Thymus and Mediastinum

Clinical Features

• Uncommon; constitutes less than 10% of mediastinal cysts

• May be congenital or acquired

• Found in the anterior mediastinum but may occur in ectopic locations such as neck, pleura, and posterior mediastinum

• Invariably benign

• Age range: 20 to 50 years, often asymptomatic; larger cysts can present with cough, dyspnea, and chest pain

• Acquired thymic cysts are associated with inflammatory processes and have been found in association with mediastinal Hodgkin lymphoma or its treatment, occasionally non-Hodgkin lymphoma, germinoma, yolk sac tumor, thymoma, thymic carcinoma, Langerhans cell granulomatosis, congenital syphilis, or prior thoracotomy for other diseases

• Radiologic findings: well-circumscribed mass in the anterior mediastinum measuring up to 18 cm in diameter

Gross Pathology

• Typically presents as a large encapsulated mass attached directly to thymic remnant or attached by a pedicle

• Calcifications may be present in the cyst wall

• Two types

  • Unilocular (congenital): thin-walled cyst filled with serous fluid

  • Multilocular (acquired): thick-walled cyst filled with thick, turbid hemorrhagic fluid

Histopathology

• Unilocular cysts usually have a flat or cuboidal lining; thymic remnants are not usually appreciated in their walls ( Figure 5.1 )

  

• Multilocular cysts have a lining that is usually flattened but may be stratified squamous, cuboidal, columnar, or ciliated

• The cyst lining is often in continuity with thymic remnants in the wall of the cyst and may be traced to dilated Hassall corpuscles

• Inflammatory infiltrate is present in the walls of the cysts, often with hyperplastic follicles with prominent germinal centers

• Cholesterol cleft granulomas are often present in the cyst wall

• No cartilage, smooth muscle, or other differentiated mesenchymal tissue present within the cyst wall

Special Stains and Immunohistochemistry

• Cytokeratin may highlight the epithelium and demonstrate thymic tissue in the wall

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

Clinical Features

• The foregut cysts of the mediastinum are believed to represent congenital developmental anomalies

  a Cystic neoplasms are discussed with the corresponding tumor types.

• Bronchial and esophageal cysts may be asymptomatic or present with cough, dyspnea, pain, or dysphagia due to compression

Gross Pathology

• Round and usually unilocular

• Size varies from a few millimeters up to 15 cm

Histopathology

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

Clinical Features

• Typically found at the costophrenic angle; may occur in the mediastinum

• Affects men and women of all ages; more common in adults than children

• When attached to pericardium, is designated as a pericardial cyst

Gross Pathology

• Thin-walled cyst filled with clear serous fluid

• Typically unilocular

• Pericardial cysts may have mucoid contents

Histopathology

• Typically has an attenuated mesothelial lining with fibrous tissue within the cyst wall

• Lacks smooth muscle, specialized epithelium, and cholesterol granulomas

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

Clinical Features

• Seen in children and occasionally in adults after chemotherapy for malignancy

• May be associated with hyperthyroidism, myasthenia gravis, or another autoimmune disease

Gross Pathology

• Thymic enlargement with increase in volume and normal weight of the gland

Histopathology

• Normal lobular architecture with normal distribution of lymphocytes and epithelial cells

• Preservation of corticomedullary differentiation

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

Clinical Features

• Associated with myasthenia gravis, rheumatoid arthritis, systemic lupus erythematosus, and other autoimmune disorders

Gross Pathology

• Thymus is of normal size and weight in most cases

Histopathology

• Thymic hyperplasia is characterized by numerous follicles with germinal centers

Special Stains and Immunohistochemistry

• Follicles are composed of normal B-cells and will show reactivity with CD20

Other Techniques for Diagnosis

• Flow cytometry or molecular diagnostic techniques—that is, gene rearrangement—can rule out clonality if lymphoma is in the differential

Differential Diagnosis

Clinical Features

• Rare tumor

• Peak incidence in young adults

• Often large; patients are symptomatic (dyspnea, cough) as a result of compression of adjacent structures

Gross Pathology

• Thymus gland is enlarged but soft, with preserved lobulation

• Yellow cut surface with whitish fibrous strands

Histopathology

• Mature adipose tissue interspersed with strands of unremarkable thymic tissue

• Thymic component may be well populated with lymphocytes

Special Stains and Immunohistochemistry

• Noncontributory

Other Techniques for Diagnosis

• Noncontributory

Differential Diagnosis

Clinical Features

• Most commonly found in adults; peak incidence is in the fifth decade

• Most common solid primary neoplasm of the mediastinum

• Typically located in anterosuperior mediastinum; may also arise from thymic rests: pleura, pulmonary hilum, pericardium, posterior or middle mediastinum and thyroid

• Radiograph shows a lobulated mass that is occasionally calcified

• Clinical associations

  • Myasthenia gravis

  • Lambert-Eaton syndrome

  • Pure red cell aplasia

  • Hypogammaglobulinemia

• Other associations

  • Systemic lupus erythematosus

  • Rheumatoid arthritis

  • Scleroderma

  • Polymyositis

• Prognosis and staging: thymomas exhibit a range of biologic behavior from noninvasive encapsulated tumors to aggressive infiltrative tumors

  • Most noninvasive tumors are cured by surgical resection

  • The most important predictor of clinical course is the presence and extent of invasion into other mediastinal structures

• The staging system used for thymomas reflects this range of behavior (Modified Masaoka staging)

  • Stage I: completely encapsulated (including microscopic invasion into the capsule)

  • Stage IIa: microscopic invasion through the capsule

  • Stage IIb: macroscopic invasion into surrounding fatty tissue or pleura/pericardium

  • Stage III: macroscopic invasion of neighboring organs (pericardium, great vessels, or lung)

  • Stage IVa: pericardial or pleural implants

  • Stage IVb: Hematogenous or lymphatic dissemination

Gross Pathology

• Most are lobulated and encapsulated with a solid gray-white cut surface

• Larger tumors may show extensive cystic changes

Histopathology

• Thymomas exhibit a range of histologic features

• Generally encapsulated with a distinct fibrous capsule

• Dual cell population composed of neoplastic proliferation of thymic epithelial cells admixed with variable numbers of nonneoplastic T lymphocytes

• Most T lymphocytes are of the cortical type (immature)

• Most thymomas display organotypic morphology, meaning that the tumors show features distinctive of the normal thymus, including

  • Fibrous bands forming angulated tumor lobules

  • Variable numbers of immature T lymphocytes

  • Proliferation of bland-appearing thymic epithelial cells

  • Dilated perivascular spaces

  • Foci of so-called medullary differentiation (rounded areas with lower lymphocyte density)

  • No significant cytologic atypia or pleomorphism

• Neoplastic epithelial cells may be of two types

  • Oval or spindle cells with bland nuclei and dispersed chromatin with occasional small chromocenters

  • Round or polygonal (epithelioid) cells with abundant lightly eosinophilic or amphophilic cytoplasm and distinct round eosinophilic nucleolus

• The histologic classification is still a matter of debate; the most commonly accepted scheme is the one proposed by the World Health Organization (WHO; Travis et al., 2015)

  • WHO thymoma type A: composed primarily of benign-appearing spindle cells ( Figure 5.3 )

    

  • WHO thymoma type AB: composed of small spindle cells (type A) admixed with abundant lymphocytes

  • WHO thymoma type B: composed of round or polygonal epithelial cells with varying amounts of immature and mature T lymphocytes ( Figure 5.4 ); this group is subdivided into three types (B1–B3) based on a progressive decrease in the proportion of lymphocytes to epithelial cells and a progressive increase in cytologic atypia of neoplastic epithelial cells

    • Type B1: large number of T lymphocytes containing few, isolated, scattered round or polygonal thymic epithelial cells with minimal cytologic atypia ( Figure 5.5 )

      

    • Type B2: about equal number of T lymphocytes and thymic epithelial cells showing mild to minimal cytologic atypia

    • Type B3: large number of polygonal epithelial cells admixed with few lymphocytes; the epithelial cells show enlarged nuclei with an increased chromatin pattern, occasional prominent nucleoli, and rare mitotic figures; they contain abundant eosinophilic cytoplasm with sharp cell borders ( Figure 5.6 )

      

    

  • WHO thymomas of special types, including micronodular thymoma, metaplastic thymoma, microscopic thymoma, thymoma with anaplasia, and thymic carcinoma

• Limitations of this scheme include difficulties in interobserver reproducibility, overlap in cytologic features for the various categories due to tumor heterogeneity, conflicting results of clinical survival studies for the various categories, lack of a biologic substrate for the classification, and the existence of numerous morphologic variants that do not fit into any of the standard categories

• Unusual morphologic variants include thymomas with clear cells, glandlike structures, cribriform areas, macrocystic and microcystic structures, papillary structures, rhabdomyomatous cells, heavy plasma cell stromal infiltration, extensive areas of infarction and necrosis, starry-sky pattern, storiform pattern (in spindle cell thymoma), hemangiopericytic pattern (in spindle cell thymoma), rosette-like structures (in spindle cell thymoma), spindle cell pseudosarcomatous stroma, massive stromal sclerosis, and others

• Classification of thymomas

  • There has been considerable controversy in recent years regarding which (if any) of these histologic features predict clinical behavior or reflect the differentiation of the tumor cells

  • Table 5.1 shows the numerous classification schemes for thymoma

    TABLE 5.1

    Comparison of Classifications Of Thymoma

    World Health Organization (Travis, 2004)	Traditional (Bernatz et al., 1961)	Histogenetic (Marino and Müller-Hermelink, 1969)	Suster and Moran (1999)
    Type A	Spindle cell thymoma	Medullary thymoma	Thymoma, well differentiated
    Type AB	—	Mixed thymoma	Thymoma, well differentiated
    Type B1	Lymphocyte-rich thymoma	Cortical thymoma	Thymoma, well differentiated
    Type B2	Lymphoepithelial thymoma	Predominantly cortical	Thymoma, well differentiated
    Type B3	Epithelium-rich thymoma	Well-differentiated thymic carcinoma	Atypical thymoma (moderately differentiated)
    Thymic carcinoma (formerly thymoma type C)	Thymic carcinoma	Thymic carcinoma	Thymic carcinoma (poorly differentiated thymic epithelial neoplasm)

• Features used for classification

  • Type of epithelial cell (spindle versus round or polygonal)

  • Organotypic organization

  • Relative proportion of epithelial cells and lymphocytes

  • Degree of epithelial atypia

• Features predictive of invasion or metastatic potential include:

  • Predominance of polygonal epithelial cells

  • Epithelial pleomorphism and atypia

  • Loss of organotypic features

• Thymic tumors with overtly malignant epithelium are called thymic carcinomas (see under “Thymic Carcinoma”)

Special Stains and Immunohistochemistry

• Have limited role in diagnosis

• Cytokeratin: highlights epithelial cells, particularly in lymphocyte-rich tumors

• P63 and PAX8: nuclear positivity in thymic epithelial cells

• CD3: highlights T-cell population

• CD1a/CD99: highlight immature T lymphocytes

• CD20: may be positive in epithelial cells of some thymomas

Other Techniques for Diagnosis

• Electron microscopy: very limited role; can demonstrate tonofilaments, tight intercellular junctions, desmosomes, elongated cytoplasmic processes, and basal lamina of epithelial cells; high potential for sampling error

• Flow cytometry: can be misleading in cases of lymphocyte-rich thymoma by showing an immature terminal deoxynucleotidyl transferase (TdT)–positive lymphoblastic population, which can lead to an erroneous diagnosis of lymphoblastic lymphoma

• Gene rearrangement studies: no clonality is found in the lymphocytes of thymoma

• Molecular genetic testing: approximately 80% of type A and type AB thymomas harbor GTF2I somatic point mutations

Differential Diagnosis

Clinical Features

• Thymic epithelial neoplasm with cellular atypia and a generally aggressive clinical course

• No association with paraneoplastic syndromes of thymoma, such as myasthenia gravis or pure red cell aplasia

• May arise from malignant progression in a long-standing preexisting thymoma

• Predominantly found in middle age to late adulthood

• Patients may present with chest pain, dyspnea, or superior vena cava syndrome

• Primary thymic carcinomas are rare; secondary invasion of the thymus by primary carcinoma of the lung or metastatic tumor in mediastinal lymph nodes is more common

• Thymic carcinoma is a diagnosis of exclusion; extensive clinical and radiologic studies must be undertaken to rule out the possibility of an occult or late metastasis from another organ before rendering this diagnosis

Gross Pathology

• Usually not encapsulated

• Gray-white tumor with a hard, gritty cut surface often showing hemorrhage and necrosis

• Stroma may be desmoplastic, but these tumors do not have the broad fibrous septa seen in thymoma

• Some variants may have prominent cystic changes