AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Historic Review
• Embryology
• Anatomy
• Histology
• Physiology
• Thymic Hyperplasia
• Thymic Neoplasms
• Myasthenia Gravis
• Medication
• References

HISTORIC REVIEW

Section 2 of 11  

• Authors and Editors
• Historic Review
• Embryology
• Anatomy
• Histology
• Physiology
• Thymic Hyperplasia
• Thymic Neoplasms
• Myasthenia Gravis
• Medication
• References

The origin of the name thymus is unclear. It may have been named because the gland resembles the herb thyme, or the name may have been derived from a Greek word meaning the soul or the heart, relating to the intimate anatomical relationship between the gland and the heart.

• The first description of the thymus gland was by the Italian anatomist Giacomo da Capri (1470-1550).
• The Swiss physician Felix Platter reported the first case of suffocation due to hypertrophy of the thymus gland in 1614.
• The first indication of an association between myasthenia and the thymus gland was in 1901, when the German neurologist Hermann Oppenheim reported a tumor found growing from the thymic remnant at necropsy in a patient with myasthenia.
• The report by Hermann Oppenheim led the German thoracic surgeon Ernst Sauerbruch to perform a cervical thymectomy in 1911 on a 20-year-old woman with a radiologically enlarged thymus who had myasthenia. He reported that the myasthenia was markedly improved after the surgery, but resection of thymomas in patients with myasthenia at that time was accompanied by a high mortality rate.
• In 1936, Alfred Blalock performed a transsternal total thymectomy during a remission period from severe myasthenia.¹ By 1944, he had accumulated experience in 20 cases, firmly establishing the role of thymectomy in the treatment of these patients.²

EMBRYOLOGY

Section 3 of 11  

• Authors and Editors
• Historic Review
• Embryology
• Anatomy
• Histology
• Physiology
• Thymic Hyperplasia
• Thymic Neoplasms
• Myasthenia Gravis
• Medication
• References

In mammals, the thymus gland develops from the ventral portion of the third branchial pouch as tubular primordia elongate caudally and fuse at the midline, losing their connection with the pharynx and leaving the definitive thymus in the mediastinum.

The thymus is the first lymphoid organ that develops. Normal peripheral lymph nodes depend on seeding by small lymphocytes from the thymus. The thymus reaches its greatest size at puberty, after which time it undergoes slow involution and both cortical and T lymphocytes are reduced in peripheral blood.

Anomalies of the thymus

• Cervical thymic cysts may form from persistent remnants of the tubular upper end of the primitive organ. This is an extremely rare clinical condition.
• Undescended thymus can be bilateral, but it is more commonly unilateral on the left side. Undescended thymus is usually diagnosed in childhood.
• Accessory thymus body along the line of embryonic descent is common but not clinically significant (may be found in 25% of the population).
• Thymic agenesis is an autosomal recessive disease often associated with agenesis of the parathyroid glands (DiGeorge syndrome), which leads to early death from infections or cardiac defects. Thymus and parathyroid transplant are the only possible treatment.
• In thymic aplasia, the thymus is small. Usually, reticular cells and large lymphocytes are present without the small lymphocyte and Hassall bodies. Thymus and fetal liver implants to reconstitute T- and B-cell function has met with some success.

ANATOMY

Section 4 of 11  

• Authors and Editors
• Historic Review
• Embryology
• Anatomy
• Histology
• Physiology
• Thymic Hyperplasia
• Thymic Neoplasms
• Myasthenia Gravis
• Medication
• References

• The thymus is composed of 2 distinct lobes, each surrounded by a collagenous capsule with septa extending into the corticomedullary junction, dividing the cortex further into lobules.
• Arterial supply to the thymus varies. It could be derived from the internal mammary artery, the inferior thyroid artery, and from these two plus the superior thyroid artery.
• A single vein frequently leaves each side of the medial lobe. The veins join to form a short, wide vein that drains into the left brachiocephalic vein. A lateral vein drains from the right side of the gland into the superior vena cava and from the left side into the left brachiocephalic vein.
• A hypothalamic-thymic neural pathway has been suggested to explain the numerous neurological, social, psychological, and environmental factors that have been shown to influence the thymic hormones and the immune system.

HISTOLOGY

Section 5 of 11  

• Authors and Editors
• Historic Review
• Embryology
• Anatomy
• Histology
• Physiology
• Thymic Hyperplasia
• Thymic Neoplasms
• Myasthenia Gravis
• Medication
• References

The thymus gland contains 3 major cell populations—epithelial, hemopoietic, and accessory cells.

Epithelial cells

Epithelial cells are mainly responsible for the creation of the necessary microenvironments and their factors. Epithelial cells promote different steps of intrathymic T-cell differentiation and maturation.

Previously, epithelial cells were referred to as pale and dark cells. The cortex contains pale cells, and the medulla contains both pale and dark cells. Recently, these cells were categorized into 6 types, with intermediate gradation.

• Type 1 - Subcapsular-perivascular cells
• Type 2 - Pale epithelial cells, predominate in the outer cortex
• Type 3 - Probably thymic nurse cells that have the unique feature of emperipolesis
• Type 4 - Dark cells that are typical in the medulla
• Type 5 - Undifferentiated cells that are typical in the medulla
• Type 6 - Large medullary cells that are found around and in the Hassall corpuscles, characteristic of the medulla and may contain (in addition to epithelial cells) various cell types and have the ability to accumulate antigen

Hemopoietic cells

Three main morphologically distinct types of lymphoid cells of the adult human thymus exist—subcapsular, cortical, and medullary. These seem to correspond to the 3 functional subsets of thymocytes recognized by the identification of cluster of differentiation antigens (ie, classes I, II, and III). The human thymus, especially in the fetus, supports erythropoiesis and granulopoiesis. Mast cells are formed in the thymus throughout life.

Accessory cells

Macrophages secrete a thymocyte-differentiating factor that is mitogenic and induces functional maturation of the thymocyte. Interdigitating cells have a role in determining which T-cell precursors are activated (helper or killer) during an immunological challenge. Myoid cells demonstrate acetylcholine receptors and have a possible role in myasthenia gravis. They may have a role in expelling thymocytes from the glands.

PHYSIOLOGY

Section 6 of 11  

• Authors and Editors
• Historic Review
• Embryology
• Anatomy
• Histology
• Physiology
• Thymic Hyperplasia
• Thymic Neoplasms
• Myasthenia Gravis
• Medication
• References

The lymphocytes are attracted to the thymus by chemotactic factors of epithelial origin. After they colonize the epithelium, they may be bathed constantly by circulating self-antigens. These antigens enter the thymus by transcapsular route, a step believed to be critical in the process of learning and of self-recognition.

The thymic epithelium provides the principal signals of differentiation by direct cell contact (presentation of major histocompatibility complex antigens) and intermediary of multiple hormones, including the following:

• Thymopoietin depresses neuromuscular transmission, induces T-cell markers, and has a role in the generation of cytotoxic T cells and prevention of autoimmunity.
• Thymulin stimulates most T-cell functions, provided they are not too immature, in which case they would need concomitant direct contact with the thymic epithelium.
• Thymosin alpha 1

THYMIC HYPERPLASIA

Section 7 of 11  

• Authors and Editors
• Historic Review
• Embryology
• Anatomy
• Histology
• Physiology
• Thymic Hyperplasia
• Thymic Neoplasms
• Myasthenia Gravis
• Medication
• References

Hyperplasia is an increase in the volume of the thymus gland by formation of new cellular elements in a normal microscopic arrangement. Two morphological types exist: true hyperplasia and lymphofollicular hyperplasia.

True Hyperplasia

True hyperplasia is characterized by an increase in both size and weight of the thymus. Thymic hyperplasia is a very rare pathology that presents clinically or radiologically as mediastinal mass.

Three clinicopathological subtypes are identified as follows:

• Massive thymic hyperplasia
• • This is a rare pathological finding with only a few well-documented cases. Enlargement of the thymus, however, is common in infancy.
  • The cause is unknown; it may be due to thymic hyperfunction or dysfunction related to the endocrine activity of the gland.
  • Patients usually present with symptoms of irritation of the mediastinal structures; symptoms may range from none to respiratory distress.
• Thymic rebound in childhood and adolescence
• • This is described in numerous conditions, such as recovery from severe thermal burns, cardiac surgery, tuberculosis, following treatment for different malignancies, and after discontinuation of oral steroids.
  • The functionally active thymus in childhood and adolescence may be susceptible to the fluctuation in corticosteroids levels, which is thought to be a causative factor in thymic hyperplasia (reversal of elevated endogenous corticosteroids in severe burns, withdrawal of exogenous corticosteroids in malignancy treatment).
  • Patient age ranges from 2-12 years. All reported cases were detected on routine chest radiograph with no other clinical or laboratory positive finding.
  • After malignancy, thymic hyperplasia could be confused radiologically with recurrence or metastasis.
• Others: Thymic hyperplasia has been reported in association with sarcoidosis and endocrine abnormalities (thyrotoxicosis, hypothyroidism, Addison disease, acromegaly).

Workup

• Leukocytosis, lymphocytosis, and hypogammaglobulinemia were reported, but blood test results may be completely normal.
• Chest radiograph shows widening of the mediastinum; CT scan shows the enlarged thymus.

Management

• A child with a newly-recognized anterior mediastinal mass could be observed carefully if he or she is thriving and most of the alternative diagnosis possibilities have been ruled out by appropriate clinical and laboratory examinations.
• A brief course of steroids could be attempted if a corticosteroid-sensitive tumor could be ruled out. Steroids often shrink a hyperplastic thymus.
• If the steroid test is inconclusive or if hyperplasia persists for more than 2 years, a diagnostic mediastinoscopy is necessary. In case of symptomatic or calcified mass, complete resection is needed to make the diagnosis and to rule out malignancy.

Lymphofollicular Thymic Hyperplasia

Lymphofollicular thymic hyperplasia is characterized by its histological appearance, which is composed of lymph follicles with germinal centers similar to those in the lymph nodes in the medulla of a normal-sized thymus.

The number of these follicles varies considerably from one patient to another and within different parts of the same gland, which explains why the diagnosis may be overlooked on single section or small biopsies.

Lymphofollicular thymic hyperplasia has been described in the following manner:

• Chronic disseminated infections
• Endocrinopathies
• Autoimmune diseases
• • Myasthenia gravis
  • Systemic lupus erythematosus
  • Scleroderma
  • Rheumatoid arthritis
  • Periarteritis nodosa
  • Hashimoto thyroiditis
  • Autoimmune anemia
  • Behçet disease
  • Ulcerative colitis
  • Multiple sclerosis
  • Hepatic cirrhosis

THYMIC NEOPLASMS

Section 8 of 11  

• Authors and Editors
• Historic Review
• Embryology
• Anatomy
• Histology
• Physiology
• Thymic Hyperplasia
• Thymic Neoplasms
• Myasthenia Gravis
• Medication
• References

The histological classification system proposed in 1999 by the World Health Organization (WHO) is the most recent classification, which recognizes 6 different types of thymic tumors:³

• Type A - Neoplastic spindle-shaped epithelial cells without atypia or neoplastic lymphocytes
• Type AB - Tumors similar to type A but with a focus of neoplastic lymphocytes
• Type B1 - Tumors that resemble normal thymic cortex with areas similar to thymic medulla
• Type B2 - Scattered neoplastic epithelial cells with vesicular nuclei
• Type B3 - Composed predominantly of epithelial cells that exhibit mild atypia
• Type C - Thymic carcinoma

Epithelial Tumors

Previously, all of these tumors were designated as thymomas. Now they have been divided into distinct entities, which are thymomas and thymic carcinomas.

Thymoma

A thymoma is a neoplasm consisting of cytologically bland thymic epithelial cells. Thymoma is the most common primary neoplasm of the mediastinum, accounting for 15% of all mediastinal masses. Patients are aged 40-60 years, with equal incidence in males and females. Thymomas present in 50% of the cases as anterior-superior mediastinal masses discovered incidentally on routine chest radiograph.

• Clinical presentation
• • Twenty-five percent of patients describe vague chest problems.
  • Patients may present with symptoms of thoracic structural displacement (cough, dyspnea, palpitation, dysphagia, superior vena cava syndrome, or substernal aching pain).
  • In a few reported cases, thymoma presented as one of various paraneoplastic syndromes, such as myasthenia gravis, pure erythroid aplasia (poor prognosis), or acquired hypogammaglobulinemia.
  • Rarely, thymoma occurs in an ectopic location (posterior mediastinum, pulmonary parenchyma, and the base of the neck).
• Workup
• • Imaging studies
  • • Posteroanterior and lateral chest radiograph shows a small, rounded mediastinal mass. Approximately 15% of thymomas show calcification, usually amorphous patches. Clearly defined tumors smaller than 5 cm in diameter are likely to be noninvasive. On the other hand, more than 50% of tumors are larger than 8 cm, flat, irregular or poorly defined, and invasive.
    • CT scan of the thorax with contrast demonstrates the extension of the thymoma to the mediastinum or pleura. Noninvasive thymomas appear as round or oval, well-circumscribed masses within the thymus. Invasive tumors appear as irregular, ill-defined masses with obliteration of the tissue planes defined by mediastinal fat. About 30% of thymomas are invasive. CT scanning is the best nonsurgical method of detecting extension to the pleura and transpleural spread and should encompass the whole thorax to the most inferior extent of the posterior diaphragmatic sulci and the abdomen, in case of diaphragmatic involvement.
    • MRI is superior to CT scan in its ability to image coronal and sagittal planes in addition to the axial plane.
    • Pneumomediastinography, venography, and arteriography rarely are used in current practice.
    • Nuclear medicine: Bone scan identifies bone metastases. Gallium-67 citrate is taken by lymphoma and may help in the differential diagnosis.
  • Procedures
  • • Fine-needle aspiration (FNA) biopsy may allow an outpatient diagnosis for planning definite treatment or nonoperative therapy in patients who are poor candidates for anesthesia. A high success rate was reported, with a pneumothorax rate as low as 6%. Nevertheless, in predominantly lymphocytic and spindle cell thymomas, ruling out a small-cell malignant lymphoma and mesenchymal lesions may be difficult.
    • Mediastinoscopy can be performed on an outpatient basis. It provides larger tissue samples.
• Histology
• • Thymomas have a well-defined fibrous capsule with internal septation.
  • They are composed of varying proportions of neoplastic epithelial cells and lymphocytes. Mitotic activity usually is scanty, and atypical mitoses are absent.
  • Thymomas are divided into the following 3 types: (1) predominantly lymphocytic, (2) mixed lymphoepithelial, and (3) predominantly epithelial (special variant is spindle cell thymomas).
  • The most important factor in predicting the behavior of a thymoma is the clinical stage. The Masaoka staging system has gained wide acceptance.
  • • Stage I - Intact capsule
    • Stage II - Local invasion into the surrounding tissue
    • Stage IIa - Macroscopic invasion into surrounding fat or pleura
    • Stage IIb - Microscopic invasion into the capsule
    • Stage III - Gross invasion of the surrounding organs
    • Stage IVa - Disseminated disease, intrathoracic
    • Stage IVb - Lymphogenous or hematogenous extrathoracic metastasizing thymomas (extremely rare [<5%]; supposedly caused by embolic spread to the cervical lymph nodes, bones, liver, and brain)
• Genetics
• • Epidermal growth factors receptor expression was found to be present in 83% of patients with thymomas and 50% of those with thymic carcinomas.
  • • C-kit was found to be positive in 73% of patients with thymic carcinomas and 5% of those with thymomas.
    • p53 protein accumulation is present in 75% of patients with thymic carcinomas and correlates with more advanced stages and less resectability; however, mutations are infrequent.
    • These findings are valuable as prognostic and, potentially, preventive tools. They could also form a base for novel diagnostic and therapeutic approaches. Cases of dramatic response to imatinib in patients with metastatic thymic carcinoma and strong kit expression have already been reported.
• Treatment (Surgical resection is the mainstay of treatment.)
• • Preoperative details
  • • Thymic tumors are occasionally associated with pancytopenia, red cell hypoplasia, Cushing syndrome, Addison disease, and hypogammaglobulinemia. A proper workup should include investigation and correction of these abnormalities.
    • Determining if the airway is compromised is important when considering the anesthetic technique.
    • Neoadjuvant treatment before exploration should be considered if concern exists that a complete excision cannot be accomplished.
  • Intraoperative details
  • • For confirmed thymoma, a median sternotomy is the incision of choice. Transcervical thymectomies were reported mostly for tumors that were discovered at the time of surgery.
    • Lateral thoracotomies are appropriate for anterior large lateralized thymomas where controlling the pulmonary hilum is necessary.
    • Noninvasive thymomas are cured by surgical excision alone in 85-90% of cases.
    • Invasive thymoma is diagnosed by the surgeon's assessment of evidence of invasion by the tumor into the adjacent tissues. Adherent pericardium, pleura, or lung should be resected with the thymoma.
    • Radical exenteration of the anterior mediastinum is recommended strongly for thymomas without myasthenia gravis.
    • Special attention should be paid to avoid tumor spillage.
  • Postoperative details
  • • Adjuvant radiation therapy (RT) remains controversial. All series that address this issue are retrospective reviews, and the role of RT in these cases remains unclear. Some recommend it for tumors larger than 5 cm or for stage II and III tumors that have been completely resected. The benefit for a patient with a stage I tumor is marginal, at best. RT appears to decrease the recurrence rate of incompletely resected tumors.
    • Several series suggest that multimodality treatment (preoperative chemotherapy, surgery, and postoperative chemotherapy or RT) of stage III and IVa thymic tumors allows good long-term outcome; the neoadjuvant chemotherapy improves resectability and survival rates in these cases.
    • Metastasizing thymomas usually are treated solely with chemotherapy with cisplatin-based combination chemotherapy (doxorubicin, vincristine, cyclophosphamide, cisplatin). No consensus has been reached on the best approach in these cases.
    • Recurrent tumors are treated by re-excision, in addition to both chemotherapy and radiation therapy (7-y survival rate is 70%).
    • Bulky unresectable masses are treated primarily with chemotherapy, surgical debulking, and radiation therapy. Some studies show improved survival (especially at 5 y) with debulking, while other authors argue that this provides no additional benefit over biopsy.
  • Follow-up: CT scan is recommended as a baseline test and periodically after resection to evaluate for recurrence.
• Prognosis
• • Patients older than 60 years have a higher mortality rate due to tumor growth.
  • Pure spindle cell neoplasms seem to act as benign tumors, rarely causing mortality.
  • No neoplasms smaller than 5 cm were reported to cause recurrence or death.
  • Patients with tumors 10 cm or larger have a higher mortality rate.
  • The presence of mediastinal displacement symptoms is a poor prognostic indicator.
  • The 10-year survival rate for stage I thymoma is 85-100%.
  • The 10-year survival rate for stage II thymoma is 60-84%.
  • The reported 10-year survival rate for stage III varies from 21-77%. Thoracic relapses after radiation occurred in 15%.
  • The reported 10-year survival rate for stage IV is 26-47%. Thoracic relapses after radiation occurred in 50% of patients, and 90% of these relapses were outside of the radiation field.

Thymic carcinoma

These epithelial thymic tumors are cytologically malignant. Thymic carcinomas are rare tumors with few specific pathologic findings to distinguish them from other histologically similar metastatic neoplasms (large cell lymphoma, seminoma, embryonal carcinoma, and sarcoma).

• Clinical presentation
• • Most patients present with advanced disease (stage III or IV) that manifests as mediastinal masses. These masses are revealed by routine chest radiographs.
  • They are associated more frequently with symptoms of mediastinal structural displacement and extrathoracic metastasis.
  • Myasthenia gravis, erythroid hypoplasia, and hypogammaglobulinemia have not been reported with thymic carcinoma.
• Workup
• • Alpha-fetoprotein and beta–human chorionic gonadotropin help in distinguishing the differential diagnosis of germ cell tumors.
  • Chest radiograph is indicated.
  • CT scan or MRI in addition to positron emission tomography (PET) scan is indicated in all patients with a suspected mass.
  • FNA and core needle biopsy are indicated.
  • Mediastinoscopy provides large tissue sample.
  • Immunohistochemistry provides the most useful method to differentiate thymic carcinoma from other similar neoplasms.
• Histology
• • Thymic carcinomas are typically rubbery or gritty and gray-white with areas of hemorrhage and necrosis. Cystic changes were reported in some cases.
  • Several distinctive microscopic variants are recognized as follows:
  • • Lymphoepitheliomalike squamous carcinoma
    • Keratinizing squamous carcinoma
    • Basaloid squamous carcinoma
    • Clear cell thymic carcinoma
    • Sarcomatoid carcinoma
    • Mucoepidermoid carcinoma
• Treatment
• • Complete surgical resection, if technically feasible, has the best long-term result.
  • Involved structures (anterior pericardium, lung) should be resected en bloc with the tumor.
  • Widely invasive tumors are best treated with radiotherapy, with or without cytotoxic drugs.
• Prognosis
• • The mortality rate is more than 85% in reported cases; median survival among patients with incompletely resected tumors is 12-36 months.
  • Radiotherapy and chemotherapy have offered little therapeutic benefit.

Neuroendocrine Tumors

• Thymic carcinoid tumors are rare (150-200 cases have been reported). Thirty percent of thymic carcinoid tumors are associated with Cushing syndrome. Inappropriate ectopic production of antidiuretic hormone, hypertrophic osteoarthropathy, and Eaton-Lambert syndrome also has been reported.
• Thymic oat cell carcinoma is very rare (20% of neuroendocrine tumors). Most apparent oat cell carcinomas are metastatic tumors from occult bronchogenic neoplasm, which must be ruled out clinically.

Thymic Germ Cell Tumors

• Teratomas
• Seminomas
• Embryonal carcinomas
• Yolk sac tumors
• Teratocarcinomas
• Choriocarcinomas

Thymic Lymphomas

• Hodgkin lymphoma is more common. Nodular sclerosing type is the most common variant.
• Non-Hodgkin lymphoma

MYASTHENIA GRAVIS

Section 9 of 11  

• Authors and Editors
• Historic Review
• Embryology
• Anatomy
• Histology
• Physiology
• Thymic Hyperplasia
• Thymic Neoplasms
• Myasthenia Gravis
• Medication
• References

Myasthenia gravis is an autoimmune disorder of neuromuscular transmission in which antibodies reduce the number of acetylcholine receptors at the neuromuscular junction.

History

Myasthenia gravis was first recognized by Wilks in 1877, and the term myasthenia gravis pseudoparalytica was used first by Jolly a few years after. No effective therapy existed until 1934, when Walker used physostigmine, followed by Blalock's introduction of surgical therapy.⁴

Classification

• Pediatric myasthenia gravis  
• • Neonatal (1%) - Self-limited and due to placental transfer of antibodies from the myasthenic mother
  • Juvenile (9%) - Permanent
• Adult myasthenia gravis  
• • Ocular (20%)
  • Mild generalized (30%)
  • Moderate generalized (20%)
  • Acute fulminating (11%) - Prominent respiratory symptoms
  • Late severe (9%) - Progress after 2 years of mild disease

Frequency

• Incidence is 0.5-5 cases per 100,000 population, with a prevalence rate that has been on the rise for the past 40 years.
• All ages are at risk. The peak age at onset is 20-30 years in women and older than 50 years in men.
• The female-to-male ratio is 3:2 in the general population and 5:1 in young patients.

Etiology

• Although the source of autoantibodies in myasthenia gravis is unknown, the thymus is thought to have a major role in the pathology of this disease.
• The thymic myoid cells, with their resemblance to embryonic muscle cells, serve as the antigen source for the development of these antibodies.
• The thymus role is suspected because of the following:  
• • The thymus gland is abnormal in 80% of patients (60% have follicular lymphoid hyperplasia, 10-20% have thymoma).
  • About 30-60% of patients with thymoma have (or subsequently develop) myasthenia gravis.
  • Acetylcholine receptor antibodies and antibodies to striated muscle have been demonstrated in the thymus of patients with myasthenia gravis.
  • Thymectomy has a proven beneficial therapeutic role for these patients.

Pathophysiology

The pathophysiology involves antibody-mediated destruction of the acetylcholine receptors by induction of cross linking of the receptors, resulting in accelerated endocytosis and subsequent degradation of the receptors, with a possible role for complement-mediated end plate destruction and simple binding and blockage of the receptors by the antibodies.

Clinical presentation

• Weakness or fatigability occurs with repetitive exercise and resolves with rest.
• The clinical course is unpredictable and characterized by frequent spontaneous remission and relapses.
• The muscle groups involved and the degree of their involvement vary considerably over time.
• Ocular muscles are the most frequently involved, resulting in ptosis and diplopia, which can be exaggerated by a sustained upward gaze.
• Proximal muscle groups are involved more frequently than the distal groups.
• Deep tendon reflexes are preserved.

Workup

No single test result is uniformly positive, but combination of these tests with the clinical picture establishes the diagnosis in most patients.

• Lab studies: Elevated acetylcholine receptor antibody titers are highly specific for myasthenia gravis. The sensitivity ranges from 64% in patients with only ocular symptoms to 89% in patients with generalized disease.
• Imaging studies  
• • Chest radiograph
  • CT scan to exclude the presence of thymoma
• Other studies  
• • Results of single-fiber electromyography (EMG) have been shown to be positive in 60-75% of patients with ocular myasthenia gravis, in 90% of patients with mild generalized myasthenia gravis, and in 100% of those with moderate-to-severe disease.
  • Short-acting cholinesterase medications, such as edrophonium, could be used as a diagnostic test for myasthenia gravis. When administered intravenously, they produce significant improvement in muscle strength, usually within 30-60 seconds. The sensitivity of this test is approximately 85% for ocular myasthenia gravis and 95% for generalized disease.

Differential diagnosis

• Muscular atrophy
• Amyotrophic lateral sclerosis
• Hyperthyroidism
• Psychoneurosis
• Organophosphate intoxification, snakebites, and drug-induced (penicillamine, procainamide, and aminoglycoside) myasthenia
• Botulism
• Eaton-Lambert syndrome (associated with malignancy)

Treatment

• Medical therapy: The few drugs available are as follows:  
• • Cholinesterase inhibitors decrease hydrolysis of acetylcholine, hence increasing the amount of acetylcholine available in the synaptic cleft and providing symptomatic relief. They have no effect on the course of myasthenia gravis. The optimal dose of these medications varies widely, and dosage should be adjusted on a personal basis by using the minimal dose necessary to achieve an effect to avoid the muscarinic adverse effects (abdominal cramping, diarrhea, excessive salivation, diaphoresis, and bradycardia). A feared adverse effect is cholinergic crisis, which produces a depolarizing type neuromuscular blockade that could be confused clinically with myasthenic crisis.
  • • Pyridostigmine (Mestinon) - Long-duration action
    • Neostigmine (Prostigmin) - More rapid onset and shorter duration of action
    • Edrophonium (Tensilon) - Very rapid onset and short duration of action; used for diagnostic purposes
  • Corticosteroids are usually reserved for patients who fail to respond to or do not tolerate anticholinesterase therapy. They also have been used to prepare patients for thymectomy. They provide symptomatic improvement in as many as 80% of the patients, but relapse is common after discontinuation. The risk of chronic steroid use always is a concern.
  • Immunosuppression with azathioprine (Imuran) is used for patients who do not respond to or do not tolerate anticholinesterase therapy. The response rate is 70-80%. Adverse effects are common.
  • Plasma exchange: Antibody removal by plasmapheresis produces symptomatic relief in as many as 90% of patients. It is extremely effective when dramatic and rapid response is necessary. Five exchanges are required. The effects last a few weeks, which limits the use of plasmapheresis to the short term, such as during myasthenic crisis and in the perioperative period.
  • Total body irradiation has been used successfully in thymectomized patients who were refractory to other treatments, with clinical improvement lasting more than 2 years in 40% of the reported cases.
• Surgical therapy
• • The benefit of thymectomy is based on observation. The mechanism is still unknown, as is which patients are more likely to respond.
  • Patients are usually considered for thymectomy when they do not respond to treatment with cholinesterase inhibitors or when the adverse effects limit the benefit of this treatment.
  • Based on observation, patients with short duration of symptoms are most likely to benefit from the operation, which is the rationale for early consideration of patients with generalized symptoms for surgery.
  • Some studies report similar results with patients with isolated ocular symptoms. In these patients, thymectomy prevented the progression to generalized disease. Given the low morbidity of the transcervical approach, some surgeons recommend thymectomy for these patients.
  • If thymoma is present, surgery should be performed as soon as symptoms can be controlled.
  • Preoperative details
  • • Symptoms must be controlled medically before the surgery, with special attention to optimizing the respiratory mechanics.
    • Paralyzing agents should be used with caution for anesthesia. They have a rapid onset and more marked neuromuscular block, which decreases their safety margin. In addition, the rate of recovery from the block is not enhanced by neostigmine.
  • Intraoperative details
  • • Transcervical thymectomy carries low morbidity, with remission and response rates that are comparable with those of the transsternal thymectomy.
    • Transsternal thymectomy ensures the removal of all the adjacent cervical and mediastinal fat, which may contain aberrant thymic tissue.
    • Thoracoscopic thymectomy: Complete thymectomy has been shown to be feasible with comparable mid-term results and less morbidity. No prospective randomized study is available to compare it with the transsternal and transcervical approach.
  • Postoperative details
  • • Aggressive pulmonary care
    • Anticholinesterase medication (the same as is used preoperatively) is continued after extubation.
    • The benefit of the procedure may not be apparent for years.
    • Mild cases may exacerbate after thymectomy.
    • Reoperation should be considered if incomplete resection is suspected.

Outcome

• Thirty years ago, 25% of patients died of myasthenia gravis. Current treatments provide a normal life expectancy for patients.
• Age younger than 45 years, hyperplastic gland, and female sex were reported as predictors of improvement after thymectomy.
• The presence of thymoma is associated with higher likelihood of more severe symptoms and with less improvement after thymectomy.
• The complete remission rate after thymectomy is 33% in general and 17% in patients with isolated ocular symptoms, compared to 8% after medical treatment, with survival advantage after thymectomy.
• Symptomatic improvement was reported in 80-94% of patients after thymectomy.
• A small percentage of patients fare worse after thymectomy or have recurrence after improvement.

MEDICATION

Section 10 of 11  

• Authors and Editors
• Historic Review
• Embryology
• Anatomy
• Histology
• Physiology
• Thymic Hyperplasia
• Thymic Neoplasms
• Myasthenia Gravis
• Medication
• References

Drug Category: Cholinesterase Inhibitor

These agents cause acetylcholine to accumulate at cholinergic receptor sites, causing increase in the stimulation of cholinergic receptors throughout the central and peripheral nervous systems.

REFERENCES

Section 11 of 11

• Authors and Editors
• Historic Review
• Embryology
• Anatomy
• Histology
• Physiology
• Thymic Hyperplasia
• Thymic Neoplasms
• Myasthenia Gravis
• Medication
• References

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Article Last Updated: Mar 5, 2008