage, multimodality treatment includes the use of radiation therapy and chemotherapy with or without surgery. [6] [22]
Thymoma has been associated with an increased risk for second malignancies, which appears to be unrelated to thymectomy, radiation therapy, or a clinical history of myasthenia gravis. [19] [23] [24] Because of this increased risk for second malignancies and the fact that thymoma can recur after a long interval, it has been recommended that surveillance should be lifelong. [19] The measurement of interferon-alpha and interleukin-2 antibodies is helpful to identify patients with a thymoma recurrence. [25]
Although the classification of thymomas remains a source of debate, some general guidelines for a more coherent classification have emerged. The World Health Organization pathologic classification of tumors of the thymus emphasizes the importance of independent evaluations of the degree of tumor invasiveness and the tumor histology. [1] Although some thymoma histologic types are more likely to be invasive and clinically aggressive, treatment outcome and the likelihood of recurrence appear to correlate more closely with the invasive/metastasizing properties of the tumor cells. [1] [17] Therefore, some thymomas that appear to be relatively benign by histologic criteria may behave very aggressively. Independent evaluations of both the tumor invasiveness (using staging criteria) and tumor histology should be combined to predict the clinical behavior of a thymoma.
The following cellular classification of thymoma and thymic carcinoma is largely based on the classification scheme presented in a World Health Organization monograph published in 1999. [1] Although the histologic classification of thymomas may have independent prognostic significance, staging is the most important determinant of survival in thymoma patients. [2] [3] In contrast, a retrospective study of 40 patients with thymic carcinomas suggests that tumor histology is more important than stage as a prognostic indicator for survival in patients with thymic carcinoma. [4] To date, no specific chromosomal abnormalities have been associated with specific histologic types of thymoma or thymic carcinoma. [5] [6] [7] [8]
Thymoma
Thymoma is a thymic epithelial tumor in which the epithelial component exhibits no overt atypia and retains histologic features specific to the normal thymus. [1] Immature non-neoplastic lymphocytes are present in variable numbers depending on the histologic type of thymoma. The histologic types of thymoma are as follows:
Type A thymoma (also known as spindle cell thymoma and medullary thymoma) accounts for approximately 4% to 7% of all thymomas. [2] [3] Approximately 17% of this type may be associated with myasthenia gravis. [2] Morphologically, the tumor is composed of neoplastic thymic epithelial cells that have a spindle/oval shape, lack nuclear atypia, and are accompanied by few, if any, nonneoplastic lymphocytes. [1] The appearance of this tumor can be confused with that of a mesenchymal neoplasm, but the immunohistochemical and ultrastructural features are clearly those of an epithelial neoplasm. Most type A thymomas are encapsulated (see Stage Information). Some, however, may invade the capsule and, on rare occasion, may extend into the lung. Chromosome abnormalities, when present, may correlate with an aggressive clinical course. [8] The prognosis for this tumor type is excellent and have long-term survival rates (15 years or more) that are reported to be close to 100% in retrospective studies. [2] [3]
Type AB thymoma (also known as mixed thymoma) accounts for approximately 28% to 34% of all thymomas. [2] [3] Approximately 16% of this type may be associated with myasthenia gravis. [2] Morphologically, type AB thymoma is a thymic tumor in which foci having the features of type A thymoma are admixed with foci rich in nonneoplastic lymphocytes. [1] The segregation of the different foci can be sharp or indistinct, and a wide range exists in the relative amount of the two components. The prognosis for this tumor type is good and have long-term survival rates (15 years or more) that are recently reported to be approximately 90% or better in two large retrospective studies. [2] [3]
Type B1 thymoma (also known as lymphocyte-rich thymoma, lymphocytic thymoma, predominantly cortical thymoma, and organoid thymoma) accounts for approximately 9% to 20% of all thymomas and depends on the study cited. [2] [3] Approximately 57% of cases may be associated with myasthenia gravis. [2] Morphologically, this tumor resembles the normal functional thymus because it contains large numbers of cells that have an appearance almost indistinguishable from normal thymic cortex with areas resembling thymic medulla. [1] The similarities between this tumor type and the normal active thymus are such that distinction between the two may be impossible on microscopic examination. The prognosis for this tumor type is good and has a long-term survival rate (20 years or more) of approximately 90%. [2] [3]
Type B2 thymoma (also known as cortical thymoma and polygonal cell thymoma) accounts for approximately 20% to 36% of all thymomas and depends on the study cited. [2] [3] Approximately 71% of cases may be associated with myasthenia gravis. [2] Morphologically, the neoplastic epithelial component of this tumor type appears as scattered plump cells with vesicular nuclei and distinct nucleoli among a heavy population of nonneoplastic lymphocytes. [1] Perivascular spaces are common and on occasion very prominent. A perivascular arrangement of tumor cells that results in a palisading effect may be seen. This type of thymoma resembles type B1 thymoma in its predominance of lymphocytes, but foci of medullary differentiation are less conspicuous or absent. Long-term survival is decidedly worse than for thymoma types A, AB, and B1. The 20-year survival rate (as defined by freedom from tumor death) for this thymoma type is approximately 60%. [2]
Type B3 thymoma (also known as epithelial thymoma, atypical thymoma, squamoid thymoma, and well-differentiated thymic carcinoma) accounts for approximately 10% to 14% of all thymomas. Approximately 46% of this type of tumor may be associated with myasthenia gravis. [2] Morphologically, this tumor type is predominantly composed of epithelial cells that have a round or polygonal shape and that exhibit no atypia or mild atypia. [1] The epithelial cells are admixed with a minor component of nonneoplastic lymphocytes, which results in a sheet-like growth of neoplastic epithelial cells. The 20-year survival rate (as defined by freedom from tumor death) for this thymoma type is approximately 40%. [2]
Thymic Carcinoma
Thymic carcinoma (also known as type C thymoma) is a thymic epithelial tumor that exhibits a definite cytologic atypia and a set of histologic features no longer specific to the thymus but rather similar to those histologic features observed in carcinomas of other organs. [1] In contrast to type A and B thymomas, thymic carcinomas lack immature lymphocytes. Any lymphocytes that are present are mature and usually admixed with plasma cells. Hypothetically, thymic carcinoma may arise from malignant transformation of a pre-existing thymoma. [9] This hypothetical evolution could account for the existence of thymic epithelial lesions that exhibit combined features of thymoma and thymic carcinoma within the same tumor. [10]
Thymic carcinomas are usually advanced when diagnosed and have a higher recurrence rate and worse survival compared with thymoma. [4] [11] In a retrospective study of 40 patients with thymic carcinoma, the 5-year and 10-year actuarial overall survival rates were 38% and 28%, respectively. [4] In contrast to the thymomas, the association of thymic carcinoma and autoimmune disease is rare. [12]
Histologic subtypes of thymic carcinoma include the following:
This type of thymic carcinoma exhibits clear-cut cytologic atypia. In routinely stained sections, the keratinizing form exhibits equally clear-cut evidence of squamous differentiation in the form of intercellular bridges and/or squamous pearls, while the nonkeratinizing form lacks obvious signs of keratinization. Another subtype, basaloid carcinoma, is composed of compact lobules of tumor cells that exhibit peripheral palisading and an overall basophilic staining pattern caused by the high nucleocytoplasmic ratio and the absence of keratinization.
This type of thymic carcinoma has morphologic features indistinguishable from those of lymphoepithelial carcinoma of the respiratory tract. The differential diagnosis with germ cell tumors, particularly seminomas, can be difficult but important for treatment.
This is a type of thymic carcinoma in which part or all of the tumor resembles one of the types of soft tissue sarcoma.
This is a type of thymic carcinoma composed predominantly or exclusively of cells with optically clear cytoplasm.
This type of thymic carcinoma has an appearance similar to that of mucoepidermoid carcinoma of the major and minor salivary glands.
This type of thymic carcinoma grows in a papillary fashion. This histology may be accompanied by psammoma body formation, which may result in a marked similarity with papillary carcinoma of the thyroid gland.
This is a rare type of thymic carcinoma that grows in a solid undifferentiated fashion but without exhibiting sarcomatoid (spindle cell or pleomorphic) features.
Combined Thymoma
Combinations of the above histologic types can occur within the same tumor. For these cases, the term combined thymoma can be used, followed by a listing of the components and the relative amount of each component. [1]
Histologic classification of thymoma is not sufficient to distinguish biologically benign thymomas from malignant thymomas. The degree of invasion or tumor stage is generally thought to be a more important indicator of overall survival. [1] [2] [3]
Evaluating the invasiveness of a thymoma involves the use of staging criteria that indicate the presence and degree of contiguous invasion, the presence of implants, and lymph node or distant metastases regardless of histologic type. Although no standardized staging system exists, the one proposed by Masaoka in 1981 is commonly employed and is shown below. [4]
| Stage | Description |
|---|---|
| I | Macroscopically, completely encapsulated; microscopically, no capsular invasion |
| II | Macroscopic invasion into surrounding fatty tissue or mediastinal pleura; microscopic invasion into capsule |
| III | Macroscopic invasion into neighboring organs (pericardium, lung, and great vessels) |
| IVa | Pleural or pericardial dissemination |
| IVb | Lymphogenous or hematogenous metastases |
For the purposes of discussion of treatment in this summary, these stages are grouped as either noninvasive or invasive.
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 (stages 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.
Application of this staging system to a series of 85 surgically treated patients confirmed its value in determining prognosis, 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. [4] [5] 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. [1]
Some investigators maintain that the Masaoka staging system does not accurately predict outcome for thymic carcinoma. [6] [7] In one retrospective study evaluating 43 cases of thymic carcinoma, prognosis was found to be dependent solely on tumor invasion of the innominate artery. [7]
Computed tomography (CT) may be useful in the diagnosis and clinical staging of thymoma, especially for noninvasive tumors. CT is usually accurate in predicting tumor size, location, and invasion into vessels, the pericardium, and the lung. CT cannot predict, however, invasion or resectability with accuracy. [3] [8] Appearance of the tumor on CT may be related to the World Health Organization histologic type. [9] A retrospective study involving 53 patients who underwent thymectomy for thymic epithelial tumors indicates that smooth contours and a round shape are most suggestive of type A thymomas, whereas irregular contours are most suggestive of thymic carcinomas. Calcification is 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. [10]
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 stage II patients and in 27% to 44% of stage III patients. Postoperative radiation therapy is generally employed for stage II and stage 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.
Standard treatment options:
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with thymoma and thymic carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Standard treatment options:
Operable:
Inoperable (stages III and IV with vena caval obstruction, pleural involvement, pericardial implants, etc.):
Treatment options under clinical evaluation:
Of uncertainty is whether combination chemotherapy regimens are more effective than single agents; no prospective comparisons have been conducted. Transient partial responses have been reported with single-agent doxorubicin, maytansine, cisplatin, ifosfamide, and corticosteroids. Corticosteroids and many chemotherapeutic agents are lympholytic; shrinkage of thymic tumors with substantial lymphoid cell infiltration may reflect shrinkage of the nonmalignant components of the tumors rather than the malignant epithelial components.
A retrospective analysis of 17 patients treated with cisplatin alone or in combination with prednisone revealed an overall response rate of 64%. [11] Cisplatin alone (50 mg/m2 every 21 days), however, was associated with a partial response rate of only 10% (2 of 20 patients) in a phase II study (EST-2582). [12] Treatment with single-agent ifosfamide was associated with five complete responses and one partial response in 13 patients with advanced thymoma in another prospective study. [13]
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with thymoma and thymic carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)
Standard treatment options (in order of decreasing effectiveness):
Treatment options under clinical evaluation:
Of uncertainty is whether combination chemotherapy regimens are more effective than single agents; no randomized comparisons have been conducted. A partial response rate of only 10% (2 of 20 patients) was observed in a phase II study (EST-2582) of cisplatin alone (50 mg/m2 every 21 days). [6] A retrospective analysis of 17 patients treated with cisplatin with or without prednisone over a 10-year period, however, revealed an overall response rate of 64%. [7] Five complete responses and one partial response were observed in 13 patients with advanced thymoma in a prospective study of single-agent ifosfamide. [8] Transient partial responses to corticosteroids have also been noted. Corticosteroids and many chemotherapeutic agents are lympholytic; shrinkage of thymic tumors with substantial lymphoid cell infiltration may reflect shrinkage of the nonmalignant components of the tumors rather than the malignant epithelial components.
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with thymoma and thymic carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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