Thymoma and Thymic Carcinoma
Patrick J. Loehrer Sr.
John Henley
Kenneth Kesler
Thymoma and thymic carcinoma represent the most common malignancies found in the anterior mediastinum. Thymomas can also rarely originate in the thyroid, lung, or pleural spaces, presumably arising from ectopic vestigial remnants of thymic tissue. According to Surveillance, Epidemiologic, and End Results (SEER) data accumulated between 1973 and 1998 from nine states within the United States, the overall incidence of thymoma was of 0.15 cases per 100,000 person-years.1
Epithelial disorders of the thymus exhibit a wide spectrum of histologic features and clinical behavior. Thymic hyperplasia displays an invariably benign behavior, whereas thymomas demonstrate variable degrees of local invasiveness and some have distant metastatic potential. At the other extreme are thymic carcinomas, which exhibit cytological features of carcinoma, including nuclear enlargement, pleomorphism, and hyperchromasia. These often present in advanced clinical stages.
ETIOLOGY AND PATHOGENESIS
The thymus is a spongelike scaffolding of epithelial cells soaked with T lymphocytes. It reaches its maximum development at puberty, weighing approximately 40 g, and undergoes involution and atrophy with aging. The dynamic microenvironment of the thymus contributes to the maturation of T lymphocytes, a process that depends on signals provided by the thymic stroma.2 Stromal elements include epithelial cells, macrophages, dendritic cells, fibroblasts, and matrix molecules. The topographical separation of the thymus in cortical and medullary portions reflects the functional progression of this maturation process. This is relevant to thymoma, as tumors may show histologic evidence of cortical and medullary differentiation.
Causative factors for the development of thymomas have not been identified, although Epstein-Barr virus (EBV) has been associated with cases of lymphoepithelioma-like thymic carcinoma.3
Several immunohistochemical studies have examined the expression of apoptosis-related proteins, such as bcl-2 and p53, in thymomas.4,5,6 Bcl-2 expression is notable in medullary or spindle-cell thymoma (World Health Organization [WHO] type A, see discussion that follows). The p53 gene is found to be overexpressed by immunohistochemistry (IHC) in a subset of thymomas, whereas the majority of thymic carcinoma cases are overexpressors of p53.6,7 However, on polymerase chain reaction (PCR) testing, very few cases have p53 mutations.
Genetic abnormalities, most commonly described as loss of heterozygosity (LOH), are seen throughout all thymoma subtypes. The long arm of chromosome 6 is usually involved, especially region 6q23.3 to 25.3.8,9 Other consistent abnormalities include chromosomes 3, 5, 7, 8, 13, and 17. These are rarely seen in WHO type A thymomas. Correlation of these findings with the invasive potential of thymomas has been proposed,10,11,12 but no definitive link is available to date. Another study has shown an increased incidence of aneuploidy in thymic epithelial tumors with advancing stage.13
The expression of two tyrosine kinase receptors, epithelial growth factor receptor (EGFR) and c-KIT ligand, have been examined in a relatively large number of malignant thymic tumors. EGFR and c-KIT appear to be preferentially expressed in thymoma and thymic carcinoma, respectively.14,15,16,17 Although the significance of this observation is unclear, the differential staining pattern of these markers is of potential diagnostic use in distinguishing these tumors.
The maturation process of T lymphocytes frequently becomes abnormal in patients with thymomas.18,19 Irregularities include impairment of CD4+ T-cell development, decreased interferon-gamma-induced human leukocyte antigen-DR (HLA-DR) expression on cultured thymoma epithelial cells, and lower levels of major histocompatibility complex (MHC) class II antigen expression.20 Peripheral blood lymphocytosis is commonly observed, with an increased proportion of CD45RA+CD8+ T cells as opposed to an apparent decrease in the CD4 cell population that may reverse after thymectomy.21
PATHOLOGY
Thymoma is a neoplasm arising from thymic epithelial cells. Classification of thymic epithelial tumors has been confused by a plethora of subtyping schemes.22 (Table 64.1) The difficulty in the histopathologic classification of thymomas is twofold. First, thymomas have a spectrum of appearances, ranging from lymphocyte-rich tumors in which the neoplastic epithelial cells are difficult to discern without the aid of IHC, to lymphoid-deplete tumors that approach the appearance of undifferentiated carcinoma. Second, histologic examination correlates poorly with clinical behavior.
A standard classification, based on the relative proportions of epithelial cells and lymphocytes, subdivided thymomas into predominately lymphocytic, epithelial, mixed, and spindlecell types. 23 Although simple in concept and reproducible in application, this scheme lacked the clinical relevance and ontogenetic considerations that the later schemes attempted to provide. Levine and Rosai24 divided thymic epithelial tumors into thymoma, noninvasive and invasive types, and thymic carcinoma, the latter discernible by its frankly malignant cytology. Marino and Müller-Hermelink (MM-H)25 stressed ontogenic considerations and subtyped thymomas according to the appearance of the neoplastic epithelial cells (i.e., cortical vs. medullary types). Additional descriptions of well-differentiated thymic carcinoma followed, which suggested a spectrum of tumors ranging from thymoma to unequivocal carcinoma.26 Suster and Moran,27 in an effort at simplication, proposed the distinction of thymic neoplasms based on the degree of differentiation: thymoma (well-differentiated type), atypical thymomas (moderately differentiated type), and thymic carcinomas (poorly differentiated type).27
TABLE 64.1 Pathological Classifications of Thymoma* | ||||||||||||||||||||||||||||||||||||
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The most recent classification, from the WHO Committee for the Classification of Thymic Epithelial Tumors,28 incorporates features from both the traditional and MM-H classifications. It is the classification that is currently advocated in an effort to standardize thymoma classification. The WHO scheme divides thymoma into types A, B, and C, as well as mixed forms (i.e., type AB). Type A represents spindle-cell or medullary thymoma, an indolent tumor with little propensity for aggressive behavior. Type B is further subdivided into types B-1, B-2, B-3. Type B-1 tumors are lymphocyte rich and may resemble the normal thymus, with areas of medullary differentiation. In type B-2 tumors, neoplastic epithelial cells are more numerous with larger nuclei and more prominent nuclei. Type B-3 tumors have a predominance of epithelial cells and include tumors that previous authors have called welldifferentiated thymic carcinoma and atypical thymoma. These tumors lack the cytologic atypia that warrants a diagnosis of thymic carcinoma. Type C thymoma represents thymic carcinoma; various cell types are encountered, with lymphoepitheliomalike carcinoma being the most common. These are highgrade tumors that are histologically reminiscent of their namesake, lymphoepithelial carcinoma of the nasopharynx. Other cell types include squamous cell carcinoma, small cell or neuroendocrine carcinoma, anaplastic or undifferentiated carcinoma, sarcomatoid carcinoma, adenosquamous carcinoma, and clear cell carcinoma. Although most carcinomas are highgrade malignancies, a few low-grade variants carry a more favorable prognosis and include well-differentiated squamous carci noma, low-grade mucoepidermoid carcinoma, and basaloid carcinoma. Thus, grading thymic carcinomas into low-and high-grade types is of prognostic utility.26 The WHO classification has come into criticism.29,30
Because the histology of thymic carcinomas is “nonorganotypic” (i.e., their appearance provides no recognition of their origin from the thymus), it may be difficult to unequivocally assign the organ of origin when evaluating tumors involving the region of the thymus.31,32,33,34,35,36 No immunohistochemical profile is unique to thymic carcinoma, although CD5 expression is reportedly increased.33,35 The specificity of CD5 for thymic carcinoma relative to other differential diagnostic considerations is unclear and in our experience, CD5
staining is too inconsistent to be of clinical utility. Especially when pathology reveals squamous cell carcinoma, small cell carcinoma, and clear cell carcinoma, another primary malignancy should be e xcluded before the definitive diagnosis of thymic carcinoma.37
staining is too inconsistent to be of clinical utility. Especially when pathology reveals squamous cell carcinoma, small cell carcinoma, and clear cell carcinoma, another primary malignancy should be e xcluded before the definitive diagnosis of thymic carcinoma.37
Nonepithelial tumors arising in the thymus are not considered in the tumor classifications mentioned previously, including thymic carcinoid tumors, germ cell tumors, hematopoietic malignancies, sarcomas, and benign mesenchymal neoplasms. Thymic carcinoid tumors are much more pernicious than their pulmonary counterparts and have been linked to multiple endocrine neoplasia in up to a quarter of the cases. 38
CLINICAL FEATURES
Presentation In a recent SEER database study, the mean age at presentation of thymomas and thymic carcinomas was reported as 56 years, with the incidence increasing up to the age of 77, when it neared 0.5 cases per 100,000.1 Eleven percent of cases occurred prior to 35 years of age. The incidence was slightly higher in men compared to women (0.16 vs. 0.13 per 100,000) and in blacks compared to whites (0.20 vs. 0.12 per 100,000).
The thymus is located adjacent to the pericardium and the great vessels of the chest and is limited by the neck superiorly. Thymomas encompass 20% of all mediastinal masses and 45% of anterior mediastinal tumors. Nonmalignant masses in the anterior mediastinum to be considered in the differential diagnosis include aneurysms, granulomas, pericardial and esophageal cysts, and Morgagni hernias. Other malignant masses of the anterior mediastinum include lymphoma (20%), parathyroid and thyroid tumors (15%), germ cell tumors (15%), and neurogenic and mesenchymal neoplasms.
Thymomas often present as a mediastinal mass, which may cause local symptoms (chest pains, dyspnea, hemoptysis, dysphonia, Horner syndrome, and superior vena cava compression). Alternatively, in approximately one third of patients may present with a paraneoplastic syndrome, such as myasthenia gravis (MG) or pure red cell aplasia (PRCA). Finally, one third of patients may present with a mediastinal mass incidentally discovered on radiographic imaging.
Paraneoplastic Syndromes Approximately 40% of thymoma patients have a paraneoplastic syndrome (Table 64.2), and there is a lower incidence among thymic carcinoma cases. The precise correlation of paraneoplastic phenomena with deranged intratumoral T-cell maturation has not been established.
MG is the most common paraneoplastic syndrome.39,40 The acetylcholine receptor (AChR) is transiently found on the surface of myoid cells in the thymus in patients with thymic hyperplasia, and is considered to be the stimulus for autoimmunity and generation of anti-AChR antibodies that lead to MG.41 Interestingly, in thymoma specimens, myoid cells were not detected, although cytoplasmic AChR epitopes were seen.42 Expression of the AChR P3A– α-subunit gene also correlated with MG in patients with thymoma.43 Ströbel et al.44 demonstrated a higher production of intratumorous naive CD4+ T cells in thymoma patients with MG compared to thymoma without MG.
TABLE 64.2 Paraneoplastic Syndromes Associated with Thymomas | |||||||||||||||||||||||||||||||||
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Thymoma is believed to be present in 10% of established MG cases, whereas 30% to 50% of patients with thymoma eventually develop clinical MG. Of note, MG is rarely associated with thymic carcinoma or WHO subtypes A or AB. In the study of Okumura et al.,45 which excluded thymic carcinoma cases, 69% of MG cases had thymomas of B subtype (Table 64.3), and 80% were of B subtype in the series of Evoli et al.46 Some studies suggest that HLA A24 and B8 are predictive for the presence of thymoma in patients with MG.47
Anti-titin antibodies represent one type of antiskeletal muscle antibodies that is frequently present in patients with thymoma or late-onset MG. One study revealed a sensitivity of 68% for presence of thymoma in newly diagnosed MG patients.48 However, anti-titin antibodies have not been found to be helpful in predicting thymoma recurrences.49
Acquired PRCA occurs in approximately 5% of patients with thymoma,50 and approximately 10% of patients with this syndrome harbor a thymoma.51 PRCA is suspected in the presence of isolated anemia and a low reticulocyte count and is confirmed with a bone marrow examination. Alternative diagnoses such as myelodysplastic syndromes, underlying chronic lymphocytic leukemia, and parvovirus (erythrovirus) B19 infection need to be entertained. The etiology of PRCA in the setting of a thymoma has not been definitely established, although mouse and in vitro studies suggested the presence of a possible erythropoiesis inhibitor.52 A T cell-mediated process has also been proposed.53,54,55
TABLE 64.3 Association with Myasthenia Gravis according to the World Health Organization Histologic Classification System for Thymic Epithelial Tumors | |||||||||||||||||||||||||||||
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Hypogammaglobulinemia (Good syndrome) also o ccurs in patients with thymic epithelial malignancies 56,57 and is frequently associated with recurrent sinopulmonary i nfections. Good syndrome leads to severe manifestations in less than 5% of cases. Cytomegalovirus infections (colitis, retinitis) have been reported. 58 Masci et al. 59 demonstrated the presence of an oligoclonal population of CD8+ T cells in the bone marrow of five patients with thymoma-associated hypogammaglobulinemia. Lymphopenia has also been reported 56 and frequently coexists with hypogammaglobulinemia.
Second neoplasms were found to occur with increased incidence (up to 28%) in patients who had a history of thymoma according to several reports. 1,60,61 The most common was colorectal, and reasons for this association are largely unknown. The recent SEER review, however, could not definitely establish an increased incidence of malignancies other than B-cell non-Hodgkin lymphomas (4.7-fold increased incidence, persisting up to 10 years after thymoma diagnosis) and soft tissue sarcomas. 1
Diagnostic Evaluation The diagnosis of thymomas is established by a core needle biopsy computed tomography (CT) guidance, mediastinoscopy with biopsy, or open or video-assisted thoracotomy. Fine needle aspiration (FNA) may reveal the diagnosis in a subset of cases, 62 but are error prone in 5% to 10% of cases (usually confused with lymphoma). 63 There is a possibility that only lymphoid material, rather than epithelial cells, will be present. 64 Flow cytometry and T-cell receptor rearrangement studies 65 may be helpful in assessing the possibility of lymphocyte clonality. FNA also does not allow assessment of capsular invasion. In ancillary testing, a careful and often history-directed immunohistochemical panel (see previous discussion under “Pathology”) can assist in the differentiation between lymphoid neoplasms, non-small cell lung cancer (thyroid transcription factor-1 [TTF-1] positive in approximately 60% to 70% of cases), thyroid, and germ cell tumors. Given the fact that thymomas are relatively uncommon, and that alternative diagnoses carry important treatment implications (such as germ-cell tumor, lung cancer, or lymphoma), pathology specimens are best reviewed by individuals and at institutions with experience in the evaluation of mediastinal neoplasms.
Especially when the mediastinal mass is described as a poorly differentiated malignancy, it is important to confirm and be sure of the diagnosis. Aspects of importance in the history include the age and gender of the patient, the amount of tobacco exposure, and a careful search for paraneoplastic syndromes. In the p hysical exam, a thorough lymph node exam should be performed, especially when it is not clear if the m ediastinal mass is originating from the anterior or posterior mediastinum. Thymomas and germ cell tumors generally may present with or supraclavicular adenopathy; bilateral or peripheral lymphadenopathy should lead one to suspect lymphoma. In patients with undiagnosed masses or poorly differentiated malignancies, serum α-fetoprotein (AFP) and human chorionic gonadotropin (HCG) levels should be o btained. Imaging studies can be helpful when showing p leural-based metastases that are typical of thymic malignancies. Lastly, chromosomal evaluation with the presence of isochromosome 12p with fluorescence in-situ hybridization (FISH) would lead to a diagnosis of germ cell tumors.
When there is a high clinical suspicion for thymoma, based on an encapsulated mediastinal mass on chest CT scans, no evidence of metastases and normal serum AFP and HCG levels, then definitive resection can be planned without biopsies being obtained. The direct surgical procedure without a previous biopsy avoids the concern of tumor seeding, which has been raised by some authors.
The pattern of spread may be helpful in distinguishing from other malignancies. Thymomas characteristically spread to pleural surfaces. Although uncommon, liver, bone, kidney, and brain metastases may also occur. In the face of metastatic pleural implants on CT scans, representative percutaneous u ltrasound or CT-guided core biopsies can be obtained to establish the diagnosis.
Thymomas often express somatostatin receptors. Although indium-labeled octreotide scans lack diagnostic specificity, they are frequently positive in thymomas 66,67,68 and are helpful when considering treatment with octreotide. Indium-labeled octreotide can be helpful in distinguishing a thymoma from thymic hyperplasia.
Kubota et al.69 examined the role of positron emission tomography (PET) scans in 22 patients with anterior mediastinal masses. It was found that both noninvasive thymomas
and invasive thymomas can demonstrate increased uptake, although the invasive subtypes and thymic carcinomas appeared to have higher standard uptake values (SUV). Another study did not find significant differences in 18F-fluorodeoxyglucose PET uptake between patients with invasive and noninvasive thymomas.70 The use of PET scans in the evaluation and management of thymomas remains investigational at this time.
and invasive thymomas can demonstrate increased uptake, although the invasive subtypes and thymic carcinomas appeared to have higher standard uptake values (SUV). Another study did not find significant differences in 18F-fluorodeoxyglucose PET uptake between patients with invasive and noninvasive thymomas.70 The use of PET scans in the evaluation and management of thymomas remains investigational at this time.
TABLE 64.4 Staging of Thymomas | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Staging In 1981, Masaoka et al.71 published a clinical staging system based on the degree of invasion of thymomas (Table 64.4). This classification has been validated and established 5-year overall survivals of 92.6%, 85.7%, 69.6%, and 50% for stages I, II, III, and IV, respectively. These data support the indolent nature of this disease even for many patients with advanced disease. Of note, patients with subtotal
resections received radiation therapy (RT) postoperatively in that series.
resections received radiation therapy (RT) postoperatively in that series.
Another system, from the French Groupe d’Etudes des Tumeurs Thymiques (GETT), was proposed in 1991, 72 and is based on pathological postoperative staging (Table 64.4). Although generally felt to be equivalent to the Masaoka stage in terms of prognosis,73 the GETT system (when compared with Masaoka) downstages invasion into neighboring organs, if complete resection was achieved. Additionally, in the Masaoka classification, microscopic invasion through the capsule was found to have prognostic significance. Microscopic invasion is not taken into account in the GETT classification. These slight differences have some implication regarding prognosis. For instance, Masaoka stage II-GETT stage I patients tend to have a better disease-free survival than the Masaoka stage II-GETT stage II patients. The current TNM staging greatly reflects the original Masaoka system 74 (Table 64.4).
One study evaluated the correlation of computer tomography with the ability to predict capsular invasion.75 Invasive thymomas were more likely to have lobulated or irregular contours than noninvasive thymomas, as well as a higher prevalence of low attenuation areas and foci of calcification within the tumor than noninvasive thymomas. However, the findings are unlikely to be of enough specificity to substitute for pathological staging during thymectomy.
PROGNOSTIC FACTORS
Interpretation of the current literature regarding the factors affecting individual prognosis in thymic malignancies is difficult. Studies that investigate prognostic determinants have been hindered by the use of different histologic classifications and by their retrospective nature, which potentially introduces selection biases into results. Furthermore, treatment differences among series, including the extent and expertise of the surgical resection, further confound prognostic associations.
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