Thymoma

A third of all people with a thymoma have symptoms of superior vena cava syndrome, dysphagia, cough, or chest pain caused by compression of the surrounding organs by an expansive mass. 

Thymomas have a tendency towards local progression rather than metastatic, by contrast thymic carcinomas have a higher risk of metastatic spread.

Compression symptoms of thymoma include: superior vena cava syndrome, dysphagia, cough, or chest pain.

 

One-third of patients thymomas are recognized  because they have an associated autoimmune disorder. 

 

A tumor originating from the epithelial cells of the thymus that may be benign or malignant. 

Approximately 1/3 of patients with thymoma are asymptomatic, 1/3 have local symptoms, and 1/3 have autoimmune disorders at the time of diagnosis.

Thymomas are frequently associated with the neuromuscular disorder myasthenia gravis, and  is found in 20% of such patients.

 

Men and women are equally affected by thymomas. 

The incidence is 0.13 cases per 100,000.

1-1.5 cases per million persons per year.

Most patients are between 40-60 years of age with equal frequency among males and females.

About one third to one half of the patients have symptoms.

Represents 20% of all anterior mediastinal neoplasms in adults.

The rare, immunodeficiency Good’s syndrome is associated with thymoma.

Thymoma is characterized by dysregulation of the immune system, manifesting as auto immunity and increased susceptibility to infections.

Thymoma patients have combined B and Tcell deficiencies with CD 4+ lymphopenia, impaired proliferative responses to mitogens and increased numbers of naïve and effector CD8 positive cells.

Most patients present with an immunodeficient state and recurrent sinopulmonary infections in their 4th or 5th decade of life. 

The immunodeficiency abnormalities may occur before or after the diagnosis of a thymoma.

It is an immunodeficiency involves both deficient humoral and cellular immunity, with low total serum antibodies. 

The thymoma may inhibit the thymus’s normal role to produce self-tolerant T lymphocytes. 

These T-lymphocytes then attack the B cell precursors in the marrow, preventing maturation and ultimately resulting in hypogammaglobulinemia.

Thymoma is characterized by increased susceptibility to bacterial, viral, and fungal infections.

Anti-Auto antibodies to interleukin 23 is associated with opportunistic infections in patients with thymoma.

Most patients with thymoma have infection complications.

Patients have increased infections with encapsulated bacteria, especially recurrent sinopulmonary infections and bacteremia with most common agents being Streptococcus pneumoniae, Haemophilus influenzae, pseudomonas, species, and klebsiella species.

There is a high prevalence of chronic diarrhea in approximately half of the patients due to infection with salmonella species or Campylobacter jejuni.

Opportunistic Infections associated with thymoma are mycobacterial, bacterial and fungal infections.

Symptoms are usually related to pressure from the tumor on surrounding structures or invasion and include chest pain, shortness of breath, cough and the superior vena cava syndrome.

The prognosis is closely linked to underlying condition.

Thymic carcinomas are the most aggressive subtype and constitute over 10% of thymic tumors.

Thymic carcinomas are often not resectable, and tend to metastasize widely, and are associated with a shorter survival than are thymoas.

Evaluation includes chest x-ray, CT scan of the chest to demonstrate an anterior mediastinal lesion.

A CT  scan is generally performed to estimate the size and extent of the tumor, and the lesion is sampled with a CT-guided needle biopsy. 

 

 

Increased vascular enhancement on CT scans can be indicative of malignancy, as can be pleural deposits.

 

 

Needle biopsies are associated with a very small risk of pneumomediastinum or mediastinitis.

 

 

Biopsies have  very lowrisk of damaging the heart or large blood vessels. 

One-third to one-half of all persons with thymoma have no symptoms.

 

 

A thymoma mass can be identified on a chest X-ray or CT/CAT scan performed for an unrelated problem.

 

Laboratory tests used to look for associated problems or possible tumor spread: blood count, protein electrophoresis, antibodies to the acetylcholine receptor, electrolytes, liver enzymes and renal function.

Tumors are characterized by marked morphologic heterogeneity.

Extrathoracic metastases occur in less than 7% and metastatic to the ipsilateral lung are unusual.

Associated with paraneoplastic disorders including myasthenia gravis, pure red cell aplasia and hypogammaglobulinemia.

Other associated processes include:  acute pericarditis, agranulocytosis, alopecia areata, ulcerative colitis, Cushing’s disease, hemolytic anemia, limbic encephalopathy, myocarditis, nephrotic syndrome, panhypopituitarism, pernicious anemia, polymyositis, rheumatoid arthritis, sarcoidosis, scleroderma, sensorimotor radiculopathy, stiff person syndrome, systemic lupus erythematosus and thyroiditis.

Good’s syndrome is the immunodeficiency associated with thymoma and has humoral and cellular abnormalities and occurs in about 10% of patients.

Good Syndrome is associated with other autoimmune conditions including pure red cell aplasia and myasthenia gravis.

Hypogammaglobulinemia seen in 6-11% of patients.

In Good’s syndrome low or absent B cells may be present, CD4+ T cells nay be decreased, and CD4+ to CD8+ ratio may be less than 1.

Among the most common tumors of the anterior mediastinum.

Does not represent the benign counterpart of thymic carcinoma.

Approximately 10-15% of patients with myasthenia gravis have a thymoma and conversely about 40% of patients with thymoma is associated with a paraneoplastic syndrome, of which myasthenia gravis is the most common

Myasthenia gravis is the most common associated paraneoplastic disorder.

Other paraneoplastic syndromes associated with thymoma include: limbic encephalitis, stiff person syndrome, neuromyotonia, polymyositis, and myoclonic dystrophy.

Can present with a wide spectrum of processes including: myocarditis, hypogammaglobulinemia, pure red cell aplasia, pseudo obstruction of the bowel, graft versus host disease, mixed connective tissue disease, and thyroiditis among others.

Pure red cell aplasia occurs in 5-15% of patients.

Myasthenia gravis and pure red blood cell aplasia may respond to thymectomy.

Patients at increased risk for the development of another malignancy.

Usually slow growing with 5-year survival of 70%.

5-year survival is 50% with local invasion and 75% without invasion.

10-year survival 30% with local invasion and 60% without local invasion.

Prognosis worsens if tumor invades through the capsule into surrounding fat, pericardium or pleura, is greater than 10 cm., occurs in patients under the age of 30, has epithelial and mixed histologies, or occurs with a paraneoplastic syndrome.

Surgical resection is the preferred treatment and it is unclear if adjuvant radiotherapy or chemotherapy improve survival.

In study of 324 patients who underwent complete resection of her thymoma between 1970 and 2005 134 patients receiving mediastinal postoperative radiation surgical resection alone was sufficient in Masaoka stage I and II, and in those with WHO cell types A, AB, and B1: No significant improvement in survival was noted to patients who were treated with postoperative radiation compared to those without. (Utsumi, T).

Amplification of EGFR gene is associated with more invasive and aggressive disease.

Invasive thymomas may require additional treatment with radiotherapy and chemotherapy.

 

 

Recurrences of thymoma are described in 10-30% of cases up to 10 years after surgical resection.

 

 

The majority of cases also pleural recurrences can be removed. 

 

 

Invasive thymomas uncommonly can also metastasize, generally to pleura, bones, liver or brain in approximately 7% of cases.

 

 

A study found that slightly over 40% of observed patients with stage III and IV tumors survived for at least 10 years after diagnosis. 

 

 

The median age of these patients at the time of thymoma diagnosis was 57 years. 

 

 

Following thymectomy for thymoma possible severe side effects after yellow fever vaccination caused by inadequate T-cell response to live attenuated yellow fever vaccine. 

 

Complete remissions have been reported for a combination of octreotide and prednisone in patients with pure-red cell aplasia.

4 basic cell types: lymphocyte rich, epithelial, mixed lymph epithelial and spindle cell.

Thymoma-WHO classification:Type A-spindle-cell features, resembling medullary epithelial cells, with sparse lymphocytes appearing as mature thymocytic type cells.

Only 11% invasive and the lesions are usually resectable with an average stage of 1.2 with 0% recurrences and a 100% 20 year survival.

Type AB-Mixed epithelial and lymphocytic features of A and B with 42% invasive lesions, 99% complete resection, average stage 1.5 with 5% recurrences and 87% 2 year survival.

Type B1-Sparse cortical and medullary epithelial cells with predominant immature cortical thymocyte lymphocytes with 47% invasiveness, 95% resectability. 1.7 average stage and 9% recurrence rate with a 20 year survival rate of 91%.

Type B2-More numerous cells of the type B2 with predominantly immature thymocytes and 69% invasiveness, 91% resectability, 2.3 average stage, 18% recurrence and 59% 20 year survival.

Type B3-Predominant oval nuclei with clear cytoplasm and atypia, sparse immature cortical thymocytes, 85% invasiveness, 92% resectable, average stage 2.5 29% recurrence rate and 20 year survival of 36%.

Thymomas with a predominance of lymphocytes include types B1 and B2.

Masaoka staging system is most commonly used and correlates well with survival.

The Masaoka Staging System is used and is based on the anatomic extent of disease at the time of surgery.

 

 

I: Completely encapsulated

 

 

IIA: Microscopic invasion through the capsule into surrounding fatty tissue

 

 

IIB: Macroscopic invasion into capsule

 

 

III: Macroscopic invasion into adjacent organs

 

 

IVA: Pleural or pericardial implants

 

 

IVB: Lymphogenous or hematogenous metastasis to distant  sites

Epithelial histology, poor Karnofsky performance in advanced stages III and IV associated with poor prognosis.

In the absence of Good’s syndrome prognosis for patients following thymectomy have a survival similar to that of the general population (Maggi).

Removal of the thymus in adults does not appear induce immune deficiency. 

 

 

In children, postoperative immunity may require vaccinations.

Current management:

Surgery is the primary treatment for thymoma. 

 

 

In apparently invasive and large masses neoadjuvant chemotherapy and/or radiotherapy may be used to decrease the size and improve resectability, before surgery is attempted. 

 

Early stage Masaoka I-IIB), no further therapy is necessary. 

Stage I-completely encapsulated-95-100% 5 year survival with surgical resection.

Stage IIA-microscopic capsular invasion-86-95% 5 year survival with surgical resection, adjuvant radiation if positive margins

Stage IIB-macroscopic capsular invasion-86-95% 5 year survival with surgical resection, adjuvant radiation if positive margins.

stage IIIA-macroscopic pleural or pericardial invasion, no great vessel involvement-56-70% 5 year survival with neoadjuvant chemotherapy followed by surgery or surgery followed by adjuvant chemotherapy.

Stage IIIB-macroscopic pleural or pericardial invasion with great vessel involvementwith 56-70% 5 year survivaland treatment with neoadjuvant chemotherapy followed by surgery.

Stage IVA-pleural or pericardial dissemination with a 11-50% 5 year survival treated with neoadjuvant chemotherapy followed by surgery.

Stage IVB-distant metastatic disease with 11-50% 5 year survival treated with chemotherapy.

Chemotherapy regimens include cyclophosphamide 500 mg meter squared on day 1, doxorubicin 20 mg meter squared by continuous infusion on days 1 through 3, cisplatin 30 mg/m² days one through 3 and prednisone 100 mg daily ×5 days Kim ES et al).

the percentage of patients that receive a response to chemotherapy is less than 50%.

Sunitinib a C-KIT inhibitor has some activity in because of the high expression of c-KIT in thymic carcinoma.

Response rate to sunitunib is about 25%.

PD-L! is expressed in thymic carcinomas and has a 22% response rate overall, with a 60% response rate in patients with high expression.