Pediatric Thymoma: Background, Pathophysiology, Epidemiology (original) (raw)

Overview

Background

Thymoma is a neoplasm of thymic epithelial cells. This definition excludes other tumors that may affect the thymus, such as lymphoma and germ cell tumors. Although rare, thymoma is the most common tumor of the anterior superior mediastinum. The term lymphoepithelioma has been used in cases in which the thymoma contains a large number of lymphoid cells. [1]

Normal thymic epithelium tissue arises from the third branchial cleft and the third and fourth branchial pouches. Dendritic cells and macrophages found in large quantities at the corticomedullary junction arise from mesodermal tissues (bone marrow). The epithelial cells and these other stromal tissues of the thymus influence the selection and maturation of the T lymphocytes. Dysregulation of this system in thymoma is believed to be a cause of accompanying paraneoplastic syndromes.

In the normal thymus, bone marrow–derived precursor cells destined to become thymocytes (or T lymphocytes) enter the thymus at the corticomedullary junction and differentiate as they pass through the thymus. These cells can be characterized in their developmental progression by changes in expression of 3 cell surface markers: CD4, CD8, and the T-cell receptor (TCR)–CD3 complex.

Initially, the cells undergo positive selection; thus, those cells that fail to receive a signal (ie, do not recognize self) die by apoptosis or become inactive. The cells that pass through the corticomedullary junction undergo negative selection; the thymocytes expressing TCRs that have an excessively high affinity for self-proteins are eliminated. These cells are believed to recognize self too strongly and to have autoimmune potential. From the corticomedullary junction, the cells enter the medulla or circulate in the periphery to other lymphoid structures (ie, lymph nodes). The lymphocytes' selection process and developmental progression are influenced by direct contact between the TCR-CD3 complex on the thymocyte and the major histocompatibility complex (MHC)–antigen complex on thymic epithelial cells, dendritic cells, and B lymphocytes. The cytokines involved in thymocyte development and selection include interleukin (IL)–1, IL-2, IL-3, IL-4, IL-6, and IL-7. [2, 3]

Pathophysiology

Patients with thymoma may experience dysregulation of the lymphocyte negative and positive selection process leading to abnormal proliferation, autoimmunity, and/or immunodeficiency. Autoimmunity also may be caused by cross-immunity of antigens in other tissues with thymoma-associated antigens.

Thymomas are usually encapsulated, locally spreading tumors. More than one system of classifying thymoma has been established (see Histologic Findings, Staging). Seventy percent of thymomas are associated with paraneoplastic syndromes such as myasthenia gravis (MG), red cell aplasia, pemphigus, and immunoglobulin (Ig) deficiency.

Myasthenia gravis

As many as 50% of patients with thymoma have MG, and approximately 15% of patients with MG have thymoma. [4] MG is caused by autoantibodies to postsynaptic nicotinic acetylcholine receptors (anti-AChRs) at the neuromuscular junction, causing weakness of skeletal muscles. Some patients with thymoma-associated MG have an inflammatory myopathy of striated and cardiac muscles. Cardiac myositis may cause heart failure, cardiac arrhythmia, and sudden death. [5, 6]

Neuromyotonia can also be associated with thymoma. Patients with neuromyotonia have hyperactivity of peripheral motor nerves, which causes muscle cramps, muscle twitching, and, sometimes, muscle hypertrophy. Muscle biopsy samples demonstrate patchy inflammatory infiltrates. Antibodies against a presynaptic structure, the voltage-gated potassium channels of peripheral nerves, have been detected in patients with neuromyotonia with or without thymoma. These channels regulate nerve excitability. Neuromyotonia and antibodies to the voltage-gated potassium channels have also been found in patients with MG. Twenty percent of patients with MG and neuromyotonia have been demonstrated to have thymoma. [5, 7, 8]

In addition to these autoantibodies, patients with thymoma-associated MG produce autoantibodies to various neuromuscular antigens, including antibodies to the skeletal muscle calcium release channel (ryanodine receptor of sarcoplasmic reticulum) and antibodies to cytoplasmic filamentous proteins (particularly titin) or neurofilaments. Myoid (muscle-like) thymic epithelial cells express epitopes shared by the target antigens for some of these antibodies. Autoreactive T lymphocytes are assumed to be generated in the thymic tumor and, subsequently, stimulate antibody production against various muscle antigens. MG with myositis tends to be severe, with poor response to resection of the thymoma. [5, 7, 6]

Apart from MG, one study reported that approximately 15% of thymomas are associated with other paraneoplastic diseases, and the onset of these diseases can herald the presence of a treatable tumor. [9] These paraneoplastic diseases included neurologic paraneoplastic diseases (eg, limbic encephalitis, neuromyotonia, polymyositis, subacute hearing loss, psychosis, sleep disorders) as well as non-neurologic paraneoplastic diseases, with predominantly hematologic and cutaneous disorders. [9]

Lambert-Eaton myasthenic syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease characterized by reduced quantal release of acetylcholine from the motor nerve terminal. The patient with LEMS develops muscle weakness, myalgias, and fatigability. LEMS predominantly involves the proximal muscles of the legs. Unlike MG, LEMS spares the extraocular muscles. The muscle strength is reduced at rest and transiently improves with repetitive muscle action. LEMS is associated with an antibody to the presynaptic calcium channel. Underlying cancer is found in 50-60% of persons with LEMS. [10] In individuals with LEMS, the most commonly reported tumor is small cell lung cancer; however, thymoma has also been one of the associated neoplasms. [5, 7]

Subacute sensory neuronopathy

Subacute sensory neuronopathy is a rare disorder associated with small cell lung cancer and other thoracic malignancies, including thymoma and esophageal carcinoma. The patient develops painful paresthesias in the lower extremities that may ascend to involve the trunk and face. Marked sensory loss can lead to truncal ataxia, although motor strength is normal. The characteristic destruction of the dorsal root ganglia is believed to be antibody mediated. [5]

Red cell aplasia

Of patients with thymoma, 5% develop pure red cell aplasia; 10-50% of patients with red blood cell aplasia have thymoma. Thrombocytopenia, granulocytopenia, and autoantibody formation are sometimes observed. In two thirds of individuals with red cell aplasia, morphologically, the thymoma is the spindle cell variety. Approximately 30% of patients with the disorder resume normal hematopoiesis after thymectomy. [11, 12, 13, 14]

Immunodeficiency

Common variable immunodeficiency (CVID) with thymoma, Good syndrome, and immunodeficiency with thymoma are characterized by hypogammaglobulinemia or agammaglobulinemia in association with thymoma. Thymoma is associated with approximately 10% of hypogammaglobulinemia cases, and combined humoral and cell-mediated immunodeficiency is often noted. [15] Immunodeficiency has been demonstrated to occur years after thymoma resection. [5, 13]

Good described Good syndrome in 1954. The syndrome usually occurs in individuals aged 40-70 years and only rarely occurs in children. However, an 8-year-old boy reportedly developed fatal chickenpox 4 months after resection of a benign thymoma. [16, 17] The immunodeficiency in Good syndrome affects both T and B lymphocytes, typically manifested as low B-cell numbers and inverted CD4+/CD8+ cell ratio. [18] The thymic tumors are usually of the spindle cell type and are benign. Good syndrome is associated with recurrent bacterial sinopulmonary infections, chronic diarrhea of unclear etiology, and opportunistic infections. Autoimmune disorders are also associated with these acquired immunodeficiencies.

Epidemiology

Frequency

Primary tumors and cysts of the mediastinum are uncommon and represent approximately 3% of tumors of the chest. Primary anterior mediastinal neoplasms account for 50% of all mediastinal masses, and 45% of anterior mediastinal masses are thymomas. [4] Other anterior mediastinal malignancies include lymphoma (20%), parathyroid or thyroid tumors (15%), germ cell neoplasms (15%), and neurogenic or mesenchymal tumors (5% each). [19]

Demographics

Men and women are equally affected by thymoma.

Most patients are older than 40 years. Thymomas are rare in children and adolescents; however, thymomas in this age group are highly aggressive. [15] In one of the largest series of 1470 patients of thymomas carried out by the Thymic International Group spanning across 14 institutions of 11 countries, none of the cases were in patients younger than 12 years old. [20] A Japanese institutional review of 806 patients (676 adults and 130 children) showed that thymomas accounted for approximately 4% of pediatric mediastinal tumors, compared with 36% of adult mediastinal tumors. (Neurogenic tumors, germ cell tumors, lymphomas, and congenital cysts comprised most pediatric mediastinal tumors.20)

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Author

Coauthor(s)

Cecilia P Mikita, MD, MPH Associate Professor of Pediatrics and Medicine, Uniformed Services University of the Health Sciences; Staff Allergist/Immunologist, Walter Reed National Military Medical Center

Cecilia P Mikita, MD, MPH is a member of the following medical societies: American Academy of Allergy Asthma and Immunology