Clinical presentation and management of thymoma and thymic carcinoma

INTRODUCTION — Thymic tumors are rare neoplasms that arise in the anterior mediastinum. The clinical presentation, diagnosis, staging, and management of thymoma and thymic carcinoma are reviewed here.

The pathology of thymic carcinomas, the initial approach to patients with an anterior mediastinal mass, and the diagnosis and management of thymic neuroendocrine tumors are discussed separately. (See "Pathology of mediastinal tumors", section on 'Thymoma' and "Pathology of mediastinal tumors", section on 'Thymic carcinoma' and "Approach to the adult patient with a mediastinal mass" and "Thymic neuroendocrine (carcinoid) tumors".)

EPIDEMIOLOGY — In adults, thymomas and thymic carcinomas are the most common neoplasms arising in the thymus. Thymomas account for about 20 percent of mediastinal neoplasms (table 1). Most thymoma patients are between 40 and 60 years of age, and there is a similar incidence in males and females [1]. There are no known risk factors, and there is a strong association with myasthenia gravis and other paraneoplastic syndromes.

CLINICAL PRESENTATION — Thymomas and thymic carcinomas typically present in one of three major ways:

●As an incidental finding identified on imaging in an asymptomatic patient (image 1)

●Due to local (thoracic) symptoms

●Due to symptoms from a paraneoplastic syndrome

Thymoma

Thoracic manifestations — Thymomas typically are localized to the thymic gland and surrounding organs. Thoracic symptoms due to an anterior mediastinal mass are related to the size of the tumor and its effects on adjacent organs (eg, chest pain, shortness of breath, cough, phrenic nerve palsy). Some patients present with superior vena cava syndrome. (See "Malignancy-related superior vena cava syndrome", section on 'Clinical features'.)

Pleural or pericardial effusions are the most common manifestation of more disseminated disease and may also cause thoracic symptoms.

Paraneoplastic disorders — The most common paraneoplastic syndrome associated with thymoma is myasthenia gravis. However, a wide range of other autoimmune paraneoplastic syndromes has been reported, and a partial list is provided (table 2).

Paraneoplastic syndromes may antedate the presentation with thymoma, be diagnosed concurrently with the thymic tumor, or occur after treatment (with or without evidence of tumor recurrence).

Myasthenia gravis and several other important paraneoplastic syndromes associated with thymoma are briefly discussed in this section. More detailed discussions are presented separately.

●Myasthenia gravis – Myasthenia gravis is an autoimmune disorder caused by interference by auto-antibodies with acetylcholine receptors of voluntary muscle at the neuromuscular junction. Common symptoms include diplopia, ptosis, dysphagia, weakness, and fatigue. (See "Clinical manifestations of myasthenia gravis" and "Pathogenesis of myasthenia gravis".)

Up to one-half of patients with thymoma have symptoms consistent with myasthenia gravis [1]. Myasthenia gravis is common with all types of thymoma, but is rare in thymic carcinoma. Males and females are equally affected.

Patients with thymoma and myasthenia gravis usually present with less advanced disease than those without myasthenia gravis, possibly because neuromuscular symptoms may lead to an earlier diagnosis [2-4]. In patients with thymoma and myasthenia gravis, thymectomy usually results in an attenuation of the severity of myasthenia gravis, although some symptoms persist in most patients [5]. (See "Overview of the treatment of myasthenia gravis" and "Role of thymectomy in patients with myasthenia gravis".)

●Pure red cell aplasia – Pure red cell aplasia results from an autoimmune-mediated hypoproliferation of erythrocyte precursors in the bone marrow. This paraneoplastic disorder occurs in 5 to 15 percent of patients with thymoma and is more common in older adult females. Pure red cell aplasia is usually seen with tumors that have spindle cell morphology [6,7]. (See "Acquired pure red cell aplasia in adults".)

Although older reports suggested that thymectomy resulted in normalization of the marrow in up to 40 percent of cases [8,9], subsequent observations suggest that remission following surgical excision alone is uncommon [10]. Nonetheless, surgical resection of the thymoma is usually undertaken if pure red cell aplasia is found.

The management of pure red cell aplasia is discussed separately. (See "Acquired pure red cell aplasia in adults", section on 'Management'.)

●Immunodeficiency – Hypogammaglobulinemia and pure white blood cell aplasia are present in fewer than 5 percent of patients with thymoma, most commonly in older adult females [6]. Conversely, up to 10 percent of patients with acquired hypogammaglobulinemia have an associated thymoma (Good syndrome), typically of spindle cell histology [9]. (See "Primary humoral immunodeficiencies: An overview" and "Immune neutropenia".)

Patients usually have recurrent infections, diarrhea, and lymphadenopathy. As an example, in a review of 51 cases of thymoma-associated immunodeficiency, 19 patients had recurrent sinopulmonary infection, 12 had candidiasis (including 1 with candidemia), 7 had bacteremia, 12 had cytomegalovirus (only 5 with clinical manifestations), 6 had diarrhea, and several had a variety of other infections (including 3 with pneumocystis pneumonia) [11]. Thymectomy does not reliably lead to the return of normal immunoglobulin levels. (See "Primary humoral immunodeficiencies: An overview" and "Immune neutropenia".)

●Thymoma-associated multiorgan autoimmunity – Several case reports have described a syndrome of thymoma-associated multiorgan autoimmunity (TAMA) that is similar to graft-versus-host disease [12,13]. Patients presented with variable combinations of a morbilliform skin eruption, chronic diarrhea, and liver enzyme abnormalities. Histopathology of the skin or bowel mucosa is similar to that seen with graft-versus-host disease. (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

Thymic carcinoma — Thymic carcinomas are more aggressive than thymomas; evidence of invasion of mediastinal structures is present in the majority of these patients [14]. As with thymomas, most patients present with cough, chest pain, phrenic nerve palsy, or superior vena cava syndrome. Extrathoracic metastases are seen in fewer than 7 percent of patients at presentation, most commonly to the liver and bone, but may virtually develop in any site, including the brain, kidney, extrathoracic lymph nodes, adrenals, and thyroid [15].

INITIAL EVALUATION, DIAGNOSIS, AND STAGING

Diagnostic evaluation — The initial evaluation of a patient with an anterior mediastinal mass should include thoracic imaging (computed tomography [CT] and/or magnetic resonance imaging [MRI]), which can often show whether the thymoma is well circumscribed (image 2) or if it infiltrates surrounding structures (image 3). This imaging establishes the presence of an anterior mediastinal mass and provides the initial information to determine whether or not such a mass is resectable. The evaluation of patients with an anterior mediastinal mass is discussed separately in more detail. (See "Approach to the adult patient with a mediastinal mass", section on 'Thymoma and thymic carcinoma' and "Approach to the adult patient with a mediastinal mass", section on 'Tissue diagnosis'.)

Imaging findings may provide initial evidence that a tumor is thymic carcinoma rather than thymoma. Carcinomas often contain necrotic, cystic, or calcified areas (image 4) [16]. The tumor contour is often irregular compared with thymoma, which tends to be smooth [17]. Differences in MRI signal pattern and positron emission tomography (PET) scan appearance may also provide the initial evidence that distinguishes between thymomas and thymic carcinomas [18,19]. PET scans are often negative in more well-differentiated thymomas, but are highly positive in carcinomas [20,21].

Key elements of the differential diagnosis of an anterior mediastinal mass include not only thymoma and thymic carcinoma, but also retrosternal thyroid, lymphoma, and mediastinal germ cell tumor. Thus, preoperative evaluation may include germ cell tumor markers (beta-human chorionic gonadotropin [hCG] and alpha fetoprotein), as well as pulmonary function tests.

The definitive diagnosis of a thymoma or thymic carcinoma requires a tissue diagnosis:

●For patients thought to have a thymoma that will be amenable to complete resection, the initial step in management is surgical resection, which can definitively establish the diagnosis. (See 'Resectable disease' below.)

●For patients with a tumor that is not considered amenable to complete resection or in whom surgery is contraindicated because of age or comorbidity, a tissue diagnosis with a core needle biopsy or an open biopsy is required prior to therapy.

The World Health Organization (WHO) system is widely used to classify thymic neoplasms based upon their histologic appearance (table 3) [22]. Histologic classification may be difficult, particularly when classification is based upon a biopsy with a relatively limited amount of tissue. Furthermore, it may be impossible to determine whether a thymoma is invasive based upon a biopsy. The pathology of thymomas and thymic carcinoma is discussed in detail elsewhere and correlates with the biologic behavior of the tumor and with prognosis. (See "Pathology of mediastinal tumors", section on 'Thymoma' and "Pathology of mediastinal tumors", section on 'Thymic carcinoma' and 'Prognosis' below.)

Staging

Staging systems — Thymomas and thymic carcinomas are staged according to the tumor, node, metastasis (TNM) staging of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) (table 4). Thymic neuroendocrine tumors, which are also staged using this system, are discussed separately. (See "Thymic neuroendocrine (carcinoid) tumors", section on 'Staging classification'.)

The rationale for inclusion of thymic cancers staging in the eighth edition of the Tumor, Node, Metastasis (TNM) staging system is to provide a common platform that will allow direct comparisons of results between different series [23]. For the eighth edition of the AJCC TNM staging system, data on survival outcomes of 10,808 patients were analyzed.

Other staging systems have also been used to stage thymic carcinomas, including the Masaoka staging system, which has been used in many studies and continues to be widely used (table 5) [24-29]. In this topic, the AJCC staging system is used, unless otherwise noted. However, the majority of the data supporting treatment decisions have been based on patients staged using the Masaoka system, which is indicated when relevant.

Pathologic considerations — Staging of thymic neoplasms, including both thymomas and thymic carcinoma, is based upon the extent of the primary tumor and the presence of invasion into adjacent structures and/or dissemination. In approximately two-thirds of thymomas and thymic carcinomas, preoperative chest CT can accurately predict the pathologic TNM stage [30].

The AJCC TNM staging system does not require distinguishing between encapsulated tumors and tumors that invade through the capsule into the surrounding adipose tissue (picture 1). The presence of transcapsular spread should be noted when it is identified. Microscopic examination of possible invasion of adjacent organs and structures including the pericardium, mediastinal pleura, phrenic nerves, lung, and large vessels, amongst others, should also always be mentioned. Pleural implants and metastases need to be microscopically confirmed.

Thymomas and thymic carcinomas may be adherent to adjacent structures without invasion. In such cases, the surgeon should designate the site of adhesion on the specimen so that the pathologist can take sections from that area. An inflammatory fibrous reaction can also lead to the false impression of tumor invasion. The resection specimen should be oriented by the surgeon to identify the exact margins of resection, which should then be inked. Furthermore, lymph nodes need to be sampled from the resection specimen for microscopic evaluation, noting their location in the mediastinum (N1 [anterior [perithymic]] versus N2 [deep intrathoracic or cervical]). Further details on the pathology of mediastinal tumors are discussed separately. (See "Pathology of mediastinal tumors".)

MANAGEMENT OF LOCALIZED DISEASE

General approach — There are no randomized clinical trials that provide definitive guidance for the management of these patients. The following approach is consistent with guidelines from the National Comprehensive Cancer Network (NCCN) [26] and by the Cancer Care Ontario program [24].

Further studies are needed to determine the indications and benefits associated with combined-modality approaches. International efforts are underway through the International Thymic Malignancy Interest Group and other groups to standardize therapy definitions and reporting guidelines for thymic tumors so that more can be understood about the role of various treatments, including various doses and forms of radiation therapy (RT) [31].

Resectable disease — Surgery is indicated as the initial treatment for patients in whom a complete, R0 resection is considered feasible, ie, those with completely encapsulated tumors or those with tumors invading readily resectable structures, such as the mediastinal pleura, pericardium, or adjacent lung. Histopathologic examination of the resection specimen is required for definitive staging and determines whether postoperative RT or chemotherapy are recommended. (See 'Postoperative radiation therapy' below and 'Chemotherapy regimens' below.)

Because of the increased surgical risks, patients with myasthenia gravis should be carefully evaluated preoperatively; if signs or symptoms of myasthenia gravis are present, these should be treated medically prior to surgery, and care should be taken by the anesthesiology team during and after the operation in order to avoid respiratory failure due to myasthenia gravis. (See "Role of thymectomy in patients with myasthenia gravis", section on 'Perioperative management' and "Overview of the treatment of myasthenia gravis" and "Anesthesia for the patient with myasthenia gravis" and "Anesthesia for patients with an anterior mediastinal mass".)

For most patients, surgical management typically includes total (ie, extended) resection of the thymus and lymph node dissection. Various surgical approaches can be used (eg, traditional median sternotomy, video- or robotic-assisted approaches) and are discussed in more detail elsewhere [23]. (See "Thymectomy", section on 'Procedure'.)

The ability to completely resect a thymoma or thymic carcinoma is determined by the extent of tumor, including the degree of invasion and/or adhesion of the tumor to contiguous structures [32]. Resection of the pericardium as well as accompanying lung parenchyma is sometimes required to achieve a complete resection with histologically negative margins. The likelihood of long-term survival depends upon the completeness of surgical resection [32,33]. (See 'Prognosis' below.)

An inflammatory fibrous reaction can mimic tumor invasion, and tumor may be adherent to adjacent structures without being invasive. In such cases, the surgeon should identify the site of adhesion on the resection specimen, so the pathologist can take careful sections from that area.

For those with early stage resectable thymoma (ie, Masaoka stage I or II) without myasthenia gravis, total (ie, extended) thymectomy is typically the standard of care. Although the use of partial thymectomy is becoming more frequent, particularly in Asia, many clinicians in the United States consider it to be investigational. (See "Thymectomy", section on 'Extent of resection'.)

Potentially resectable disease — For patients in whom a complete resection is not considered feasible as the initial treatment (eg, those with tumor invasion into the innominate vein, phrenic nerve(s), or heart/great vessels [34]), multimodality therapy incorporating preoperative chemotherapy and postoperative RT is indicated [24,26]. Such disease is considered potentially resectable if neoadjuvant therapy allows for a partial or complete response. (See 'Chemotherapy regimens' below and 'Postoperative radiation therapy' below.)

Our approach to potentially resectable disease is as follows:

●Combination chemotherapy followed by radical resection with or without postoperative adjuvant RT or chemotherapy offers a chance for prolonged disease-free survival in patients not initially resectable [35]. Biopsy to establish the diagnosis of thymic neoplasm is required prior to treatment. The optimal timing, duration, and agents for neoadjuvant chemotherapy have not been defined. The choice of regimens is generally the same as those for unresectable disease.

●Patients should be reevaluated following neoadjuvant chemotherapy to determine whether their disease has responded sufficiently to be considered resectable. If disease is resectable, patients should have surgery. Aggressive surgical approaches in cases of locoregional tumor extension have ranged from pleurectomy to extrapleural pneumonectomy. Whether such an aggressive approach is going to lead to prolonged disease-free survival in thymic carcinomas is controversial. Surgery should be followed by postoperative RT. (See 'Postoperative radiation therapy' below.)

•Response rates with neoadjuvant chemotherapy or chemoradiotherapy have ranged from 70 to 100 percent in small retrospective series. Resectability rates following induction chemotherapy vary between 36 and 69 percent [36-38]. As an example, in a pilot trial from four institutions, 21 patients were treated with induction chemotherapy (cisplatin plus etoposide), which was combined with 45 Gy of thoracic RT [38]. Following induction therapy, 17 patients underwent a complete, R0 resection; three patients had minimal residual disease; and one patient could only undergo debulking.

●If complete resection cannot be accomplished at the time of surgery, patients should undergo maximum debulking followed by postoperative RT if technically feasible, which may control residual disease and provide long-term, disease-free survival for some patients. For those with thymic carcinoma and residual disease after surgery, chemotherapy may be recommended as well. (See 'Postoperative radiation therapy' below and 'Chemotherapy regimens' below.)

Resection of tumor extending along one or both phrenic nerves is challenging since iatrogenic phrenic nerve injury can result in hemidiaphragm paralysis and impaired respiratory function; the risk of respiratory morbidity is greater with bilateral phrenic nerve involvement. In patients with tumor extending along one or both phrenic nerves, the risk of respiratory compromise following phrenic nerve division should be estimated preoperatively by measuring baseline respiratory function (with pulmonary function tests) and the degree to which the phrenic nerve contributes to this function (with a fluoroscopic or ultrasonographic sniff test). Subsequent management is described separately. (See "Thymectomy", section on 'Pulmonary function testing' and "Thymectomy", section on 'Handling the phrenic nerves'.)

Unresectable disease — Systemic therapy, RT, or chemoradiotherapy may be indicated for patients who present with extensive pleural and/or pericardial metastases, unreconstructable great vessel, heart, or tracheal involvement or otherwise technically unresectable disease, including those with distant metastases. Additionally, such treatments are offered to those who are medically unfit for surgery due to age or comorbidity. Treatments are individualized according to the patient’s extent of disease, symptoms, and performance status. Debulking surgery may also provide benefit to select patients with initially unresectable disease, so continued involvement of a multidisciplinary team, including a thoracic surgeon, is important. As examples:

●Patients with locally advanced, unresectable disease (American Joint Committee on Cancer [AJCC] stage IIIB), thymoma, or thymic carcinoma should be treated with chemoradiotherapy when feasible. Extrapolating from treatment paradigms for locally advanced lung cancer, RT doses of 60 Gy are appropriate.

●Chemoradiotherapy can improve long-term survival benefit and control the symptoms of the disease in a subset of patients with AJCC stage IVA disease, including those with nodal or localized metastatic disease [39]. For example, if pleural metastases are the only site of metastatic disease in patients with thymoma, an aggressive multimodality approach may still be possible and may achieve prolonged disease control.

●For patients with initially unresectable disease, it is appropriate to evaluate select patients for debulking surgery, as this approach may improve survival outcomes [39].

●RT alone can be particularly useful to palliate thoracic symptoms. Patients with unresectable disease are generally given a total dose of 60 Gy or more [26].

●Chemotherapy is the primary palliative treatment modality for patients with more widespread disease. (See 'Management of metastatic disease' below.)

Recurrent disease

●Aggressive local approaches to localized recurrent disease may result in prolonged survival in carefully selected patients with a localized lesion (eg, a "drop" pleural metastasis).

For most patients with isolated resectable recurrences and no distant metastases, we offer curative-intent therapy (eg, surgical resection with or without adjuvant radiation therapy) [40-42]. In rare cases of less resectable foci of disease (eg, local recurrences in the thymic bed and/or within the pleural cavity where an R0 resection is unattainable), a combination of surgery for the resectable foci and stereotactic body radiotherapy for the unresectable foci may be feasible [43].

●For patients with unresectable recurrences, options include definitive radiation [44] or stereotactic body radiotherapy [43].

●For those with more widespread disease, chemotherapy or palliative RT are appropriate, similar to the indications for unresectable disease. (See 'Unresectable disease' above and 'Chemotherapy regimens' below.)

The potential role of surgery to manage a localized recurrence was illustrated in a series of 395 patients, in which tumor recurred in 67 [40]. Of these, 22 (33 percent) underwent reresection. Survival following the second surgery varied depending upon the histology of the primary tumor, with World Health Organization (WHO) B1, B2, and B3 tumors having five-year survival rates of 100, 56, and 60 percent, respectively (table 3).

Postoperative radiation therapy

●Indications – Retrospective data have led to the following approach in regard to postoperative RT (PORT):

For patients with thymoma, our approach to PORT is as follows, using the AJCC staging system (Masaoka clinical system in parentheses):

•Stage I thymoma (Masaoka stage I to II)

-For patients with no capsular invasion, we offer observation given the low risk of recurrence and lack of overall survival benefit with postoperative RT (PORT). Such patients should be followed with annual imaging of the chest (computed tomography [CT]/magnetic resonance imaging [MRI]) for a minimum of ten years due to the risk of late recurrences. (See 'Surveillance after treatment' below.)

-For patients with invasion into the mediastinal fat or pleura and microscopic or grossly positive surgical margins, we suggest the addition of PORT, as this approach reduces the risk of recurrence to that of patients with R0 resections and lower-risk features. However, observation is an appropriate alternative given limited data. (See 'Surveillance after treatment' below.)

•Stage II to III thymoma (Masaoka stage III) – PORT is indicated in such patients given a higher risk of local recurrence.

•Stage IV thymoma (Masaoka stage IV) – RT should be individualized to the needs of the patient. RT can be used for palliation and possibly as curative therapy in oligometastatic disease.

For patients with thymic carcinoma:

•Patients with stage I to III thymic carcinoma (Masaoka stage I to III) are at a higher risk of local recurrence than those with thymoma. Retrospective data suggest a survival advantage with PORT for resected thymic carcinoma, and PORT is recommended, regardless of the presence of other risk factors or stage. It should be recognized, however, that data are limited in regards to which particular stages derive benefit [45,46]. In the presence of a positive margin or residual disease, PORT may be supplemented with systemic chemotherapy, although the evidence in favor is weak. (See 'Chemotherapy regimens' below.)

•Stage IV (Masaoka stage IV) thymic carcinoma – The use of PORT should be restricted to palliation of local symptoms.

Data in support of this approach are limited to retrospective series, given the low incidence of this disease. Several studies indicate that PORT does not improve survival in patients with stage I and II disease if a complete resection has been achieved and that there are no other factors suggesting an increased risk of recurrence [47-49]. For patients at increased risk of recurrence because of the extent of disease, retrospective series demonstrate that RT is associated with decreased risk of recurrence and improved survival in select patients [46,48,50-54].

One of the largest retrospective series to address the role of PORT for both thymoma and thymic carcinoma was conducted by the Japanese Association for Research on the Thymus (JART) [51]. The series analyzed 1265 patients with Masaoka stage II or III thymoma or thymic carcinoma and demonstrated that while PORT was associated with improved relapse-free survival (RFS) in patients with thymic carcinoma, it was not associated with an overall survival (OS) benefit in these patients. For patients with thymoma, there was no benefit in either RFS or OS.

By contrast, a survival benefit associated with PORT for thymoma has been observed in other retrospective analyses [46,50,53-56]. For example, in a study of 1263 patients with Masaoka stage II or III thymoma registered in a database by the International Thymic Malignancy Interest Group, 55 percent of whom were treated with PORT, receipt of PORT was associated with improved OS at five years (95 versus 90 percent) and at 10 years (86 versus 79 percent), a benefit that was observed in both Masaoka stage II and III disease [53]. A separate study of over 4000 patients in the National Cancer Center Database with any-stage thymoma, half of whom received PORT, suggested improved OS with PORT (hazard ratio [HR] 0.72, 95% CI 0.59-0.87 on multivariate analysis), particularly for those with Masaoka stage IIB or III thymoma or with positive margins. The benefit of PORT for Masaoka stage I to IIA disease did not reach statistical significance [46]. Among those with thymic carcinoma, PORT was associated with improved OS (HR 0.79, 95% CI 0.64-0.97). However, the differences in OS associated with PORT were not statistically significant for any of the stage subgroups.

In a study of 529 patients with thymoma in the Surveillance, Epidemiology, and End Results (SEER) database, when compared with those who did not receive PORT, the 345 patients (65 percent) who received PORT had a superior OS rate (76 versus 66 percent) and disease-free survival rate (91 versus 81 percent) at seven years. Subgroup analyses suggested that the OS benefit was limited to patients with stage III or IV disease.

●Dose and schedule – The RT dose and schedule used in the adjuvant setting or for those with close margins following surgery has varied. Generally, 45 to 50 Gy in 1.8 to 2 Gy daily fractions over five weeks are administered to the tumor bed and adjacent mediastinum. RT doses up to 60 Gy in 2-Gy daily fractions may be indicated if microscopic or gross residual disease is present following a partial resection [26].

●Toxicities – Potential radiation-related toxicities include esophagitis, pneumonitis and pulmonary fibrosis, pericarditis, and very rarely, radiation myelitis. Late radiation sequelae include radiation lung fibrosis in the lung included in the high-dose area, and a small risk of constrictive pericarditis if a very large volume of heart was included in the RT field. Acceleration of coronary artery disease with an increase in cardiac events such as myocardial infarcts and an increased risk of second cancers in the RT field are potential late complications that are a special concern in young patients who have many decades of expected survival after treatment of their thymic tumors. (See "Radiation-induced lung injury" and "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

•Option to use proton beam therapy – Advances in radiation treatment planning and delivery may potentially permit the administration of higher doses safely. With contemporary three-dimensional treatment planning, and proton beam RT [57], some of the toxicities associated with RT can be minimized depending upon the volume that needs to be irradiated. The NCCN notes that proton beam therapy should be considered for certain patients, given that it has been shown to improve the dosimetry compared with intensity-modulated RT, allowing less toxicity to normal organs and favorable results in regards to local control [58].

Chemotherapy regimens — Chemotherapy may have a role as a component of neoadjuvant therapy for patients with potentially resectable disease, those with unresectable disease, and those with more widespread or recurrent disease. (See 'Management of metastatic disease' below.)

The following are examples of widely used chemotherapy regimens for the treatment of thymic neoplasms [26]. Chemotherapy is offered in the neoadjuvant setting for those with potentially resectable thymoma or thymic carcinoma, or as primary therapy (with or without RT) for those with unresectable thymoma or thymic carcinoma. For patients with resected thymic carcinoma with a positive margin, PORT may be supplemented with systemic chemotherapy, although the evidence in favor of this is weak. For those with thymic carcinoma and macroscopic residual disease after resection, chemoradiotherapy may be utilized.

The same regimens are used in the neoadjuvant setting for potentially resectable disease as in the treatment of unresectable disease. Although several regimens are acceptable, cyclophosphamide, doxorubicin, and cisplatin (CAP) and cisplatin and etoposide (PE) have been used successfully for thymomas or thymic carcinomas. The combination of carboplatin and paclitaxel is also used extensively, especially in patients with thymic carcinoma. If chemotherapy is given concurrently with RT, our preferred regimens are PE or carboplatin and paclitaxel.

•CAP – Cyclophosphamide (500 mg/m² intravenous [IV] day 1), doxorubicin (50 mg/m² IV day 1), and cisplatin (50 mg/m² IV day 1), repeated every three weeks. In a United States intergroup study, 29 patients with metastatic or progressive thymoma were treated with CAP. The overall and complete response rates were 50 and 10 percent, respectively, and the median survival was 38 months [59].

•PE – Cisplatin (60 mg/m² IV day 1) and etoposide (120 mg/m² IV days 1 to 3), repeated every three weeks [60]. In a European Organisation for Research and Treatment of Cancer (EORTC) study, 16 patients with advanced thymoma received etoposide plus cisplatin every three weeks [60]. The overall and complete response rates were 56 and 31 percent, respectively, and the median progression-free and overall survival durations were 2.2 and 4.3 years, respectively.

•CAP with prednisone – Cyclophosphamide (500 mg/m² IV day 1), doxorubicin (20 mg/m²/day as a continuous infusion, days 1 to 3), cisplatin (30 mg/m² IV days 1 to 3), and prednisone (100 mg/day on days 1 to 5), repeated every three weeks. In a series of 22 patients given induction chemotherapy with the CAP with prednisone regimen, partial responses were observed in 14 cases and complete responses in three cases for an overall 77 percent response rate [36].

•Carboplatin (area under the curve [AUC] 6) and paclitaxel (225 mg/m² IV) every three weeks – In a prospective, multicenter study of patients with advanced disease, three complete responses and six partial responses were observed in 21 patients with thymoma (overall response rate, 43 percent) [61]. There were five partial responses and no complete responses among the 23 patients with thymic carcinoma (overall response rate, 22 percent).

•ADOC – Cisplatin (50 mg/m² IV day 1), doxorubicin (40 mg/m² IV day 1), vincristine (0.6 mg/m² IV day 3), and cyclophosphamide (700 mg/m² IV day 4), repeated every three weeks. In another series, 37 patients with advanced disease were treated with ADOC [62]. The overall and complete response rates were 92 and 43 percent, respectively, and the median survival was 15 months.

•VIP – Etoposide (75 mg/m² IV days 1 to 4), ifosfamide (1.2 g/m² IV on days 1 to 4), and cisplatin (20 mg/m² IV days 1 to 4), repeated every three weeks. In an intergroup trial that included 28 patients with advanced thymoma or thymic carcinoma, nine partial responses (32 percent) were observed [63].

MANAGEMENT OF METASTATIC DISEASE — Systemic therapy is generally used to treat advanced or metastatic thymomas and thymic carcinomas. Patients are encouraged to enroll in clinical trials, where available. (See 'Investigational agents' below.)

Initial therapy — For patients with thymomas or thymic carcinomas who have inoperable recurrent disease or disseminated metastases, we suggest initial treatment with a platinum-based chemotherapy regimen rather than other systemic regimens. Available chemotherapy regimens are discussed separately. (See 'Chemotherapy regimens' above.)

Subsequent therapy

Pembrolizumab — For patients with thymic carcinoma who progress on initial chemotherapy and have no history of autoimmune disease, we suggest single-agent pembrolizumab rather than vascular endothelial growth factor (VEGF) inhibitors. In clinical trials, pembrolizumab demonstrated durable responses in patients with thymic carcinoma, which may be more pronounced those whose tumors express PD-L1 [64-66]. These patients should be carefully monitored for possible severe immune-related adverse events (irAEs), including myocarditis, myasthenia gravis, and hepatitis.

We do not offer immunotherapy to those with thymoma, as high rates of irAEs have been reported in these patients [67-70]. Other systemic agents are available for this population. (See 'Later-line therapy' below and "Toxicities associated with immune checkpoint inhibitors".)

Additionally, pembrolizumab is not offered to patients with thymic carcinoma and autoimmune disease. In such patients, a VEGF inhibitor is a reasonable alternative. (See 'VEGF inhibitors' below.)

Pembrolizumab is an accepted option in patients with thymic carcinoma refractory to initial chemotherapy, based on nonrandomized phase II data [65-67]. There are no randomized trials directly comparing immunotherapy with other subsequent-line regimens, such as chemotherapy. Data for pembrolizumab are as follows:

●In one phase II study, 40 patients with thymic carcinoma were managed with pembrolizumab for up to two years [65,66]. All patients had widespread disease and had received at least one prior systemic therapy. There were nine objective responses (22.5 percent), including one complete response. Responses were relatively durable, with a median duration of approximately three years and five-year survival of 18 percent [66]. Severe irAEs were seen in six cases, including two with myocarditis.

●Data suggest suggests high rates of irAEs among those with thymoma [67,70]. In a non-randomized phase II trial, 33 patients with thymic tumors refractory to platinum-based chemotherapy received pembrolizumab [67]. Partial responses were seen in 5 of 26 patients (19 percent) with thymic carcinoma and in two of seven patients (29 percent) with thymoma. Median progression-free survival was approximately six months for both groups, and duration of response was approximately 10 months for the entire study population. However, grade ≥3 irAEs were higher for those with thymoma relative to those with thymic carcinoma (71 versus 15 percent), with toxicities including myasthenia gravis, myocarditis, and hepatitis. These findings led investigators to halt the inclusion of patients with thymoma or previous autoimmune disease in the trial.

VEGF inhibitors — We offer either sunitinib or lenvatinib to patients with thymic carcinoma who progress on chemotherapy and progress on (or are ineligible for) immunotherapy. These systemic therapies that inhibit multiple tyrosine kinases, including VEGF and c-KIT, are an appropriate option in patients with thymic carcinomas refractory to initial chemotherapy, based on data from phase II trials and retrospective studies [71-73].

Sunitinib — In a single-arm, open-label phase II trial, 41 patients with thymic carcinoma or thymoma refractory to platinum-based chemotherapy were treated with sunitinib 50 mg daily in six-week cycles (four weeks on and two weeks off treatment) [71]. At a median follow-up of 17 months, partial responses were seen in 6 of 23 patients with thymic carcinoma (26 percent) and 1 of 16 patients with thymoma (6 percent). Grade ≥3 toxicities included lymphocytopenia fatigue, mucositis (20 percent each), and decreased left ventricular ejection fraction (8 percent). One patient died of potential treatment-related cardiac arrest.

Lenvatinib — In a single-arm, open-label phase II trial (REMORA) conducted in Japan, 42 patients with thymic carcinoma refractory to platinum-based chemotherapy were treated with lenvatinib 24 mg once daily [73]. After a median follow-up of approximately 16 months, partial responses were seen in 16 patients (38 percent), and stable disease was seen in 24 patients (57 percent). Common treatment-related adverse events included hypertension, diarrhea, hand-foot syndrome, proteinuria, hypothyroidism, and thrombocytopenia.

Later-line therapy — Later-line options for treatment-refractory thymomas and thymic carcinomas include etoposide, ifosfamide, pemetrexed, octreotide [74], fluorouracil (FU) plus leucovorin, gemcitabine with or without capecitabine, and paclitaxel [75].

There is no clear role for nivolumab or avelumab in patients with relapsed thymic carcinoma, as clinical trials evaluating these agents showed limited activity and significant toxicity [76,77]. Similarly, everolimus is not routinely used due to severe toxicity (pneumonitis), despite initial studies that suggest some efficacy in relapsed thymoma and thymic carcinoma [78].

Investigational agents — Other agents have been evaluated in the treatment of metastatic thymoma and thymic carcinoma, but their use remains investigational. Clinical trials (www.clinicaltrials.gov) are encouraged, where available.

●Immunotherapy plus antiangiogenic therapy - The combination of immune checkpoint inhibitors and antiangiogenic therapy remains investigational in patients with thymic carcinoma refractory to initial chemotherapy.

As an example, the combination of avelumab plus axitinib was evaluated in an open-label, single-arm phase II trial (CAVEATT) of 32 patients with thymic carcinoma or thymoma who progressed on platinum-based chemotherapy [79]. At median follow-up of approximately two years, the overall response rate was 34 percent in the entire cohort and 47 percent in those not previously treated with antiangiogenic agents. Among the 27 patients with thymic carcinoma, overall responses were seen in nine patients (33 percent). Among the five patients with thymoma or mixed type B3 thymoma and thymic carcinoma, partial responses were seen in two patients. Median PFS and OS were 8 and 27 months, respectively. Median duration of response was six months. Severe irAEs were seen in four patients (12 percent), including three cases of polymyositis.

●KIT inhibitors — Although KIT mutations are seen in less than 10 percent of thymic carcinomas, the frequency of c-KIT overexpression ranges between 46 to 80 percent [80,81]. Imatinib has shown activity in case reports of thymic carcinomas with KIT exon 9 mutations, but not for tumors that are unselected for or lack KIT mutations [82,83]. Sorafenib has shown activity in thymic carcinomas independent of KIT mutations, with a disease control rate of 80 percent in one observational series [84].

●GFT2I inhibitors — A potential target of clinical interest is the single nucleotide mutation in the GFT2I gene (L424H), which is expressed in approximately 39 percent of type A and AB thymomas [81]. However, no GFT2I inhibitors are clinically available.

PROGNOSIS — Thymomas usually are slow-growing tumors, whereas thymic carcinomas are more aggressive and are associated with a poorer prognosis [85,86].

The main factors influencing prognosis are the stage of disease (table 4) and the complete resectability of the tumor. Tumor histology has also been found to have prognostic value, with a major distinction between thymomas and thymic carcinomas. The subclassification of thymomas according to WHO criteria (table 1) has been difficult to reproduce in some series. (See 'Staging' above and "Pathology of mediastinal tumors", section on 'Thymoma' and "Pathology of mediastinal tumors", section on 'Thymic carcinoma'.)

The relationship between stage of disease and tumor histology, and their combined impact on prognosis, is illustrated by a German series of 228 patients [33]. With a median follow-up of five years following treatment, patient outcomes in this series were strongly influenced by the extent of the initial resection:

●The overall prognosis was excellent for patients with Masaoka stage I and stage II disease. Three relapses were observed among the 110 patients (3 percent) undergoing total surgical resection. Although the prognosis for patients with Masaoka stage II disease was excellent, tumor-related deaths were observed in some patients more than 10 years after surgery.

●Among those with Masaoka stage III disease, the prognosis was worse following complete resection, with 27 percent developing recurrent disease. In patients in whom only an incomplete surgical resection was feasible, 62 percent developed tumor relapses. For patients with stage III disease, survival appeared to plateau after five years, with a 10-year survival rate of 83 percent.

●By contrast, those with Masaoka stage IV disease had continuing mortality, with a 10-year survival rate of 47 percent.

●There were no tumor-related deaths in patients with type A, AB, or B1 disease, which were mostly Masaoka stage I and II disease. In patients with B2, B3, or thymic carcinoma, of which approximately 50 to 60 percent were Masaoka stage III to IV, tumor caused death in 9, 19, and 17 percent of cases, respectively.

SURVEILLANCE AFTER TREATMENT — Although there are no clinical trials providing evidence of benefit, monitoring for recurrences with thoracic imaging on an annual basis is warranted. For patients with recurrent disease detected on surveillance, early intervention may be more feasible and effective [87]. Surveillance for subsequent primary cancers is also indicated, as higher incidence of other tumor types has been reported in patients with thymomas [88]. (See 'Recurrent disease' above and "Overview of cancer survivorship care for primary care and oncology providers", section on 'Risk of subsequent primary cancer'.)

Although there are no trials demonstrating the benefits of computed tomography (CT) scan, the guidelines from the National Comprehensive Cancer Network (NCCN) are reasonable. These guidelines recommend CT every six months for two years, then annually for five years for thymic carcinoma, and annually for 10 years for thymoma [87].

Recurrence of thymoma may not become apparent for many years after initial treatment. As an example, in a series of 126 patients who underwent complete resection of a thymoma, 24 eventually recurred [89]. The time to recurrence ranged from 4 to 175 months (mean, 68 months). The initial sites of recurrence were pleural, local, or distant in 22, 6, and 5 cases, respectively.

Patients with thymoma are also at risk for the development of second malignancies, which have been reported in 17 to 28 percent of patients following thymectomy [2,90-93]. In a series of 849 cases of thymoma identified through the Surveillance, Epidemiology, and End Results (SEER) database, the risk was significantly increased for B cell non-Hodgkin lymphoma, gastrointestinal cancers, and soft tissue sarcomas (standardized incidence ratios [SIR] 4.7, 1.8, and 11.1, respectively, compared with the number of cases expected in the general population) [91].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Thymomas and thymic carcinomas".)

SUMMARY AND RECOMMENDATIONS

●Clinical presentation – Thymomas and thymic carcinomas are rare tumors that arise in the anterior mediastinum. Thymomas may be an incidental diagnosis discovered at chest imaging, and patients may present with symptoms due to the presence of a mass in the thorax or to a paraneoplastic phenomenon such as myasthenia gravis. (See 'Clinical presentation' above.)

●Prognosis – The prognosis for patients with thymoma or thymic carcinoma depends upon the stage of disease, complete resectability, and histologic type. (See 'Prognosis' above.)

●Resectable disease – Complete surgical resection is the initial treatment approach for all patients when preoperative evaluation suggests that a complete resection will be feasible and there are no medical contraindications to surgery. The surgical resection provides additional staging information that can guide further therapy (table 4). (See 'Resectable disease' above.)

●Approach to postoperative radiation therapy – For patients with resected disease, the approach to postoperative radiation therapy (RT) is based on stage (table 5) (see 'Postoperative radiation therapy' above):

•Stage I thymoma – For patients with stage I thymoma (Masaoka stage I to II) and no capsular invasion, we offer observation given the low risk of recurrence and lack of overall survival benefit with postoperative RT (PORT). Such patients should be followed with annual imaging of the chest (computed tomography [CT]/magnetic resonance imaging [MRI]) for a minimum of ten years due to the risk of late recurrences.

For patients with invasion into the mediastinal fat or pleura and microscopic or grossly positive surgical margins, we suggest the addition of PORT (Grade 2C), which may reduce the risk of recurrence to that of patients with R0 resections and lower-risk features. However, observation is an appropriate alternative given limited data. (See 'Surveillance after treatment' above.)

•Stage II to III thymoma – For patients with stage II to III thymoma (Masaoka stage III) who have undergone resection, either complete or incomplete, we suggest PORT (Grade 2C). However, contemporary studies have not demonstrated a consistent advantage in this approach, and observation is an appropriate alternative.

•Stage I to III thymic carcinoma – For patients with stage I to III thymic carcinoma (Masaoka stage I to III), we suggest PORT regardless of stage or other risk factors (Grade 2C), given the risk of local recurrence and evidence of improved survival associated with PORT. In the presence of a positive margin, PORT may be supplemented with systemic chemotherapy, although the evidence in favor is weak. If macroscopic residual thymic carcinoma is present, chemoradiotherapy may be utilized.

•Stage IV thymoma or thymic carcinoma – For patients with stage IV thymoma or thymic carcinoma, the use of PORT should be restricted to palliation of local symptoms.

●Potentially resectable disease – For patients with potentially resectable disease (tumor invasion into great vessels or one/both phrenic nerves), we recommend initial treatment with neoadjuvant chemotherapy (Grade 1B). If the response to chemotherapy is sufficient to permit surgery and the patient's overall condition permits, we suggest surgical resection (Grade 2B) followed by adjuvant RT. (See 'Potentially resectable disease' above.)

●Unresectable disease – RT alone, chemotherapy, or the combination is appropriate for patients in whom surgery is not technically feasible or is contraindicated, and may be of curative potential. (See 'Unresectable disease' above.)

●Surveillance – For patients who achieve a complete response with either surgery or a combined-modality approach, prolonged follow-up is indicated since late relapses are possible. We agree with the guidelines from the National Comprehensive Cancer Network (NCCN), which recommend CT every six months for two years, then annually for five years for thymic carcinoma, and annually for 10 years for thymoma, given the risk of late recurrences. (See 'Surveillance after treatment' above.)

●Recurrent resectable disease – For most patients with isolated resectable recurrences and no distant metastases, we offer curative-intent therapy (eg, surgical resection with or without adjuvant RT). For those with unresectable disease, other options include RT or stereotactic body radiotherapy. (See 'Recurrent disease' above.)

●Recurrent unresectable or metastatic disease

•Initial therapy – For patients with thymomas or thymic carcinomas who have inoperable recurrent disease or disseminated metastases, we suggest initial treatment with a platinum-based chemotherapy regimen rather than other systemic regimens (Grade 2C). (See 'Initial therapy' above and 'Chemotherapy regimens' above.)

•Disease refractory to chemotherapy – For patients with thymic carcinomas refractory to chemotherapy, we suggest immunotherapy with pembrolizumab rather than a VEGF inhibitor (Grade 2C), with close monitoring for immune-related adverse events (irAEs). (See 'Pembrolizumab' above.)

-We do not offer immunotherapy to patients with thymomas due to concerns about irAEs. Other systemic agents are available for this population. (See 'Later-line therapy' above.)

-Similarly, we also do not offer immunotherapy to patients with thymic carcinoma and autoimmune disease; for such patients, a VEGF inhibitor is a reasonable alternative. (See 'VEGF inhibitors' above.)

•Subsequent therapy – For those with thymic carcinoma who progress on chemotherapy and immunotherapy, we offer VEGF inhibitor therapy with sunitinib or lenvatinib. (See 'VEGF inhibitors' above.)

Patients should be encouraged to enroll in formal clinical trials whenever possible. (See 'Investigational agents' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Andrea Bezjak, BMedSc, MDCM, MSc, FRCPC, and Giuseppe Giaccone, MD, PhD, who contributed to earlier versions of this topic review.