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Pulmonary Sarcoidosis Associated with Leydig Cell Testicular Neoplasm
months later disclosed the patient to be asymptomatic with normal hematologic and immunologic indices. DISCUSSION
Tocainide is an orally active analog of lidocaine utilized in the chronic management of symptomatic ventricular arrhythmias. Adverse effects from tocainide are common; gastrointestinal (nausea, vomiting) and neurologic (dizziness, tremor, parasthesia) side effects predominate and affect approximately 50 percent of patients and require termination of the drug in 15 percent.l-" Neutropenia is a rare complication of tocainide, with an estimated incidence of 0.18 percent.' Drug-associated neutropenia is a rare but potentially fatal complication for which three different mechanisms have been identified: (1) immunologically mediated leukocyte destruction in peripheral blood and bone marrow (2) toxic depression of bone marrow precursors, and (3) development of a lupus-like illness." A previously reported case of fatal tocainide-associated neutropenia with bone marrow hypocellularity and granulocytic precursor depression was presumed to be secondary to toxic bone marrow depression. 4 Our case is the first report of tocainide-associated .neutropenia in association with a lupus-like illness. Drugs previously implicated in the development of neutropenia in a lupus-like illness include hydralazine and procainamide. The neutropenia associated with a lupus-like illness is characterized by peripheral blood neutrophil depletion in association with persistence of granulocytic precursors in bone marrow" Clinically a drug-induced lupus-like illness may be characterized by anyone, or a combination of, the following: arthralgia, constitutional symptoms, dermatitis, hepatosplenomegaly or pleuropericarditis. Neurologic and renal complications, frequent manifestations with systemic lupus erythematosus, are infrequently observed with druginduced lupus-like syndromes. Immunologically drug-induced lupus is. associated with a positive antinuclear antibody; in the absence of anti-DNA antibody; and with normal serum complement. .Autoantibodies directed at red blood cells (positive Coombs' test) may be present. 5 In this case report, the development of neutropenia in association with clinical and immunologic features of lupus shortly after the introduction of oral tocainide suggests that tocainide was responsible for a drug-induced lupus syndrome.Tocainide-associated neutropenia is arare but potentially serious com plication. Surveillance of patients on tocainide for the development of neutropenia has been recommended by the marketing company 6 REFERENCES
1 Roden DM, Woosley RL. Tocainide. N Engl J Med 1986; 315:4145 2 Kutalek SE Morganroth J, Horowitz LN. Tocainide: A new oral antiarrhythmic agent. Ann Intern Med 1985; 103:387-91 3 Pisciotta v: Drug-induced agranulocytosis. Drugs 1978; 15:13243 4 Volosin K, Greenberg RM, Greenspoon AJ. Tocainide associated agranulocytosis. Am Heart J 1985; 109:1392-93 5 Alarcon-Segovia D. Drug induced antinuclear antibodies and lupus syndromes. Drugs 1976; 12:69-77 6 Tonocard direction circular. West Point, Pa: Merck & Co, Inc, November 1984
428
Pulmonary Sarcoidosis Associated with Leydig Cell Testiclliar Neoplasm* Alberto Biglino;M.D.; Giuseppe Cariti, M.D.; Marina Musset, M.D.; and PaoloGioannini, M.D.
The first case of association between Leydig cell testicular tumor and sarcoidosis is reported. From a review of the literature, this is the ninth case of association between a testicular tumor and Besniers disease. Lung biopsy should always be performed in patients with testicular cancer when retroperitoneal lymph node involvement cannot be demonstrated in order to avoid unnecessary antineoplastic chemotherapy
T
he association between neoplastic diseases and sarcoidosis is well known. 1 Among many types of tumor, some testicular neoplasms have also been associated with the development of intrathoracic sarcoid lesions.>" We report here the first case of association between Leydig cell testicular tumor and biopsy-proven pulmonary sarcoidosis. CASE REPORT
A 33-year-old man came for observation in March, 1985 because of a moderate fever with exertional dyspnea and multiple bilateral opacities on chest roentgenogram (Fig 1). He was submitted in May 1984 to a left orchiectomy at another hospital because of a painless mass, diagnosed as seminoma on frozen sections. However, the final diagnosis on routinely-processed sections was a Leydig cell tumor. The slides were reviewed at the Department of Pathology PaulBrousse Hospital, Paris, where the diagnosis of a Leydig cell tumor was confirmed. Levels of beta-HCG and alpha-fetoprotein were within normal limits, while serum angiotensin-converting enzyme was at the upper normal level. Chest roentgenogram taken at admission showed bilateral multiple lung infiltrates interpreted as metastases, while retroperitoneal lymphangiogram raised some doubts about lymph node involvement. For this reason, and considering that a small percentage of Leydig-cell tumors are indeed malignant, treatment with adriamycin (VP-16) and cisplatin was started. Other treatments with cisplatin, vinblastine and bleomycin followed in November, 1984 and january 1985, with no appreciable change on chest roentgenogram. A second retroperitoneal lymphangiogram was normal. At this point, lung biopsy (performed through a left thoracotomy) showed typical sarcoid tissue involving lung parenchyma free of metastatic tumor cells (Fig 2). We started treatment with prednisone 60 (rug/day gradually tapered to 25 mg) and continued therapy for ten months. Treatment was followed by a sharp improvement in both chest roentgenogram (Fig 3) and spirometric values, where the most striking effect was represented by the disappearance of diffusion troubles but persistence of moderate restriction. The patient is now in good health and chest roentgenogram is unchanged ten months after discontinuing steroid therapy *From the Institute of Infectious Diseases, University of Torino, Torino, Italy; and Service des Maladies Sanguines et Tumorales, Hopital Paul-Brousse, Paris, France. Reprint requests: Dr. Biglino, Ospedale Arnedeo di Savoia, C. s. Svizzera 164, Torino, Italy 1-10149 Pulmonary Sarcoidosis and Testicular Neoplasm(Biglino et al)
FIGURE 1. Chest roentgenogram after four courses of chemotherapy, before corticosteroid treatment. Multiple bilateral parenchymal infiltrates are evident. DISC U SSIO N
Although Brincker and Wilbe k, 1 in a study perform ed on 2,544 patients, reported a significan t association be tween neoplastic dis eas es and sarcoidosis, Rome r"·9-after a careful reevaluation of the same population- demonstrate d a total lack of significant linkage between the two even ts. For thi s reason it has been hypothesized th at the appearance of sarcoid manifestations in ne opl astic patients could be int erpreted as sarcoid -like granulomatous reacti ons, possibl y du e to one or more of the following mec ha n isms : 1) rele ase of tumor antigens or complex produ ct s by suffering cance r cells during ch emotherapy or radiation treatm ent, 2) incr eased susceptibility to the hypoth etic age n t of sarcoidos is in neoplastic patients du e to an immune syste m imbalan ce, or 3) nonspecific enhance ment of granulomatous reactions elicite d by an tine oplastic drugs and/o r radiation treatm en t. The hypothesis of a sarcoid -li ke r eaction has b e en strengthened by evide nce, in most reported cases , of a simple mediastinal lymph node involvem ent sparing lun g parenchyma. In our case , on the contrary, lun g tissu e was d eepl y involved by sarcoid tissu e , as is gene rally observed in Besnier's disease . Furthermore, a sho rt course of pr ed ni sone therapy was followed by a nearly total regres sion of lun g
FIGURE 2. Lung biopsy specimen showingepithelioid nodules with giant cells and areas of fibrosis. There is no evidence of necrosis.
FIGURE 3. Chest roentgenogram after ten months of corticosteroid treatment. Regression of parenchymal infiltrates with residual fibrosis is evident. opaci ties and by a sharp improvement in spirome tric parame ters; such a re sult would have been hard to ob tain in the case oflung me tastases (albeit exce ptional in Leydigoma), In conclu sion, our case enables us to rul e out a simple sar coid-like reaction confine d to me dias tinal lymph nod es, and point s to th e possibility th at a neopl astic disease (par ticularly a testicul ar tumor) could be associate d with th e d evelopment of sarco idosis. For thi s reason, lung biopsy should be include d in th e dia gno stic workup of pati ents with testicul ar cancer and sus pe cte d lung metastases when a re trope rito ne al lymph nod e involvem ent cannot be demonstrate d. ACKNOWLEDGMENTS: We are grateful to Prof. Alessandro Tizzani, Institute of Urology, University of Torino, Italy, for critical contribution. R E FERE NC ES
1 Brincker H, Wilbek E. The incidence of malignant tumors in patients with respiratory sarcoidosis. Br ] Cancer 1979; 29: 247-51 2 Trump DL, Ettinger OS, Feldman M], Dragon LH. "Sarcoidosis" and sarcoid-like lesions. Their occurrence after cytotoxic and radiation therapy of testis cancer. Arch Int ern Med 1981; 141: 37-38 3 Gefter WB, Glick ]H, Epstein OM, Miller WT. Sarcoidosis: a cause of intrathoracic lymphadenopathy after treatment of testicular carcinoma. Am J Radio11982; 139:820-21 4 Colebunders R, Parizel PM. Sarcoidosis after testicular carcinoma treatment. Am ] Radio11983; 140:831 5 Geller RA, Kuremsky DA, Copeland ]S, Stept R. Sarcoidosis and testicular neoplasms: an unusual association. ] Urol 1977; 118:487 6 Blacher E], Maynard ]F. Seminoma and sarcoidosis: an unusual association. Urology 1985; XXVI:288-89 7 Allison RE, Urbanski S]. More about association of seminoma and sarcoidosis. Urology 1986; XXVII:86 8 Romer FK. Sarcoidosis and cancer-a critical view. In: Jones W\v, Davies BH, eds. Eighth international conference on sarcoidosis and other granulomatous diseases. Cardiff: Alpha Omega, 1980:201-05 9 Romer FK. Sarcoidosis and cancer. N Engl] Med 1982; 306:1490 CHEST I 94 I 2 I AUGUST, 1988
429
Tocainide is an orally active analog of lidocaine utilized in the chronic management of symptomatic ventricular arrhythmias. Adverse effects from tocainide are common; gastrointestinal (nausea, vomiting) and neurologic (dizziness, tremor, parasthesia) side effects predominate and affect approximately 50 percent of patients and require termination of the drug in 15 percent.l-" Neutropenia is a rare complication of tocainide, with an estimated incidence of 0.18 percent.' Drug-associated neutropenia is a rare but potentially fatal complication for which three different mechanisms have been identified: (1) immunologically mediated leukocyte destruction in peripheral blood and bone marrow (2) toxic depression of bone marrow precursors, and (3) development of a lupus-like illness." A previously reported case of fatal tocainide-associated neutropenia with bone marrow hypocellularity and granulocytic precursor depression was presumed to be secondary to toxic bone marrow depression. 4 Our case is the first report of tocainide-associated .neutropenia in association with a lupus-like illness. Drugs previously implicated in the development of neutropenia in a lupus-like illness include hydralazine and procainamide. The neutropenia associated with a lupus-like illness is characterized by peripheral blood neutrophil depletion in association with persistence of granulocytic precursors in bone marrow" Clinically a drug-induced lupus-like illness may be characterized by anyone, or a combination of, the following: arthralgia, constitutional symptoms, dermatitis, hepatosplenomegaly or pleuropericarditis. Neurologic and renal complications, frequent manifestations with systemic lupus erythematosus, are infrequently observed with druginduced lupus-like syndromes. Immunologically drug-induced lupus is. associated with a positive antinuclear antibody; in the absence of anti-DNA antibody; and with normal serum complement. .Autoantibodies directed at red blood cells (positive Coombs' test) may be present. 5 In this case report, the development of neutropenia in association with clinical and immunologic features of lupus shortly after the introduction of oral tocainide suggests that tocainide was responsible for a drug-induced lupus syndrome.Tocainide-associated neutropenia is arare but potentially serious com plication. Surveillance of patients on tocainide for the development of neutropenia has been recommended by the marketing company 6 REFERENCES
1 Roden DM, Woosley RL. Tocainide. N Engl J Med 1986; 315:4145 2 Kutalek SE Morganroth J, Horowitz LN. Tocainide: A new oral antiarrhythmic agent. Ann Intern Med 1985; 103:387-91 3 Pisciotta v: Drug-induced agranulocytosis. Drugs 1978; 15:13243 4 Volosin K, Greenberg RM, Greenspoon AJ. Tocainide associated agranulocytosis. Am Heart J 1985; 109:1392-93 5 Alarcon-Segovia D. Drug induced antinuclear antibodies and lupus syndromes. Drugs 1976; 12:69-77 6 Tonocard direction circular. West Point, Pa: Merck & Co, Inc, November 1984
428
Pulmonary Sarcoidosis Associated with Leydig Cell Testiclliar Neoplasm* Alberto Biglino;M.D.; Giuseppe Cariti, M.D.; Marina Musset, M.D.; and PaoloGioannini, M.D.
The first case of association between Leydig cell testicular tumor and sarcoidosis is reported. From a review of the literature, this is the ninth case of association between a testicular tumor and Besniers disease. Lung biopsy should always be performed in patients with testicular cancer when retroperitoneal lymph node involvement cannot be demonstrated in order to avoid unnecessary antineoplastic chemotherapy
T
he association between neoplastic diseases and sarcoidosis is well known. 1 Among many types of tumor, some testicular neoplasms have also been associated with the development of intrathoracic sarcoid lesions.>" We report here the first case of association between Leydig cell testicular tumor and biopsy-proven pulmonary sarcoidosis. CASE REPORT
A 33-year-old man came for observation in March, 1985 because of a moderate fever with exertional dyspnea and multiple bilateral opacities on chest roentgenogram (Fig 1). He was submitted in May 1984 to a left orchiectomy at another hospital because of a painless mass, diagnosed as seminoma on frozen sections. However, the final diagnosis on routinely-processed sections was a Leydig cell tumor. The slides were reviewed at the Department of Pathology PaulBrousse Hospital, Paris, where the diagnosis of a Leydig cell tumor was confirmed. Levels of beta-HCG and alpha-fetoprotein were within normal limits, while serum angiotensin-converting enzyme was at the upper normal level. Chest roentgenogram taken at admission showed bilateral multiple lung infiltrates interpreted as metastases, while retroperitoneal lymphangiogram raised some doubts about lymph node involvement. For this reason, and considering that a small percentage of Leydig-cell tumors are indeed malignant, treatment with adriamycin (VP-16) and cisplatin was started. Other treatments with cisplatin, vinblastine and bleomycin followed in November, 1984 and january 1985, with no appreciable change on chest roentgenogram. A second retroperitoneal lymphangiogram was normal. At this point, lung biopsy (performed through a left thoracotomy) showed typical sarcoid tissue involving lung parenchyma free of metastatic tumor cells (Fig 2). We started treatment with prednisone 60 (rug/day gradually tapered to 25 mg) and continued therapy for ten months. Treatment was followed by a sharp improvement in both chest roentgenogram (Fig 3) and spirometric values, where the most striking effect was represented by the disappearance of diffusion troubles but persistence of moderate restriction. The patient is now in good health and chest roentgenogram is unchanged ten months after discontinuing steroid therapy *From the Institute of Infectious Diseases, University of Torino, Torino, Italy; and Service des Maladies Sanguines et Tumorales, Hopital Paul-Brousse, Paris, France. Reprint requests: Dr. Biglino, Ospedale Arnedeo di Savoia, C. s. Svizzera 164, Torino, Italy 1-10149 Pulmonary Sarcoidosis and Testicular Neoplasm(Biglino et al)
FIGURE 1. Chest roentgenogram after four courses of chemotherapy, before corticosteroid treatment. Multiple bilateral parenchymal infiltrates are evident. DISC U SSIO N
Although Brincker and Wilbe k, 1 in a study perform ed on 2,544 patients, reported a significan t association be tween neoplastic dis eas es and sarcoidosis, Rome r"·9-after a careful reevaluation of the same population- demonstrate d a total lack of significant linkage between the two even ts. For thi s reason it has been hypothesized th at the appearance of sarcoid manifestations in ne opl astic patients could be int erpreted as sarcoid -like granulomatous reacti ons, possibl y du e to one or more of the following mec ha n isms : 1) rele ase of tumor antigens or complex produ ct s by suffering cance r cells during ch emotherapy or radiation treatm ent, 2) incr eased susceptibility to the hypoth etic age n t of sarcoidos is in neoplastic patients du e to an immune syste m imbalan ce, or 3) nonspecific enhance ment of granulomatous reactions elicite d by an tine oplastic drugs and/o r radiation treatm en t. The hypothesis of a sarcoid -li ke r eaction has b e en strengthened by evide nce, in most reported cases , of a simple mediastinal lymph node involvem ent sparing lun g parenchyma. In our case , on the contrary, lun g tissu e was d eepl y involved by sarcoid tissu e , as is gene rally observed in Besnier's disease . Furthermore, a sho rt course of pr ed ni sone therapy was followed by a nearly total regres sion of lun g
FIGURE 2. Lung biopsy specimen showingepithelioid nodules with giant cells and areas of fibrosis. There is no evidence of necrosis.
FIGURE 3. Chest roentgenogram after ten months of corticosteroid treatment. Regression of parenchymal infiltrates with residual fibrosis is evident. opaci ties and by a sharp improvement in spirome tric parame ters; such a re sult would have been hard to ob tain in the case oflung me tastases (albeit exce ptional in Leydigoma), In conclu sion, our case enables us to rul e out a simple sar coid-like reaction confine d to me dias tinal lymph nod es, and point s to th e possibility th at a neopl astic disease (par ticularly a testicul ar tumor) could be associate d with th e d evelopment of sarco idosis. For thi s reason, lung biopsy should be include d in th e dia gno stic workup of pati ents with testicul ar cancer and sus pe cte d lung metastases when a re trope rito ne al lymph nod e involvem ent cannot be demonstrate d. ACKNOWLEDGMENTS: We are grateful to Prof. Alessandro Tizzani, Institute of Urology, University of Torino, Italy, for critical contribution. R E FERE NC ES
1 Brincker H, Wilbek E. The incidence of malignant tumors in patients with respiratory sarcoidosis. Br ] Cancer 1979; 29: 247-51 2 Trump DL, Ettinger OS, Feldman M], Dragon LH. "Sarcoidosis" and sarcoid-like lesions. Their occurrence after cytotoxic and radiation therapy of testis cancer. Arch Int ern Med 1981; 141: 37-38 3 Gefter WB, Glick ]H, Epstein OM, Miller WT. Sarcoidosis: a cause of intrathoracic lymphadenopathy after treatment of testicular carcinoma. Am J Radio11982; 139:820-21 4 Colebunders R, Parizel PM. Sarcoidosis after testicular carcinoma treatment. Am ] Radio11983; 140:831 5 Geller RA, Kuremsky DA, Copeland ]S, Stept R. Sarcoidosis and testicular neoplasms: an unusual association. ] Urol 1977; 118:487 6 Blacher E], Maynard ]F. Seminoma and sarcoidosis: an unusual association. Urology 1985; XXVI:288-89 7 Allison RE, Urbanski S]. More about association of seminoma and sarcoidosis. Urology 1986; XXVII:86 8 Romer FK. Sarcoidosis and cancer-a critical view. In: Jones W\v, Davies BH, eds. Eighth international conference on sarcoidosis and other granulomatous diseases. Cardiff: Alpha Omega, 1980:201-05 9 Romer FK. Sarcoidosis and cancer. N Engl] Med 1982; 306:1490 CHEST I 94 I 2 I AUGUST, 1988
429