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National Cancer Institute
Ultima Vez Modificado: 17 de septiembre del 2012
Thymomas and thymic carcinomas are epithelial tumors of the thymus. 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 The overall incidence of thymoma is 0.15 cases per 100,000, based on data from the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) Program. 3 Thymic carcinomas are rare and have been reported to account for only 0.06% of all thymic neoplasms. 4 In general, thymomas are indolent tumors with a tendency toward local recurrence rather than metastasis. Thymic carcinomas, however, are typically invasive, with a higher risk of relapse and death. 5 6
Most patients with thymoma or thymic carcinoma are aged 40 through 60 years. 7
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. 7
World Health Organization pathologic classification of tumors of the thymus and stage correlate with prognosis. 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 10 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.
Thymoma-associated autoimmune disease involves an alteration in circulating T-cell subsets. 12 13 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. 14 In addition to T-cell defects, B-cell lymphopenia has been observed in thymoma-related immunodeficiency, with hypogammaglobulinemia (Good syndrome) and opportunistic infection. 15 16 Patients with thymoma-associated myasthenia gravis can produce autoantibodies to a variety of neuromuscular antigens, particularly the acetylcholine receptor and titin, a striated muscle antigen. 17 18
Approximately 50% of thymomas are diagnosed when they are localized within a capsule and do not infiltrate.
At the time of diagnosis, the majority of patients with thymoma or thymic carcinoma are asymptomatic. 7 Typical clinical symptoms and signs that are indicative of anterior mediastinal mass effects include the following:
Although the oncologic prognosis of thymoma is reported to be more favorable in patients with myasthenia gravis than in patients without myasthenia gravis, 8 25 data are conflicting as to whether the presence of myasthenia gravis is an independent predictor of better outcome. Patients with myasthenia gravis are diagnosed with earlier stage disease and more often undergo complete surgical resection. 25 Treatment with thymectomy may not significantly improve the course of thymoma-associated myasthenia gravis. 26 27
Thymoma has been associated with an increased risk for second malignancies. In a review of the SEER database of thymoma cases in the United States between 1973 and 1998, 849 cases were identified (overall incidence 0.15 per 100,000 person-years). 3 In this study, there was an excess risk of non-Hodgkin lymphoma and soft tissue sarcomas.
Standard primary treatment for patients with these types of tumors is surgical resection with en bloc resection for invasive tumors, if possible. 5 7 8 29 Depending on tumor stage, there are multimodality treatment options, which include the use of radiation therapy and chemotherapy with or without surgery. 7 30
Thymic carcinomas have a greater propensity to capsular invasion and metastases than thymomas. Patients more often present with advanced disease, with a 5-year survival of 30% to 50%. 31 Owing to the paucity of cases, optimal management of thymic carcinoma has yet to be defined. As with thymoma, primary treatment is surgical resection; however, multimodality treatment with surgery, radiation, and chemotherapy are often used because of the more advanced stage and greater risk of relapse.
Because of the 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. 27 The measurement of interferon-alpha and interleukin-2 antibodies is helpful to identify patients with a thymoma recurrence. 32
The following cellular classification of thymoma and thymic carcinoma is largely based on the classification scheme presented in a World Health Organization (WHO) monograph published in 1999. 1 Malignant thymoma is invasive disease (as defined either macroscopically or microscopically) that continues to retain typically "bland" cytologic characteristics. Thymomas are a mixture of epithelial cells and lymphocytes, often T-cells, and the malignant component is represented by the epithelial cells. Malignant cytologic characteristics are considered thymic carcinomas.
Both histologic classification of thymomas and stage may have independent prognostic significance. 2 3 A few series have reported the prognostic value of the WHO classifications. In large, retrospective analyses of 100 and of 178 thymoma cases, disease-free survivals at 10 years were 95% to 100% for type A, 90% to 100% for type AB, 83% to 85% for type B1, 71% to 83% for type B2, 36% to 40% for type B3, and 28% for type C. 4 5 In both series, stage and complete resection were significant independent prognostic factors. An analysis of 273 patients treated over a 44-year period found 20-year survival rates of 100%, 87%, 91%, 59%, and 36% for patients with type A, AB, B1, B2, and B3 tumors, respectively. 2
Recurrent karyotype abnormalities have been documented in thymomas. 6 Type A thymomas have chromosome 6q deletions including the HLA locus and p21. Type B2 and B3 thymomas have additional chromosome 5q (adenomatous polyposis coli locus), 13q (retinoblastoma locus), and 17p (p53) deletions. 7 Amplifications in regions of chromosome 16 (cadherin-encoding gene) and chromosome 18 (bcl-2) have also been seen. 8 Gene expression profiling study has shown a correlation of expression of a number of genes including adhesion molecule cten, ets-1 oncogene and glycosylphosphatidyl inositol-anchored protein with thymoma stage. 9 10 11
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. 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. 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. (Refer to the 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. (Refer to the Stage Information for Thymoma and Thymic Carcinomas of this summary for more 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. of this summary for more 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. 12 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. 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. 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. 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 ) that are recently reported to be approximately 90%. 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 ) that are recently reported to be approximately 90%. 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. 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. 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%. 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. 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. 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%. 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. 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%. 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 (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. 13 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. 14
Thymic carcinomas are usually advanced when diagnosed and have a higher recurrence rate and worse survival compared with thymoma. 15 16 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. 15 In contrast to the thymomas, the association of thymic carcinoma and autoimmune disease is rare. 17
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.
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
Computed tomography (CT) with intravenous contrast may be useful in the diagnosis and clinical staging of thymoma, especially for noninvasive tumors. CT is usually accurate in predicting the following:
However, CT cannot predict invasion or resectability with accuracy. 1 2 Appearance of the tumor on CT may be related to the World Health Organization (WHO) histologic type. 3 A retrospective study involving 53 patients who underwent thymectomy for thymic epithelial tumors 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. 4
An evaluation for sites of metastases may be warranted for these patients.
Positron emission tomography of 18-flouro-deoxyglucose (FDG-PET) as well as thallium single-photon emission computed tomography have been reported in small series for diagnosis and evaluation of therapeutic outcomes in thymic carcinoma. 5 6 7 8 Two small series reported that FDG uptake was related to the invasiveness of thymic carcinoma. 7 8 This raises the possibility of FDG-PET utilization for diagnosis, treatment planning, and monitoring for recurrence. Sensitivity, specificity impact on clinical therapeutic decisions, remains to be defined.
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 9 10
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. 11 It was revised in 1994 and is shown below. 11
|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.|
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. 11 13 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. 9
In a retrospective analysis of 130 resected, thymoma patients, the WHO pathological classification was tightly correlated with stage and by multivariate analysis, tumor size, completeness of resection, histologic subtype, and stage were significant prognostic factors for survival. Of note, only four patients received neoadjuvant cisplatin-based chemotherapy and complete resection was possible in 95% of cases. The 5-year survival rate of the 11 stage IV patients was 47%. 12
Some investigators maintain that the Masaoka staging system does not accurately predict outcome for thymic carcinoma. 14 15 In one retrospective study evaluating 43 cases of thymic carcinoma, prognosis was found to be dependent solely on tumor invasion of the innominate artery. 15
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 complete, surgical resection is recommended for patients with either stage I or stage II disease. A complete resection of all tumors can be achieved in nearly all stage I and stage II patients and in 27% to 44% of stage III patients. Postoperative radiation therapy (PORT) 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 PORT with or without chemotherapy.
Most patients with thymic carcinoma have evidence of invasion of contiguous mediastinal structures at presentation.
Treatment options include the following: 1
For patients with clinically resectable disease, surgical resection is often the initial therapeutic intervention. For clinically borderline or frankly unresectable lesions, neoadjuvant (preoperative) chemotherapy or thoracic radiation therapy, or both, is given. 2 Patients presenting with locally advanced disease should be 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.
Excellent long-term survival can be obtained following complete surgical excision for a pathologic stage I thymoma. There appears to be no benefit to adjuvant radiation therapy following complete resection of encapsulated noninvasive tumors. 1 2 For patients with stage II thymomas with pathologically demonstrated capsular invasion, adjuvant radiation therapy following complete surgical excision has been considered a standard of care despite the lack of prospective clinical trials. 3 4
Most studies use 40 Gy to 70 Gy with standard fractionation scheme (1.82.0 Gy/fraction). Some, but not all, retrospective clinical studies show improved local control and survival with the addition of postoperative radiation therapy (PORT). 5 6 7 8[Level of evidence: 3iiiDiv] More recent retrospective studies have found no outcome difference in patients treated with or without PORT following complete resection of the thymic tumor. 8 9 10 11 12
In the largest series reported to date, data was obtained from 1,320 Japanese patients. 8 The Masaoka clinical stage was found to correlate well with prognosis of thymoma and thymic carcinoma. Patients with stage I thymoma were treated with surgery only, and patients with stage II thymoma underwent surgery and additional radiation therapy. Prophylactic mediastinal radiation therapy did not appear to prevent local recurrences effectively in patients with totally resected stage II thymoma.
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 where adjacent organs are within a few millimeters or involve of the surgical margin as determined by both pathological and intraoperative findings.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I thymoma and stage II thymoma. 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.
Stage III thymoma may be difficult to identify prior to surgery as invasion of adjacent subtle invasion to the adjacent organs may only be identified at the time of mediastinal exploration. Such patients often receive aggressive surgical resection including wide surgical margins with consideration of adjuvant radiation therapy. Invasion of local organs can be apparent on pretreatment computed tomographic imaging. Such patients may be offered combined modality treatment with chemotherapy followed by surgery and/or radiation therapy. 13 14 15 16 17 18 19 20 The optimal strategy for induction therapy, which minimizes operative morbidity and mortality and optimizes resectability rates and ultimately survival, currently remains unknown.
Two large series have reported outcomes. In the first study, data was obtained from 1,320 Japanese patients. 8 The Masaoka clinical stage was found to correlate well with prognosis of thymoma and thymic carcinoma. Patients with stage III thymoma underwent surgery and additional radiation therapy. Patients with stage IV thymoma were treated with radiation therapy or chemotherapy. For patients with stage III or stage IV thymoma, the 5-year survival rates were 93% for patients treated with total resection, 64% for patients treated with subtotal resection, and 36% for patients whose disease was inoperable. Prophylactic mediastinal radiation therapy did not appear to prevent local recurrences effectively in patients with totally resected stage III thymoma. Adjuvant therapy including radiation or chemotherapy did not appear to improve the prognosis in patients with totally resected stage III or stage IV thymoma. 8
In the second study, 1,334 patients diagnosed and treated between 1973 and 2005 were identified in a SEER database. At a relatively short median follow-up of 65 months, radiation therapy did not appear to increase the risk of cardiac mortality or secondary malignancy. Routine use of PORT did not appear to improve long-term survival. 20
Most invasive thymomas have been found to be relatively sensitive to cisplatin-based combination chemotherapy regimens. The combinations that follow have reported objective response rates from 79% to 100% with subsequent resectability rates ranging between 36% and 69%: 13 14 15 16 17 18 19 21
Long-term survival rates following induction chemotherapy and surgery with or without radiation therapy and consolidation chemotherapy have ranged from 50% at 4 years, 77% at 7 years and, respectively, 86% and 76% for stage II
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