THYMOMAS AND THYMIC TUMORS

1 The thymus, a key immune system organ, can be the site of manydifferent benign and malignant TUMORS (Table ). According toRosai and Levine,1it should be emphasized that the term thymoma is restricted to neoplasms of the THYMIC epithelial cells. A detailed his-torical review of the thymus gland and THYMOMAS has been published first description of a THYMIC tumor is credited to Sir AstleyPaston Cooper, a surgeon from London, in 1832. The British micro-scopist Arthur Hill Hassall described in 1849 the corpuscles unique to thethymus. The first association between myasthenia gravis (MG) and thy-moma was discovered by the German neurologist Hermann Oppenheim,in 1899. The first thymectomy for MG was performed in 1911 by ErnstFerdinand Sauerbruch in Zurich, Switzerland.

2 The thymus showedhyperplasia but no tumor , and myasthenia improved markedly aftersurgery. Alfred Blalock at Vanderbilt University in Nashville pioneeredthe surgical technique of total thymectomy in 1936 (case published in1939) and advocated it for the treatment of AND ETIOLOGYT hymomas are usually slowly growing TUMORS with about equalincidence in men and women; they occur through a wide age range,with a peak in the 40s and 5 THYMOMAS are rare, and moreaggressive, in are currently no known etiologic factors for 23 patients with thymoma, Cohen and colleagues noted that 2had received radiation for an enlarged thymus in childhood, 17 and 28years before the diagnosis of thymoma, the past, thatpractice was based on the belief that such physiologic enlargement ofthe thymus in some infants could cause sudden death (status thymi-colymphaticus).

3 1 Such radiation has been shown to lead to anincreased incidence of cancer, particularly of the thyroid and ,7 The role of Epstein-Barr virus (EBV) in the etiology of a subtype ofthymic carcinoma, the lymphoepithelioma variety, has now been doc-umented, as discussed PATHOGENESISEMBRYOLOGY ANDANATOMYThe thymus is embryonically derivedfrom the endodermal epithelium of the third pharyngeal pouches(which also give rise to the lower pair of parathyroid glands) and, lessconstantly, the fourth ones as ,5 The right and left THYMIC anlagenmigrate downward into the anterosuperior mediastinum, joiningtogether without complete fusion to form a bilobate THYMIC TUMORS are located in the anterosuperior mediastinum,variations in migration account for the findings of gross or micro-scopic THYMIC tissue anywhere between the hyoid bone superiorly andthe diaphragm exposure of the mediastinum and eventhe neck is therefore necessary, if surgical removal of the entire thymusis indicated, as in patients with thymoma or those with myastheniagravis (with or without associated thymoma).

4 8 The absolute weight ofthe thymus reaches its peak in the pubertal years (mean, 34 15 gbetween age 10 and 15 years) and then gradually decreases, althoughthis age-related involution normally is never , the normal thymus shows distinctive lobules with asharp demarcation between the cortex, rich in lymphocytes, and themedulla rich in epithelial cells and characteristic Hassall s corpuscles,formed by concentric layers of mature epithelial thymus plays a critical role in the maturation of bone mar-row derived lymphocytes into T cells and, as such, in cell-mediatedimmunity. It has a rich blood supply but no afferent lymphatics. Effer-ent lymphatics apparently originate from perivascular spaces and draininto the mediastinal and lower cervical OFTHYMOMASD istinctive features reminiscent of thenormal thymus make the pathologic diagnosis of thymoma easy inmost cases.

5 A fibrous capsule surrounds the tumor and sends thick,fibrous septa, dividing the tumor into well-demarcated ,9 11 Microscopically, there is a distinctive dual cell population, includinglymphocytes (small with dark nuclei) and epithelial cells (larger andlighter) (Plate19, Fig. ). Quantitatively, the lymphocyte depithe-lial cell ratio varies widely (average about 2).12 Even though there is acontinuum among the extremes, THYMOMAS are often classifiedaccording to the relative ratio of cells between predominantly lym-phocytic, mixed epithelial lymphocytic, and predominantly 4% of cases only epithelial cells are THYMOMAS aredefined as neoplasms of THYMIC epithelial cells, pure lymphocytictumors are not THYMOMAS and should raise the possibility of lym-phoma.

6 The epithelial cells represent the neoplastic component of appear cytologically bland; mitosis and cellular atypiaare rare. They are typically round or oval, but sometimes have a spin-dle-shaped nucleus, which may represent the predominant cell inabout 5 to 12% of THYMOMAS , justifying the term spindle cell thy-moma, which tends to grow more slowly and to be associated with redcell hypoplasia or hypogammaglobulinemia rather than ,9 Thelymphocytes are not considered neoplastic and, as in the normal thy-mus, are constituted mainly of T cells in various stages of often exhibit mitotic figures. A higher percentage of epithelialcells has been reported to have a negative prognostic influence, as seenin cases with recurrent tumor or more advanced 14 There are no reliable histologic features of malignancy for thy-momas.

7 The malignant behavior of a thymoma is indicated by micro-scopic or macroscopic invasion of the tumor capsule or of surround-ing organs or by the presence of metastasis. Therefore, it is the grossexamination of the tumor at surgery which is critical in suspecting orestablishing the malignant nature of a thymoma. About 30 to 40% ofthymomas are invasive. On the other hand, a well-encapsulated thy-moma may, on occasion, recur years after surgical resection. This leadssome to suspect that all THYMOMAS are potentially malignant andshould be treated as the term malignant can also causeconfusion with THYMIC carcinomas, where the epithelial cells appearcytologically malignant (see below), it is best to avoid it and dividethymomas into encapsulated and invasive was recently postulated that THYMOMAS may be further subdi-vided into those with cortical, medullary, and mixed differentiation,reflecting the anatomy of the normal thymomascontain large epithelial cells with vesicular chromatin and prominentnucleoli, whereas medullary THYMOMAS show oval to spindle-shapedepithelial cells with dispersed chromatin and inconspicuous THYMOMAS contain both cortical and medullary compo-nents.

8 Medullary and mixed THYMOMAS appear to follow a more benigncourse than cortical ones. They show a lower incidence of invasive-ness, lower incidence of MG, lower recurrence rate, and better sur-vival, even when capsular invasion is ,17 This classificationhas also been correlated with the size of epithelial cell nuclei usingmorphometric THYMOMAS have larger epithelialcell nuclei than do medullary ones. The prognostic value of nuclearDNA content measured by flow cytometry is the percentage of cells in the S-phase does not appear tohave any prognostic significance, some studies have found that aneu-ploidy correlates with poorer AND THYMICTUMORSA. PHILIPPECHAHINIAN, MD Table TumorsTumors of the THYMIC epitheliumGerm cell tumorsThymomas (encapsulated or invasive)SeminomasThymic carcinomasTeratomasLymphoid tumorsCarcinomasHodgkin s diseaseOthersOther lymphomasThymolipomaNeuroendocrine tumorsThymic cystsThymic carcinoidsMetastasesOat cell carcinoma1314 SECTION 28 / Neoplasms of the Thoraxsity by magnetic resonance imaging (MRI), but the role of that tech-nique in detecting possible capsular invasion as well as vascular inva-sion as compared with CT, needs further use of positronemission tomography (PET)

9 With 18-fluorodeoxyglucose has beenevaluated to distinguish malignant from benign mediastinal carcinomas and invasive THYMOMAS show high uptake,whereas noninvasive THYMOMAS show low uptake. It should be empha-sized, however, that surgical exploration and pathologic evaluationremain the most reliable means to assess invasiveness of PARANEOPLASTIC SYNDROMEST here is a remarkable number of paraneoplastic syndromes asso-ciated with thymoma that are mostly related to autoimmune mecha-nisms. They are dominated by three characteristic entities (Table ).MYASTHENIAGRAVISMG occurs in about a third to a half of patientswith thymoma, and about one-tenth of patients who have MG have ,25 Such patients are usually older than those with MGwithout thymoma, although the clinical signs of MG are similar inboth groups.

10 Few features distinguish the histologic appearance of thy-momas in patients with MG; predominantly spindle cell thymomasare rare in this group, and the surrounding THYMIC tissue reveals thepresence of lymphoid follicles with germinal centers in about 50% ofthe cases (versus only 5 to 8% in THYMOMAS without MG).1MG is anautoimmune disorder characterized by the presence of antibodies tothe acetylcholine receptors of the neuromuscular junction. Such serumantibodies are found in 90% of patients with generalized mechanisms are unknown. Myoid cells in the normal thy-mus raise the possibility of in situ striationalantibodies directed against elements of the sarcomere, such as titin,have also been detected in 80% of patients with MG and thymoma andin 25% of patients with thymoma but without thymec-tomy rather than thymomectomy is indicated in patients with MG,even in the absence of a thymoma (see Surgery below).