Pediatric Thymoma 

Updated: Oct 14, 2021
Author: Richard A Bickel, MD; Chief Editor: Harumi Jyonouchi, MD 

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)

 

Presentation

History

One third of patients with thymoma present with local symptoms. An additional one third of patients with thymoma are asymptomatic and are diagnosed as the result of abnormality on a chest radiograph (eg, mediastinal widening on posteroanterior [PA] views, retrosternal opacification on lateral views). Thirty percent of patients present with myasthenia gravis (MG).[1]

  • Structural problems, such as compression syndromes that involve the bronchi or lungs or superior vena cava syndrome (SVCS), can occur from local spread of benign thymoma, thymic cysts, or thymic carcinoma.

    • Presenting symptoms may include chest pain, SVCS, dyspnea, dysphagia, and cough.

    • Areas of benign thymoma can become highly vascular or necrotic and lead to bleeding.

    • Noninvasive large thymomas can be present for extended periods without symptoms. Takanami et al (1999) described a patient with a noninvasive thymoma that was present and asymptomatic for 21 years prior to the development of a compression syndrome.[21]

  • Clinical manifestations include paraneoplastic syndromes and immunodeficiency. Approximately 70% of patients with thymoma are symptomatic for other illnesses, including MG (50%), hypogammaglobulinemia (5%), pure red blood aplasia (5%), and one or more of the immune or endocrinologic diseases (10%).

  • Patients with Good syndrome present with recurrent bacterial, viral, and fungal infections. Recurrent upper and lower respiratory tract infections with encapsulated and atypical bacteria are also reported. In addition, opportunistic infections, including mucocutaneous candidiasis, recurrent herpes simplex virus, varicella-zoster virus, cytomegalovirus, and Pneumocystis carinii pneumonia have also been reported. Chronic diarrhea without clear etiology may also be present.[22]

Physical

One third of patients with thymoma present with local symptoms (eg, chest pain, SVCS, dyspnea, dysphagia, cough). An additional one third of patients with thymoma are diagnosed as the result of abnormality on a chest radiograph, such as mediastinal widening on PA views or retrosternal opacification on lateral views.

  • Consider imaging studies to exclude thymoma in individuals with paraneoplastic syndromes (eg, pemphigus, common variable immunodeficiency [CVID], red cell aplasia) or in those with a compression syndrome.

  • Observe patients with acquired hypogammaglobulinemia at regular intervals for the development of thymoma.[11]

  • Inversely, if thymoma is present, consider appropriate laboratory studies to screen for these disorders (see Laboratory Studies).

 

DDx

Diagnostic Considerations

Other medical problems associated with thymomas include the following:[15, 13]

  • Dermatomyositis

  • Polymyositis

  • Autoimmune thyroiditis

  • Ulcerative colitis

  • Pernicious anemia

  • Scleroderma

  • Rheumatoid arthritis

  • Raynaud phenomenon

  • Regional enteritis

  • Diabetes

  • Amyloidosis

  • Chronic hepatitis

  • Cushing syndrome

  • Addison disease

  • Undifferentiated thymic carcinoma (found to be associated with Epstein-Barr virus in a 12-year-old girl)[11]

Other abnormal growths of the anterior mediastinum include thymic cysts or thymic carcinoma (also referred to as malignant thymoma).

Other mediastinal masses in the differential diagnosis include the following:[15]

  • Thymolipoma

  • Mediastinal germ cell tumor

  • Mediastinal lymphangioma (rare tumors that predominantly occur in children)

  • Mediastinal goiter

  • Mediastinal parathyroid adenomas (uncommon and rarely cause a discernible mass)

Levels of serum beta-subunit human chorionic gonadotrophin (beta-HCG) or alpha-fetoprotein (AFP) may be elevated in germ cell tumors.

Differential Diagnoses

 

Workup

Laboratory Studies

A CBC count reveals associated anemia, thrombocytopenia, or granulocytopenia.

Quantitative immunoglobulins (Igs) in patients with thymoma should be routinely drawn to assess Ig levels. Panhypogammaglobulinemia is noted in patients with acquired immunodeficiency and thymoma. Functional antibody responses to immunizations may be impaired in some patients.[11] Therefore, prevaccination and postvaccination antibody levels against protein and polysaccharide vaccines should be measured to assess humoral immune responses.

Immunophenotypic analysis of peripheral blood lymphocytes shows absent or very low B-cell counts and decreased absolute CD4+ T-cell numbers.[23]

Imaging Studies

Chest radiography

One third of patients with thymoma are diagnosed as the result of an abnormality on a chest radiograph, such as mediastinal widening on posteroanterior (PA) views or retrosternal opacification on lateral views.

Chest CT scanning or MRI

These tests provide more definitive methods to exclude or characterize the thymoma.

CT scan or MRI can reveal the morphology of the mass and detect fat invasion, cysts, or necrosis.

Although uncommon, distant metastases occur with thymoma in 30-40% of patients with advanced disease; other scans may be warranted, depending on clinical symptoms.

Adenopathy in the middle or posterior mediastinum suggests lymphoma or lung carcinoma.

Calcification of cysts suggests germ cell tumor.

Functional imaging with oncotropic tracers and radioligands

These images have also proven useful.[24]

Oncotropic tracers concentrate in thymic tumors and correlate with tumor grades and cellularity; these include thallium TI 201 chloride, technetium Tc 99m sestamibi, and fluorine F 18 fluorodeoxyglucose.

The radioligands bind to specific receptors: [111In-DTPA-D-Phe1]-octreotide binds to the somatostatin receptor subtype 2; [111In-DTPA-Arg1]-substance P binds to receptors that are mainly expressed in the thymuses of patients with autoimmune diseases.

Although [111In-DTPA-D-Phe1]-octreotide concentrates in most thymomas, it does not concentrate in benign lymphofollicular hyperplasia and can assist in distinguishing these 2 pathologies in patients with myasthenia gravis (MG).[25]

Other Tests

Cell-mediated immune responses are evaluated with delayed-type hypersensitivity (DTH) skin testing and in vitro T-cell responses to mitogens.[23] Patients with decreased cell-mediated immunity have absent DTH responses and decreased T-cell responses to mitogens.

Anti-AChR antibodies are appropriate because they are present in 90% of patients with MG and occasionally in patients with thymoma without muscle weakness.[26]

Perform additional studies to diagnose these and other paraneoplastic syndromes as indicated by history and physical examination findings.

Procedures

Adequate tissue samples are important for histologic preparation and possible flow cytometry.

Fine-needle aspiration is considered inferior to a larger sample (eg, obtained by core biopsy or a limited anterior mediastinal sternotomy).

Mediastinoscopy does not provide adequate access to the anterior mediastinal compartment.

Histologic Findings

Thymomas are characterized by a mixture of epithelial and lymphoid tissue and are usually encapsulated. In proposing a new classification system, Muller-Hermelink and Marx describe the traditional classification system as follows:[27]

Traditionally, thymic epithelial tumors (TET) have been classified histologically into four categories: predominantly spindle cell, predominantly lymphocytic, predominantly mixed lymphocytic and epithelial, and predominantly epithelial thymoma on the basis of lymphocyte/epithelial cell ratio and the shape of epithelial cells. To obtain better clinical and prognostic relevance, Levine and Rosai use tumor invasiveness (ie, stage) and cytological atypia to differentiate between benign thymomas and malignant thymomas of categories I and II ('thymic carcinoma'). Malignant thymomas belonging to category II were subsequently classified as squamous cell carcinoma, mucoepidermoid carcinoma, etc, according to the standard rules of extrathymic carcinomas.

Muller-Hermelink and Marx proposed a histogenetic or functional classification of TET based on the morphologic resemblance of neoplastic epithelial cells to subtypes of normal thymic epithelial cells. This method of classification excludes thymic carcinoma as belonging to category II (nonorganotypic) TET.

The World Health Organization (WHO) recently developed terminology based on the following criteria: Thymomas are divided into 2 major types depending on whether the neoplastic epithelial cells have a spindle or oval shape (type A) or whether they have a dendritic or epithelioid appearance (type B). Tumors that combine these features are designated as type AB. Type B thymomas are further divided based on an increasing epithelial lymphocyte ratio and emergence of atypia of the neoplastic epithelial cell into 3 subtypes, respectively designated B1, B2, and B3. Nonorganotypic thymic carcinomas, which generally resemble tumors arising outside the thymus, are regarded as type C thymoma.[27]

Table 1. Comparison of the Different Classifications of Thymic Epithelial Tumors [27] (Open Table in a new window)

Clinicopathologic Classification

WHO Type

Terminology of the Histogenetic Classification for the Histologic Subtypes of Thymic Epithelial Tumors

Benign thymoma

A

AB

Medullary thymoma

Mixed thymoma

Malignant thymomas,

Category I

B1

B2

B3

Predominantly cortical thymoma

Cortical thymoma

Well-differentiated thymic carcinoma

Malignant thymomas,

Category II

C

Epidermoid keratinizing (squamous cell) carcinoma

Epidermoid nonkeratinizing carcinoma

Lymphoepithelioma-like carcinoma

Sarcomatoid carcinoma (carcinosarcoma)

Clear cell carcinoma

Mucoepidermoid carcinoma

Undifferentiated carcinoma

Staging

Areas of the thymus can become cystic, hemorrhagic, or necrotic, although most thymomas are solid. Although lacking the histologic features of malignancy, approximately one third of thymomas may invade through the capsule extending into the mediastinal fat, pleura, pericardium, great vessels, right atrium, and/or the lung (ie, invasive thymoma). Although rare (3-6%), transdiaphragmatic extension and drop metastases may occur; however, hematologic or lymph node metastases rarely occur.[11, 28, 3, 29]

The Masaoka staging system is the most widely used staging system and is based on the extent of invasion. It has been shown to correlate well with the 5-year and 10-year survival rates, based on WHO schema.[30] Loehrer summarizes the Masaoka staging system for thymomas as follows:[19]

  • Stage I - Macroscopically completely encapsulated with no microscopic capsular invasion

  • Stage II

    • Macroscopic invasion into the surrounding fatty tissue, mediastinal pleura, or both

    • Microscopic invasion into the capsule

  • Stage III - Macroscopic invasion into neighboring organs (eg, pericardium, great vessels, lung)

  • Stage IVa - Pleural or pericardial dissemination

  • Stage IVb - Lymphogenous or hematogenous metastases

Loehrer summarizes the Groupe d'Etudes des Tumeurs Thymiques (GETT) classification, which is based on the extent of surgical resection, as follows:[19]

  • Stage IA - Encapsulated tumor, totally resected

  • Stage IB - Macroscopically encapsulated tumor, totally resected, but with a suspicion of mediastinal adhesions and potential capsular invasion

  • Stage II - Invasive tumor, totally resected

  • Stage IIIA - Invasive tumor, subtotally resected

  • Stage IIIB - Invasive tumor, biopsy

  • Stage IVA - Supraclavicular metastasis or distant pleural implants

  • Stage IVb - Distant metastasis

Lymphofollicular thymitis or follicular thymus hyperplasia is a type of pathology found in approximately 70% of patients with MG. Lymphoid follicles with germinal centers appear in the perivascular spaces with destruction of the basal membrane between the perivascular spaces and thymic medulla. Myoid cells in the medulla form abnormal complexes with antigen-presenting dendritic cells. The concept of an intrathymic pathogenesis of MG in lymphofollicular thymitis is now generally accepted.

According to this postulate, AChRs derived from thymic myoid cells are ingested, processed, and presented by dendritic cells to potentially AChR-reactive T cells that then activate autoantibody-producing B cells and initiate plasma cell differentiation. In these patients, the thymus is the organ with the highest autoantibody production against AChR, at least in the early phase of MG. Dissemination of the autoreactive T cells from the thymus via the blood to peripheral lymphoid organs is an early event. Therefore, thymectomy can initiate complete remission in a large number of patients, provided it is performed early enough to prevent the establishment of a systemic anti-AChR response.[27]

See Thymoma Staging for summarized information.

 

Treatment

Medical Care

Postoperative radiotherapy has been used for invasive thymoma and incompletely resected thymoma.

  • Commonly, radiotherapy has treated T tumors demonstrated to be unresectable on CT scan or with supraclavicular extension.

  • Primary radiotherapy in unresectable stage III or stage IVa disease has controlled local disease with a 5-year survival rate of 45-50%.[2]

  • Combination chemotherapy using cisplatin has been reported to have a response rating of 70-80%. Doxorubicin, vincristine, and cyclophosphamide have been used in combination chemotherapy.

The acquired immunodeficiency associated with thymoma should be treated with monthly replacement immunoglobulin (Ig) therapy. Replacement Igs may be intravenously or subcutaneously administered. Doses of intravenous Igs should be 300-400 mg/kg every 3 weeks or 400-500 mg/kg every 4 weeks with dose adjustment to maintain trough IgG levels above 500-600 mg/dL. In addition, prophylactic antibiotics may be required in addition to Ig replacement therapy to prevent bacterial infections in immunodeficient patients. Aggressive and long-term antibiosis is often required to treat bacterial infections in these patients.[22]

See Thymoma Treatment Protocols for more information.

Surgical Care

Because thymoma is usually well encapsulated and characterized by local spread, thymectomy can be curative in the early stages.

Encapsulated (stage I) tumors can usually be completely excised, and the local relapse rate is less than 5%. Currently, adjuvant radiotherapy and chemotherapy are not recommended for stage I thymomas that are completely resected.[31] The relapse rate increases in more invasive stages.

Surgery can be challenging because of the tendency of the tumor to surround blood vessels, bronchi, and other mediastinal structures. Excessive bleeding can complicate thymectomy of large tumors that have become vascular or lacunar.

Tumor recurrence can occur even after complete resection.[32]

Eighty-five percent of patients with myasthenia gravis (MG) have some histologic abnormality of the thymus.

Thymectomy is considered a routine treatment for MG. Reportedly, resection of the thymoma is associated with improvement in weakness in 25% of patients, and almost one half of patients without thymoma improve after thymectomy.[13]

A study of 153 patients by Werneck et al compared thymectomy with conservative treatment groups in paired patients at similar stages and found no statistical difference between the conservative treatment and thymectomy groups.[33]

Thymectomy is believed to improve muscle weakness in 25% of individuals with MG and thymoma and in 50% of patients with MG without thymoma.

Thymectomy results in resolution of red cell aplasia in 30% of persons with this disorder.

The acquired immunodeficiency phenotype does not improve after thymectomy, and, in some persons, immunodeficiency has occurred years after resection of a thymoma.[34]

 

Medication

Medication Summary

Although the treatment of choice for thymoma is surgical resection, chemotherapy and/or radiation has been shown to decrease the rate of tumor recurrence when complete excision is not possible.[35] Radiation therapy alone in patients with invasive or bulky tumors has demonstrated a 50-70% recurrence rate.

The use of surgery as a sole treatment heavily depends on the stage of the thymoma, and complete resection has been shown to be a significant predictor of 5-year survival in Masoaka stages I, II, and III.[36]

Various treatment protocols have been used, but those based on a combination of cisplatin and doxorubicin appear to have the best overall success rates. Additionally, National Comprehensive Cancer Network (NCCN) Guidelines currently recommend cisplatin/doxorubicin/cyclophosphamide as the primary treatment regimen.[31]

Fornasiero and colleagues studied 32 patients with stage III and IV thymomas treated with cisplatin, doxorubicin, vincristine, and cyclophosphamide; they reported a 91% radiologically defined response rate with 47% complete remission.[37]

Macchiarini's group demonstrated an 80% survival rate in 20 patients given preoperative chemotherapy with cisplatin, epirubicin, and etoposide; surgery for those whose condition responded to treatment; and subsequent postoperative radiation.[38]

Loehrer's group studied 26 adults with limited-stage unresectable thymoma who were administered cisplatin, doxorubicin, and cyclophosphamide, followed by radiation; the study demonstrated 5 complete responses, 11 partial responses, and a 5-year-survival rate of 52.5%.[39]

Venuta's group prospectively studied 65 patients who were undergoing surgical resection of stage I, II, and III thymomas.[40] The patients were treated with adjuvant or neoadjuvant chemotherapy with cisplatin, epirubicin hydrochloride, and etoposide. The 8-year-survival rates for patients with stages I, II, III, and IV thymomas were 95%, 100%, 92%, and 68%, respectively.

A Japan Clinical Oncology Group studied 23 patients who received cisplatin/vincristine/doxorubicin/etoposide before resection and/or radiotherapy. The overall survival rate at 5 years was 85%.[41]

Somatostatin analogue–based therapy is a more recent treatment modality and shows promise in the treatment of unresponsive thymomas. Palmieri reported the outcome of 17 patients with extensive advanced thymoma selected because of the significant uptake of indium-labeled octreotide, indicating the presence of somatostatin receptors.[42]

The patients had previously been treated with chemotherapy, and the thymomas were no longer responsive to conventional therapies. The patients received one of the somatostatin analogues plus prednisone. Octreotide (1.5 mg/d SC) was changed to the longer-acting lanreotide (30 mg IM q14d) if the shorter-acting preparation was well tolerated; the accompanying prednisone dose of 0.6 mg/kg/d usually was reduced after 3 months to 0.2 mg/kg/d. Of the 13 patients available for follow-up study after 25 months, 2 showed complete response, 5 showed partial response, and 6 had stable disease. One patient showed resolution of associated red cell aplasia.[42]

Treatment protocols

Table. Macchiarini et al (1991) [38] (Open Table in a new window)

Cisplatin

75 mg/m2 on day 1

3 courses repeated q3wk

Epirubicin

100 mg/m2 on day 1

Etoposide

120 mg/m2 on days 1, 3, and 5

Surgery and radiation

in patients with

complete or partial

response to chemotherapy

4500 cGy if complete

resection

6000 cGy if incomplete

resection

 

Table. Loehrer et al (1997) [39] (Open Table in a new window)

Cisplatin

50 mg/m2

2-4 cycles q3wk

Doxorubicin

50 mg/m2

Cyclophosphamide

500 mg/m2

Followed by radiation

54 Gy to the primary tumor and lymph nodes

Table. Venuta et al (1997) [40] (Open Table in a new window)

Cisplatin

75-100 mg/m2 on day 1

Repeated q3wk 3 times before surgery and 2 or 3 times after surgery

Epirubicin hydrochloride

100 mg/m2 on day 1

Etoposide

120 mg/m2 on days 1, 3, and 5

Postoperative radiation in patients with radical resection

30 Gy

Delivered in 3 wk with 5 fractions per wk

Postoperative radiation in

patients with incomplete resection

50 Gy

Delivered in 5 wk with 5 fractions per wk

Table. Palmieri et al (1999) [42] (Open Table in a new window)

Octreotide

1.5 mg/d SC

In patients shown to have

somatostatin receptors

Lanreotide

30 mg/d SC q14d

Switch to this longer-acting

somatostatin analogue or depot form of octreotide if short-acting octreotide

is well tolerated

Prednisone

0.6 mg/kg/d PO

for 3 mo, then

decreasing to 0.2 mg/kg

 

Antineoplastic agents

Class Summary

Combination chemotherapy using cisplatin is reported to have a response rate of 70-80%. Doxorubicin, vincristine, and cyclophosphamide have been used in combination chemotherapy.

Cisplatin (Platinol)

Inhibits DNA synthesis and, thus, cell proliferation by causing DNA cross-links and denaturation of the double helix.

Doxorubicin (Adriamycin, Rubex)

Inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA. Combination of these 2 events can inhibit growth of neoplastic cells.

Vincristine (Vincasar PFS, Oncovin)

Mechanism of action is uncertain. May involve decrease in reticuloendothelial cell function or increase in platelet production.

Epirubicin (Ellence)

Cell cycle phase–nonspecific anthracycline derivative of doxorubicin with maximum cytotoxic effects on the S and G2 phases.

Cyclophosphamide (Neosar, Cytoxan)

Chemically related to nitrogen mustards. As an alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Etoposide (Toposar, VePesid)

Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G2 portion of cell cycle.

Somatostatin analogues

Class Summary

These agents are used in patients with somatostatin receptors. Octreotide, like natural somatostatin, inhibits secretion of growth hormone, insulin, and glucagon. Following IV administration of somatostatin analogues, basal serum growth hormone, insulin, and glucagon levels are lowered. They also inhibit prolactin secretion via vasoactive intestinal peptide-mediated and thyrotropin-releasing hormone-mediated secretion of prolactin. They are used in the treatment of acromegaly and hormone-secreting tumors.

Octreotide (Sandostatin)

Acts primarily on somatostatin receptor subtypes II and V. Inhibits GH secretion and has multitude of other endocrine and nonendocrine effects, including inhibition of glucagon, VIP, and GI peptides.

Lanreotide (Somatuline Depot)

Indicated for long-term treatment of acromegaly in patients who experience inadequate response to other therapies. Octapeptide analogue of natural somatostatin. Inhibits a variety of endocrine, neuroendocrine, exocrine, and paracrine functions. Elicits high affinity for human somatostatin receptors 2, 3, and 5. Inhibits basal secretion of motilin, gastric inhibitory peptide, and pancreatic polypeptide. Markedly inhibits meal-induced increases in superior mesenteric artery blood flow and portal venous blood flow. Also significantly decreases prostaglandin E1—stimulated jejunal secretion of water, sodium, potassium, and chloride. Reduces prolactin levels in acromegalic patients when treated long term.

Corticosteroids

Class Summary

These agents elicit anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Prednisone (Deltasone)

May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Uroprotective antidote

Class Summary

Mesna is a prophylactic detoxifying agent used to inhibit hemorrhagic cystitis caused by ifosfamide and cyclophosphamide. In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react with acrolein, the ifosfamide and cyclophosphamide metabolite considered responsible for urotoxicity.

Mesna (Mesnex)

Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity.

 

Follow-up

Complications

Complications may include the following:

  • Structural problems, such as compression syndromes that involve the bronchi or lungs or superior vena cava syndrome (SVCS), can occur from local spread of benign thymoma, from thymic cysts, or from thymic carcinoma. Presenting symptoms may include chest pain, SVCS, dyspnea, dysphagia, and cough.

  • Areas of benign thymoma can become highly vascular or necrotic and lead to bleeding.

  • Clinical manifestations include paraneoplastic syndromes and immunodeficiency.

Prognosis

Adverse predictive factors include the following:[43, 44]

  • Invasive or metastatic tumor

  • Tracheal or vascular compression

  • Age younger than 30 years

  • Epithelial or mixed histology

  • Tumor size of more than 8 cm[45]

The presence of myasthenia gravis (MG) with thymomas is no longer considered a poor prognostic factor and is actually thought to be a favorable prognostic factor.[46]

Based on WHO classification, the 5-year and 10-year survival rates are as follows:[47, 48]

  • Type A - 100% and 95%, respectively

  • Type AB - 93% and 90%, respectively

  • Type B1 - 89% and 85%, respectively

  • Type B2 - 82% and 71%, respectively

  • Type B3 - 71% and 40%, respectively

  • Type C - 23% (5-year survival rate)

Recurrence of thymoma can occur after resection. A study surgical outcomes after recurrence of thymic epithelial tumors in 67 patients showed an overall survival rate at 10 years of 70% in those undergoing re-resection.[32]

For patients with Masaoka stage IVA thymomas, a study of 18 patients reported survival rates at 3 years (91%), 5 years (78%), and 10 years (65%).[49] These patients underwent multimodality therapy, including surgical resection, preoperative chemotherapy, and even postoperative radiation therapy (in select patients).