Sukhmani K. Padda, Bryan M. Burt, and Heather A. Wakelee

INTRODUCTION

Epidemiology

Thymic epithelial tumors (TETs), including thymomas and thymic carcinomas, are derived from thymic epithelium and occur in the anterior mediastinum. The thymus is a critical organ that cultivates the immune system’s T-cell repertoire (1). Because of the role of the thymus in the immune system, TETs (thymomas more so than thymic carcinomas) are associated with autoimmune paraneoplastic syndromes, and a higher risk of second malignancies (2,3). Thymomas are rare, with an estimated incidence of 0.13 per 100,000 person-years in the United States (2) and 1.4 million per year (1.7 million per year for all TETs) in Europe (4). Thymic carcinoma is even rarer than thymoma. The incidence of TETs is similar in both men and women. In the United States, thymoma is uncommon in children and young adults, but the incidence rises with age, peaking in the seventh decade (2).

Etiology

The etiology of TETs is unknown and their biology is complex. There are no known infectious or environmental risk factors.

International Thymic Malignancy Interest Group

The International Thymic Malignancy Interest Group (ITMIG) was formed to advance research in TETs and its inaugural meeting was held in August 2009 (5). The goals of the organization are to tackle research priorities for TETs (e.g., tissue banking), to provide standardized language among researchers (e.g., uniform staging system, standard outcome measures), and to develop and analyze the ITMIG worldwide retrospective and prospective patient databases (www.itmig.org). Throughout this chapter, ITMIG guidelines and policies are prioritized.

HISTOLOGY OF TETs

The 2015 WHO Classification of Tumors of the Thymus, fourth edition, has recently been published (6,7). All thymomas have malignant potential and should not be categorized as benign, even if they appear to be noninvasive early stage tumors. The very rare exceptions are microscopic and micronodular thymomas, for which no tumor-related deaths have been reported. Updates in the classification of TETs from the new edition are detailed here.

WHO Classification

Thymomas are classified into the following categories: A, AB, B1, B2, and B3 (6,7). The WHO fourth edition has implemented “obligatory/indispensable” criteria and “optional” criteria for the classification of thymomas to make the system more reproducible (Table 15.1). The two major types of thymoma are type A and type B. They differ in the shape of the epithelial tumor cell (A—bland, spindle-shaped; B—polygonal or dendritic). Type B is further categorized by the degree of atypia of the epithelial cells and the relative abundance of the lymphocytic infiltrate. Thymomas that have features of both type A and type B1 are classified as type AB. In mixed tumors with more than one histologic subtype, all subtypes should be listed with the most prominent listed first and minor components quantified in 10% increments. The exceptions are type AB thymoma, which is its own distinct entity, and tumors containing both thymic carcinoma and thymoma, which are classified as combined thymic carcinoma. In the ITMIG retrospective database, the most common to least common histologic types are: B2 (28%), AB (23%), B3 (21%), B1 (17%), and A (11%) (8). The many subtypes of thymic carcinoma are listed in Table 15.1, with the most frequent being squamous cell carcinoma.

Immunohistochemistry to Assist in the Diagnosis of TETs

Immunohistochemistry (IHC) can be useful when the diagnosis of TET is not clear (6). Pan-cytokeratin antibodies stain epithelial cells of normal thymus, thymoma, and neuroendocrine tumors, although there are rare cytokeratin-negative thymomas. Cytokeratin 19 is expressed on epithelial cells of normal thymus, thymoma, and thymic carcinoma, while cytokeratin 20 is not expressed in normal thymus and thymoma, but may be found in thymic adenocarcinoma. P63 and P40 antibodies stain the nuclei of normal and neoplastic thymic epithelial cells. TdT antibodies stain immature T cells in the normal thymus and in greater than 90% of thymomas. CD5 is found on immature and mature T cells of the thymus and greater than 90% of thymomas, and on epithelial cells in 70% of thymic carcinomas. CD20 antibodies stain normal and neoplastic B-cells, and epithelial cells in 50% of type A and AB thymomas. CD117 (c-kit) is expressed on the epithelial cells in 80% of thymic carcinomas.

PROGNOSTIC FACTORS

Masaoka and Masaoka-Koga Stage

Stage, as defined by the Masaoka and Masaoka-Koga classification systems, is an independent prognostic factor for thymoma (8). These staging systems are discussed in more detail in the following and in Table 15.2. In the ITMIG retrospective database, overall survival and cumulative incidence of recurrence (CIR) progressively worsened in patients who underwent R0 (complete) resection as stage increased from stages I/II to III to IVA to IVB. The prognostic significance of stage was also validated in a multivariate analysis.

WHO Histologic Classification

The prognostic impact of the WHO histologic classification is controversial (8). In a broad review of the literature, patients with thymic carcinoma consistently had worse clinical outcomes than those with thymoma, and those with type B3 thymoma appeared to have intermediate outcomes (13). However, the association of the other WHO subtypes with clinical outcome is less consistent. In the ITMIG retrospective database, there was a significant association between histology and stage, with relatively equivalent early stage distribution in types A and AB thymoma, but increasingly higher stage representation in B1, B2, and B3 thymoma (8). After adjusting for age, stage, and resection status, histology was not an independent factor associated with overall survival. However, histology was an independent factor associated with CIR, and histology may be more prognostic in earlier stage disease.

Resection Status

The prognostic significance of stage and histology can be overcome by achieving a complete (R0) resection. In a multivariate analysis of the ITMIG retrospective database, resection status was an independent prognostic factor (8). In a report from Japan, the 5-year survival rates for patients who underwent total resection or subtotal resection, or were inoperable 93%, 64%, and 36%, respectively, in stage III and IV thymoma, and 67%, 30%, and 24%, respectively, in thymic carcinoma (14).

DIAGNOSIS

History and Physical Exam

TETs are commonly found incidentally as an anterior mediastinal mass on imaging studies performed for other reasons. However, one-third of patients with TETs present with local symptoms, including pain, superior vena cava syndrome, dyspnea, cough, or tachycardia, or systemic symptoms including weight loss or fever. Thymomas are associated with a variety of autoimmune paraneoplastic syndromes, most commonly myasthenia gravis, which occurs in up to 40% of patients (15,16). Thus, special attention should be paid to the neurologic exam. Hypogammaglobulinemia (Good’s syndrome) and pure red cell aplasia are observed in less than 1% of patients as reported in the ITMIG retrospective database.

Laboratory

Routine laboratory evaluation should include a complete blood count and a reticulocyte count (12,17). A serum anti-acetylcholine receptor (AChR) antibody level should be sent to evaluate for myasthenia gravis. Serum immunoglobulins and additional immunologic tests (e.g., flow cytometry for B-cell and T-cell subsets) may be evaluated, especially if there is a suspicion of Good’s syndrome. Tumor markers to rule out germ cell tumors, such as serum beta-human chorionic gonadotropin (β-hCG) and alpha-fetoprotein (AFP) may be sent if clinically appropriate.

Imaging

Differential Diagnosis of Mediastinal Masses

Primary anterior mediastinal tumors comprise 50% of all mediastinal masses (18,19). Although thymoma is the most common tumor of the anterior mediastinum, additional malignant considerations include thymic carcinoma, thymic neuroendocrine tumor, mediastinal germ cell tumor (10%–15% of anterior mediastinal masses), lymphoma, and metastases from other primary sites. The presence of a paraneoplastic syndrome with an anterior mediastinal mass essentially clinches the diagnosis of thymoma (20). Benign conditions that can cause abnormal mediastinal masses include thymic hyperplasia, thymic cyst (3% of anterior mediastinal masses), mediastinal goiter, mediastinal parathyroid adenoma, aortic aneurysm, granulomatous disease, and pericardial cyst (18,19). It is important to differentiate between TETs and other entities, both benign and malignant, since management can be drastically different.

Chest Radiography

On chest radiography, thymoma appears as a smooth, ovoid mass with well-defined margins, located anywhere from the thoracic inlet to the cardiophrenic angle (21). An irregular pulmonary border suggests invasiveness into the lung, while an elevated hemidiaphragm indicates invasion of the phrenic nerve. Metastatic pleural nodules may also be seen on chest radiography.

Computed Tomography

The initial workup for a mediastinal mass must include a CT chest with contrast (12,17,21,22). Contrast should be given if there are no contraindications since it is critical for clinical staging. Although formal staging is based on pathologic findings, CT imaging and clinical staging are essential in guiding therapy. The diagnosis of thymoma is strongly suggested by a CT scan demonstrating a well-circumscribed, solid, anterior mediastinal mass without low-density areas representing the cystic and fatty components of a teratoma (20). Most thymomas appear solid and homogeneous, but up to a third may be necrotic, hemorrhagic, or cystic. CT scan has been shown to be equal or superior to MRI in diagnosing anterior mediastinal masses, except thymic cysts for which MRI is superior (diagnostic accuracy CT 46% vs. MRI 71%) (22).

ITMIG has formulated “standard report terms” that should be used to describe the characteristics of an anterior mediastinal mass that is suspicious for thymoma on CT (Table 15.3) (23).

CT Factors Associated With Invasiveness and Resectability

Many studies have examined the association of CT features with the invasiveness of thymoma. In one study of 99 patients, a multivariate analysis found that tumor size ≥7 cm, lobulated contour, and infiltration of mediastinal fat were associated with invasive thymoma (Masaoka stage III–IV) (24). In another study of 133 patients who underwent surgery, the degree of abutment of adjacent vessels and pleural nodularity was associated with an incomplete resection (25). These studies emphasize the importance of the radiologist in the management of TETs as some of these features may help in deciding whether or not to administer preoperative chemotherapy or to proceed directly to surgery.

Magnetic Resonance Imaging

MRI of the chest should be performed in patients in whom a CT with contrast is contraindicated, such as those with iodine allergy or renal insufficiency, for adequate evaluation of mediastinal vessels and clinical staging (21). MRI also has an advantage over CT as a follow-up exam, because of the lack of cumulative radiation. A variety of MRI techniques, such as chemical shift imaging, dynamic imaging, and multishot spiral sequencing, can be used to differentiate normal thymus from tumor or thymoma from other mediastinal tumors and to identify phrenic nerve involvement. The major disadvantage of MRI is that nonradiologists are more comfortable interpreting CT images than MRI images.

Positron Emission Tomography-CT

Positron emission tomography-CT (PET-CT) is optional in the workup of TETs (12,17). On ¹⁸F-fluorodeoxyglucose (FDG)–PET, thymomas have a variable standard uptake value (SUV), but it is generally low, while thymic carcinomas tend to have a higher SUV. However, benign lesions (e.g., thymic hyperplasia) and other malignant lesions in the mediastinum (e.g., lymphoma) may also be highly FDG-avid. PET may be most useful in patients with aggressive thymic tumors (type B3 thymoma or thymic carcinoma), in advanced disease, and in recurrent disease. Several reports have correlated the level of metabolic PET activity (i.e., SUV) with histology, but the association with stage is less robust (26,27). Although the hope was that PET would improve identification of stage III disease, it has not been able to reliably differentiate early stage from more advanced stage disease (21).

Octreotide Scan

Indium-111 octreotide scan is used to help identify patients with unresectable/metastatic tumors who may respond to treatment with octreotide after failure of conventional chemotherapy (12). An octreotide scan is not generally indicated at initial diagnosis.

Biopsy

TETs do not need to be biopsied if the clinical and radiographic characteristics are highly suspicious and the mass is deemed primarily resectable (28). If a biopsy is necessary, then a variety of approaches can be employed depending on the location of the mass, including fine needle aspiration (FNA), core needle biopsy, and surgical biopsy (video-assisted thoracoscopic surgery [VATS], anterior mediastinotomy, mini-thoracotomy, Chamberlain procedure). Caution should be taken when biopsying mediastinal cystic lesions given the potential for infection. For the most common location of thymoma in the anterior mediastinum, transthoracic ultrasound or CT-guided FNA and biopsy are generally used. The sensitivity and specificity of mediastinal biopsy are 71% to 100% and 77% to 100%, respectively, for transthoracic FNA, and 40% to 93% and 76% to 90%, respectively, for percutaneous core biopsy (28). The sensitivity for surgical biopsy is much higher (>90%). Surgical dogma dictates that a biopsy will disrupt the capsule of an early stage thymoma, resulting in tumor seeding of the biopsy tract. However, reports of such outcomes are exceedingly rare (29–31). For example, there is a case report in which CT-guided biopsy of a stage I thymoma resulted in seeding of the chest wall with recurrence 12 years later (29). VATS biopsy of an anterior mediastinal mass in which thymoma is on the differential should be avoided due to the potential for spread into the pleural space, which has been reported in the literature (32,33). If core needle biopsy fails and a diagnosis is required, a Chamberlain procedure (anterior mediastinotomy) could be performed. FNAs and biopsies should be interpreted carefully given the heterogeneity of TETs and the limited tissue specimen obtained. Pathologic findings should always be correlated with clinical findings.

STAGING

Masaoka-Koga Staging

Despite the malignant potential of thymoma and thymic carcinoma, there is no official American Joint Committee on Cancer (AJCC) or Union for International Cancer Control (UICC) staging system. Many staging systems have been proposed for thymoma. ITMIG has stated that the Masaoka-Koga staging system should be used until a validated tumor-node-metastasis (TNM) system is defined for the 2017 edition of the AJCC/UICC staging manuals (Table 15.2) (6,9). In summary, the Masaoka-Koga staging system describes the primary tumor (encapsulated or not), degree of involvement of surrounding structures (adherence or invasion), and the presence or absence of metastases (pleural/pericardial or distant). Some of the criticisms of this system include the lack of a survival difference between stage I and II disease, the heterogeneity of stage III disease, and heavy reliance on pathologic information making it poorly applicable to clinical staging.

Nuances of Masaoka-Koga Staging

The Capsule: The emphasis on the tumor capsule is not consistent with other staging systems, since the capsule is not an anatomic landmark, but rather a desmoplastic reaction caused by the tumor (9). Invasion into the capsule, but not through the capsule, is considered stage I. In tumors where the capsule is partially absent, the pathology report should explain that capsular invasion cannot be fully assessed, but the tumor should not be categorized as stage II. An unencapsulated tumor interfacing with adjacent tissue is also still considered stage I, not invasive stage IIA disease.

Microscopic Confirmation Essential: A significant ITMIG clarification is that the final Masaoka-Koga stage assignment is based only on the confirmation of microscopic invasion, and not on suspected macroscopic invasion.

Pleura and Pericardium—Differentiating Stages IIB and III Disease: Stage IIB tumors are macroscopically invasive and can extend up to the mediastinal pleura and pericardium without involving these structures. However, it is difficult to discern stage IIB from stage III disease. If the tumor invades the mediastinal pleura or pericardium, even partially, it is considered stage III disease. The mediastinal pleura should be labeled since it is difficult to identify retrospectively. The term “adherence” is also difficult to define in relation to stage IIB disease; however, if the tumor is so close to the pleura or pericardium that it must be resected, it should be considered “adherent.”

Masaoka-Koga Stage IVB Disease: Stage IVB disease includes distant metastases and any level of lymph node involvement, including nodes in the anterior mediastinal, intrathoracic, or low or anterior cervical regions. Since some distinction should be made for distant metastases (i.e., those outside the cervical/perithymic region), it has been proposed that these sites should be labeled “pulmonary and extrathoracic metastases” rather than hematogenous metastases in order to describe the anatomical site rather than a hypothetical mechanism of spread.

Distribution of Masaoka-Koga Stage and Outcome

In a study of 8,145 patients, the distribution of Masaoka and Masaoka-Koga stage was stage I 33%, stage II 27%, stage III 23%, stage IVA 7%, and stage IVB 5% (10). The 10-year overall survival rate and CIR per Masaoka-Koga stage are shown in Table 15.2.

IASLC/ITMIG Proposed Staging for the Eighth Edition of the TNM Classification

In 2009, ITMIG and the International Association for the Study of Lung Cancer (IASLC) partnered to redefine the TET staging classifications (11). The proposed staging system is based on 10,808 patients from the databases of ITMIG and the Chinese Alliance for Research of Thymoma. These were further supplemented by the databases from the Japanese Association for Research in the Thymus (JART) and the European Society of Thoracic Surgeons (ESTS). The purpose was to develop a TNM-based staging system that applies to both thymoma and thymic carcinoma, recognizing the biologic differences between these tumors, but realizing the benefit of having a consistent system. The separation of T, N, and M categories and stage groupings were based at least partly on the ability to separate groups prognostically, examining endpoints of CIR and overall survival (Table 15.2). However, the TNM categories were also chosen based on simplicity, applicability to clinical staging, and reliability.

This staging classification is meant to describe the anatomic extent of disease. T stage is based on level of involvement, with assignment based on the highest level of structures involved, even if lower structures are uninvolved (Table 15.2). The nodal groups are based on their proximity to the thymus, including N1, anterior perithymic nodes, and N2, deep intrathoracic or cervical nodes. The nodes outside of these regions are considered metastatic disease. Metastatic disease is subdivided into M1a, separate pleural or pericardial nodules, and M1b, intraparenchymal pulmonary nodules or distant metastases. Stage groupings for stages I to IIIB are primarily based upon the T component, while stage IVA disease is determined by the presence of N1 or M1a disease and stage IVB disease by the presence of N2 or M1b disease. Overall, as stage increases, the risk of recurrence and death also increases.

MANAGEMENT OF TETs

Guidelines

The National Comprehensive Cancer Network (NCCN) has recently published an updated guideline for thymoma and thymic carcinoma (17). The European Society of Medical Oncology (ESMO) also published guidelines for TETs in 2015 (12). An experienced multidisciplinary team that includes a radiologist, pathologist, thoracic surgeon, radiation oncologist, medical oncologist, and pulmonologist should evaluate all patients with TETs given the rarity of the disease and complexity of management.

Resectable Disease

The primary decision for treatment of TETs is whether or not the tumor is resectable. If primary complete resection is possible, the patient should go directly to surgery without the need for biopsy. This usually applies to Masaoka-Koga stage I/II and some stage III tumors (Table 15.2). Thereafter, depending on the resection status, stage, and histology, surgery may be followed by radiation therapy (RT) and/or infrequently chemotherapy (34). The schema for treatment per stage is given in Figure 15.1.

Preoperative Evaluation of Myasthenia Gravis

All patients with suspected thymoma should be evaluated for myasthenia gravis because of its potential perioperative complications (35). This evaluation usually begins with a careful assessment for ocular, bulbar, and/or limb muscle weakness. The diagnosis of myasthenia gravis requires two positive confirmatory tests among pharmacologic (Tensilon test), serologic (anti-AChR antibodies), and electrodiagnostic (EMG) studies. If there is any suggestion of myasthenia gravis on initial presentation, the patient should undergo preoperative evaluation by a neurologist. Medical optimization prior to surgery using a combination of cholinesterase inhibitors, intravenous immunoglobulin, plasmapheresis, and/or corticosteroids, can help to avoid respiratory failure in the perioperative period.

Stay updated, free articles. Join our Telegram channel

Join