Masses in the anterior mediastinum can be neoplasms (eg, thymomas, thymic carcinomas, or lung metastases) or non-neoplastic conditions (eg, intrathoracic goiter). Thymomas are the most common primary tumor in the anterior mediastinum, although they are rare. Thymic carcinomas are very rare. Thymomas and thymic carcinomas originate in the thymus. Although thymomas can spread locally, they are much less invasive than thymic carcinomas. Patients with thymomas have 5-year survival rates of approximately 78%. However, 5-year survival rates for thymic carcinomas are only approximately 40%. These guidelines outline the evaluation, treatment, and management of these mediastinal tumors.

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview

Thymomas are the most common primary tumor in the anterior mediastinum, although they are rare (1.5 cases/million).1-3 Thymic carcinomas are very rare. Thymomas and thymic carcinomas originate in the thymus. Although thymomas can spread locally, they are much less invasive than thymic carcinomas.1 Patients with thymomas have 5-year survival rates of approximately 78%.4 However, 5-year survival rates for thymic carcinomas are only approximately 40%.5,6 These guidelines outline the evaluation, treatment, and management of these mediastinal tumors.

Mediastinal Masses

Masses in the anterior mediastinum can be neoplasms (eg, thymomas, lymphomas, thymic carcinomas, thymic carcinoids, thymolipomas, germ cell tumors, lung metastases) or nonneoplastic conditions (eg, intrathoracic goiter, thymic cysts, lymphangiomas, aortic aneurysms).2,7,8 Many mediastinal masses are benign, especially those occurring in asymptomatic patients; however, symptomatic patients often have malignant mediastinal lesions. All patients with a mediastinal mass should be evaluated to determine the type of mass and the extent of disease before treatment (see “Initial Evaluation,” page 4). It is essential to differentiate between thymic malignancies and other conditions (eg, lung metastases, lymphoma, goiter, and germ cell tumors) before treatment, because management differs for these conditions.9 Most masses in the mediastinum are metastases from a primary lung cancer (eg, non-small cell lung cancer). However, most primary cancers in the anterior mediastinum are thymomas.

Patients with thymomas often have an indolent presentation, whereas those with lymphoma or germ cell tumors have a rapid onset of symptoms.9 Lymphomas typically manifest as generalized disease but can also be primary anterior mediastinal lesions (ie, nodular sclerosing Hodgkin disease, non-Hodgkin’s lymphomas [diffuse large B-cell lymphoma and acute lymphoblastic lymphoma]); patients typically have lymphadenopathy (see the NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines] for Non-Hodgkin’s Lymphomas and Hodgkin Lymphoma; to view the most recent version of these guidelines, visit NCCN.org).8,10 Thymic carcinoids are rare tumors that are discussed in the NCCN Guidelines for Neuroendocrine Tumors (available at NCCN.org); they are associated with multiple endocrine neoplasia type 1 syndrome (MEN1).11,12 Lung carcinoids are discussed in the NCCN Guidelines for Small Cell Lung Cancer (see “Lung Neuroendocrine Tumors”; available at NCCN.org). Extragonadal germ cell tumors are rare tumors that occur in teenagers and young adults (http://www.cancer.gov/cancertopics/types/extragonadal-germ-cell). Recommended tests for assessing mediastinal masses include chest CT with contrast and blood chemistry studies (see “Initial Evaluation,” page 564).13-15 On CT, a thymoma is usually a well-defined round or oval mass in the thymus.13,16 Recently, low-dose CT (LDCT) was found to be useful for detecting lung cancer in high-risk individuals (see the NCCN Guidelines for Lung Cancer Screening; available at NCCN.org).17 Mediastinal masses (eg, thymomas, thymic carcinomas) may be detected in individuals undergoing lung cancer screening.

F1NCCN Clinical Practice Guidelines in Oncology: Thymomas and Thymic Carcinomas, Version 2.2013

Version 2.2013, 10-10-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 5; 10.6004/jnccn.2013.0072

F2NCCN Clinical Practice Guidelines in Oncology: Thymomas and Thymic Carcinomas, Version 2.2013

Version 2.2013, 10-10-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 5; 10.6004/jnccn.2013.0072

F3NCCN Clinical Practice Guidelines in Oncology: Thymomas and Thymic Carcinomas, Version 2.2013

Version 2.2013, 10-10-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 5; 10.6004/jnccn.2013.0072

In patients who cannot tolerate iodinated contrast, MRI of the chest may be useful.13 Combined PET/CT may be useful for determining whether distant metastases are present.18 PET/CT provides better correlation with anatomic structures than PET alone. Alpha-fetoprotein (AFP) levels and beta-human chorionic gonadotropin (β-hCG) levels may be measured to rule out germ cell tumors (see “Initial Evaluation,” page 564). Thyroid-stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4) levels may be measured to rule out mediastinal goiter.

Thymic Masses

All patients with thymic malignancies should be evaluated by radiation oncologists, surgeons, medical oncologists, diagnostic imaging specialists, and pulmonologists to determine the optimal plan of care before treatment.19 It is critical to determine whether the mass can be surgically resected; a board certified thoracic surgeon should make this decision. Total thymectomy and complete surgical excision of the tumor are the gold standard of treatment and are recommended whenever possible for most resectable tumors (see “Principles of Surgical Resection,” page 567).4,5,9,20,21 During thymectomy, the pleural surfaces should be examined for metastases. To achieve a complete gross resection, removal of pleural metastases may be appropriate in some patients.22-24 Core-needle or open biopsy is recommended for locally advanced unresectable thymic masses.7

Minimally invasive procedures are not typically recommended, because long-term data are not available regarding recurrence and survival. However, minimally invasive procedures may be considered if standard oncologic goals can be met (as described previously) and if performed in specialized centers with surgeons with expertise in these techniques.25-28 Although several staging systems exist, the Masaoka staging system is the most widely accepted system for management and determination of prognosis for both thymomas and thymic carcinomas (see Table 1 in the complete version of these guidelines, available at NCCN.org [ST-1]).4,5,29-35 The International Thymic Malignancy Interest Group (ITMIG) suggests using the Masaoka-Koga stage classification.29 The TNM staging system is less commonly used (see Table 2 in the complete version of these guidelines, available at NCCN.org [ST-1]).36 Patients with stage I to III thymomas have a 5-year survival rate of approximately 85% versus 65% for stage IV disease.4,37,38 In approximately 50% of patients, mortality is not related to thymoma.30 In approximately 20% of patients, mortality is related to myasthenia gravis.

The WHO histologic classification system can be used to distinguish among thymomas, thymic carcinomas, and thymic carcinoids (see Table 3 in the complete version of these guidelines, available at NCCN.org [ST-2]).36,39 The WHO classification is also used to differentiate among different histologic types of thymomas (ie, A, AB, B1, B2, B3); however, thymomas are difficult to classify.40 Thymic carcinomas are type C in the WHO classification, although they are very different from thymomas and are not advanced thymomas (see “Thymic Carcinomas,” page 572).41 However, the histologic subtype is less important for management than the extent of resection (ie, R0, R1, R2) (see “Postoperative Management,” page 565).5,42-45 For stage III to IV thymomas, 5-year survival rates have been reported to be 90% in patients with total resection.5 For thymic carcinomas, 5-year survival rates are lower, even in those with total resection.46

Thymomas

Thymomas typically occur in adults 40 to 70 years of age; they are rare in children or adolescents.9 Although some patients are asymptomatic, others present with chest pain, cough, or dyspnea. Approximately 30% to 50% of patients with thymomas have myasthenia gravis; therefore, patients should be evaluated for myasthenia gravis (eg, by history and/or measuring serum antiacetylcholine receptor antibody levels).37 Although thymomas can be locally invasive (eg, pleura, lung), they uncommonly spread to regional lymph nodes or distant sites.4,37 Surgery (ie, total thymectomy and complete excision of tumor) is recommended for all resectable thymomas for patients who can tolerate the surgery. For resected stage I and II thymomas, the 10-year survival rate is excellent (approximately 90% and 70%, respectively).9,47 Completeness of resection is the most important predictor of outcome.

Surgical biopsy is not necessary if a resectable thymoma is strongly suspected based on clinical and radiologic features (eg, patients have myasthenia gravis and a characteristic mass on CT).9 A transpleural approach should be avoided during biopsy of a possible thymoma.48,49 Small biopsy sampling (fine-needle or core-needle biopsy) does not always indicate whether invasion is present.50 The ITMIG has established procedures for reporting the surgical and pathologic findings from resection specimens.51

Before any surgical procedure, all patients suspected of having thymomas (even those without symptoms) should have their serum antiacetylcholine receptor antibody levels measured to determine whether they have myasthenia gravis to avoid respiratory failure during surgery. Symptoms suggestive of myasthenia gravis include drooping eyelids, double vision, drooling, difficulty climbing stairs, hoarseness, and/or dyspnea. If patients have myasthenia gravis, they should receive treatment by a neurologist with experience in myasthenia gravis before undergoing surgical resection.48,52-54

Adjuvant therapy is not recommended for completely resected (R0) stage I thymomas.20,55,56 For incompletely resected thymomas, postoperative radiation therapy (RT) is recommended (see “Postoperative Management,” page 565).20,57 Note that extensive elective nodal radiation is not recommended, because thymomas do not typically metastasize to regional lymph nodes.4,58 CT-based treatment planning is highly recommended before RT (see “Principles of Radiation Therapy,” page 568).59 RT should be given using the 3D conformal technique to reduce damage to surrounding normal tissue (eg, heart, lungs, esophagus, spinal cord).

Use of intensity-modulated RT (IMRT) may decrease the dose to the normal tissues.59,60 However, if IMRT is used, guidelines from the Advanced Technology Consortium (ATC)/NCI and American Society for Radiation Oncology/American College of Radiology (ASTRO/ACR) should be followed (http://rrp.cancer.gov/content/docs/imrt.doc).61-64 Although the normal tissue constraints recommendations for lung cancer may be used (see the “Principles of Radiation Therapy” in the NCCN Guidelines for Non-Small Cell Lung Cancer; to view the most recent version of these guidelines, visit NCCN.org), more conservative limits are recommended to minimize the dose volumes to all of the normal structures.65,66 Because these patients are younger and usually long-term survivors, the total dose to the heart should be limited to 30 Gy or less.

A definitive total dose of 60 to 70 Gy is recommended for patients with unresectable disease. For adjuvant treatment, a total dose of 45 to 50 Gy is recommended for clear or close margins; a total dose of 54 Gy is recommended for microscopically positive resection margins (see “Principles of Radiation Therapy,” page 568).59,60 However, a total dose of 60 Gy or more (1.8-2.0 Gy/fraction per day) is recommended for patients with gross residual disease after surgery.67,68

Postoperative RT can be considered in patients with thymoma and thymic carcinoma who have capsular invasion after an R0 resection, although this is a category 2B recommendation (see “Postoperative Management,” page 565).56,59,69-71 Patients with stage III (with macroscopic invasion into neighboring organs) thymoma or those with thymic carcinoma have higher risks of recurrent disease and, therefore, postoperative radiation is recommended to maximize local control.72,73 Increasing evidence suggests that patients with stage II thymoma may not benefit from postoperative radiation.20,55,56,70 Postoperative chemotherapy is also not beneficial.74

For advanced disease, chemotherapy with (or without) RT is recommended (see “Principles of Chemotherapy for Thymic Malignancies,” page 569).56,75-87 Although 6 different combination regimens are provided in the NCCN algorithm, cisplatin/doxorubicin-based regimens seem to yield the best outcomes; the panel feels that cisplatin/doxorubicin/cyclophosphamide is the preferred regimen for thymoma.20,88,89 However, nonanthracycline regimens (eg, cisplatin/etoposide [with or without ifosfamide], carboplatin/paclitaxel) may be useful for patients who cannot tolerate the more aggressive regimens.89,90 For thymic carcinoma, the panel recommends carboplatin/paclitaxel.90,91 Induction therapy followed by surgery may be useful for thymic malignancies initially considered unresectable.46,83,92,93

Second-line systemic therapy includes etoposide, ifosfamide, pemetrexed, octreotide (long-acting release [LAR]; with or without prednisone), 5-FU, gemcitabine, and paclitaxel.75,76,89,94-97 However, none of these agents have been assessed in randomized trials. Octreotide may be useful in patients with thymoma who have a positive octreotide scan or symptoms of carcinoid syndrome. After resection, surveillance for recurrence should include annual chest CT.13 Given the risk of later recurrence for thymoma, surveillance should continue for at least 10 years. Patients with thymoma also have an increased risk for second malignancies, although no particular screening studies are recommended.98

Thymic Carcinomas

Thymic carcinomas are rare aggressive tumors that often metastasize to regional lymph nodes and distant sites; thus, they have a worse prognosis than thymomas (5-year survival rates, 30%-50%).2,5,6,8,44,45,99,100 These tumors can be distinguished from thymomas because of their malignant histologic features and their different immunohistochemical and genetic features.7,36,41 However, thymic carcinomas should be differentiated from primary lung malignancies that metastasize to the thymus and have a similar histologic appearance.101,102 Thymic carcinomas often cause pericardial and pleural effusions. The Masaoka staging system can also be used to stage thymic carcinomas (see Table 1 in the complete version of these guidelines, available at NCCN.org [ST-1]).29,103,104 It is important to note that thymic carcinomas are very different from thymomas.41

Similar to thymomas, patients with completely resected thymic carcinomas have longer survival than those with either incompletely resected or are unresectable disease.44,46 Thus, management depends on the extent of resection. After resection of thymic carcinomas, postoperative management includes RT with (or without) chemotherapy, depending on the completeness of resection (see “Postoperative Management,” page 565).44,45,59 For unresectable or metastatic thymic carcinomas, chemotherapy with (or without) RT is recommended (see “Principles of Radiation Therapy” and “Principles of Chemotherapy for Thymic Malignancies,” pages 568 and 569).88

Unfortunately, thymic carcinomas respond poorly to chemotherapy; carboplatin/paclitaxel is recommended, because it has the highest response rate among thymic carcinomas in clinical trials.86,90,105-112 Data suggest that the ADOC (cisplatin, doxorubicin, vincristine, and cyclophosphamide) regimen is also effective, but it is more toxic than carboplatin/paclitaxel.110 Data are lacking regarding second-line chemotherapy for thymic carcinomas.75 Most of the second-line agents in the NCCN algorithm are appropriate for thymomas.76 However, S-1 (an oral fluorouracil) appears to be active in patients with thymic carcinomas.113,114 Targeted therapy (eg, sunitinib, sorafenib) may be useful for patients with c-Kit mutations; however, these mutations are rare in thymic carcinomas (<10%).115-118 Patients with thymomas do not have c-Kit mutations.101

Individual Disclosures for the NCCN Thymomas and Thymic Carcinomas Panel

T1

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    NCCN Clinical Practice Guidelines in Oncology: Thymomas and Thymic Carcinomas, Version 2.2013

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    NCCN Clinical Practice Guidelines in Oncology: Thymomas and Thymic Carcinomas, Version 2.2013

    Version 2.2013, 10-10-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Clinical Practice Guidelines in Oncology: Thymomas and Thymic Carcinomas, Version 2.2013

    Version 2.2013, 10-10-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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