American Journal of Pathology, Vol. 140, No. 4, April 1992 Copyright C) American Association of Pathologists
Immunocytochemical Characteristics of Small Cell Lung Carcinoma Associated with the Lambert-Eaton Myasthenic Syndrome Christine S. Morris,* Margaret M. Esiri,* Alexander Marx,t and John Newsom-Davis* From the Departments of Neuropathology and Clinical Neurology,* University of Oxford, Radcliffe Infirmary, Oxford, United Kingdom; and the Pathologisches Institut der Universitat Wurzburg,t Wurzburg, Federal Republic of
Germany
The Lambert-Eaton myasthenic syndrome (LEMS) is characterized by the presence of IgG antibodies to motor nerve terminals, and associates with small cell lung carcinoma in more than 60% of cases. We have carried out a comparative immunocytochemical study on small cell lung carcinoma (SCLC) in five LEMS cases and six non-LEMS cases, using antibodies to tumor markers, MHC Class I and II, macrophages and lymphocytes. The authors found a reduced expression of the 200Kd neurofilament antigen and of MHC Class I antigens in the LEMS cases as well as a greater infiltration of activated macrophages. It is suggested that these findings are consistent with the view thatSCLC antigenic determinants trigger the autoantibody response in SCLC-LEMS. (Am J Pathol
1992, 140:839-845)
Certain cancers can exert remote effects on the nervous system.' These paraneoplastic neurologic disorders include the Lambert-Eaton myasthenic syndrome (LEMS), subacute sensory neuropathy, encephalomyelitis, cerebellar ataxia and retinopathy, each of which can associate with small cell lung carcinoma (SCLC). Evidence is increasing that the immune system is implicated in their etiology. In all of them, for example, antibodies to the target neurologic tissue have been identified, and in many, these have been shown to crossreact with tumor determinants.2? Only in LEMS, however, has the principal criterion of an antibody-mediated autoimmune disorder been met, namely transfer of the disorder to experi-
mental animals by injection of patients' immunoglobuins.2 LEMS is characterized by a reduction in Ca2+dependent quantal release of acetylcholine from motor nerve terminals at the neuromuscular junction,10 leading to muscle weakness and depressed tendon reflexes. About 60% of cases associate with SCLC,11 the neurologic syndrome preceding radiologic evidence of the tumor by up to 5 years. In both the paraneoplastic and nonparaneoplastic forms, LEMS associates with particular immune response genes.12 Freeze fracture, electron microscopy of LEMS muscle shows a reduction in the number of active zone particles, believed to represent voltage-gated calcium channels (VGCC) and a loss of their usual orderly arrangement in double parallel rows.13 Patients' IgG injected into mice transfers the principal physiologic14 15 and morphologic16 changes. The findings are consistent with a 40% reduction in the number of nerve terminal VGCCs,15 brought about by crosslinking of adjacent active zone particles by the IgG antibodies; 17 monovalent (papain-digested) IgG was without effect. Anti-VGCC antibodies can be detected in a proportion of patients using 1251-w-conotoxin labelled VGCCs,1"20 and in longitudinal studies the titer appears to correlate inversely with disease severity.20 Several lines of evidence implicate SCLC in triggering the disorder. These tumors, which may be of neuroectodermal origin, express VGCCs.21 K+-stimulated (voltage-gated) 45Ca21 flux into cultured SCLC cells is significantly inhibited in the presence of LEMS IgG.22 This inhibition correlates with disease severity,23 and specific tumor therapy (resection and irradiation) may be followed by improvement or remission in the neurologic deficit,24 suggesting that tumor VGCC determinants are driving the autoantibody response.24 Moreover, they apparently initiate it at an early stage (up to 5 years before tumor Supported by grant Ki370/1-1 from the Deutsche Forschungsgemeinschaft (A. Marx). Accepted for publication November 15, 1991. Address reprint requests to Dr. M. M. Esiri, Department of Neuropathology, University of Oxford, Radcliffe Infirmary, Oxford 0X2 6HE, UK.
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diagnosis). At that time, the tumor is presumably small, suggesting either that it is immunogenic, or that the patients who have paraneoplastic/LEMS symptoms are high responders, or both. Evidence in favor of the latter is the increased frequency of particular immunoglobulin heavy chain gene markers, and perhaps of HLA-B8 and DR3, in LEMS cases with SCLC.12 In the light of these findings, it is of interest to investigate the characteristics of the tumor and of the cellular infiltrate in LEMS. In this immunocytochemical study, we compared the findings in five LEMS cases with those in six non-LEMS controls.
Materials and Methods
Clinical Details and Specimens Tumor tissue was obtained from 1 1 patients. Five of these patients had typical clinical features of LEMS, which had been present for 0.8-5 years at the time of death (Table 1). The diagnosis of LEMS was confirmed by electrophysiologic studies that showed a reduced amplitude of the compound muscle action potential (range, 1.2-6.6; normal >8.5 mv), and an increment in amplitude following 15 seconds maximum voluntary contraction of muscle of 188-1233% (normal
Immunocytochemical Characteristics of Small Cell Lung Carcinoma Associated with the Lambert-Eaton Myasthenic Syndrome Christine S. Morris,* Margaret M. Esiri,* Alexander Marx,t and John Newsom-Davis* From the Departments of Neuropathology and Clinical Neurology,* University of Oxford, Radcliffe Infirmary, Oxford, United Kingdom; and the Pathologisches Institut der Universitat Wurzburg,t Wurzburg, Federal Republic of
Germany
The Lambert-Eaton myasthenic syndrome (LEMS) is characterized by the presence of IgG antibodies to motor nerve terminals, and associates with small cell lung carcinoma in more than 60% of cases. We have carried out a comparative immunocytochemical study on small cell lung carcinoma (SCLC) in five LEMS cases and six non-LEMS cases, using antibodies to tumor markers, MHC Class I and II, macrophages and lymphocytes. The authors found a reduced expression of the 200Kd neurofilament antigen and of MHC Class I antigens in the LEMS cases as well as a greater infiltration of activated macrophages. It is suggested that these findings are consistent with the view thatSCLC antigenic determinants trigger the autoantibody response in SCLC-LEMS. (Am J Pathol
1992, 140:839-845)
Certain cancers can exert remote effects on the nervous system.' These paraneoplastic neurologic disorders include the Lambert-Eaton myasthenic syndrome (LEMS), subacute sensory neuropathy, encephalomyelitis, cerebellar ataxia and retinopathy, each of which can associate with small cell lung carcinoma (SCLC). Evidence is increasing that the immune system is implicated in their etiology. In all of them, for example, antibodies to the target neurologic tissue have been identified, and in many, these have been shown to crossreact with tumor determinants.2? Only in LEMS, however, has the principal criterion of an antibody-mediated autoimmune disorder been met, namely transfer of the disorder to experi-
mental animals by injection of patients' immunoglobuins.2 LEMS is characterized by a reduction in Ca2+dependent quantal release of acetylcholine from motor nerve terminals at the neuromuscular junction,10 leading to muscle weakness and depressed tendon reflexes. About 60% of cases associate with SCLC,11 the neurologic syndrome preceding radiologic evidence of the tumor by up to 5 years. In both the paraneoplastic and nonparaneoplastic forms, LEMS associates with particular immune response genes.12 Freeze fracture, electron microscopy of LEMS muscle shows a reduction in the number of active zone particles, believed to represent voltage-gated calcium channels (VGCC) and a loss of their usual orderly arrangement in double parallel rows.13 Patients' IgG injected into mice transfers the principal physiologic14 15 and morphologic16 changes. The findings are consistent with a 40% reduction in the number of nerve terminal VGCCs,15 brought about by crosslinking of adjacent active zone particles by the IgG antibodies; 17 monovalent (papain-digested) IgG was without effect. Anti-VGCC antibodies can be detected in a proportion of patients using 1251-w-conotoxin labelled VGCCs,1"20 and in longitudinal studies the titer appears to correlate inversely with disease severity.20 Several lines of evidence implicate SCLC in triggering the disorder. These tumors, which may be of neuroectodermal origin, express VGCCs.21 K+-stimulated (voltage-gated) 45Ca21 flux into cultured SCLC cells is significantly inhibited in the presence of LEMS IgG.22 This inhibition correlates with disease severity,23 and specific tumor therapy (resection and irradiation) may be followed by improvement or remission in the neurologic deficit,24 suggesting that tumor VGCC determinants are driving the autoantibody response.24 Moreover, they apparently initiate it at an early stage (up to 5 years before tumor Supported by grant Ki370/1-1 from the Deutsche Forschungsgemeinschaft (A. Marx). Accepted for publication November 15, 1991. Address reprint requests to Dr. M. M. Esiri, Department of Neuropathology, University of Oxford, Radcliffe Infirmary, Oxford 0X2 6HE, UK.
839
840
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AJP April 1992, Vol. 140, No. 4
diagnosis). At that time, the tumor is presumably small, suggesting either that it is immunogenic, or that the patients who have paraneoplastic/LEMS symptoms are high responders, or both. Evidence in favor of the latter is the increased frequency of particular immunoglobulin heavy chain gene markers, and perhaps of HLA-B8 and DR3, in LEMS cases with SCLC.12 In the light of these findings, it is of interest to investigate the characteristics of the tumor and of the cellular infiltrate in LEMS. In this immunocytochemical study, we compared the findings in five LEMS cases with those in six non-LEMS controls.
Materials and Methods
Clinical Details and Specimens Tumor tissue was obtained from 1 1 patients. Five of these patients had typical clinical features of LEMS, which had been present for 0.8-5 years at the time of death (Table 1). The diagnosis of LEMS was confirmed by electrophysiologic studies that showed a reduced amplitude of the compound muscle action potential (range, 1.2-6.6; normal >8.5 mv), and an increment in amplitude following 15 seconds maximum voluntary contraction of muscle of 188-1233% (normal
