Thymic Tumors

Demographics and Clinical Presentation

Thymomas are rare neoplasms arising from the thymic epithelial cells. They are characterized by an extreme variability in histologic appearance, as well as in clinical behavior. The actual incidence of these diseases is unknown, but data from 2003 show an overall incidence in the United States of 0.15 cases/100,000 person-years. Thymomas are the most common anterior mediastinal tumors in adults, accounting for about 50% of all mediastinal tumors. They can occur in all ages, but a peak in the incidence of thymomas associated with myasthenia gravis has been noted among individuals between the ages of 30 years and 40 years. A peak has also been noted among people (primarily women) aged between 60 years and 70 years who do not have myasthenia gravis. Although in most series the gender distribution differs, the difference is not significant, and men and women are equally affected, especially when clinical series of more than 100 patients are considered. Other malignant lesions (e.g., lymphoma, parathyroid and thyroid tumors, germ cell tumors, and mesenchymal and neurogenic neoplasms) as well as nonmalignant masses in the anterior mediastinum (e.g., aneurysms, granulomas, pericardial and esophageal cysts, and Morgagni hernias, as well as thymic hyperplasia) should be taken into account in the differential diagnosis. About 30% of patients with thymoma are asymptomatic. In these cases, the lesion is incidentally discovered, usually on chest radiographs. Among symptomatic patients, approximately 40% have local symptoms related to the intrathoracic mass, 30% have systemic symptoms, and the remaining have symptoms related to associated myasthenia gravis. The most common local symptoms are chest pain, cough, and shortness of breath. In case of invasive neoplasms, common symptoms include superior vena cava (SVC) syndrome ( Fig. 56.1 ), hemidiaphragm paralysis caused by phrenic nerve involvement ( Fig. 56.2 ), and hoarseness due to recurrent laryngeal nerve infiltration. Pleural effusion and chest pain have also been noted in cases of pleural spread of the tumor.

Systemic paraneoplastic diseases occur in about 40% of patients with thymoma ( Table 56.1 ).

Diagnostic Imaging Techniques

Imaging plays a central role in diagnosing and staging thymoma. The initial decision to either perform surgery or further investigate the tumor with tissue analysis is primarily based on the findings of computed tomography (CT), magnetic resonance imaging (MRI), and/or positron emission tomography (PET)/CT. The chosen imaging modality should allow the physician to determine the tumor size, local invasion, and the presence of distant spread of the disease. Based on the information, the physician decides if direct surgery is indicated or if preoperative (induction) therapy (stage III or IV disease) is needed. Follow-up imaging of treated patients is used to identify recurrence and resectable recurrent disease. Patients with completely resected recurrent disease have similar outcomes to those without recurrence. Conventional chest radiography is usually the chosen imaging modality for the initial investigation of thymoma, followed by chest CT. It is important to differentiate between nonneoplastic thymic enlargement and thymoma. In young children, the thymus and the hyperplastic thymus can mimic a mediastinal mass. On CT images, thymic hyperplasia appears as a diffusely and symmetrically enlarged thymus with smooth borders and preservation of the normal thymic shape. It may also alter the shape to a more nodal appearance, and it can even show an uptake of ¹⁸ F-2-deoxy- d -glucose (FDG). Chemical-shift magnetic resonance (MR), with in-phase and out-of-phase gradient echo sequences, may be helpful for differentiation because it identifies the normal fatty infiltration that is unlikely in thymoma.

CT with an intravenous contrast medium is the imaging modality of choice for evaluating thymoma and can help distinguish thymoma from other anterior mediastinal abnormalities ( Fig. 56.3 ). Typically, on CT images, thymomas appear as spherical or ovoid, smooth, 5-cm to 10-cm anterior mediastinal masses. They have been described as ranging from a few millimeters to 34 cm in diameter. The tumor enhances homogeneously and may present with lobulated borders. In cases of hemorrhage or necrosis, it becomes heterogeneous or even cystic. The tumor can be partially or completely outlined by fat and may contain punctate, coarse, or curvilinear calcifications. Ipsilateral pleural nodules are suggestive of stage IVA (disseminated pleural) disease. CT has been thought to have a limited role in the detection of tumor invasiveness. Retrospective studies showed that partial or complete obliteration of fat planes around the tumor was not helpful in differentiating stage I thymoma from more advanced disease. Lobulated or irregular contours, cystic or necrotic regions within the tumor, and multifocal calcifications were more suggestive of invasive thymoma.

Although the use of MR has decreased with the advances in multidetector CT and has been insufficiently studied for staging and follow-up, it still plays an important role in the investigation of the anterior mediastinal masses and in the staging of thymoma in patients with contraindication to CT. Thymoma presents with low to intermediate signal intensity on T1-weighted images and with high signal intensity on T2-weighted images. Signal intensity is heterogeneous in tumors with necrosis, hemorrhage, or cystic change. Especially in patients with cystic masses, MR allows a distinction between congenital cyst and cystic thymoma, because fibrous septa and/or mural nodules are typically present in cystic thymoma but absent in a congenital cyst. These septa and nodules are often not evident on CT. Although CT is superior to MRI in the depiction of calcification within thymomas, MRI can occasionally reveal fibrous septa within the mass and can permit better evaluation of the tumor capsule. The presence of fibrous septa was shown to be associated with a less aggressive histologic classification. In addition, the predominance of a necrotic or cystic component and heterogeneous enhancement were seen as signs of aggressiveness and were much more common with thymic cancer than with thymoma.

Nuclear medicine plays a minor role in the routine evaluation of thymoma. Indium-111 octreotide shows uptake in thymoma and is used to identify patients who may respond to treatment with octreotide, which is considered to be the second or third choice of therapy when conventional chemotherapy fails. The precise role of FDG-PET in the management of thymomas is unclear. One difficulty is that increased physiologic FDG uptake is common in a normal or hyperplastic thymus, especially in children and in adults younger than 40 years of age.

Histologic Diagnosis

When the results of imaging techniques are equivocal for a diagnosis of a thymic tumor, cytohistologic diagnosis is required. In the past, it was suggested that, to obtain a definite diagnosis, every anterior mediastinal lesion should be subjected to biopsy before deciding on final treatment. In more recent years, however, refinements in imaging techniques have resulted in an improved diagnostic yield, and the need for a mediastinal biopsy has dramatically decreased. In a survey among European Society of Thoracic Surgeons (ESTS) members, 90% of the interviewed centers stated that they do not routinely look for a histologic confirmation of a suspected thymoma. However, there is a general agreement that biopsy should be considered in the case of undefined CT findings that may suggest lymphoma, or in the case of unresectable tumors before induction chemotherapy or definitive chemoradiation therapy.

Staging Systems

Before an official stage classification system for thymic malignancies has been defined by the Union Internationale Contre le Cancer and The American Joint Commission on Cancer, several different systems (Masaoka, Masaoka–Koga, TNM Classification of Malignant Tumours [TNM], Groupe d’Etude des Tumeurs Thymique) are actually being used. Historically, the proposed staging systems were designed on single-center experience of small series of patients who had surgery. In most cases these systems are empirically derived. Although several studies have provided some correlation with outcomes, the limited number of patients and infrequent validation in an independent set of patients generally provide little basis for choosing between one system and another.

Thymoma

Thymomas are epithelial tumors mixed with reactive lymphocytes. They are ultrastructurally characterized by desmosomes and tonofilaments and are primarily found in the anterosuperior mediastinum. Atypical localization within the thyroid, the pericardium, the lung parenchyma, and hilum is documented, and they can even coat the pleura in a mesothelioma-like fashion.

Overall, thymomas are generally solid, lobulated, yellow-gray tumors. Eighty percent are encapsulated, and the remainder infiltrates the surrounding structures. Foci of necrosis and cystic degeneration, with eventual hemorrhage, are common, sometimes making a differential diagnosis against multilocular thymic cyst difficult.

The histologic classification of thymomas has been debated for more than 50 years. Lattes and Jonas (in 1957) and Bernatz et al. (in 1961) proposed a classification based on the major morphologic pattern, including predominantly lymphocytic, predominantly epithelial, predominantly mixed, and predominantly spindle-cell-type thymoma. In 1978, Levine and Rosai separated thymoma from a variety of other thymic neoplasms, such as thymic carcinoid, various lymphomas, and germ cell tumors. They divided thymomas into benign, or noninvasive, and malignant, or invasive, tumors. In 1985, Muller-Hermelink and Marino proposed a system that used both topography and morphology. Their system included six subtypes: medullary, mixed, predominantly cortical, cortical, well-differentiated carcinoma, and thymic carcinoma. Lastly, in 1999, WHO reached a consensus on thymoma classification based on both morphology and the epithelial cell-to-lymphocyte ratio. Six subtypes were identified: type A (spindle cell, medullary), type AB (mixed), type B1 (organoid), type B2 (cortical), type B3 (well-differentiated thymic carcinoma), and type C (thymic carcinoma).

Type A thymomas consist of cells with a spindle- or oval-shaped nucleus and a uniform bland cytology, reminiscent of cells in the atrophic adult thymus ( Fig. 56.4 ). Rosette-like, storiform, or gland-like formations can be seen. Few intermingled lymphocytes are found. In nearly all cases, the epithelial tumor cells are positive for CK19, and in 50% of cases, they are positive for the B lymphocyte marker CD20. If staining for CK19 is negative, monophasic synovial sarcoma, or solitary fibrous tumor, must be ruled out. Reticulin stains are very useful in assessing the spindle cell, type A pattern. A well-recognized variant is called micronodular thymoma with lymphoid stroma, presenting epithelial micronoduli with intraepithelial CD1a-positive immature T cells and florid lymphoid follicular hyperplasia of the stroma. Myasthenia gravis occurs less frequently with type A thymomas, although secondary mucosa-associated lymphoid tissue (extranodal marginal zone B cell) lymphoma may develop.

Type B thymomas consist of round or polygonal epithelioid cells. They are further subdivided based on the proportional increase in epithelial cell content in relation to the reactive lymphocytes and the degree of cytologic atypia: from B1 (number of lymphocytes greater than number of epithelial cells) to B2 (number of lymphocytes epithelial cells equal) to B3 (number of lymphocytes less than number of epithelial cells). B1 thymomas are lymphocyte rich (organoid), containing only small nonatypical, CK19-positive epithelial cells. They resemble a normal functional thymus: cortical areas have CD1a-positive lymphocytes; edematous perivascular spaces include CD20-positive lymphocytes; and nodularity is vague. Unfortunately, positivity for epithelial CK19 and lymphocytic CD1a is physiologic in the cortex. Thus the differential diagnosis between normal thymus, thymoma, and lymphoblastic lymphoma may be very challenging, particularly with evaluation of a frozen section. In newborns and children less than 3 years of age, it will mostly be a true thymic hyperplasia, but in older children or adolescents, T-cell lymphoblastic lymphoma must be ruled out. Although thymomas in children are unusual, a few documented cases have occurred in children around puberty. Thymomas are p63 positive, but this marker may also be present in mediastinal B-cell lymphomas.

In type B2 thymomas (cortical), scattered plump tumor cells show vesicular nuclei with prominent nucleoli. Perivascular spaces eventually include palisading of lymphocytes, and Hassall bodies are rare. In type B3 thymomas (epithelial, atypical), proliferative invasive CK19-positive epithelium is associated with immature lymphocytes positive for CD99 and CD1a ( Fig. 56.5 ). A diagnosis of combined thymoma is made if, for example, the components B2 and B3 both achieve 50% of tumor surface. Thymomas combining type A with type B features are designated as type AB (mixed) and they contain lymphocyte-rich and lymphocyte-poor areas. Rare thymomas include the metaplastic, the microscopic, and the sclerosing variant, and the so-called lipofibroadenoma.

With the challenging criteria, it is evident that the opportunity for achieving interobserver agreement on histologic classification of thymomas is limited. The recent proposal of major and minor morphologic and immunohistochemical criteria to better individualize each thymic epithelial tumor entity aims at addressing those issues and has been integrated into the updated WHO classification. As previously mentioned, immunohistochemistry may be valuable, and a list of useful markers is integrated into the WHO classification.

Diagnosis on evaluation of core biopsies may differ from the follow-up analysis of whole tumor sections. To overcome these problems, Suster and Moran, in 2008, proposed a simplified classification into three subtypes: thymoma (well-differentiated tumors), atypical thymomas (intermediate differentiation), and thymic carcinomas (poorly differentiated tumors); others, maintaining the WHO classification, demonstrated that among the six subtypes, only three WHO categories were prognostically significant: types A, AB, and B1; types B2 and B3; and type C. Ultimately, thymoma subtyping on small biopsies is usually not needed for the therapeutically relevant distinction between lymphoma and solid tumor. In any case, diagnostic discrepancies between core-needle and resection specimen histology can be anticipated, given the frequent occurrence of histologic tumor heterogeneity that may be missed due to sampling error. Of note, histologic switch from lymphocytic lesions to more epithelial tumors has been reported, and may be related to tumor heterogeneity, as well as the effect of previous corticosteroid and chemotherapy treatment.

Thymic Carcinoma

The 2004 WHO update maintained the range from type A to B3, but separated thymic carcinomas from thymomas with the rationale that thymomas are organotypic, unique tumors, because the combination of epithelial tumor cells with reactive lymphocytes may not be found in other organs ( Table 56.3 ). For this reason, the C category was abandoned. Thymic carcinomas display the common neoplastic morphologies found in other body sites, and they do not have the capacity to promote the maturation of intratumoral immature T cells. For thymic carcinomas, 11 histologic variants are recognized. The most common are squamous cell carcinomas, lymphoepithelioma-like carcinomas, and neuroendocrine tumors (considered as a separate entity in some series). As in other organs, the precise clinical relevance concerning therapy and prognosis is difficult to assess, and tumor heterogeneity is often found.

Most patients with thymic carcinomas are symptomatic, reflecting the high stage III to stage IV at diagnosis. Autoimmune phenomena associated with thymoma, such as myasthenia gravis or pure red cell aplasia, are rarely found. Lymph node and distant metastases are common. Squamous cell carcinoma may be keratinizing or nonkeratinizing, and no thymopoiesis or autoimmunity is present. Immunohistochemistry is of some help for the differential diagnosis. In contrast to lung squamous cell carcinoma, staining for CD117 (c-Kit) may be positive in thymic squamous cell carcinomas, but less than 10% of patients have a CD117 mutation. Epstein-Barr virus may be found in lymphoepithelioma-like carcinomas and in nasopharyngeal carcinomas. Many thymic adenocarcinomas are CD5 positive, a lymphocyte marker considered to be rare in carcinomas, but negative for thyroid transcription factor 1 and thyroglobulin.