Introduction
Thymomas are rare neoplasms that arise from tissue elements of the thymus and develop in the anterior mediastinum. Although usually slow-growing tumors, thymomas are considered to be malignant because of their potential invasiveness: Invasion beyond the capsule is a major prognostic factor that correlates with a worse outcome.
Surgery is usually the first step in the management of thymomas, and radiotherapy is used widely for invasive thymomas and by some authors for noninvasive thymomas. Chemotherapy is no longer controversial and should be used more in the future.
Normal Thymus Development
The thymus gland is a lymphatic organ involved in lymphoid cell development and maturation. However, its embryologic origins come from the endoderm as epithelial outgrowths of the lower portion of the third pharyngeal pouches. Cells of these epithelial outgrowths grow into the surrounding mesenchyma and subsequently constitute the medullary areas of the lobules of the thymus.
In some areas, epithelial cells accumulate and undergo keratinization and degeneration, leading to distinct structures called Hassall’s corpuscles, which are localized in the medulla of the lobules. Lymphocytes derived from hematopoietic stem cells of the bone marrow are secondarily localized within the spaces between the epithelial cells of the cortex of the lobules. The lymphoid cells are generally concentrated in the periphery of the cortex, while medullary areas of the lobules of the mature thymus contain mostly epithelial cells and few lymphocytes.[1] These epithelial cells have a major role in the production of humoral factors necessary for lymphoid differentiation, which occurs in fetal and early postnatal life.
The thymus gland reaches its maximal size in the adolescent, weighing 30 to 40 g. Lymphoid components gradually disappear after puberty and the gland involutes, leading to a fatty residue. Hassall’s corpuscles remain, and the thymus never completely disappears. Although the gland is usually situated beneath the upper part of the sternum, thymic tissue can be found in ectopic areas, such as the retrocarinal adipose tissue.
Pathology
Thymomas emerge from the epithelium of the thymus. The tumors always arise from the epithelial elements, although lymphocytic cells may be present, sometimes in a high percentage. Although epithelial neoplastic cells usually grow slowly and do not show cytologic characteristics of malignancy, all thymomas are considered to be malignant neoplasms because of their potential for invasion.
Immunohistochemical studies of thymomas have shown that the thymic epithelium expresses hormones, HLA antigens, acetylcholine receptor epitopes, and cytokeratin. Such studies have also investigated the tumors’ lymphocytic cells and have substantiated the nonneoplastic nature of these cells.
Classification Systems
Several pathologic classifications of thymomas have been proposed.
Rosai and Levine System--The most widely used classification system is that of Rosai and Levine,[1] which defines thymomas as neoplasms of thymic epithelial cells, regardless of the presence of a lymphoid component. In 1978, Rosai and Levine modified the definition such that thymic tumors containing cells with the cytologic aspect of malignancy were separately classified as thymic carcinomas,[2] which have a very different clinical outcome.[3,4]
Walker et al recently[5] summarized the classification system of Rosai and Levine. Thymomas are divided into three types depending on the predominant cell-type. The tumor is called a lymphocytic thymoma or epithelial thymoma if the predominant cells derive from the lymphocytes or epithelial cells, respectively. If these two cellular components are found in equal parts, the tumor is designated a lymphoepithelial, or mixed, thymoma. In all cases, the number of mitotic cells is low.[6,7] Some also suggest a spindle-shaped type[8] and an oval-cell type, which are thought to be variants of the principal types.
The prognostic significance of pathologic classification is controversial. Histologic aspects of noninvasive and invasive tumors can be identical,[9-12] and the division into lymphocytic, epithelial, or lymphoepithelial types may remain subjective. The supposed influence of histologic subtypes disappears when linked with strong prognostic factors, such as stage or extent of surgical resection.[4,13] Whereas some reports demonstrate that epithelial[7,14] or lymphoepithelial subtypes have a poor outcome,[3] others associate lymphocytic or spindle-cell subtype with a favorable outcome.[15-17]
Classification by Malignant Cell Ontogeny--Another system classifies thymomas according to malignant cell ontogeny. When neoplastic cells look like those found in the cortex of the normal thymus, the thymoma is designated a cortical thymoma. Otherwise, the term "medullary lymphoma" is used to describe a proliferation of cells thought to represent the neoplastic equivalents of normal thymic medullary cells. When both cortical and medullary cells are present in the malignant proliferation, the tumor is called a mixed corticomedullary thymoma.[18]
Staging
Masaoka Staging System
Staging of thymomas is usually based on invasiveness, as considered in the classifications of Bergh et al,[19] Wilkins et al,[20] Curran et al,[21] and Verley and Hollmann.[7] However, the most widely used system is that devised by Masaoka and colleagues,[22] which takes into account the anatomic extent of involvement, as defined clinically and histopathologically (Table 1).
The invasiveness of the tumor is one of the most important prognostic factors in thymomas. Tumor invasion beyond the capsule is associated with an unfavorable outcome.[3,7,13,15,21-27] Noninvasive thymomas have a very low[26] or zero[21,23-25] relapse rate, and an extensive review[28] reported an average 80% survival rate for noninvasive thymomas, as compared with < 50% for invasive tumors.
Pleural or pericardial effusion of the tumor is the most common form of metastatic involvement. Involvement of regional nodes is rare. Metastasis to distant organs is very unusual (< 10% at presentation), and the most common extrathoracic sites of disease involvement are the liver, kidney, brain, and spleen.
GETT Staging System
Among invasive tumors, disease-free survival is usually worse with higher stages although the differencesare not always statistically significant.[3,7,21,22] However, because the extent of surgery is a prognostic factor of major importance, a staging system based on the surgical and pathologic features of the tumor was described by the French Study Group on Thymic Tumors (GETT) (Table 2).[29,30]
In the GETT staging system, the predominant feature is the extent of sur-gical resection: completely resected, noninvasive tumors are stage I and completely resected invasive tumors are stage II tumors, whereas incompletely resected tumors are stage III tumors. In the Masaoka staging system, contiguous spread to the pericardium is a stage III tumor, whereas in the GETT system, in case of total resection, it becomes a stage II tumor. Conversely, an encapsulated totally resected GETT stage I tumor is designated a stage II-2 tumor in the Masaoka system if there is microscopic invasion of the capsule.
In a series of 163 patients,[23] our group studied the correspondence of the two staging systems and showed that they were concordant in 88% of cases. However the Masaoka system tended to upgrade GETT stage I and II tumors; 61% and 20% of GETT stage I and II tumors, respectively, were Masaoka stage II and III thymomas. Analysis of disease-free survival showed that the Masaoka II-GETT I patients experienced a better outcome than the Masaoka II-GETT II patients and should be managed differently. Similarly, the Masaoka III-GETT II patients had a better prognosis than the Masaoka III-GETT III patients. The disease-free survival of GETT I thymomas differs significantly from the disease-free survival of GETT II thymomas, and the disease-free survival of GETT II differs significantly from the disease-free survival of GETT III. These findings indicate that the GETT classification seems to be the best staging system.
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