Thymoma and Thymic Carcinoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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Thymoma and Thymic Carcinoma Treatment

Purpose of This PDQ Summary

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:

  • Diagnosis.
  • Etiology.
  • Signs and symptoms.
  • Cellular classification.
  • Staging.
  • Treatment options by cancer stage.

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.

General Information

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.

References:

1. Rosai J: Histological Typing of Tumours of the Thymus. New York, NY: Springer-Verlag, 2nd ed., 1999.
2. Fornasiero A, Daniele O, Ghiotto C, et al.: Chemotherapy of invasive thymoma. J Clin Oncol 8 (8): 1419-23, 1990.
3. Greene MA, Malias MA: Aggressive multimodality treatment of invasive thymic carcinoma. J Thorac Cardiovasc Surg 125 (2): 434-6, 2003.
4. Ogawa K, Toita T, Uno T, et al.: Treatment and prognosis of thymic carcinoma: a retrospective analysis of 40 cases. Cancer 94 (12): 3115-9, 2002.
5. Blumberg D, Burt ME, Bains MS, et al.: Thymic carcinoma: current staging does not predict prognosis. J Thorac Cardiovasc Surg 115 (2): 303-8; discussion 308-9, 1998.
6. Schmidt-Wolf IG, Rockstroh JK, Schüller H, et al.: Malignant thymoma: current status of classification and multimodality treatment. Ann Hematol 82 (2): 69-76, 2003.
7. Cameron RB, Loehrer PJ Sr, Thomas CR Jr: Neoplasms of the mediastinum. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 845-58.
8. Levy Y, Afek A, Sherer Y, et al.: Malignant thymoma associated with autoimmune diseases: a retrospective study and review of the literature. Semin Arthritis Rheum 28 (2): 73-9, 1998.
9. Thomas CR, Wright CD, Loehrer PJ: Thymoma: state of the art. J Clin Oncol 17 (7): 2280-9, 1999.
10. Hoffacker V, Schultz A, Tiesinga JJ, et al.: Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease. Blood 96 (12): 3872-9, 2000.
11. Buckley C, Douek D, Newsom-Davis J, et al.: Mature, long-lived CD4+ and CD8+ T cells are generated by the thymoma in myasthenia gravis. Ann Neurol 50 (1): 64-72, 2001.
12. Ströbel P, Helmreich M, Menioudakis G, et al.: Paraneoplastic myasthenia gravis correlates with generation of mature naive CD4(+) T cells in thymomas. Blood 100 (1): 159-66, 2002.
13. Tarr PE, Sneller MC, Mechanic LJ, et al.: Infections in patients with immunodeficiency with thymoma (Good syndrome). Report of 5 cases and review of the literature. Medicine (Baltimore) 80 (2): 123-33, 2001.
14. Montella L, Masci AM, Merkabaoui G, et al.: B-cell lymphopenia and hypogammaglobulinemia in thymoma patients. Ann Hematol 82 (6): 343-7, 2003.
15. Cucchiara BL, Forman MS, McGarvey ML, et al.: Fatal subacute cytomegalovirus encephalitis associated with hypogammaglobulinemia and thymoma. Mayo Clin Proc 78 (2): 223-7, 2003.
16. Ritter JH, Wick MR: Primary carcinomas of the thymus gland. Semin Diagn Pathol 16 (1): 18-31, 1999.
17. Okumura M, Ohta M, Tateyama H, et al.: The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: a clinical study of 273 patients. Cancer 94 (3): 624-32, 2002.
18. Budde JM, Morris CD, Gal AA, et al.: Predictors of outcome in thymectomy for myasthenia gravis. Ann Thorac Surg 72 (1): 197-202, 2001.
19. Evoli A, Minisci C, Di Schino C, et al.: Thymoma in patients with MG: characteristics and long-term outcome. Neurology 59 (12): 1844-50, 2002.
20. Strollo DC, Rosado-de-Christenson ML: Tumors of the thymus. J Thorac Imaging 14 (3): 152-71, 1999.
21. Moore KH, McKenzie PR, Kennedy CW, et al.: Thymoma: trends over time. Ann Thorac Surg 72 (1): 203-7, 2001.
22. Ogawa K, Uno T, Toita T, et al.: Postoperative radiotherapy for patients with completely resected thymoma: a multi-institutional, retrospective review of 103 patients. Cancer 94 (5): 1405-13, 2002.
23. Pan CC, Chen PC, Wang LS, et al.: Thymoma is associated with an increased risk of second malignancy. Cancer 92 (9): 2406-11, 2001.
24. Engels EA, Pfeiffer RM: Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies. Int J Cancer 105 (4): 546-51, 2003.
25. Buckley C, Newsom-Davis J, Willcox N, et al.: Do titin and cytokine antibodies in MG patients predict thymoma or thymoma recurrence? Neurology 57 (9): 1579-82, 2001.

Cellular Classification

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

    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

    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

    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

    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

    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:

  • Squamous cell (epidermoid) thymic carcinoma

    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.

  • Lymphoepithelioma-like thymic carcinoma

    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.

  • Sarcomatoid thymic carcinoma (carcinosarcoma)

    This is a type of thymic carcinoma in which part or all of the tumor resembles one of the types of soft tissue sarcoma.

  • Clear cell thymic carcinoma

    This is a type of thymic carcinoma composed predominantly or exclusively of cells with optically clear cytoplasm.

  • Mucoepidermoid thymic carcinoma

    This type of thymic carcinoma has an appearance similar to that of mucoepidermoid carcinoma of the major and minor salivary glands.

  • Papillary thymic adenocarcinoma

    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.

  • Undifferentiated thymic carcinoma

    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]

References:

1. Rosai J: Histological Typing of Tumours of the Thymus. New York, NY: Springer-Verlag, 2nd ed., 1999.
2. Okumura M, Ohta M, Tateyama H, et al.: The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: a clinical study of 273 patients. Cancer 94 (3): 624-32, 2002.
3. Chen G, Marx A, Wen-Hu C, et al.: New WHO histologic classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China. Cancer 95 (2): 420-9, 2002.
4. Ogawa K, Toita T, Uno T, et al.: Treatment and prognosis of thymic carcinoma: a retrospective analysis of 40 cases. Cancer 94 (12): 3115-9, 2002.
5. Zettl A, Ströbel P, Wagner K, et al.: Recurrent genetic aberrations in thymoma and thymic carcinoma. Am J Pathol 157 (1): 257-66, 2000.
6. Zhou R, Zettl A, Ströbel P, et al.: Thymic epithelial tumors can develop along two different pathogenetic pathways. Am J Pathol 159 (5): 1853-60, 2001.
7. Inoue M, Marx A, Zettl A, et al.: Chromosome 6 suffers frequent and multiple aberrations in thymoma. Am J Pathol 161 (4): 1507-13, 2002.
8. Penzel R, Hoegel J, Schmitz W, et al.: Clusters of chromosomal imbalances in thymic epithelial tumours are associated with the WHO classification and the staging system according to Masaoka. Int J Cancer 105 (4): 494-8, 2003.
9. Suster S, Moran CA: Thymic carcinoma: spectrum of differentiation and histologic types. Pathology 30 (2): 111-22, 1998.
10. Suster S, Moran CA: Primary thymic epithelial neoplasms showing combined features of thymoma and thymic carcinoma. A clinicopathologic study of 22 cases. Am J Surg Pathol 20 (12): 1469-80, 1996.
11. Blumberg D, Burt ME, Bains MS, et al.: Thymic carcinoma: current staging does not predict prognosis. J Thorac Cardiovasc Surg 115 (2): 303-8; discussion 308-9, 1998.
12. Levy Y, Afek A, Sherer Y, et al.: Malignant thymoma associated with autoimmune diseases: a retrospective study and review of the literature. Semin Arthritis Rheum 28 (2): 73-9, 1998.

Stage Information

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]

Thymoma Staging System of Masaoka

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]

References:

1. Okumura M, Ohta M, Tateyama H, et al.: The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: a clinical study of 273 patients. Cancer 94 (3): 624-32, 2002.
2. Chen G, Marx A, Wen-Hu C, et al.: New WHO histologic classification predicts prognosis of thymic epithelial tumors: a clinicopathologic study of 200 thymoma cases from China. Cancer 95 (2): 420-9, 2002.
3. Sperling B, Marschall J, Kennedy R, et al.: Thymoma: a review of the clinical and pathological findings in 65 cases. Can J Surg 46 (1): 37-42, 2003.
4. Masaoka A, Monden Y, Nakahara K, et al.: Follow-up study of thymomas with special reference to their clinical stages. Cancer 48 (11): 2485-92, 1981.
5. Cameron RB, Loehrer PJ Sr, Thomas CR Jr: Neoplasms of the mediastinum. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 845-58.
6. Ritter JH, Wick MR: Primary carcinomas of the thymus gland. Semin Diagn Pathol 16 (1): 18-31, 1999.
7. Blumberg D, Burt ME, Bains MS, et al.: Thymic carcinoma: current staging does not predict prognosis. J Thorac Cardiovasc Surg 115 (2): 303-8; discussion 308-9, 1998.
8. Rendina EA, Venuta F, Ceroni L, et al.: Computed tomographic staging of anterior mediastinal neoplasms. Thorax 43 (6): 441-5, 1988.
9. Rosai J: Histological Typing of Tumours of the Thymus. New York, NY: Springer-Verlag, 2nd ed., 1999.
10. Tomiyama N, Johkoh T, Mihara N, et al.: Using the World Health Organization Classification of thymic epithelial neoplasms to describe CT findings. AJR Am J Roentgenol 179 (4): 881-6, 2002.

Treatment Option Overview

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.

Noninvasive Thymoma and Thymic Carcinoma

STANDARD TREATMENT OPTIONS:

1. Surgical resection: Complete resection of a well-encapsulated, noninvasive thymoma is usually curative and has a risk of local recurrence of less than 2%.[1] In patients with myasthenia gravis, operative mortality can 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. Radiation therapy should be considered, however, in rare cases when a noninvasive thymoma is incompletely resected, and when the patient is a poor surgical risk.[1]

Current Clinical Trials

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.

References:

1. McKenna WG, Bonomi P, Barnes MM, et al.: Malignancies of the thymus. In: Roth JA, Ruckdeschel JC, Weisenburger TH: Thoracic Oncology. Philadelphia, Pa: WB Saunders Co, 1989, pp 466-477.

Invasive Thymoma and Thymic Carcinoma

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:

1. En bloc surgical resection if possible. In patients with myasthenia gravis, operative mortality can 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 stage IVa patients. Retrospective clinical studies show improved local control and survival with the addition of postoperative radiation therapy.[1,2,3][Level of evidence: 3iiiDiv]

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% of the cases. 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.[4,5,6][Level of evidence: 3iiiDiv] Of uncertainty is whether patients who undergo tumor debulking have a better prognosis than 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. Combination chemotherapy has been reported to produce both complete and partial remissions; however, 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 three complete responses. The median duration of response was 12 months, and the 5-year survival rate was 32%.[7] [Level of evidence: 3iiiDiv] In another series, the ADOC regimen (doxorubicin, cisplatin, vincristine, cyclophosphamide) produced a 92% response rate (34 of 37 patients), including complete responses in 43% of the patients.[8] A study of combined chemotherapy with cisplatin and etoposide produced responses in 9 of 16 patients treated, with a median response duration of 3.4 years and a median survival of 4.3 years.[9] In yet another study, 9 of 28 patients with invasive thymoma or thymic carcinoma who received four cycles of etoposide, ifosfamide, and cisplatin at 3-week intervals had partial responses.[10] The median duration of response was 11.9 months (range, <1 to 26 months), and the median overall survival was 31.6 months. The 1-year and 2-year survival rates were 89% and 70%, respectively.[10][Level of evidence: 3iiiDiv] Other combination chemotherapy regimens remain under evaluation (E-1C99).

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]

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 stage III or stage 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] Another similar study of 12 patients reported 100% survival and 73% disease-free survival at 7 years.[16][Level of evidence: 3iiiDiv] Additional clinical studies are needed to confirm the value of preoperative chemotherapy before it can be recommended for routine use in this disease.
3. Combined chemotherapy and radiation therapy for unresectable tumors: An intergroup study of patients with unresectable disease who received the PAC regimen (cisplatin, doxorubicin, and cyclophosphamide) followed by thoracic radiation reported a 5-year survival rate of 52%.[17][Level of evidence: 3iiiDiv]

Current Clinical Trials

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.

References:

1. Ariaratnam LS, Kalnicki S, Mincer F, et al.: The management of malignant thymoma with radiation therapy. Int J Radiat Oncol Biol Phys 5 (1): 77-80, 1979.
2. Penn CR, Hope-Stone HF: The role of radiotherapy in the management of malignant thymoma. Br J Surg 59 (7): 533-9, 1972.
3. Curran WJ Jr, Kornstein MJ, Brooks JJ, et al.: Invasive thymoma: the role of mediastinal irradiation following complete or incomplete surgical resection. J Clin Oncol 6 (11): 1722-7, 1988.
4. Ciernik IF, Meier U, Lütolf UM: Prognostic factors and outcome of incompletely resected invasive thymoma following radiation therapy. J Clin Oncol 12 (7): 1484-90, 1994.
5. Jackson MA, Ball DL: Post-operative radiotherapy in invasive thymoma. Radiother Oncol 21 (2): 77-82, 1991.
6. Mornex F, Resbeut M, Richaud P, et al.: Radiotherapy and chemotherapy for invasive thymomas: a multicentric retrospective review of 90 cases. The FNCLCC trialists. Fédération Nationale des Centres de Lutte Contre le Cancer. Int J Radiat Oncol Biol Phys 32 (3): 651-9, 1995.
7. Loehrer PJ Sr, Kim K, Aisner SC, et al.: Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol 12 (6): 1164-8, 1994.
8. Fornasiero A, Daniele O, Ghiotto C, et al.: Chemotherapy for invasive thymoma. A 13-year experience. Cancer 68 (1): 30-3, 1991.
9. Giaccone G, Ardizzoni A, Kirkpatrick A, et al.: Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 14 (3): 814-20, 1996.
10. Loehrer PJ Sr, Jiroutek M, Aisner S, et al.: Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial. Cancer 91 (11): 2010-5, 2001.
11. Park HS, Shin DM, Lee JS, et al.: Thymoma. A retrospective study of 87 cases. Cancer 73 (10): 2491-8, 1994.
12. Bonomi PD, Finkelstein D, Aisner S, et al.: EST 2582 phase II trial of cisplatin in metastatic or recurrent thymoma. Am J Clin Oncol 16 (4): 342-5, 1993.
13. Highley MS, Underhill CR, Parnis FX, et al.: Treatment of invasive thymoma with single-agent ifosfamide. J Clin Oncol 17 (9): 2737-44, 1999.
14. Rea F, Sartori F, Loy M, et al.: Chemotherapy and operation for invasive thymoma. J Thorac Cardiovasc Surg 106 (3): 543-9, 1993.
15. Macchiarini P, Chella A, Ducci F, et al.: Neoadjuvant chemotherapy, surgery, and postoperative radiation therapy for invasive thymoma. Cancer 68 (4): 706-13, 1991.
16. Shin DM, Walsh GL, Komaki R, et al.: A multidisciplinary approach to therapy for unresectable malignant thymoma. Ann Intern Med 129 (2): 100-4, 1998.
17. Loehrer PJ Sr, Chen M, Kim K, et al.: Cisplatin, doxorubicin, and cyclophosphamide plus thoracic radiation therapy for limited-stage unresectable thymoma: an intergroup trial. J Clin Oncol 15 (9): 3093-9, 1997.

Recurrent Thymoma and Thymic Carcinoma

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):

1. Repeat surgical resection, particularly for local recurrences and, in some cases, pleural and pericardial implants. Postoperative radiation therapy has been used 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. Because of the rarity of these cancers, all series of patients have been relatively small and reflect weak evidence. Combination chemotherapy, however, 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 three complete responses. The median duration of response was 12 months, and 5-year survival was 32%.[2][Level of evidence: 3iiiDiv] In another study, the ADOC regimen (doxorubicin, cisplatin, vincristine, cyclophosphamide) produced a 92% response rate (34 of 37 patients), including complete responses in 43% of patients.[3] One study of combined chemotherapy with cisplatin and etoposide produced responses in 9 of 16 patients treated, with a median response duration of 3.4 years and a median survival of 4.3 years.[4] Nine of 28 patients with invasive thymoma or thymic carcinoma who received four cycles of etoposide, ifosfamide, and cisplatin at 3-week intervals had partial responses.[5] The median duration of response was 11.9 months (range, <1 to 26 months), and the median overall survival was 31.6 months. The 1-year and 2-year survival rates were 89% and 70%, respectively.[5][Level of evidence: 3iiiDiv]

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.

Current Clinical Trials

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.

References:

1. Urgesi A, Monetti U, Rossi G, et al.: Aggressive treatment of intrathoracic recurrences of thymoma. Radiother Oncol 24 (4): 221-5, 1992.
2. Loehrer PJ Sr, Kim K, Aisner SC, et al.: Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol 12 (6): 1164-8, 1994.
3. Fornasiero A, Daniele O, Ghiotto C, et al.: Chemotherapy for invasive thymoma. A 13-year experience. Cancer 68 (1): 30-3, 1991.
4. Giaccone G, Ardizzoni A, Kirkpatrick A, et al.: Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 14 (3): 814-20, 1996.
5. Loehrer PJ Sr, Jiroutek M, Aisner S, et al.: Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial. Cancer 91 (11): 2010-5, 2001.
6. Bonomi PD, Finkelstein D, Aisner S, et al.: EST 2582 phase II trial of cisplatin in metastatic or recurrent thymoma. Am J Clin Oncol 16 (4): 342-5, 1993.
7. Park HS, Shin DM, Lee JS, et al.: Thymoma. A retrospective study of 87 cases. Cancer 73 (10): 2491-8, 1994.
8. Harper PG, Highly M, Rankin E, et al.: Ifosfamide monotherapy demonstrates high activity in malignant thymoma. [Abstract] Proceedings of the American Society of Clinical Oncology 10: A-1049, 300, 1991.

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Date Last Modified: 2008-05-08

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