Myasthenia Gravis with Thymoma
by Robert E. Lovelace, MD, and David S. Younger, MD

Reprinted from Neurology, Volume 48, Supplement 5, pgs.S76-81.

Progress in the pathogenesis, diagnosis, and treatment of thymomatous myasthenia gravis (MG) has been made in the past several decades. These advances have occurred along diverse lines of immunology, molecular genetics, and tumor cytopathology. The most widely used classification for thymoma closely correlates with tumor biology, prognosis, and the likelihood of association with MG. There is a sensitive immunoassay for the detection of striational autoantibodies, which are closely related to the presence of thymoma, although their precise origin is still debated. Chest computed tomography (CT) can delineate a thymoma with extraordinary accuracy and sensitivity. The goal of treatment is complete removal of the tumor and remission or sustained improvement of MG. This is usually achievable with trans-sternal maximal thymectomy and chronic immunosuppressant medication. In this article, we consider aspects of the historical background, pathogenesis, diagnosis, and treatment of thymomatous MG.

Historical background
There was no mention of thymic abnormalities in the classic descriptions of myasthenia patients by Wilks, Erb, Goldflam, and Jolly, or among the autopsies reported by Campbell and Bramwell at the turn of the century until 1901 when Laquer and Weigert described a patient with myasthenia and a thymic tumor. Later, Bell, Blalock, and others found that the thymus gland in myasthenia was enlarged or the site of a tumor in the majority of patients at surgery or autopsy. Thymectomy, with the intention to resect the gland totally became standard treatment.

The estimated overall frequency of thymoma in MG varies from 15 to 30%. It is more common with increasing age, with an estimated frequency of 3% for age 20 years or younger, 12% for ages 21 to 45, and 35% for age 46 years and older. Although detection of thymoma most often follows the clinical diagnosis of MG, myasthemia may follow detection and removal of the tumor in patients up to age 22 years.

Associated autoimmune disorders
Patients with thymoma have an increased tendency for associated autoimmune disorders in keeping with Simpson's assertion, including limbic encephalitis, neuromyotonia and peripheral neuropathy, polymyositis and dermatomyositis, pure red blood cell aplasia, pancytopenia, rheumatoid arthritis, hyperthyroidism, systemic lupus erythematosis, giant cell myocarditis, Addisons disease, and cryoglobulinemia. Extrathymic neoplasms also occur with increased frequency including those of the breast, liver, lung, stomach, thyroid, lymphoproliferative cancers, and carcinoid tumors. Whereas Lambert-Eaton myasthenic syndrome (LEMS) and MG can occur separately with thymoma, and both LEMS and MG have at times been documented together in the same patient, the presence of all three together has not been convincingly shown.

Histopathology
For the purpose of this discussion, we consider thymic epithelial cell neoplasms. Thymic lymphoid malignancy rarely occurs in association with MG. Thymomas constitute approximately 15% of all mediastinal masses. They usually contain a mixture of small lymphocytes and plump ovoid epithelial cells associated with perivascular spaces cuffed by lymphocytes. They are usually well encapsulated by dense calcified plaque. In up to a third of tumors there is variable extension beyond the capsule with deposition of discrete nodules or implants in the pleura, pericardium, and anterior mediastinum; however, there are no true hematogenous or lymphatic metastases. Traditional classifications that distinguished between epithelial and lymphoid types based on the predominant cell type in a pathologic specimen did not accurately predict tumor behavior. Moreover, the cellular composition often differed in adjacent lobules making firm designations difficult. A histologic classification (table) based on the cellular differentiation of thymic medullary or cortical epithelium is prognostically useful in predicting invasiveness, metastatic behavior and the tendency for association with MG. It has been repeatedly validated, even in separate geographic groups where pathogenetic factors may differ. Six categories of thymic epithelial tumors are recognized, including four categories of thymoma: medullary, cortical, predominantly cortical, mixed; and two subgroups of thymic carcinoma: well differentiated thymic carcinoma (WDTC) and high grade carcinomas. Medullary and mixed thymomas are benign tumors with no risk of recurrence, even when capsular invasion is present, and have a low association with MG. Compared to the other tumor types, they seldom require adjuvant therapy after surgical resection. Cortical and predominantly cortical thymomas, which are most often associated with MG, demonstrate intermediate invasiveness and a low but significant risk of late relapse. WDTC are generally invasive and carry a significant risk of relapse with high mortality.

Immunopathogenesis
The origin of MG in association with thymoma is not well understood but epithelial-thymocyte interactions appear to be a prerequisite to the process of thymoma-related autoimmunity. Thymic epithelial cells, present in both normal and abnormal hyperplastic and thymoma glands are the source of thymosin and thymopoiten. They participate in the instruction of immature thymocytes to become more immunocompetent forms and trigger the autoimmune response to native acetylcholine receptor (AChR). Thymosin alpha-1 immunoreactivity is increased in thymoma tissue extracts using a mouse monoclonal antibody (Mab) assay. Myoid cells, the only thymic elements capable of expressing intact AChR, are rarely found in thymomas except in tumor free adjacent residual thymus tissue. In contrast to hyperplastic thymus, thymomas do not express significant levels of AChR-specific RNA. Nonetheless virtually all patients with thymoma have elevated AChR antibody titers. The observed autoantibody response to the AChR may originate in the tumor itself. Non-myoid cells might express both AChR and myogen as suggested by the finding of AChR alpha-subunit and myogen mRNAs in several thymoma specimens from patients with MG when analyzed by polymerase chain reaction immunocytochemistry.

Two findings in thymic epithelial tumors appear to correlate with the occurrence of MG: the expression of an AChR-like epitope in the neoplastic epithelium, and the preservation of thymus-like features in the neoplasms as indicated by the presence of immature thymocytes. CD1⁺ immature lymphocytes are the hallmark of nearly all thymic tumors. The interaction of CD1⁺ cells and thymoma epithelial cells are believed to be important in the selection and expression of tumor-associated AChR epitopes by the thymoma. Epithelial cells that stain positively with Mabs to the medullary and cortical epitopes MR19 and MR3, respectively, are observed in hyperplastic and thymomatous glands, but not in normal thymuses, suggesting a possible common origin for thymic neoplasms. Neoplastic epithelial cells also bind to an AChR-specific Mab 155 which recognizes a highly immunogenic cytoplasmic epitope of the AChR alpha-subunit. The binding of Mab 155 can be correlated with tumor histologic subtypes and is greatest in cortical thymomas and well differentiated thymic carcinomas which exhibit high MG association, intermediate in predominantly cortical thymomas, and virtually negative in medullary and mixed thymoma subtypes.

The role of genetic predisposition in thymomatous MG is still unclear. There are inconsistent reports of the association of HLA class II allelic determinants with some reports of positive correlation with the DQB1*0604 DRB1*1202 and HLA-B8 halplotypes, with other reports negative or inconsistent.

Diagnosis
The clinical diagnosis of MG is made by recognizing the characteristic pattern of weakness in cranial and limb muscles, and confirmed by unequivocal and reproducible improvement with intravenous edrophonium chloride, a decremental response to 3/sec repetitive nerve stimulation, and elevation of the serum AChR antibody titer. An important consideration is whether there is an associated thymoma. Apart from MG, which is often more severe at presentation, symptoms related to the presence of the tumor or even local invasion are surprisingly uncommon. However, an unexplained persistent cough, dysphonia suggesting recurrent laryngeal nerve involvement, and elevation of a hemidiaphgram implicating a phrenic nerve lesion, may all be clues to underlying invasive thymoma. Virtually all patients with thymomatous MG have elevated AChR antibody titers, and their serum should be appropriately analyzed for the presence of AChR antibody activity. Experience suggests that the accuracy of diagnosing associated thymoma is probably better than 95% when striational autoantibody (StrAb) serology and contrast CT of the chest and mediastinum are performed.

The StrAb enzyme immunoassay (EIA) employs a mixture of muscle proteins as antigen and is equivalent in sensitivity and specificity to the indirect immunofluorescence assay. The incidence of StrAb seropositivity increases with age, as does thymoma. They are detected in high titers in 80 to 90% of patients with thymoma and MG and in 25% of patients with thymoma without clinically manifest MG, and in lower titers in 11 to 30% of myasthenic patients without thymoma. The stimulus for production of these antibodies is not well understood. Titin has been proposed as a target of StrAb autoimmunity. Up to 97% of patients' serum with thymomatous MG demonstrate IgG anti-titin autoantibodies. They are restricted to the sera of patients with thymomatous MG and bind to striated elements in medullary myoid cells supporting the hypothesis that titin is a major specificity for IgG StrAbs. It has been suggested that titin autoimmunity results from cross-reactivity of other tumor antigens, or might be a secondary phenomenon that follows its release from skeletal muscle. Components of the sarcoplasmic reticulum may also be relevant antigens in thymomatous MG because up to one-half of thymomatous MG sera demonstrated IgG autoantibodies to the ryanodine receptor.

The radiographic detection of thymoma has been extensively studied. CT was 85% sensitive, 98.7% specific, and 95.8% accurate overall, in the preoperative diagnosis of thymoma. Chest CT is the recommended screening study for thymoma and tumor recurrence in all ages. The radiographic evaluation of thymoma may however be complicated by the fat content of the thymus gland which normally increases with age, and the variability of the size of the gland. Starting at about age 20, cellular elements in the thymus gland gradually decrease in extent and are replaced by fatty infiltration. This so-called involution is complete by age 60, at which time 90% or more of the gland consists of fat. Despite increasing age, microscopic remnants of thymus are always present. Interpretive errors resulting in missed small tumors may occur in patients age 20 years or younger due to partial preservation of adjacent dense thymic parenchyma, and glandular hyperplasia in those age 21 to 45 years. CT scanning was most accurate in still older patients with predominant fatty involution. Magnetic resonance imaging (MRI) does not appear to be superior to CT scanning in the detection of thymomas.

Treatment
The clinician must choose the appropriate sequence and timing of thymectomy, cholinergic and immunosuppressant medication, and adjuvant therapies for the patient with thymomatous MG, sadly without the benefit of clinical trials. The chief reason for thymectomy was to prevent the spread of the tumor. There is now a general consensus that all patients with thymomatous MG should undergo early and total thymectomy with complete removal of the thymoma and adherent structures, to prolong survival, prevent thymoma recurrence, and to induce remission or asymptomatic status. At the Columbia-Presbyterian Medical Center between 1977 and 1985, 65% of patients with non-malignant thymomatous MG were free of myasthenic symptoms when evaluated 6 months to 7 years after maximal thymectomy, including 13% in sustained remission, 6.5% on minimal doses of cholinergic medication, and 45.5% on prednisone or azathioprine therapy alone or in combination. Maximal thymectomy with en-bloc exenteration of the tumor and all thymic tissue is the preferred procedure in patients with thymoma, with inspection of the entire chest cavity for tumor implants including the diaphragms.

The case against trans-cervical thymectomy, limited trans-sternal, and other potentially incomplete procedures in thymomatous MG is based on the observations of incidental thymomas at operation, the later development of a tumor, recurrent thymoma, the possible spread of tumor in the course of an incomplete resection, the overall lower rates of remission or improvement with the more limited resections, residual thymus found at reoperation after earlier transcervical surgery and the subsequent. improvement with trans-sternal exenteration. The prognosis of thymomatous MG is best predicted by stage of the tumor determined intraoperatively and is poorer in patients with incomplete resection than in those with complete resection. Nevertheless, there are still advocates of the transcervical approach. In major centers, the maximal. operation carries a negligible morbidity and mortality in virtually all ages due to technical refinements in anesthesia, surgery, and postoperative care, and the judicious use of preoperative plasmapheresis, intravenous gammaglobulin, and oral immunosuppressive agents to improve serious myasthenia.

There is no definite consensus about several related issues. Should surgery be considered in the extremes of age, in the “elderly”who are more likely to have serious co-morbid illnesses, and in children in whom there is fear of potential acquired immunodeficiency? It appears that the term “elderly” has become increasingly difficult to define, and patients of increasingly advanced age have undergone the maximal operation without difficulty. There were no permanent effects in several children who underwent resection of thymoma and coexisting thymic tissue. Another area of uncertainty is the role of postoperative radiation therapy and adjuvant chemotherapy in thymoma. Although there has been no prospective controlled trial of postoperative adjuvant radiation or chemotherapy in patients with thymoma of different tumor types or degrees of myasthenia, it stands to reason that the long-term prognosis for recurrence, distant spread, and the later development of more serious MG should be improved by postoperative radiation and chemotherapy especially in the more malignant tumor types. For example, WDTC and cortical thymomas, which demonstrate high or intermediate degrees of malignancy, respectively, and are more apt to be considered for adjuvant therapy than medullary or mixed thymomas, which are always encapsulated, show mild invasion through the capsul, and are typically cured surgically.

Controversy also abounds in the choice of chronic immunusuppressive agents in thymomatous MG. Although prednisone is standard and customary therapy for both the thymoma and MG, there is persistent uncertainty as to suggested dosages and regimens, the appropriate duration of therapy before deeming treatment failure or apparent benefit.. There are also potentially serious side effects. The basis of thymoma sensitivity to prednisone is unclear. There are reports of radiologically visible tumors becoming both smaller or larger in the course of prednisone therapy, and of dramatic responses in disseminated thymoma, but there is no evidence to date of corticosteroid receptors on the surface of human thymoma cells to explain the observed sensitivity.

Azathioprine (Imuran) has been increasingly used in the treatment of MG and thymoma, both as an antineoplastic agent for the tumor and to treat the more fulminant MG symptoms and relapses. It has less side effects than prednisone, but limitations to its use include idiosyncratic gastrointestinal effects, serum transaminase enzyme elevations, intercurrent infection, the expected long delay in effectiveness, and the necessity of dosage adjustments because of bone marrow suppression, which requires regular monitoring. We customarily give 2.5 mg/kg total body weight per day of azathioprine, rounding off the daily dose to the nearest 25 mg. The final dose is usually in the range of 150 to 175 mg/day. Most patients respond by the eighth to fifteen week. It is often necessary to begin with plasmapheresis and daily or alternate day prednisone while awaiting the beneficial effects of azathioprine, with slow tapering of prednisone afterwards. Anti-neoplastic agents alone or in combination may be used as adjuvant chemotherapy for malignant thymomas.

Crisis has been a feature of the natural course of thymomatous and non-thymomatous MG over the decades despite our best efforts at successful long-term management. Up to a two-fold increased frequency of crisis was observed in the patients with a thymoma. Whether patients with thymomas MG are truly at increased risk for a crisis is still debatable. Nevertheless, it is still good practice to exercise extreme caution in the care of these patients particularly when progressive myasthenic weakness and oropharyngeal symptoms follow intercurrent infection and medication adjustments, all of which may herald or precede a crisis.

Acknowledgements
The authors have been privileged to work with many outstanding clinicians and researchers at Columbia-Presbyterian Medical Center over many years. In particular, we express sincere gratitude to Lewis P. Rowland MD, Chair of Neurology, for his dedication and leadership in the care of patients with myasthenia gravis.

References
A complete list of references can be found in Neurology, Volume 48, Supplement 5, pgs.S79-S81.