Hospital Medicine

Thymoma

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Thymoma

I. What every physician needs to know.

The most common masses found in the anterior mediastinum are thymomas, lymphomas, germ cell tumors, cysts (pericardial, bronchogenic, thymic and thoracic duct type, parathyroid cysts) and intrathoracic thyroid tissue.

Thymoma is the most common neoplasm of the anterior mediastinum, originating within the epithelial cells of the thymus. The anterior mediastinum lies anterior to the pericardium and includes lymphatic tissue, the thymus and the part of the aorta lying outside the pericardium, its branches and the great veins. Thymomas are rare in children but represent 20% of all mediastinal neoplasms in adults.

A patient's prognosis and the biological behavior of the tumor is dependent upon the cellular composition of the thymoma as described below. Thymomas can be benign or malignant.

The thymus gland plays an important role in the development of the immune system. Its cells form a part of the body's normal immune system. The gland is somewhat large in infants, grows gradually until puberty, and then gets smaller and is replaced by fat as one ages. If the thymus gland remains large and is abnormal with respect to its growth then an adult can develop a thymoma.

In thymoma, the thymus gland contains some clusters of immune cells indicative of lymphoid hyperplasia. Usually this type of condition is usually found only in the spleen and lymph nodes during an active immune response. Some individuals with myasthenia gravis develop thymomas.

The relationship between the thymus gland and myasthenia gravis is not yet fully understood. Some researchers have suggested that the thymus gland may give "incorrect instructions" to developing immune cells. Ultimately, this results in autoimmunity and the production of the acetylcholine receptor antibodies, thereby setting the stage for an attack on neuromuscular transmission which occurs in myasthenia gravis.

II. Diagnostic Confirmation: Are you sure your patient has Thymoma?

The diagnosis of thymoma is based largely on the biopsy of the gland (generally performed by a surgeon specialized in cardiothoracic surgery) and it's histological classification. Biopsy size may impede the pathologist's ability to determine the degree of invasion.

Histological diagnosis of thymomas is a challenge. There is a continuum of differentiation from thymoma to thymic carcinoma and primary thymic epithelial neoplasms can have features of both. Carcinoma and thymoma can occur simultaneously or cancer can develop within a preexisting thymoma.

The WHO (World Health Organization) Classification system is commonly used to describe thymomas:

Type A: composed of bland spindle cells and a few lymphocytes.

Type AB: composed of two components; one resembles Type A thymoma and the other with"plump" cells and predominant lymphocytic infiltration.

Type B1: composed of epithelial cells with vesicular nuclei and small nucleoloi and an abundant lymphocytic population.

Type B2: predominantly lymphocytic thymoma in which scattered plump cells with vesicular nuclei are seen.

Type B3: predominantly composed of polygonal or round epithelial cells with mild atypia. This category includes what is called the "atypical" thymoma that shows variable degree of cytologicatypia.

Type C: thymic carcinoma; it is composed of highly atypical cells with cytoarchitectural features of carcinoma similar to those seen in other organs. Though many lymphocytes can be seen in its troma, they are of B cell type and mature T cell type. Thymic cancer lacks immature T cell lymphocytes that are present in thymoma.

Histological heterogeneity is common among thymomas so that various histologic subtypes can be present within one tumor so as a result histological subclassification can be very difficult.

A. History Part I: Pattern Recognition:

Clinical signs and symptoms are often related to the size of the tumor and its effects on surrounding organ tissues causing compression and manifesting in the patient as symptoms of chest pain, shortness of breath, cough, phrenic nerve palsy, and sometimes superior vena cava syndrome. "B" symptoms can also occur although they are not as common; "B" symptoms include fever, night sweats and weight loss.

Pleural or pericardial effusions are the most common manifestation of thymoma leading to many of the symptoms listed above.

It should be noted that up to 50% of thymomas are diagnosed as incidental findings on radiologic imaging in asymptomatic patients. Therefore, 50% of patients with thymoma are asymptomatic.

B. History Part 2: Prevalence:

Associated conditions that are present in patients with thymomas include: paraneoplastic syndromes in cancer as well as noncancer patients, myasthenia gravis, patients with pure red cell aplasia, hypogammaglobulinemia and patients with multiorgan system autoimmunity disease states.

Most thymoma patients are between 40-60 years old.

There are no known risk factors for thymomas but there appears to be a male predominance.

Thymic carcinomas are rare and account for less than 1% of thymic malignancies.

Paraneoplastic syndromes are seen in 50-60% of patients with thymoma and include autoimmune, endocrine, hematologic, neuromuscular conditions:

Autoimmune:

Systemic Lupus Erythmatosus

Polymyositis

Myocarditis

Sjogren Syndrome

Ulcerative Colitis

Hashimoto thyroiditis

Sarcoidosis

Scleroderma

Endocrine:

Addison disease

Hyperthyroidism

Hyperparathyroidism

Panhypopituitarism

Hematologic:

Red cell aplasia

Hypogammaglobulinemia

T-cell deficiency

Pancytopenia

Amegakaryocytic thrombocytopenia

Neuromuscular syndromes

Myasthenia gravis

Eaton Lambert syndrome

Myotonic dystrophy

Myositis

Miscellaneous conditions:

Hypertrophic pulmonary osteoarthropathy

Nephrotic Syndrome

Minimal change disease

Pemphigus

Chronic mucocutaneous candidiasis

It is important to know that up to one half of patients with thymoma may have symptoms consistent with myasthenia gravis. It is common in all types of thymoma but is rare in thymic carcinoma. Men and women are affected equally.

C. History Part 3: Competing diagnoses that can mimic Thymoma.

Other neuromuscular diseases can mimic myasthenia gravis which, as mentioned above, is present in up to 50% of patients with thymoma. Guillain-Barré is one of these. This is a disorder in which the body's immune system attacks part of the peripheral nervous system. Initial symptoms include varying degrees of weakness and/or parathesias in the legs. In many instances, the weakness and tingling can spread to the arms and upper body. This condition can be very serious leading to respiratory failure and ultimately death.

In contrast, however, most individuals with isolated myasthenia gravis have a normal life expectancy and the disease itself is very treatable. Myasthenia gravis is a chronic autoimmune disease characterized by varying degrees of weakness of the skeletal muscles. The hallmark of the condition is muscle weakness that increases during periods of activity and improves after periods of rest. Certain muscles such as those that control eye and eyelid movement, facial expression, chewing, talking, and swallowing are usually involved in the disorder but not always. The respiratory muscles are less likely to be affected whereby in Guillain-Barré their involvement is more common.

However, when myasthenia gravis is seen in those with thymoma it can be much more serious depending upon the Stage of thymoma.

D. Physical Examination Findings.

In thymoma there are no specific physical exam findings unless there is associated myasthenia gravis. Such patients may present with diplopia, ptosis, dysphagia, weakness and fatigue. Patients may complain of difficulty in lifting their hand to brush their hair or brushing their teeth.

Patients with thymoma and myasthenia gravis usually present with less advanced disease than those without myasthenia. This may simply be that neuromuscular symptoms lead patients to seek medical attention earlier.

E. What diagnostic tests should be performed?

This is discussed above under Section II.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

No specific laboratory studies are recommended; however, if there is concern for malignancy or other autoimmune disease, then certainly a complete blood count (CBC) with differential, comprehensive metabolic panel (CMP) with Calcium and Magnesium, erythrocyte sedimentation rate (ESR) and other testing for vasculitic diseases may help confirm the existence of a paraneoplastic process as described above in Section IIB.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

When a thymoma is suspected, first a chest x-ray (PA and lateral) should be obtained to verify the presence of a mediastinal mass. Once it's presence is confirmed, then a high resolution computed tomography (CT) scan of the chest should be ordered to further delineate the mass and to further evaluate the lung fields for any evidence of other underlying lung conditions.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

NA

III. Default Management.

There are no randomized clinical trials that provide definitive guidance for the management of patients with thymoma or thymic cancer. Retrospective studies have shown that complete surgical resection is the treatment of choice for nonmetastatic thymoma and thymic carcinoma, even when the tumor has advanced locally. Chemotherapy before and/or after surgery and radiation therapy may be used as adjunctive treatments in certain patients.

In cases where complete surgical resection is not possible, radiotherapy is used to prevent mediastinal disease progression. The role of radiation after complete resection of aggressive thymoma (WHO B2, B3 and C) remains unclear. As such, the use of radiation should be considered on an individual basis.

Adjuvant chemotherapy is not necessary with complete surgical resection, however, in cases of thymic malignancies or advanced disease, chemotherapy can be considered. Platinum-based combinations are standard of care.

A. Immediate management.

Preoperative pulmonary function tests may be ordered by hospitalist during an inpatient or outpatient preoperative evaluation to help determine the extent of respiratory compromise if division of the phrenic nerve is deemed necessary by the surgeon upon surgical resection especially if he or she discovers that the tumor has extended along one or both of the phrenic nerves.

B. Physical Examination Tips to Guide Management.

As described in Section above, if the patient with a thymoma becomes symptomatic in the way of chest pain, dyspnea, cough, phrenic nerve palsy, or signs of superior vena cava (SVC) syndrome an emergent surgical consultation is warranted.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

There are none recommended.

D. Long-term management.

It is unclear whether surveillance CT scanning or chest x-ray is preferable to monitoring for recurrence of thymoma once surgical resection has occurred. There are currently no clinical trials to show evidence of any benefit of these types of surveillance modalities. However, monitoring for recurrences with yearly CT scan or even x-ray may be warranted. Such monitoring might be discussed with the patient because of the potential of long term effects of exposure to radiation by performing such imaging over time.

E. Common Pitfalls and Side-Effects of Management.

Exposure to radiation with repetitive surveillance imaging over time has not borne out to be effective for lack of evidence-based studies as described in Section III D above.

Secondary malignancies can arise in those with thymoma and include B cell non-Hodgkin lymphoma, gastrointestinal cancers and soft tissue sarcomas.

IV. Management with Co-Morbidities.

Patients with underlying cardiac or pulmonary comorbidities may not be good candidates for surgical resection. A preoperative evaluation with cardiac risk stratification is warranted in such patients.

A. Renal Insufficiency.

NA

B. Liver Insufficiency.

NA

C. Systolic and Diastolic Heart Failure.

NA

D. Coronary Artery Disease or Peripheral Vascular Disease.

NA

E. Diabetes or other Endocrine issues.

Paraneoplastic Syndromes seen in thymomas are discussed above in Section IIB.

F. Malignancy.

As described above in Sections I and II.

G. Immunosuppression (HIV, chronic steroids, etc).

NA

H. Primary Lung Disease (COPD, Asthma, ILD).

NA

I. Gastrointestinal or Nutrition Issues.

NA

J. Hematologic or Coagulation Issues.

NA

K. Dementia or Psychiatric Illness/Treatment.

NA

A. Sign-out considerations While Hospitalized.

If the patient shows compressive symptoms secondary to the size of the thymoma described above, then you might worry about respiratory compromise requiring an emergent airway.

B. Anticipated Length of Stay.

As long as there is no respiratory compromise, the workup for thymoma can be performed as an outpatient. If the patient is asymptomatic there is really no need for hospitalization.

C. When is the Patient Ready for Discharge.

The patient is ready for discharge when there is no sign of respiratory compromise.

D. Arranging for Clinic Follow-up.

N/A

1. When should clinic follow up be arranged and with whom.

Once the diagnosis of thymoma has been established, follow up should be with an oncologist specializing in the treatment of thymoma (regardless of whether or not it is a benign or malignant tumor), with a cardiothoracic surgeon if consideration is being given to surgical resection, and to a neurologist if the presence of myasthenia gravis has been made or further evaluation for this condition is warranted.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

The imaging tests described in Section E2.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

The tests as described in Section E3.

E. Placement Considerations.

Following surgical resection, thymoma patients usually require a prolonged hospitalization for healing of the surgical chest wound, pain control and return to ambulation with the aide of physical therapy. Rehab placement may be warranted in those patients deemed to be very weak, debilitated or have other comorbidities hindering their recuperation. Obtaining a Physical Therapy consult may be warranted to help determine if a rehab is appropriate for a short period of time post surgical resection of a thymoma.

F. Prognosis and Patient Counseling.

Staging of thymoma is based on the Masaoka system and correlates with overall 5-year survival rates:

Stage I - 94-100% survival

Stage II - 86-95% survival

Stage III -56-69% survival

Stage IV - 11-50% survival

A. Core Indicator Standards and Documentation.

There are no Joint Commission on Accreditation of Healthcare Organizations core indicators that are referable to this thymoma.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

DVT prophylaxis is indicated on admission particularly if the thymoma is felt to be associated with any paraneoplastic process where a patient might be hypercoagulable - such as in cancer or SLE - or if the patient is postop after surgical resection of the thymoma.

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