Introduction
Background
Thymic tumors occupy the anterior mediastinum, which is immediately posterior to the sternum and the anterior surface of the pericardium and great vessels. Tumors of thymic, lymphatic, or germ cell origin most commonly occur in this compartment, though aberrant parathyroid or thyroid tissue masses are sometimes found, along with vascular and mesenchymal tissue masses.
About one half of all thymic tumors are malignant in individuals aged 20-40 years, and one third are malignant in persons younger than 20 years and those older than 40 years.
Approximately two thirds of all mediastinal tumors and cysts are symptomatic in children, whereas only a third are symptomatic in adults. When all age groups are considered, nearly 55% of patients with benign mediastinal masses are asymptomatic at presentation, compared with only approximately 15% of those in whom masses are found to be malignant.
Related eMedicine topics:
Thymoma
Germ Cell Tumors
Dermoid Cyst
Surgery of the Thymus Gland
Related Medscape topics:
Specialty Site Radiology
Specialty Site Oncology
Resource Center Biologic Therapies in Cancer
Resource Center Hodgkin's Lymphoma Resource Center
CME Oncology Insights: 2008 Annual ASCO Meeting Highlights Edition
CME Immune Reconstitution (Slides With Transcript)
Pathophysiology
Thymic epithelial tumors are classified into 3 groups:
- Benign thymoma
- Type 1 malignant thymoma (invasive thymoma), which is characterized by local invasion and/or metastasis; cytoarchitecturally, it is often indistinguishable from benign thymoma
- Type 2 malignant thymoma (thymic carcinoma) has true malignant epithelial tumor features
Thymomas are further subclassified into medullary, mixed, and cortical thymomas. Cortical thymoma often follows a locally aggressive clinical course. Thymic carcinomas often comprise diverse histologic subtypes. The intermediate form has been classified as atypical thymoma.
Thymic carcinomas usually lack a well-defined capsule. Areas of necrosis and hemorrhage are frequent within the gritty, gray-white tumor. Cystic changes are prominent in carcinomas arising from a thymic cyst.
The association between thymic tumors and leukemia has been recognized for over a century. In 1974, Kaplan et al confirmed lymphoblastic lymphoma, a cancer of thymus-derived lymphocytes.1 These tumors are further classified as poorly differentiated and undifferentiated.
On histologic evaluation, large-cell lymphomas are typically sclerotic. They are morphologically classified as follicular center-cell lymphomas; they involve either large cleaved cells or large noncleaved cells. Residual thymic structures are commonly identified. Persistent thymic tissue may form epithelium-lined cysts.
Non-Hodgkin lymphomas (NHLs) include a low-grade lymphoma of the thymus that histologically resembles the lymphomas in mucosa-associated lymphoid tissue (MALT). They have prominent germinal centers. Various T-cell lymphomas had been described on the basis of histologic differentiation.
Mediastinal Hodgkin disease is thought to originate from reticulum cells of the thymus and should be distinguished from other forms of Hodgkin disease. Four types are described: nodular sclerosis, mixed cellularity, lymphocyte predominant, and lymphocyte depleted.
Focal involvement of the thymus by histiocytosis X is described. Histiocytosis X is a lesion of the Langerhans cell. Lesions can be encapsulated or infiltrative. Extrathoracic lesions might occur. Tumors may occur in association with other neoplasms, including those of Hodgkin disease, NHL, leukemia, and carcinoma.
Metastases to the thymus can occur from the lung or from extrathoracic sites, as with spread from primary tumors of the genitourinary tract, gastrointestinal tract, or breast. Common primary sites include the kidney, testis, colon, rectum, ovary, prostate, breast, bladder, and stomach. Melanomas and sarcomas uncommonly metastasize to this site. Metastases can also occur from an unknown primary tumor.
Most teratomas arise in the anterior superior mediastinum. In only a few cases have they been reported to originate in the posterior mediastinum. Overall, 15-20% of mediastinal teratomas are classified as malignant.
Seminomas are the most common primary malignant mediastinal germ cell tumor. They almost always arise in the anterior mediastinum and are often intimately associated with the thymus.
Nonseminomatous germ cell tumors include endodermal sinus tumor (yolk-sac tumor), embryonal carcinoma, choriocarcinoma, teratocarcinoma, and mixed germ cell tumors. They behave like seminomas.
Thymic carcinoids histologically resemble thymoma, but they are aggressive. They are often encapsulated and large (mean diameter, 11 cm). On microscopy, they resemble carcinoid tumors from other sites.
Mediastinal paragangliomas are more common in the anterior compartment than in the posterior mediastinum. The anterior ones are called aortic body tumors; those in the posterior compartment are aorticosympathetic lesions, paravertebral lesions, or paragangliomas. Patients may have several paragangliomas.
Tumors of neural origin are usually posterior, though in rare cases they occur in the anterior mediastinum. These tumors include neurofibroma, schwannoma, malignant schwannoma, ganglioneuroma, ganglioneuroblastoma, and neuroblastoma.
Thymolipoma is a rare, benign tumor of the anterior mediastinum; it is characterized by adipose tissue with interspersed strands of thymus. Like thymomas, thymolipomas can be associated with myasthenia gravis. In addition, they are described in patients with aplastic anemia, hypogammaglobulinemia, Graves disease, Hodgkin disease, or chronic lymphocytic leukemia.
Lipomas may occur in the anterior mediastinum and can be large, measuring up to 30 cm in diameter. They are composed of mature adult adipose tissue with occasional lymphocytes. No thymic tissue is identified.2,3
Frequency
United States
The incidence of thymic masses, as well as the clinical presentation, vary in accordance with patients' ages. In adults, the thymic masses that occur with greatest frequency are thymomas, followed by neurogenic tumors, lymphomas, and germ cell tumors. Neurogenic tumors are the most common tumors in children and infants, followed by foregut cysts, germ cell tumors, lymphomas, lymphangiomas and angiomas, tumors of the thymus, and pericardial cysts.
- Hodgkin disease and NHL account for approximately 20% of all anterior mediastinal tumors. Lymphoblastic lymphoma accounts for one third to one half of cases of NHL in childhood. They account for 5% of cases of NHL in adults and have a bimodal distribution, with the first peak at 16 years and the second peak after the age of 40 years. Hodgkin disease also has a bimodal distribution, with a peak in the late 20s, followed by a decline until the age of 45 years. The incidence then steadily increases with age.
- See also Sex and Frequency.
Mortality/Morbidity
- Invasive thymomas and thymic carcinomas together represent about 0.2-1.5% of all malignancies. Thymic carcinomas account for only 0.06% of all thymic neoplasms. Thymomas are indolent tumors that have a tendency for local recurrence rather than metastasis. Thymic carcinomas are typically invasive; they are associated with a high risk of relapse and death.
- Suster and Rosai examined 60 patients with thymic carcinoma.4 The patients were aged 10-76 years; the male-to-female ratio was 1.5:1. Overall survival rates were 57%, 40%, and 33% at 1, 3, and 5 years, respectively.
Sex
- Thymomas occur with slightly greater frequency in females than in males. In a review of nearly 800 cases, the female-to-male ratio was 1.2 to 1.5
- Lymphoblastic lymphoma is approximately twice as common in males as in females.
- Seminomas typically occur almost exclusively young men (90%) in the third decade of life. They occur rarely and sporadically in females. Nonseminomatous malignant germ cell tumors also affect young men in the third decade of life.
- Among 70 thymic carcinoids reported in the literature, male patients outnumbered female patients by a ratio of 3:1.6
- For aortic-body paraganglioma, the male-to-female ratio is 17:24; for paravertebral paragangliomas, the male-to-female ratio is 20:11.
- Suster and Rosai examined 60 patients with thymic carcinoma.4 The patients were aged 10-76 years; the male-to-female ratio was 1.5:1. Overall survival rates were 57%, 40%, and 33% at 1, 3, and 5 years, respectively.
Age
The incidence of thymic masses, as well as the clinical presentation, vary in accordance with patients' ages. See also Frequency and Sex.
- Thymomas generally occur in patients older than 30 years. About 70% of lesions are found in adults in the fifth and sixth decades. Thymomas are rare in children and teenagers. In 6 series involving 875 thymomas, patients were aged 2-90 years; the mean age was 50 years.7,8,9,10,11,12 Female patients outnumbered male patients at a rate of 53% to 47%.
- In 1 series, 70 patients with thymic carcinoids were aged 9-87 years with a median age of 43 years.
- Suster and Rosai examined 60 patients with thymic carcinoma.4 The patients were aged 10-76 years; the male-to-female ratio was 1.5:1. Overall survival rates were 57%, 40%, and 33% at 1, 3, and 5 years, respectively.
- Most mediastinal teratomas occur in children and young adults. Malignant teratomas occur most frequently in young adults.
- For paragangliomas of the aortic body, the mean age of patients is approximately 49 years; for paravertebral paragangliomas, the mean age is approximately 29 years.
- Thymolipoma may occur in people of any age, including children as young as 4 years of age. In a literature review of 91 cases, the mean age was in the third decade of life .13
- Hodgkin disease and NHL account for approximately 20% of all anterior mediastinal tumors. Lymphoblastic lymphoma accounts for one third to one half of NHLs in childhood. They account for 5% of NHLs in adults; they have a bimodal pattern distribution, with the first peak at 16 years and the second peak after the age of 40 years. Hodgkin disease also has a bimodal pattern of distribution, with a peak in the late 20s, after which there is a decline until the age of 45 years. The incidence then steadily increases with age.
- Seminomas typically occur almost exclusively in young men (90%) in the third decade of life. They rarely and sporadically occur in females. Nonseminomatous malignant germ cell tumors affect young men in the third decade of life.
Anatomy
The thymus is located in the anterior mediastinum. Mediastinal tumors are often among the most difficult lesions to examine. Many different types of lesions occur in the mediastinum. Biopsy specimens are often inadequate, small, and crushed (see Images 1-2).
Although the thymus may appear to be a single structure, it consists of a right lobe and a left lobe; the lobes are situated close to each other in the anterior mediastinum. The left lobe is usually slightly larger than the right, and it is the main caudal extension of the organ. In children, it is usually prominent. It usually extends from the level of the fourth costal cartilages to the lower poles of the thyroid gland. The sternohyoid and sternothyroid muscles, the manubrium, and the upper part of the body of the sternum and their adjacent costal cartilages lie in front of thymus. Behind it are the pericardium; the arch of the aorta, with its 3 large branches; the left brachiocephalic vein; and the trachea.
The thymus is the site of lymphocyte maturation for the immune system. The thymus is predominantly composed of epithelial cells and lymphocytes. Precursor cells migrate to the thymus and differentiate into lymphocytes. Most of these lymphocytes are destroyed; those that are not destroyed migrate to tissues to become T lymphocytes.
Ectopic intrathyroidal thymomas are rare, and they can be challenging to identify. Most patients present with an apparent thyroid nodule that is identified on imaging studies or clinical examination. Results of fine-needle aspiration are often misleading or indeterminate. Proper diagnosis requires appropriate histopathologic assessment and staining; a high clinical index of suspicion leads to the correct diagnosis.
The morphology of the thymus varies drastically with age, and its normal size, weight, and consistency vary widely. Knowledge of these variations is essential for proper interpretation of imaging studies.
In the neonate and young infant, the thymus weighs about 20 g. By puberty, it reaches a maximum weight of about 30 g. During this time, thymic parenchyma consists of a dense population of lymphocytes, separated by thin, fibrous septa. After puberty, involution takes place over a period of 5-15 years. A gradual reduction in the lymphocyte population is associated with fatty infiltration of the atrophied thymic follicles. By the age of 40 years, fatty tissue dominates, and by approximately 60 years of age, the thymic remnant that is left is made up of fat.
The inferior thyroid and internal thoracic arteries and corresponding veins vascularize the thymus. Efferent channels of lymphatics drain into parasternal, tracheobronchial, and brachiocephalic nodes. The thymus does not receive any afferent lymphatics.14
Presentation
Thymic hyperplasia
Thymic hyperplasia is more commonly associated with myasthenia gravis than is thymoma. About two thirds of patients with myasthenia gravis have thymic hyperplasia; 25-50% of these patients are likely to have a normal thymus on CT scanning. Histologic analysis of the thymic medulla reveals numerous lymphoid follicles with active germinal centers.
Thymic hyperplasia may accompany other diseases, including Graves disease, Addison disease, and acromegaly.
Thymoma
Thymoma is a benign or low-grade epithelial neoplasm of the thymus. It is commonly located in the anterosuperior mediastinum; however, when the thymus is ectopic, thymomas can be found in the other regions of the mediastinum, as well as in the neck, pulmonary hilum, thyroid gland, lung, or pleura. Thymoma is a common anterior mediastinal tumor, though it is a rare thoracic tumor. It often occurs in adults in the fifth and sixth decades. In rare cases, it occurs in patients younger than 16 years. There is a slight female predominance.
On histologic examination, thymomas contain a variable admixture of lymphocytes and epithelial cells. They are cytologically benign and are classified as invasive and noninvasive. Encapsulated thymomas are usually noninvasive or are locally invasive. Most thymomas measure 5-10 cm, though they vary in size. One third of thymomas adhere to or invade neighboring structures, including the great vessels, mediastinal pleura, and pericardium. In advanced cases, transdiaphragmatic spread occurs. Distant metastases are rare.
About 10-15% of individuals with myasthenia gravis have thymoma, and about one third of patients with thymoma have myasthenia gravis. Approximately 40% of thymomas are found incidentally on routine radiographs.
Symptoms, when present, include cough, chest pain, dyspnea, dysphagia, and/or superior vena cava syndrome; constitutional symptoms may include fever and weight loss. About 10% of patients have associated red cell aplasia, hypogammaglobulinemia, and collagen vascular diseases.
Thoracotomy with histopathology is best for assessing the prognosis. Encapsulated tumors rarely recur after total excision; radiotherapy has a role in completely or incompletely resected thymomas. Although the natural history of ectopic cervical thymomas and the associated prognosis are not well established, most reports suggest a generally benign course, with the possibility of cure after surgical resection of fully encapsulated tumors.
Boman first described ectopic thymoma in the cervical region in 1941. These rare tumors appear to be more common in female patients than in male patients (ratio, 7:1). They are typically found in the lower, anterolateral aspect of the neck. Thymomas are often adjacent to the lower thyroid pole or are located in the lower pole of the thyroid itself. When they are intrathyroidal, they are often misdiagnosed as Hashimoto thyroiditis or lymphoma of the thyroid on fine-needle aspiration.
Intrathyroidal and other cervical thymomas must be differentiated from related tumors of thymic or branchial pouch origin, including hamartomatous thymomas, spindle epithelial tumors with thymus-like differentiation (SETTLE), and carcinoma showing thymus-like differentiation (CASTLE), which differ both histologically and clinically.
Germ cell tumors
Germ cell tumors are most commonly seen during the second to fourth decades. They are often found in the anterior mediastinum; they rarely occur in the posterior mediastinum. They often occur within or are adjacent to the thymus. Remnants of primitive germ cell layers, ectoderm, endoderm, or mesoderm give rise to these tumors. In the absence of gonadal primary and retroperitoneal nodes, they are considered malignant germ cell tumors of primary mediastinal origin.
Mature teratomas are benign. Malignant germ cell tumors often include seminoma or nonseminoma. Malignant mediastinal germ cell tumors occur more commonly in males than females, whereas benign germ cell tumors occur equally in the 2 sexes.
Mature teratoma
Mature teratoma is the most common benign germ cell tumor of the mediastinum. It accounts for 60-75% of all cases. The tumors are cystic and multilocular, and they often contain gelatinous or sebaceous fluid.
Seminoma
Seminoma is the most common malignant germ cell tumor of the mediastinum.
Thymic lymphoma
About 60-70% of cases mediastinal Hodgkin disease involve the thymus through infiltration. Approximately 5-10% of patients with lymphoma present with primary mediastinal lesions; these lesions account for 10-20% of all primary mediastinal masses.
Thymic neuroendocrine tumors
Thymic carcinoids are the most common thymic neuroendocrine neoplasm. They are invasive, often infiltrating and invading adjacent structures. Spread often involves the lungs, lymph nodes, liver, and bone. They are called neuroendocrine because one third are associated with Cushing syndrome secondary to excess production of adrenocorticotropic hormone (ACTH). Approximately 15-20% involve multiple endocrine neoplasia.
CT scanning is often useful in the diagnosis, though the findings may be nonspecific and may not be useful for differentiating these lesions from other thymic masses.
Thymic carcinoma
Thymic carcinoma belongs to a group of uncommon epithelial neoplasms. These tumors are characterized by cytologic atypia and anaplasia. CT scans often show central necrosis in a large tumoral mass, with invasion and infiltration of adjacent structures in the mediastinum. Because of their aggressive nature, they are likely to produce hematogenous and lymphatic spread locally and distally.
Thymolipoma
Thymolipoma is one of the benign thymic neoplasms. This rare neoplasm is encapsulated. It is composed of mature adipose tissue, with islands of thymic tissue interspersed within the tumor. Thymolipomas gradually increase in size; at the time of diagnosis, they are usually large.
Thymolipomas are more common in children and young adults than in older individuals.
Thymic cysts may be found in their normal location in the anterior mediastinum, or they may be found anywhere along the their course of development; they may also be ectopic in foci. They are classified as congenital, inflammatory, degenerative, or neoplastic. Congenital thymic cyst develops as a unilocular cyst from a persistent thymopharyngeal duct. Inflammatory thymic cysts are characteristically multilocular. Various neoplasms, including thymomas, germ cell tumors, and lymphomas, are associated with cystic degeneration in the thymus itself. At times, cystic degeneration in the thymus may occur after the treatment of mediastinal neoplasms.
Rebound thymic hyperplasia
Rebound thymic hyperplasia is thought to be true hyperplasia of thymus; it is characterized by an increase in the size and weight of the thymus gland. Hypertrophy involves the whole gland, including the cortex and medulla.
The thymus is known to become involuted in association with prolonged chronic illness, chemotherapy, Cushing syndrome, or general stress. Several months after recovery, the thymus may rebound with regrowth; such regrowth occurs more commonly in young adults and children than in adults.15
Preferred Examination
CT is most valuable in the diagnosis of thymic lesions and anterior mediastinal masses. MRI may also be used.
Differential Diagnoses
Other Problems to Be Considered
Acquired dysplasia
Acute thymic involution
Aplasia
Benign disorders
Carcinoid tumor
DiGeorge Syndrome
Ectopic cervical thymus tissue
Follicular hyperplasia
Germ cell tumor
Histoeosinophilic granuloma
Lymphoma
Seminoma
Teratocarcinoma
Teratoma
Thymic hyperplasia
Thymolipoma
Thymoma
Thymus cysts
More on Thymus, Lesions |
 Overview: Thymus, Lesions |
| Imaging: Thymus, Lesions |
| Follow-up: Thymus, Lesions |
| Multimedia: Thymus, Lesions |
| References |
| Next Page » |
References
Kaplan J, Mastrangelo R, Peterson WD Jr. Childhood lymphoblastic lymphoma, a cancer of thymus-derived lymphocytes. Cancer Res. Mar 1974;34(3):521-5. [Medline].
Higuchi T, Taki J, Kinuya S, et al. Thymic lesions in patients with myasthenia gravis: characterization with thallium 201 scintigraphy. Radiology. Oct 2001;221(1):201-6. [Medline].
Rosado-de-Christenson ML, Galobardes J, Moran CA. Thymoma: radiologic-pathologic correlation. Radiographics. Jan 1992;12(1):151-68.
Suster S, Rosai J. Thymic carcinoma. A clinicopathologic study of 60 cases. Cancer. Feb 15 1991;67(4):1025-32. [Medline].
Fraser RS, Pare PD, Coleman N. Anterior mediastinal masses. In: Fraser RS, Muller NL, Colman N, Pare PD. Fraser and Pare's Diagnosis of Diseases of the Chest. 4th ed. Philadelphia, Pa: WB Saunders;. 1994: 2884.
Viebahn R, Hiddemann W, Klinke F, von Bassewitz DB. Thymus carcinoid. Pathol Res Pract. Oct 1985;180(4):445-51.
Hofmann W, Muller P, Manke HG, Otto HF. Thymoma. A clinicopathologic study of 98 cases with special reference to three unusual cases. Pathol Res Pract. Jan 1985;179(3):337-53. [Medline].
Verley JM, Hollmann KH. Thymoma. A comparative study of clinical stages, histologic features, and survival in 200 cases. Cancer. Mar 1 1985;55(5):1074-86. [Medline].
Lewis JE, Wick MR, Scheithauer BW, et al. Thymoma. A clinicopathologic review. Cancer. Dec 1 1987;60(11):2727-43. [Medline].
Kornstein MJ, Curran WJ Jr, Turrisi AT 3rd, Brooks JJ. Cortical versus medullary thymomas: a useful morphologic distinction?. Hum Pathol. Nov 1988;19(11):1335-9. [Medline].
Pescarmona E, Rendina EA, Venuta F, et al. Analysis of prognostic factors and clinicopathological staging of thymoma. Ann Thorac Surg. Oct 1990;50(4):534-8.
Wilkins EW Jr, Grillo HC, Scannell JG, et al. J. Maxwell Chamberlain Memorial Paper. Role of staging in prognosis and management of thymoma. Ann Thorac Surg. Jun 1991;51(6):888-92. [Medline].
Nishimura O, Naito Y, Noguchi Y, et al. Thymolipoma: a report of three cases. Jpn J Surg. Mar 1990;20(2):234-7. [Medline].
Sinnathamby CS. Last's Anatomy Regional and Applied. 10th ed. Edinburgh: Churchill Livingstone;1999.
Doppman JL, Oldfield EH, Chrousos GP, et al. Rebound thymic hyperplasia after treatment of Cushing''s syndrome. AJR Am J Roentgenol. Dec 1986;147(6):1145-7. [Medline].
Siegel MJ, Glazer HS, Wiener JI, Molina PL. Normal and abnormal thymus in childhood: MR imaging. Radiology. Aug 1989;172(2):367-71. [Medline].
Fujishita T, Kishida M, Taki H, Shinoda C, Miyabayashi K, Fujishita M, et al. Detection of primary and metastatic lesions by [18F]fluoro-2-deoxy-D-glucose PET in a patient with thymic carcinoid. Respirology. Nov 2007;12(6):928-30. [Medline].
Koopmans KP, de Groot JW, Plukker JT, de Vries EG, Kema IP, Sluiter WJ, et al. 18F-dihydroxyphenylalanine PET in patients with biochemical evidence of medullary thyroid cancer: relation to tumor differentiation. J Nucl Med. Apr 2008;49(4):524-31. [Medline].
Kaiser LR. Surgical treatment of thymic epithelial neoplasms. Hematol Oncol Clin North Am. Jun 2008;22(3):475-88. [Medline].
Cameron SE, Alsharif M, McKeon D, Pambuccian SE. Cytology of metastatic thymic well-differentiated neuroendocrine carcinoma (thymic carcinoid) in pleural fluid: report of a case. Diagn Cytopathol. May 2008;36(5):333-7. [Medline].
Tsuda E, Imai T, Matsumura A, Hisahara S, Nonaka M, Shiraishi H, et al. Thyrotoxic myopathy mimicking myasthenic syndrome associated with thymic hyperplasia. Intern Med. 2008;47(5):445-7. [Medline].
Further Reading
Keywords
thymus lesions, thymus tumors, thymic lesions, thymic tumors, thymic hyperplasia, thymoma, thymic cyst, carcinoma of the thymus, carcinoid tumor of the thymus and paraganglioma (thymic neuroendocrine tumors), nonseminomatous germ cell tumors, thymolipomas, thymic involvement in lymphoma and metastases, germ cell tumors (dermoid cyst, teratoma, seminoma)
