10, NO. 1 MARCH 1990

Thymoma: Diagnosis and Management

The relationship between thymoma and myas- rese~tion.~.~~'"umor recurs after operation in thenia gravis (MG) was discovered serendipitously 19%.4 Most thymomas spread to adjacent strucwhen a 21-year-old woman undergoing thymec- tures first in the mediastinum, then pleura and tomy for thymoma achieved a long-term remission hilum. Extrathoracic metastases occur in 6.6%,73'7 in MG.'.* Since then, largs series have reported the usually to the liver and less often to kidney, extraincidence of MG in patients with thymoma to be 30 thoracic lymph nodes, and bone."I6-l7Brain metasto 59%, whereas the incidence of the tumor in pa- tases have been reported but are rare.17 Histologic Men and women criteria of malignancy are believed unreliable by tients with MG is 10 to . ~ mean age of all patients most. Recent studies have attempted to define maare equally a f f e ~ t e dThe with thymoma is 52 years; those who also have MG lignancy in terms of nuclear size and pleomorphare younger.7The discovery of the tumor usually ism,I8 but at the present time it is more useful to follows but may precede the diagnosis of MG, define malignancy in terms of capsular invasion, which, indeed, may appear up to 22 years after the spread to surrounding structures, tendency to re.'~ may be and distant m e t a ~ t a s e s . ~Tumors apparently successful removal of a t h y m ~ m a . ~ . ' . cur, ~ The causal basis of the association continues to be staged according to their degree of invasion.l"t is unclear; cells from thymic neoplasms bear acetyl- quite clear that mortality and morbidity are related choline receptor-like determinants,'' and thymoma to the size (which varies from microscopic to mascells may be responsible for stimulation of anti- sive) when first seen, the degree of involvement of body-producing B-cell clones within the thymus or adjacent structures, and the tendency to recur afel~ewhere.ll,~~ This being the case, it is surprising ter treatment.".".'"n addition, in the past the octhat so many different histologic types of thymic currence of MG has shortened survival and added , ' ~ , ' ~ , ~this ~ is disputed neoplasms are associated with MG, including pre- to the m ~ r b i d i t ~ , ~ although now that more effective agents are available for dominantly epithelial, lymphoid, mixed, and spinis more closely related to dle, but also including thymolipoma, thymic carci- treatment.4~7~"~2"nvasion noma, thymic carcinoid, and other tumors. survival than is the presence of MG; the survival at Although tumors with predominantly lymphocytic 15 years was 12.5% in the group of thymomas with . ~ occurs from carcells are most common, it is probable that thymo- invasion, but 47% ~ i t h o u tDeath mas with epithelial cell predominance are more diac tamponade and other cardiorespiratory comlikely to be associated with MG;3,6spindle cell thy- plication~.~ momas are least likely ass~ciated.~.%lltumor types may be associated with other diseases besides DIAGNOSIS MG,7313.14 90% are presumably autoimmune, and about 20% harbor a nonthymic n e o p l a ~ m . ~ . l T h e Although thymomas may present with sympmalignant potential of a thymoma usually is defined by the degree of spread of the tumor when toms related to the tumor, most are discovered acfirst resected and its tendency to recur locally, in- cidentally on imaging procedures or because the vade adjacent structures, o r metastasize following patient is being investigated for MG. The average

*Associate Professor of Neurology, Director, EMG Laboratory, Medical College o f Georgia, Augusta, Georgia 'Professor and Chairman, Department of Neurology, Medical College of Georgia, Augusta, Georgia Reprint requests: Dr. Rivner, EMG Laboratory, Medical College of Georgia, Augusta, GA 30912 Copyright O 1990 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 10016. All rights reserved.

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Michael H . Rivner, M.D.," and Thomas R. Swift, M.D.'



age at diagnosis is 50 years; when MG is present, ical improvement in MG, if present, and variable the average age is 37 y e a r s . ~ u m o r smay enlarge fall in antibody titers occur after thymectomy.'6.'7 in the anterior mediastinum, compressing and in- In one series 64% of patients with both conditions vading blood vessels or bronchi; grow into the neck were symptom-free at a mean duration of 40 months or sternum or into the pleural spaces, causing after thymect~my.'~ However, the response rate of pleural effusions; or invade the pericardium and MG to thymectomy in patients with thymoma is heart. Superior vena caval obstruction is frequent. lower than in those w i t h o ~ t . * " ~ T htumor, e its capGross invasion has occurred in 36% of cases by the sule, anterior mediastinal fat, tails leading to the time the patients are first seen.3 neck, and related tissues in the neck should be reIn patients with MG the imaging procedure ol' moved together in the so-called maximal thymecchoice is computed tomography of the chest (CT); tomy described by Jaretzki and W ~ l f f . 'The ~ resecmagnetic resonance imaging of the chest adds little tion should be carried laterally to the reflection of to diagnostic accuracy. While plain radiographs of the pleura, care being taken not to injure the the chest detect some tumors, many, particularly phrenic nerves. The structures leading to the perismaller ones, are missed. Every patient with MG cardium and the pericardium itself, if adherent, should have a chest CT to look for thymic enlarge- should be removed, and a search made for addiment: most enlarged thymuses on such studies rep- tional tumor deeper in the mediastinum, in the resent thymoma. It is possible for a thymoma to be pleural spaces, or attached to the diaphragmatic present in spite of a negative scan.7 This is partic- pleura. One-third of all thymomas are invasive at ularly true for recurrent tumor. CT with intrave- surgery."~ is unlikely that resection of any tumor nous contrast medium is preferred to demonstrate that has invaded through the capsule can ever be the relationship of the thymoma to the vascular complete. Reoperation may be necessary for local structures, to define its own degree of vascularity, regrowth after the initial ~ p e r a t i o n but , ~ has also and to guide the surgeon in removing a large tu- been done when no tumor was radiologically apmor that may involve mediastinal structures. parent in patients with MG in whom the initial reIt is our practice to obtain antistriational anti- section was followed by improvement and later body determinations in every MG patient. As first worsening of symptoms. In these cases a sudden pointed out by Strauss et al," when MG is present, surge in antistriational and in some cases antiresuch antibodies have a high correlatiorl with thy- ceptor antibody titers signifies regrowth of tumor. moma: in patients with tumor alone, 24% have an- In virtually every case reported, including our own tibodies. When both conditions are present, 80 to series, when a second operation has been per90% have antib~dies;'~ in MG without tumor, 38% formed for worsening of MG, recurrent tumor has have antibodie~.~~.*"hereis a correlation between been found, even when C T chest scans were negIn some reported cases furthe titer of antistriational antibody and the likeli- ative or incon~lusive.~~ ther improvement in MG has followed reoperation hood of a thymoma being pre~ent.'~ Likewise, titers are reported to fall after treatment with pred- with removal of additional tumor, but this does not nisone and a~athioprine;'"'~they may be used to occur invariably. Intracapsular and transcervical predict r e ~ u r r e n c e Such . ~ ~ antibodies react with a procedures remove less tumor and produce fewer variety of subcellular determinants, many being remissions in MG. contractile proteins, and may bind to A, Z, or I band regions, or several areas of the s a r ~ o m e r e . ~ ~ Such antibodies are not invariably correlated with the presence of MG, and it is unclear what role RADIATION THERAPY they play in the pathogenesis ofthat disease. They may be involved in the simultaneous occurrence of Although no adequate prospective controlled MG and myositis, or be responsible for the occur- trial of radiation therapy has been performed in rence of fibrillations seen on electrornyography in patients with thymoma, it is clear from retrospecpatients with MG.15 In our experience the appear- tive studies and individual case reports that radiaance of thymic enlargement on CT chest scan and tion therapy given after removal causes regression a high titer of antistriational antibody makes the and improves the outcome by preventing recurdiagnosis of thymoma virtually certain. r e ~ i c e . ~ ~It- "may also increase the percentage of patients with MG and resected thymoma who eventually achieve remission. All patients with a tumor, SURGICAL CONSIDERATIONS whether invasive or not, should receive postoperative radiation therapy to a total dose of 32.0 to The initial management of virtually all thy- 60.0 Gy; above 45.0 Gy the ports should be angled momas is surgical. In the majority of patients, clin- to avoid irradiating the spinal cord." For massive,

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unresectable thymomas, radiation therapy, radioactive implants, or both have been used. The ef-ficacy of such treatment is uncertain.

PHARMACOLOGIC THERAPY To date, there have been no prospective controlled trials of any pharmacologic agents in the management of thymoma. Virtually all authors of papers reporting the effect of drugs have stated that such a study is difficult or impossible to do because of the rarity of such tumors. However, in centers for the treatment of MG such tumors are not rare, and fairly large series of such tumors have been reported even from single institution^.^^*'.'^ A cooperative prospective controlled trial comparing drugs known to have some effect in the management of thymoma is feasible and needed. At the present time, small uncontrolled series and case reports are used to guide therapy; there is still no consensus about the relative value of the commonly used agents, which include corticosteroids, immunosuppressants, and antineoplastic drugs. Despite these reservations, it is clear both from the literature and from our own experience that the use of these agents results in the amelioration of tumor symptoms, reduction in tumor size, arrest of tumor progression, and improvement of the associated MG. Prednisone is the most commonly used drug in the treatment of thymoma, whether used alone or in combination chemotherapy with azathioprine or antineoplastic agents. It is very clear from case reports as well as our own experience that radiologically visible tumor becomes smaller or disappears with the use of p r e d n i ~ o n e ; ~ ~such . ~ ' ~ "tumor regression may persist for a long time but histologically is not complete because the tumor is observed to regrow when prednisone is discontinued. There have been reports of tumor regrowth even when prednisone has been continued, indicating that the tumor cells are no longer sensitive to the agent. The basis of the prednisone sensitivity of these tumors is unclear; many of them contain lymphoid cells, which are in themselves sensitive to prednisone. They have not yet been demonstrated to possess corticosteroid receptors on their surface membranes, such as have been demonstrated in radiation-induced mouse t h y m ~ m a . ~T' h e indications for the use of prednisone, the suggested dosage, and the duration of therapy are all unknown but could be delineated in controlled trials. At present, it is our practice to give prednisone to all patients with recurrent thymoma initially in high dosage (1 to 2 mglkg), and after initial response to reduce the dosage depending on the size of the tu-

mor determined radiologically and the response of the MG. If the tumor enlarges or MG worsens as the prednisone is reduced, it should be reinstituted at higher dosage; or, if this is not feasible, other agents should be added. There is little experience in the treatment of thymoma with azathioprine other than anecdotal reports (see later). Many patients receiving this drug have been on concomitant corticosteroids or have received radiation therapy, making the improvement difficult to relate to azathioprine. Azathioprine has the advantage over corticosteroids that fewer side effects occur. Its major toxicity is suppression of the white blood cell count, and occasionally red blood cells and platelets. Patients must have monthly blood counts and the dose must be reduced when suppression occurs. Megaloblastic changes in red blood cells are almost invariable and do not in themselves require a dosage reduction; indeed, if such changes are not present, one must question the efficacy of treatment. Azathioprine may also produce hepatotoxicity shown by an increase in alkaline phosphatase, serum glutamic oxaloacetic transaminase (SGO'T), gamma glutamyl transferase, and bilirubin. This also requires that the dose be lowered or discontinued. Another disadvantage of azathioprine is the duration from onset of treatment to clinical effectiveness, which is in terms of months rather than the days to weeks seen with corticosteroid drugs. A further risk with azathioprine is the concern about induction of various neoplasms. T h e patient should be warned about this potential complication. It is not clear that neuromuscular patients receiving this drug actually do have an increased risk of cancer, as d o transplant patients receiving azathioprine for control of rejection, but it is likely that they do. In our series we have had one patient with MG receiving azathioprine who developed leukemia. Clearly, a controlled trial of treatment of thymoma with azathioprine is warranted. Antineoplastic agents are reportedly beneficial in certain patients with thymoma but are not useful in others. The major antineoplastic drugs used include platinum-containing a g e n t ~ ~ Oand - ~ ~doxor ~ b i c i n , ~although ' other drugs have been used, including c y c l o p h o ~ p h a r n i d e ,d~a~c~t i~n~~ m y c i n , ~ ~ T h e responses are v i n c r i ~ t i n e , ~and ~ . ~ other^.^'.^' "~~ difficult to evaluate because different drugs and regimens are used. The series usually are small, and some of the patients are concomitantly treated with predni~one,~' which has known effects of thymoma regression. Since most of these agents are used in combination chemotherapy protocols, it is unclear about their individual efficacy in thymoma, but in combination they have been reported to produce radiographically documented 85

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tumor regression, which may be striking, and improvement in MG. Because safer agents control thymoma and because of their toxicity alone or in combination, it seems prudent to reserve the use of these agents to patients who no longer respond to corticosteroids or azathioprine and for whom further radiation therapy and surgery are not options.

MEDICAL COLLEGE OF GEORGIA EXPERIENCE Because our experience differs somewhat from what is in the literature, we include some information from our series. Of 77 consecutive patients who underwent thymectomy, 21 (27%) had thymoma. Ten had epithelioid, three had lymphoid,


V O L U M E 10, NUMBER 1 MARCH 1990

and four had mixed tumors consisting of both epithelioid and lymphoid tissue; two had thymic carcinoma and one had rlodular thymoma. Another tumor was clearly invasive radiologically, but the patient refused surgery. In the thymoma group, 13 presented with symptoms of a neuromuscular transn~issiondisorder. Of the eight who did not, five later developed symptoms of MG. Acetylcholine receptor antibodies were positive in 10 of 13 patients with thymoma. Antistriational muscle antibodies were positive in only 7 of 12 patients tested. This is a smaller percentage than usually reported. Repetitive stimulation studies were abnormal in 13 of 15 patients studied. Chest CT was abnormal in 14 of 15 patients with thymoma. Often chest CT can be useful in distinguishing malignant from benign neoplasms. Figure 1 shows four representative scans.

Figure 1. Four chest CT scans are shown. In each case a thymoma is labeled with an arrow. A: Small thymoma that did not invade the pericardium. B: Large thymoma that invaded the pericardium. In addition, a small pulmonary nodule was seen on another CT cut (not shown). C : Large thymoma that invaded the pericardium. Pleural implants are present (second arrow). D: Enlarged subcarinal lymph node. Biopsy showed thymic carcinoma.

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Thymic involution was seen in 15 patients. Their average age was 46 years and all presented with symptoms of MG. Acetylcholine receptor antibodies were present in 10 of 15 patients and antistriational muscle antibodies were detected in 4 of 14 patients. The clinical response to thymectomy was less favorable in this group with one patient requiring only anticholinesterase medication, four patients in complete remission and ten patients requiring immunosuppressive medication.

REFERENCES 1. Blalock A, Mason MF, Morgan HJ, et al. Myasthenia gravis and tumors of the thymic region: report of a case in which the turnor was removed. Ann Surg 1939;110: 544-59 2. Keynes G. T h e history of myasthenia gravis. Med Hist 1961;5:313-26 3. Bernatz PE, Khonsari S, Harrison EG, Taylor WF. Thymoma: factors influencing prognosis. Surg Clin North Am 1973;53:885-92 1. Monden Y, Uyama T, Taniki T, et al. T h e characteristics of thymoma with myasthenia gravis: a 28-year experience. J Surg Oncol 1988;38: 151-4 5. Namba 'I', Bruriner N, Groh D. Myasthenia gravis in patients with thymoma, with particular reference to onset after thymectomy. Medicine (Baltimore) 1978;57:411 6. Verley J , Hollmarin K. Thymoma: a comparative study of clinical stages. Histologic features and survival in 200 cases. Cancer 1985;55:1074-86 7. Lewis JE, Wick MR, Scheithauer RW, et al. Thymoma: a clinicopathologic review. Cancer 1987;60:272743 8. Kimura J , Van Allen MW. Post-thymectomy myasthenia gravis. Neurology (Minneap.) 1967; 17:4 13-20 9. Nan~baT, Brunner NG, Grob D. Idiopathic giant cell polymyositis. Arch Neurol 1974;3 1:27-30 10. Kirchrier T, Tzartos S, Hoppe k', et al. Acetylcholine receptor epitopes in tumor-free thymuses and thymic epithelial tumours of myasthenia gravis patients a n d nonmyasthcnic controls. In deBaets M , ed: Myasthenia Gravis: Proceedings of the First European Meeting o n Myasthenia Gravis, Basel: S. Karger, 1988 11. Heidenreich F, Vincent A, Willcox N, Newsome-Davis J . Antiacetylcholinc receptor antibody specificities in serum and in thymic cell culture supernatants from myasthenia gravis patients. Neurology (Minneap) 1988;38:1784-8 12. F u j i Y, Monden Y, Nakahara K, et al. Antibody to acetylcholine receptor in myasthenia gravis: production by lymphocytes from thymus to thymoma. Neurology (Cleve) 1984;34: 1 182-6 13. Souadjian JV, Enriquez P, Silverstein MN, Pepin JM. T h e spectrum of diseases associated with thymoma. Arch Intern Med 1974;134:374-9 14. Rosenow EC, Hurley BT. Disorders of the thymus: a review. Arch Intern Med 1984;144:763-70 15. Witt NJ, Bolton CF. Neuromuscular disorders and thymoma. Muscle Nerve 1988; 11 :398-405 16. Lattes R. Thymoma and other tumors of the thymus: a n analysis of 107 cases. Cancer 1962; 15: 1224-60 17. Nickels J , Franssila K. Thymoma metastasizing to extrathoracic sites. Acta Pathol Microbial Scand 1976;84: 331-4 18. Nornori H , Horinourhi H , Kaseda S, et al. Evaluation of the malignant grade of thyrnoma by morphometric analysis. Cancer 1988;61:982-8 19. Legg MA, Brady W-1. Pathology and clinical behavior of thymomas: a survey of 5 1 cases. Cancer 1965; 18: 113 144

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In the first (A), an anterior mediastinal mass is seen, which is indistinguishable from that seen with thymic hyperplasia. In the second (B), the very large anterior mcdiastinal mass is clearly a thymoma. In the third (C), the anterior mediastinal mass is associated with pleural implants. This is clearly a malignant thymoma. Thc final C T (D) is an example of a subcarinal lymph node that was proved to be a thymic carcinoma. In the 15 cases of malignant thymoma, six had evidence of local invasion and nine showed metastatic implants at initial evaluation. The pleura and pericardium were the most frequent sites of direct tumor spread. Less common sites of local tumor invasion were the vena cava, trachea, and esophagus. The lung was the most common site for metastatic spread, followed by the liver, lymph nodes, bone, and spinal canal. Our patients with malignant thymoma were usually treated with a combination of both immunosuppressants for MG and chemotherapy and radiation therapy. Radiation therapy was used in ten patients, in three cases alone, one combined with immunosuppressive medication and in the remaining cases combined with both immunosuppressive medication and chemotherapy. In five cases chemotherapy with cisplatin or other solid tumor agents was used. In all but one case this was combined with radiation therapy. Seven patients with malignant thymoma had worsening of MG despite therapy, four improved but remained on immunosuppressive medication, and two patients improved, ultimately requiring no medication. In one case, azathioprine suppressed tumor growth for several years; the tumor increased in size 3 months after it was discontinued. Seven patients with malignant thymoma died. The prognosis in the benign group was more favorable: one patient died because of postoperative complications, two improved on medication, and one improved without medication. The average age of patients having benign thymic neoplasms was 52 years, whereas that of patients with malignant neoplasms was 44 years. In contrast, ofthe 52 patients undergoing thymectorriy for myasthenia gravis who did not have thymoma, 34 had follicular hyperplasia. The average age of' the fbllicular hyperplasia group was 24, and all were operatctl on for myasthenia gravis. Twenty-eight of the 34 patients had acetylcholine receptor antibodies and 4 of 23 patients had antistriational muscle antibodies. Postoperatively, ten patients improved to the point that they were asymptomatic off immunosuppressive medications, six of them achieving complete remission. Clinical improvement was seen in 15 patients but they required immunosuppressive therapy. One patient remained unchanged after surgery.

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Thymoma: diagnosis and management.

SEMINARS IN NEUROLOGY-VOLUME 10, NO. 1 MARCH 1990 Thymoma: Diagnosis and Management The relationship between thymoma and myas- rese~tion.~.~~'"umor...
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