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Regression of invasive thymoma following corticosteroid therapy
The Netherlands Journal of Medicine 58 (2001) 181–184
Brief report
Regression of invasive thymoma following corticosteroid therapy A. Termeer a , *, F.J. Visser a , M. Mravunac b a
Department of Pulmonary Diseases, Canisius-Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ Nijmegen, The Netherlands b Department of Pathology, Canisius-Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ Nijmegen, The Netherlands Received 28 August 2000; received in revised form 21 December 2000; accepted 16 January 2001
Abstract A case of invasive thymoma is presented showing tumour regression after palliative treatment with prednisone. Moderate doses of prednisone resulted in a longtime palliation via remarkable anti-tumour effect. The literature of corticosteroid responses of thymomas is reviewed. 2001 Elsevier Science B.V. All rights reserved. Keywords: Thymoma; Corticosteroids
Introduction Thymoma is the most frequent primary tumour of the anterosuperior mediastinum and is defined as a tumour arising from thymic epithelial cells. Malignant thymoma is defined by invasive characteristics of the tumour to adjacent structures and organs, and the distinction between benign and malignant cannot be made on histologic criteria because the vast majority of locally invasive or widely metastatic thymomas appear to be cytologically benign. We report a case of slowly progressive locally advanced irresectable thymoma, not suitable for chemoradiotherapy, showing a dramatic response on palliative corticosteroid treatment in the preterminal stage of the disease. Case report A 38-year-old Caucasian male non-smoker pre*Corresponding author. Fax: 1 31-124-365-8978.
sented in November 1994 with a more than 6 month history of progressive right-sided chest pain, malaise, 9 kg weight loss and abnormal chest X-ray results. His medical history was unremarkable except for injury to his right arm and lumbar spine after a fall from a height of 6 m 3 years earlier. At that time the supine chest X-ray was in retrospect already clearly abnormal regarding the right heart border and axillary pleura. Physical examination showed dullness on percussion, diminished breath sounds and a pleural friction rub at many locations on the right hemithorax. There were no clinical or electromyographic signs of myastenia gravis. Blood chemistry was normal except for moderate reactive leucocytosis, and antibodies to acetylcholine receptors were positive. Chest CT confirmed a moderate amount of pleural fluid, bulky pleural masses encasing the whole lung, and a pleuro-mediastinal mass at the right heart border with a maximum diameter of 20 cm. At thoracoscopy diffuse and gross tumourous lesions on the parietal and visceral pleura were seen. Biopsies were taken from the tumour. Histologic
0300-2977 / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S0300-2977( 01 )00090-0
182
A. Termeer et al. / Regression of invasive thymoma following corticosteroid therapy
examination revealed well differentiated, epithelialrich thymoma with preserved lobular architecture, presence of dual cell population and bland appearance of the polygonal epithelial cells, which lacked overt cytological features of malignancy. Immunohistological study showed uniform cytoplasmatic reactivity for cytokeratin and CEA in epithelial cells. The lymphocytes were CD3 reactive. Because of widespread pleural dissemination surgery, radiotherapy and chemotherapy were witheld. Talc poudrage of the pleural space was performed. Symptomatic treatment consisted of nonsteroidal analgesics. The patient remained in reasonable stable condition because tumour progression was very slow, but opiates had to be prescribed at the end of 1997. In July 1998 (Fig. 1) the diffuse right sided pain in chest, upper abdomen and the
back increased in spite of large doses of morphine sulphate orally, and the suggested tumour invasion of the liver and a large portion of the dorsal chest wall on CT was confirmed by ultrasonography. Morphine was administered via epidural catheter, and in October a right-sided chordotomia was performed, that was partially successful. In December 1998, the condition of the patient deteriorated further and he was believed to be in the preterminal stage of his disease. At that time prednisone 30 mg once daily was prescribed with strictly palliative intentions. Six weeks later his condition had greatly improved, pain had decreased markedly, and the chest X-ray showed dramatic regression of the tumour volume, with clearing of the right lung fields (Fig. 2). The epidural catheter has been removed and the patient is in good general condition
Fig. 1. Large tumorous pleural lesions and mass at the right heart border.
The Netherlands Journal of Medicine 2001;58:181 – 184
A. Termeer et al. / Regression of invasive thymoma following corticosteroid therapy
183
Fig. 2. Dramatic response after moderate dose corticosteroid therapy.
and without signs of tumour progression 20 months later. The daily dose of prednisone has been tapered off to 15 mg.
Discussion The response of the thymoma in our patient on steroid therapy was dramatic in multiple ways. Firstly, the bulky tumour decreased in size very impressively, as shown on the CT images. Secondly, symptoms and performance status improved at a time that the patient was supposed to be in a preterminal phase of his disease, receiving large doses of opiates. Surgery is the most important treatment modality for thymoma and there is a role for radiotherapy, while several cisplatin-containing chemotherapy reg-
imens with high response rates are available. At first presentation in 1994, 4 years before the start of corticosteroid therapy, resection nor debulking of the tumour was thought to be feasible by the thoracic surgeon, and also radiotherapy or chemotherapy were not believed to be useful because of the very large and regionally disseminated volume and the slow progression of the tumour. Furthermore, the patient declined palliative platinum-based chemotherapy, and consultation at a tertiary reference centre did not alter his doctor’s or his own opinion. The corticosteroids were not intentionally started as anti-tumour therapy, but for palliative effect in the preterminal stage of disease. For this purpose moderate doses of prednisone (30 mg) were prescribed and tapering to a dose of 15 mg did not lead to tumour progression. This moderate dose appeared to be
The Netherlands Journal of Medicine 2001;58:181 – 184
184
A. Termeer et al. / Regression of invasive thymoma following corticosteroid therapy
remarkably effective compared to the higher doses of prednisone (40–100 mg) used in similar cases in the literature [3–7]. Also the duration of remission in our case seems longer than would be expected from similar cases with locally extensive or metastatic disease reported in the literature. Our case is exceptional just for natural history, not having been treated with any conventional therapeutic modality whatsoever, showing very slow progression and more than 5 year survival from time of diagnosis (and in retrospect more than 8 years). Since the first description of regression of a thymoma following administration of adrenocorticotropic hormone in 1952 by Sofer et al. [1] there has been a relatively small number of reports describing regression of thymomas and their metastases on corticosteroid therapy, mostly after failure on combined radiochemotherapy and surgery and regardless of co-existence of myasthenia gravis or other associated disorders. In 1977, Kodama et al. [2] reported a dramatic response of post-thymectomy myasthenia gravis with multiple metastatic lung nodules to corticosteroids. Corticosteroids were effective in 11 of 13 thymoma cases reported by Eddie and Levene in 1986 [3]. Almog et al. [4] described a patient with malignant lymphoepithelial thymoma treated with steroids because of an allergic reaction to angiografin that occurred at angiography and observed a temporally decrease to one-third of the original tumour size, stipulating that treatment of metastases of thymoma with steroids should be kept in mind as an option when more conventional therapeutic methods fail. Thymoma-associated neutropenia has been successfully treated with corticosteroids plus azathioprine and a case of non-surgical regression of thymoma treated for this intention has been reported [5]. In their review in 1992, Kirkove et al. [6] included five cases of complete response on corticosteroids as single-drug treatment, usually after failure of conventional therapy. In 1994 Shishido et al. [7] described a patient with malignant thymoma in whom the initial manifestation was pericarditis, and cardiac tamponade was relieved by corticosteroid therapy. The most recent reference found in the literature regarding the topic of regression of thymoma following monotherapy with steroids is to be found in 1998. In a reply to a letter to the editor
by Weissberg [8] regarding the article by Kodama et al., speculations are made about the mechanism of action, which still is unknown. Corticosteroids are able to deplete the lymphocyte population in the thymus. Complete responses achieved in mixed thymomas suggest that steroids are active on the epithelial component of the tumour as well. Bearing in mind the 1:5 ratio of lymphocytic versus epithelial composition of the thymoma in our patient, the dramatic response cannot solely be explained by depletion of lymphocytes. The pathologic features (e.g. predominance of lymphocytes) indeed do not seem to predict the response to corticosteroids [8]. We believe that steroid therapy is a good option in all cases of malignant thymoma, regardless of the histopathologic findings, when conventional therapies fail or are not suitable for the patient. Moderate doses may be sufficient for longtime palliation. Furthermore, corticosteroids might be used as ‘induction’ therapy for ‘irresectable’ thymoma, but this suggestion by the authors could not be found in recent literature and still has to be proven useful.
References [1] Sofer LF, Gabrilove J, Wolff BS. Effect of ACTH on thymic masses. J Clin Endocrinol Metab 1952;12:690–6. [2] Kodama K, Doi O, Higashiyama M, Yokouchi H, Yasuda T, Funai H. Dramatic response of postthymectomy myasthenia gravis with multiple lung nodules to corticosteroids. Ann Thorac Surg 1977;64:555–7. [3] Eddie HU, Levene J. Chemotherapy of malignant thymoma. Cancer 1986;57:1101–4. [4] Almog C, Pik A, Weissberg D, Herczeg E. Regression of malignant thymoma with metastases after treatment with adrenocortical steroids. Isr J Med Sci 1978;14:476–80. [5] Crawford WW, Yusin JS, Klaustermeyer WB. Nonsurgical regression of thymoma following corticosteroid / azathioprine therapy. Ann Allergy 1999;83:13–6. [6] Kirkove C, Berghmans J, Noel H, Van de Merckt J. Dramatic response of recurrent invasive thymoma to high doses of corticosteroids. Clin Oncol 1992;4:64–6. [7] Shishido M, Yano K, Ichiki H, Yano M. Pericarditis as initial manifestation of malignant thymoma. Chest 1994;106:313– 4. [8] Kodama K, Higashiyama M, Yokouchi H, Takami K, Funai H. Steroids for pulmonary metastases of thymoma. Ann Thorac Surg 1998;65:1197–8.
The Netherlands Journal of Medicine 2001;58:181 – 184
Brief report
Regression of invasive thymoma following corticosteroid therapy A. Termeer a , *, F.J. Visser a , M. Mravunac b a
Department of Pulmonary Diseases, Canisius-Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ Nijmegen, The Netherlands b Department of Pathology, Canisius-Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ Nijmegen, The Netherlands Received 28 August 2000; received in revised form 21 December 2000; accepted 16 January 2001
Abstract A case of invasive thymoma is presented showing tumour regression after palliative treatment with prednisone. Moderate doses of prednisone resulted in a longtime palliation via remarkable anti-tumour effect. The literature of corticosteroid responses of thymomas is reviewed. 2001 Elsevier Science B.V. All rights reserved. Keywords: Thymoma; Corticosteroids
Introduction Thymoma is the most frequent primary tumour of the anterosuperior mediastinum and is defined as a tumour arising from thymic epithelial cells. Malignant thymoma is defined by invasive characteristics of the tumour to adjacent structures and organs, and the distinction between benign and malignant cannot be made on histologic criteria because the vast majority of locally invasive or widely metastatic thymomas appear to be cytologically benign. We report a case of slowly progressive locally advanced irresectable thymoma, not suitable for chemoradiotherapy, showing a dramatic response on palliative corticosteroid treatment in the preterminal stage of the disease. Case report A 38-year-old Caucasian male non-smoker pre*Corresponding author. Fax: 1 31-124-365-8978.
sented in November 1994 with a more than 6 month history of progressive right-sided chest pain, malaise, 9 kg weight loss and abnormal chest X-ray results. His medical history was unremarkable except for injury to his right arm and lumbar spine after a fall from a height of 6 m 3 years earlier. At that time the supine chest X-ray was in retrospect already clearly abnormal regarding the right heart border and axillary pleura. Physical examination showed dullness on percussion, diminished breath sounds and a pleural friction rub at many locations on the right hemithorax. There were no clinical or electromyographic signs of myastenia gravis. Blood chemistry was normal except for moderate reactive leucocytosis, and antibodies to acetylcholine receptors were positive. Chest CT confirmed a moderate amount of pleural fluid, bulky pleural masses encasing the whole lung, and a pleuro-mediastinal mass at the right heart border with a maximum diameter of 20 cm. At thoracoscopy diffuse and gross tumourous lesions on the parietal and visceral pleura were seen. Biopsies were taken from the tumour. Histologic
0300-2977 / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S0300-2977( 01 )00090-0
182
A. Termeer et al. / Regression of invasive thymoma following corticosteroid therapy
examination revealed well differentiated, epithelialrich thymoma with preserved lobular architecture, presence of dual cell population and bland appearance of the polygonal epithelial cells, which lacked overt cytological features of malignancy. Immunohistological study showed uniform cytoplasmatic reactivity for cytokeratin and CEA in epithelial cells. The lymphocytes were CD3 reactive. Because of widespread pleural dissemination surgery, radiotherapy and chemotherapy were witheld. Talc poudrage of the pleural space was performed. Symptomatic treatment consisted of nonsteroidal analgesics. The patient remained in reasonable stable condition because tumour progression was very slow, but opiates had to be prescribed at the end of 1997. In July 1998 (Fig. 1) the diffuse right sided pain in chest, upper abdomen and the
back increased in spite of large doses of morphine sulphate orally, and the suggested tumour invasion of the liver and a large portion of the dorsal chest wall on CT was confirmed by ultrasonography. Morphine was administered via epidural catheter, and in October a right-sided chordotomia was performed, that was partially successful. In December 1998, the condition of the patient deteriorated further and he was believed to be in the preterminal stage of his disease. At that time prednisone 30 mg once daily was prescribed with strictly palliative intentions. Six weeks later his condition had greatly improved, pain had decreased markedly, and the chest X-ray showed dramatic regression of the tumour volume, with clearing of the right lung fields (Fig. 2). The epidural catheter has been removed and the patient is in good general condition
Fig. 1. Large tumorous pleural lesions and mass at the right heart border.
The Netherlands Journal of Medicine 2001;58:181 – 184
A. Termeer et al. / Regression of invasive thymoma following corticosteroid therapy
183
Fig. 2. Dramatic response after moderate dose corticosteroid therapy.
and without signs of tumour progression 20 months later. The daily dose of prednisone has been tapered off to 15 mg.
Discussion The response of the thymoma in our patient on steroid therapy was dramatic in multiple ways. Firstly, the bulky tumour decreased in size very impressively, as shown on the CT images. Secondly, symptoms and performance status improved at a time that the patient was supposed to be in a preterminal phase of his disease, receiving large doses of opiates. Surgery is the most important treatment modality for thymoma and there is a role for radiotherapy, while several cisplatin-containing chemotherapy reg-
imens with high response rates are available. At first presentation in 1994, 4 years before the start of corticosteroid therapy, resection nor debulking of the tumour was thought to be feasible by the thoracic surgeon, and also radiotherapy or chemotherapy were not believed to be useful because of the very large and regionally disseminated volume and the slow progression of the tumour. Furthermore, the patient declined palliative platinum-based chemotherapy, and consultation at a tertiary reference centre did not alter his doctor’s or his own opinion. The corticosteroids were not intentionally started as anti-tumour therapy, but for palliative effect in the preterminal stage of disease. For this purpose moderate doses of prednisone (30 mg) were prescribed and tapering to a dose of 15 mg did not lead to tumour progression. This moderate dose appeared to be
The Netherlands Journal of Medicine 2001;58:181 – 184
184
A. Termeer et al. / Regression of invasive thymoma following corticosteroid therapy
remarkably effective compared to the higher doses of prednisone (40–100 mg) used in similar cases in the literature [3–7]. Also the duration of remission in our case seems longer than would be expected from similar cases with locally extensive or metastatic disease reported in the literature. Our case is exceptional just for natural history, not having been treated with any conventional therapeutic modality whatsoever, showing very slow progression and more than 5 year survival from time of diagnosis (and in retrospect more than 8 years). Since the first description of regression of a thymoma following administration of adrenocorticotropic hormone in 1952 by Sofer et al. [1] there has been a relatively small number of reports describing regression of thymomas and their metastases on corticosteroid therapy, mostly after failure on combined radiochemotherapy and surgery and regardless of co-existence of myasthenia gravis or other associated disorders. In 1977, Kodama et al. [2] reported a dramatic response of post-thymectomy myasthenia gravis with multiple metastatic lung nodules to corticosteroids. Corticosteroids were effective in 11 of 13 thymoma cases reported by Eddie and Levene in 1986 [3]. Almog et al. [4] described a patient with malignant lymphoepithelial thymoma treated with steroids because of an allergic reaction to angiografin that occurred at angiography and observed a temporally decrease to one-third of the original tumour size, stipulating that treatment of metastases of thymoma with steroids should be kept in mind as an option when more conventional therapeutic methods fail. Thymoma-associated neutropenia has been successfully treated with corticosteroids plus azathioprine and a case of non-surgical regression of thymoma treated for this intention has been reported [5]. In their review in 1992, Kirkove et al. [6] included five cases of complete response on corticosteroids as single-drug treatment, usually after failure of conventional therapy. In 1994 Shishido et al. [7] described a patient with malignant thymoma in whom the initial manifestation was pericarditis, and cardiac tamponade was relieved by corticosteroid therapy. The most recent reference found in the literature regarding the topic of regression of thymoma following monotherapy with steroids is to be found in 1998. In a reply to a letter to the editor
by Weissberg [8] regarding the article by Kodama et al., speculations are made about the mechanism of action, which still is unknown. Corticosteroids are able to deplete the lymphocyte population in the thymus. Complete responses achieved in mixed thymomas suggest that steroids are active on the epithelial component of the tumour as well. Bearing in mind the 1:5 ratio of lymphocytic versus epithelial composition of the thymoma in our patient, the dramatic response cannot solely be explained by depletion of lymphocytes. The pathologic features (e.g. predominance of lymphocytes) indeed do not seem to predict the response to corticosteroids [8]. We believe that steroid therapy is a good option in all cases of malignant thymoma, regardless of the histopathologic findings, when conventional therapies fail or are not suitable for the patient. Moderate doses may be sufficient for longtime palliation. Furthermore, corticosteroids might be used as ‘induction’ therapy for ‘irresectable’ thymoma, but this suggestion by the authors could not be found in recent literature and still has to be proven useful.
References [1] Sofer LF, Gabrilove J, Wolff BS. Effect of ACTH on thymic masses. J Clin Endocrinol Metab 1952;12:690–6. [2] Kodama K, Doi O, Higashiyama M, Yokouchi H, Yasuda T, Funai H. Dramatic response of postthymectomy myasthenia gravis with multiple lung nodules to corticosteroids. Ann Thorac Surg 1977;64:555–7. [3] Eddie HU, Levene J. Chemotherapy of malignant thymoma. Cancer 1986;57:1101–4. [4] Almog C, Pik A, Weissberg D, Herczeg E. Regression of malignant thymoma with metastases after treatment with adrenocortical steroids. Isr J Med Sci 1978;14:476–80. [5] Crawford WW, Yusin JS, Klaustermeyer WB. Nonsurgical regression of thymoma following corticosteroid / azathioprine therapy. Ann Allergy 1999;83:13–6. [6] Kirkove C, Berghmans J, Noel H, Van de Merckt J. Dramatic response of recurrent invasive thymoma to high doses of corticosteroids. Clin Oncol 1992;4:64–6. [7] Shishido M, Yano K, Ichiki H, Yano M. Pericarditis as initial manifestation of malignant thymoma. Chest 1994;106:313– 4. [8] Kodama K, Higashiyama M, Yokouchi H, Takami K, Funai H. Steroids for pulmonary metastases of thymoma. Ann Thorac Surg 1998;65:1197–8.
The Netherlands Journal of Medicine 2001;58:181 – 184