Asian Cardiovasc Thorac Ann 2002;10:150-154
© 2002 Asia Publishing EXchange Pte Ltd
Thymoma Associated With Pure Red-Cell Aplasia: Clinical Features and Prognosis
Tomohiro Murakawa, MD,
Jun Nakajima, MD,
Hajime Sato, MD1,
Makoto Tanaka, MD,
Shinichi Takamoto, MD,
Masashi Fukayama, MD2
Department of Cardiothoracic Surgery
1 Department of Public Health
2 Department of Pathology Faculty of Medicine University of Tokyo Tokyo, Japan
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Tomohiro Murakawa, MD Tel: 81 3 5800 8654 Fax: 81 3 5684 3989 email: murakawa-tky{at}umin.ac.jp Department of Cardiothoracic Surgery, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
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ABSTRACT
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As information on the clinical features and prognosis of thymoma complicated by pure red-cell aplasia is limited, follow-up data on thymoma patients who had a thymectomy between 1954 and 1999 were analyzed retrospectively. Six of 166 cases were complicated by pure red-cell aplasia. In 3 of these, the pure red-cell aplasia appeared after surgical intervention. Remission was observed in 2 patients who underwent extended thymectomy. The other 4 patients subsequently died from pure red-cell aplasia. The outcome in patients with pure red-cell aplasia was poorer than that in the entire group of patients with thymoma and in those with thymoma complicated by myasthenia gravis. The possible onset of pure red-cell aplasia after thymectomy should be kept in mind during follow-up.
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INTRODUCTION
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Thymomas are relatively rare epithelial neoplasms that are known to be associated with autoimmune diseases such as myasthenia gravis (MG) or pure red-cell aplasia (PRCA). Although the clinical features and prognosis of thymomas associated with MG are evident from many clinical studies, information on thymomas complicated by PRCA is limited.1–4 In this study, the clinical features and outcome in patients with thymomas complicated by PRCA were investigated using long-term follow-up data.
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PATIENTS AND METHODS
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Follow-up data were obtained from 166 patients under-going surgical resection of thymoma between 1954 and 1999 at our institute. The follow-up period ranged from 1 month to 363 months, with a median of 67.5 months (mean, 103 ± 97 months). Clinical information including age, sex, associated diseases (MG, PRCA), and outcome were extracted from the medical records. The tumor was confirmed histopathologically as a thymoma in all cases. Thymic carcinoma and other thymic neoplasms were excluded. A retrospective analysis was performed to determine the long-term outcome after surgical resection. Thymomas were classified according to the clinical pathological staging system of Masaoka and colleagues,5 and a histological classification of the resected thymoma was performed according to the criteria proposed by Rosai and Levine,6 based on the morphology of the neoplastic epithelial cells and the degree of lymphocytic infiltration. The diagnosis of PRCA was made by hematologists.
STATISTICAL ANALYSIS
Patient characteristics (age and sex) were compared among groups classified according to the presence of MG and PRCA. Actuarial survival curves were calculated by the Kaplan-Meier method, and the log-rank test was used to compare survival rates between various subgroups.7 Subjects were presumed to enter the study on the date of surgical intervention. To focus on the prognostic effect of autoimmune disease associated with thymoma when conducting survival analyses, the endpoint of death was assumed to be when a patient died from thymoma or thymoma-related autoimmune disease, whereas patients were assumed to leave the study alive if they died from other causes.
To examine the relative importance of various prognostic factors in postoperative survival, a Cox proportional hazards model was built. Potential prognostic factors (age, sex, stage, period [1954 to 1975, 1976 to 1999], completeness of resection, postoperative radiation, mor-phology of the neoplastic cells, degree of lymphocytic infiltration, association with MG, PRCA, or other auto-immune diseases, invasion of the great vessels, pleura, phrenic nerve, pericardium, or lung, and lymph node involvement) were entered and removed with a signifi-cance level of p < 0.05, by either the forward or backward stepwise method. Proportional hazard assumption was examined by plotting the scaled Schoenfeld residuals and the partial Martingale residuals.8 Categorical or ordinal variables were modeled using dummy variables. One-way analysis of variance followed by Fisher':s post-hoc multiple comparison technique and a chi-squared test were also used. Data were analyzed using Stata version 7.0 (Stata Corporation, College Station, TX, USA).
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RESULTS
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Of the 166 patients included in the study, 6 (3.6%) had associated PRCA and 61 (36.7%) had associated MG (Table 1
). Three of the patients with PRCA had a stage I thymoma, 1 patient had a stage III thymoma, and 2 patients had a stage IVa thymoma. No statistical differences were found in the age distribution for all cases, the PRCA group, or the MG group (all cases versus PRCA group: p = 0.7635; all cases versus MG group: p = 0.3466; PRCA group versus MG group: p = 0.5341). However, the proportion of females was significantly higher in the PRCA group (all cases versus PRCA group: p = 0.0361; all cases versus MG group: p = 0.7587; PRCA group versus MG group: p = 0.0563).
The clinical features and outcome of the 6 cases of thymoma complicated by PRCA are presented in Table 2 (cases are numbered according to the date of the surgical procedure). The diagnosis of PRCA was based on the results of bone marrow analysis in 4 cases and on peripheral blood analysis in 2. According to Rosai':s proposed classification, the epithelial component was morphologically classified as spindle-shaped cells in 3 cases, and as round-oval-shaped cells in the other 3. The degree of lymphocytic infiltration was moderate to predominant in all cases, and no predominantly epithelial type of thymoma was found. The PRCA appeared after surgical intervention in 3 patients. In case no. 2, recurrence of thymoma was observed 2 years after the diagnosis of PRCA. The recurrent thymoma was histopathologically classified as stage II spindle-cell thymoma with moderate lymphocytic infiltration. Steroids and other immunosup-pressants, as well as blood transfusions for severe anemia, were used to treat PRCA. In case nos. 4 and 6, PRCA remission was observed after extended thymectomy. However, the other 4 patients died from complications associated with the treatment of PRCA, such as systemic hemochromatosis. Although other autoimmune diseases were observed in 2 patients, these diseases were not considered to have affected the outcome.
Survival rates are shown in Table 3. The outcome in the PRCA group was poorer than that of the entire group of thymoma patients or the MG group (PRCA group versus entire group: p = 0.0006; PRCA group versus MG group: p = 0.0058; MG group versus entire group: p = 0.4728). The outcome in the PRCA group was equal to that in patients with stage III and IV thymomas (stage I versus PRCA group: p = 0.0004; stage II versus PRCA group: p = 0.0002; stage III versus PRCA group: p = 0.0687; stage IV versus PRCA group: p = 0.1828; stage I versus stage II: p = 0.6113; stage I versus stage III: p = 0.0019; stage I versus stage IV: p = 0.0110; stage II versus stage III: p = 0.0137; stage II versus stage IV: p = 0.2888; stage III versus stage IV: p = 0.5706). Cox proportional hazard regression analysis disclosed that a combination of period, stage, MG, and PRCA generally predicted the mortality from thymoma or thymoma-related autoimmune diseases (Table 4). Both MG and PRCA adversely affected patient survival. The hazard ratio for death was 3.282 when the thymoma patients had MG, while the hazard ratio was 21.74 when they had PRCA.
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DISCUSSION
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Thymomas are known to be frequently associated with autoimmune diseases such as MG, PRCA, and hypo-gammaglobulinemia.4,9 Several studies have determined that MG is the most frequent complication (25% to 50%); symptoms of MG were found to improve after thymectomy in most cases (74% to 96%), although sporadic onset of MG after thymectomy was observed in 3.8%.1,2,4 Only 1.6% to 5% of thymoma patients have been reported to have PRCA, and symptoms improved in less than 25% of them.3,4,10,11 The post-thymectomy onset of PRCA has been noted only sporadically.12,13
The findings in this study of MG and PRCA in 36.7% and 3.6% of thymoma patients, respectively, agree with previous reports. The low rate of PRCA makes it difficult to analyze the features and prognosis of PRCA-associated thymomas. However, an important finding was that PRCA occurred after surgical intervention in half of the cases: within 1 year in 2 patients, and 8 years later in another. The possible onset of PRCA after thymectomy should be considered in the follow-up of thymoma patients, even after several years have elapsed. Masaoka and colleagues3 reported that in 17 cases of thymoma associated with PRCA, 75% were classified as stage I; furthermore, the epithelial component of the thymoma was spindle-shaped in all cases, and 47% of the thymomas showed scant lymphocytic infiltration. In contrast, our study found that the epithelial component was morphologically classified as spindle-shaped cells in 3 cases and as round-oval-shaped cells in the other 3. The degree of lymphocytic infiltration was moderate to predominant in all cases, and no predominantly epithelial thymomas were found. This discrepancy may be due to the small number of cases in our study.
Although some hypotheses regarding the pathogenesis and association of thymomas and PRCA are well accepted, the precise mechanism of the onset of PRCA remains unclear.3,14–18 Thymomas might produce suppressor T cells that inhibit erythroid colony formation through the inhibition of B cell differentiation. Thymus and erythro-blastic cells might share a common antigen. The PRCA might be induced by T cell clonal disorder. The onset of PRCA might also arise from the suppression of hema-topoiesis by an autoimmune mechanism of the thymus in which autoantibodies are formed against erythroblast and/or erythropoietin. Both thymomas and PRCA might occur via a common causative agent such as parvovirus-like viral infection. However, no support for any of these hypotheses was found in the 6 cases in this series, except for an elevated CD8+:CD4+ ratio in case no. 6. No clonal disorders of T cells or viral infections were detected in any of the 6 cases.
Thymectomy was found to be less effective in patients with PRCA than in those with MG.3,4,10 This is supported by the results of this study; only 2 of the 6 patients with PRCA entered remission. Interestingly, both had under-gone total resection of the thymus and thymoma, with extended thymectomy, whereas the other 4 patients did not receive an extended thymectomy. Because PRCA itself, with or without an associated thymoma, tends to be refractory and can be lethal, extended thymectomy might offer some hope of treatment. We recently experienced a case in which a patient underwent extended thymectomy for thymoma associated with stiff-man syndrome, a rare autoimmune disease. The symptoms of stiff-man syndrome disappeared postoperatively. Because the presence of thymic tissue and/or thymoma may have some correlation with the onset of PRCA, and extended or maximal thymectomy is known to be essential for complete removal of all thymic tissue including possible ectopic thymus in the surrounding tissue, extended or maximal thymectomy may affect the course of PRCA.3,14–20 Although the mechanism of onset of autoimmune diseases associated with thymoma, and the manner in which extended or maximal thymectomy affects autoimmune diseases remain unclear, extended or maximal thymectomy might be curative in patients with thymomas associated with a spectrum of autoimmune diseases including PRCA.1,4,19
In this study, patients with thymomas complicated by PRCA had a poor outcome that was similar to that of advanced-stage thymomas. Recently, a patient with thymoma and PRCA was successfully treated using a combination of octreotide and prednisone.21 As adequate control of PRCA is essential to improve the prognosis, clarifying the mechanism of PRCA and developing new therapeutic strategies are important objectives. Because the PRCA remission rate after surgical intervention is relatively low, and PRCA is an important factor influencing the outcome, the possible onset of PRCA after thymectomy should be kept in mind during follow-up.
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ABSTRACT
INTRODUCTION
