Europ. J. CancerVol. 14, pp. 133-140. Pergamon Press 1978. Printed in Great Britain
Osteosclerotic Myeloma with Polyneuropathy and Ectopic Secretion of Calcitonin j. j. ROUSSEAU,* G. FRANCK,* T. GRISAR,* M. REZNIK,I G. HEYNEN.~ and J. SALMON§ Institut de Midecine, Secteurs de *Neurologie, ~Rhumatologie, §Immunopathologie and ~fService de Neuropathologie Hdpital Universitaire de Bavi~re 4020 Liige, Belgium A b s t r a c t - - The authorsreportthe clinical observationof a patient with radiologicalfeatures of an IgA with light chains type lambda osteosclerotic myeloma, associated with progressive sensorimotorpolyneuropathy. Attention is drawn to theserarescleroticforms of myeloma and the high frequency of associated neuropathies. In this case, marked hypercalcitoninemia was discovered with no other abnormality of the phosphocalcic balance. The authors advance the hypothesis of an ectopic secretion of calcitonin by tumoral plasma cells and discuss the potential role of this hormone in the pathogenesis of myeloma osteosclerosis. In addition, thefixation of the M-Component on theperipheral nerve trunks is demonstrated by means of immunojTuorescence techniques, thus directly supporting the immunological conception of dysglobulinemic neuropathies. INTRODUCTION
C7 (Fig. la and b). An additional osteosclerotic lesion was discovered in the left postero-lateral portion of the vertebral body of D9. On examination, a few hard, mobile, painless adenopathies were felt in the right supraclavicular fossa. Cardiopulmonary condition was in the normal range. There was no hepatomegaly nor splenomegaly.
MALIGNANT plasmocyte proliferations most often induce osteolytic and/or osteoporotic radiological lesions and, far less frequently, sclerotic bone lesions [1, 2]. The secretion of an osteoclast inhibiting factor or of an osteoblast stimulating factor has been advanced to explain this osteocondensation [3]. Chronic sensorimotor polyneuropathies are frequently associated with these rare sclerotic myelomas [4]. The pathogenesis of these dysglobulinemic polyneuropathies is not clearly known. Recent observations suggest that nerve alterations may be due to immunological mechanisms [5, 6].
Neurological examination Moderate weakness was noticed in the distal muscle groups of the lower extremities. The muscle strength reflexes were normal in the upper limbs but the rotular reflexes were sluggish and the Achilleus reflexes were absent. There was no Babinski sign. Sensory examination revealed decreased vibratory sense in the distal portions of both the upper and the lower extremities. There was sock-like hypo-algesia in the lower limbs.
MATERIAL A N D M E T H O D S Case report Mr. Leonard C . . . was born in 1915. He suffered from chronic phlebopathy of the lower limbs and labile hypertension. Since 1967, he has been complaining of paroxysmal positional vertigo, transient visual disorders, and of intermittent weakness, either of the left leg, or on the right side of the body. An X-ray picture of the cervical spine showed metastatic-like homogeneous osteocondensations, located in the vertebral body of C3, in the left pedicle and in the posterior apophysis of
RESULTS General investigations The blood cells count was normal. Erythrocyte sedimentation rate was 20 mm/lst hr. Fibrinogen was 4.5 g/1 and blood proteins were 67 g/100 ml. Electrophoresis showed 60.4%of albumin, 2.8% of alpha 1-globulins, 19.2% of gamma-globulins. Serum electrolytes and a fasting blood sugar level were normal. Renal and hepatic tests were normal. Serological tests for syphilis were negative. Serum alkaline
Accepted 5July 1977.
133
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j. j. Rousseau et al.
and acid phosphates, hydroxyprolinuria were in the normal range. Glucose tolerance test was normal. Phosphocalcic values were in the normal range except for calcitonin (CT) which was highly increased to 3000 pg/ml. (In normal subjects, the basal levels of CT are between 0 and 600 pg/ml of serum with a mean of 180 pg _+ 150 [7].) Biopsy of the enlarged lymph nodes showed pseudonodular massive plasmocyte infiltration of the medullary cords, with peripheral compression of the lymphatic follicles (Fig. 2). These histological findings suggested the diagnosis of an osteosclerotic form of Kahler's disease, which was confirmed by the following techniques. Serum IgA was twice higher than the normal value: 800 mg°/o . The IgG and IgM were normal. Immunoelectrophoresis showed a pathological monoclonal immunoglobulin (MComponent), identified as an IgA with light chains type lambda. Urine examination for proteinuria was negative. Conventional tests for Bence-Jones proteins in concentrated urine ( x 100) were negative. Light microscope examination of the bone marrow showed a medullary plasmocytosis at 7 %, with many abnormal cells. Bone biopsy of C7 posterior apophysis confirmed the lesion and showed marked thickening of the spongy bone structures, with reduced medullary spaces containing a large population of plasmocytes and plasmoblasts, often bi-nucleate as already seen in the lymph nodes (Fig. 3).
Neurological investigations The cerebrospinal fluid (CSF) was normal, except for a total protein count of 55 mg/100 ml. Electrophoresis of CSF proteins was normal. Immunoelectrophoresis was not obtained. Electrodiagnostic studies showed marked alterations of motor nerve conduction velocity with no motor responses in both anterior tibial nerve trunks. In most distal muscles, electromyography showed fibrillation potentials at rest and decreased interference pattern on voluntary contraction. Biopsies of cutaneous branches of the sural nerve, were examined by light-, electron- and immunofluorescent microscopy. No morphological modification was observed by light microscopy. On transverse semi-thin sections, the nerves were almost normal (Fig. 4). However, moderate demyelinisation was already evident on some trunks (Fig. 5). Focalized alterations of myelin sheaths were confirmed by electron-microscopic examination (Fig. 6). The
morphological modifications were slight in the nerve and very partial in each nerve trunk. The amyelinic nerves seemed normal and the Schwann cells were not modified. The conjunctive structure of the nerve was morphologically intact and no fibrillar material suggesting amyloid could be found. There was no inflammatory infiltrate. The wall of some small arteries however, was thickened by an "onion bulb" proliferation of basal membranes which included cytoplasmic ramifications of endothelial cells (Fig. 7). Fresh longitudinally cut fragments of the same nerve trunk were studied with the usual two-layer immunofluorescent technique. Fluorescein-conjugated anti IgG and anti IgM antiserums stained the preparations in a nonspecific way and only a diffuse basal fluorescence was observed. In contrast, application of the fluorescein-conjugated anti IgA antiserum revealed intense staining of the perineurium and of the central portion of the nerve (Fig. 8). No specific labelling was obtained with any of the antiserums when tested on fragments of peripheral nerve trunks of three controls with osteolytic myelomas (two IgG myelomas, one IgA myeloma), but without clinical or electrical signs of polyneuropathy.
Therapy andfollow-up The patient was treated with a daily dose of cyclophosphamide (100 mg per os) and high doses of vitamin B complex. This therapy was continued from May 1974 to J u n e 1976 with gradual and marked improvement of the sensorimotor polyneuropathy. In May 1975, after one year of therapy, the motor nerve conduction velocities became subnormal and, a motor response was again elicited in the anterior tibial nerves. The radiological control showed no variations in size and aspect of the previous lesions, nor the development of any other ones. Although the patient experienced a clear improvement in his clinical state, chemotherapy did not appear to modit) the serum levels either of CT or of immunoglobulins [Table 1] while repeated immunoelectrophoresis of serum proteins showed the abnormal IgA spike throughout the clinical course.
DISCUSSION This unusual observation raises many questions but we shall discuss the two major ones only: the osteosclerotic myeloma and the myelomatous polyneuropathies.
Osteosclerotic M~eloma with Polyneuropathy and Ectopic Secretion of Calcitonin
135
]"ix. 1.
Radiograph oj eervicalspine revealing homogeneousosteocondensationsat the level of." (a ) C3 vertebral body,, (b ) C7 posterior apoplo,~is and left pediele. Fig. 2. Microscopic section qJ'lymph node showing striking infiltration by plasma cells at varying stages of maturity;. Inset: detail of large and binuclealed plasma cells ( H . E . 100 and 400 x ). Fig. 3. Mieros'copic sectionj}om C7 osteosclerotic posterior apophysis demon.strating thickened bony trabeculae and reduced marrow spaees ( H . E . 60 x ).
~.4.
Transverse ~eclion oj nerve demonstrating a normal population of large, medium and small myelinated and unmyelinated axons. ( Toluidine blue: 480 x . )
136
j. j. Rousseau et
al.
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Osteosclerotic Myeloma with Polyneuropathy and Ectopic Secretion of Calcitonin j. j. ROUSSEAU,* G. FRANCK,* T. GRISAR,* M. REZNIK,I G. HEYNEN.~ and J. SALMON§ Institut de Midecine, Secteurs de *Neurologie, ~Rhumatologie, §Immunopathologie and ~fService de Neuropathologie Hdpital Universitaire de Bavi~re 4020 Liige, Belgium A b s t r a c t - - The authorsreportthe clinical observationof a patient with radiologicalfeatures of an IgA with light chains type lambda osteosclerotic myeloma, associated with progressive sensorimotorpolyneuropathy. Attention is drawn to theserarescleroticforms of myeloma and the high frequency of associated neuropathies. In this case, marked hypercalcitoninemia was discovered with no other abnormality of the phosphocalcic balance. The authors advance the hypothesis of an ectopic secretion of calcitonin by tumoral plasma cells and discuss the potential role of this hormone in the pathogenesis of myeloma osteosclerosis. In addition, thefixation of the M-Component on theperipheral nerve trunks is demonstrated by means of immunojTuorescence techniques, thus directly supporting the immunological conception of dysglobulinemic neuropathies. INTRODUCTION
C7 (Fig. la and b). An additional osteosclerotic lesion was discovered in the left postero-lateral portion of the vertebral body of D9. On examination, a few hard, mobile, painless adenopathies were felt in the right supraclavicular fossa. Cardiopulmonary condition was in the normal range. There was no hepatomegaly nor splenomegaly.
MALIGNANT plasmocyte proliferations most often induce osteolytic and/or osteoporotic radiological lesions and, far less frequently, sclerotic bone lesions [1, 2]. The secretion of an osteoclast inhibiting factor or of an osteoblast stimulating factor has been advanced to explain this osteocondensation [3]. Chronic sensorimotor polyneuropathies are frequently associated with these rare sclerotic myelomas [4]. The pathogenesis of these dysglobulinemic polyneuropathies is not clearly known. Recent observations suggest that nerve alterations may be due to immunological mechanisms [5, 6].
Neurological examination Moderate weakness was noticed in the distal muscle groups of the lower extremities. The muscle strength reflexes were normal in the upper limbs but the rotular reflexes were sluggish and the Achilleus reflexes were absent. There was no Babinski sign. Sensory examination revealed decreased vibratory sense in the distal portions of both the upper and the lower extremities. There was sock-like hypo-algesia in the lower limbs.
MATERIAL A N D M E T H O D S Case report Mr. Leonard C . . . was born in 1915. He suffered from chronic phlebopathy of the lower limbs and labile hypertension. Since 1967, he has been complaining of paroxysmal positional vertigo, transient visual disorders, and of intermittent weakness, either of the left leg, or on the right side of the body. An X-ray picture of the cervical spine showed metastatic-like homogeneous osteocondensations, located in the vertebral body of C3, in the left pedicle and in the posterior apophysis of
RESULTS General investigations The blood cells count was normal. Erythrocyte sedimentation rate was 20 mm/lst hr. Fibrinogen was 4.5 g/1 and blood proteins were 67 g/100 ml. Electrophoresis showed 60.4%of albumin, 2.8% of alpha 1-globulins, 19.2% of gamma-globulins. Serum electrolytes and a fasting blood sugar level were normal. Renal and hepatic tests were normal. Serological tests for syphilis were negative. Serum alkaline
Accepted 5July 1977.
133
134
j. j. Rousseau et al.
and acid phosphates, hydroxyprolinuria were in the normal range. Glucose tolerance test was normal. Phosphocalcic values were in the normal range except for calcitonin (CT) which was highly increased to 3000 pg/ml. (In normal subjects, the basal levels of CT are between 0 and 600 pg/ml of serum with a mean of 180 pg _+ 150 [7].) Biopsy of the enlarged lymph nodes showed pseudonodular massive plasmocyte infiltration of the medullary cords, with peripheral compression of the lymphatic follicles (Fig. 2). These histological findings suggested the diagnosis of an osteosclerotic form of Kahler's disease, which was confirmed by the following techniques. Serum IgA was twice higher than the normal value: 800 mg°/o . The IgG and IgM were normal. Immunoelectrophoresis showed a pathological monoclonal immunoglobulin (MComponent), identified as an IgA with light chains type lambda. Urine examination for proteinuria was negative. Conventional tests for Bence-Jones proteins in concentrated urine ( x 100) were negative. Light microscope examination of the bone marrow showed a medullary plasmocytosis at 7 %, with many abnormal cells. Bone biopsy of C7 posterior apophysis confirmed the lesion and showed marked thickening of the spongy bone structures, with reduced medullary spaces containing a large population of plasmocytes and plasmoblasts, often bi-nucleate as already seen in the lymph nodes (Fig. 3).
Neurological investigations The cerebrospinal fluid (CSF) was normal, except for a total protein count of 55 mg/100 ml. Electrophoresis of CSF proteins was normal. Immunoelectrophoresis was not obtained. Electrodiagnostic studies showed marked alterations of motor nerve conduction velocity with no motor responses in both anterior tibial nerve trunks. In most distal muscles, electromyography showed fibrillation potentials at rest and decreased interference pattern on voluntary contraction. Biopsies of cutaneous branches of the sural nerve, were examined by light-, electron- and immunofluorescent microscopy. No morphological modification was observed by light microscopy. On transverse semi-thin sections, the nerves were almost normal (Fig. 4). However, moderate demyelinisation was already evident on some trunks (Fig. 5). Focalized alterations of myelin sheaths were confirmed by electron-microscopic examination (Fig. 6). The
morphological modifications were slight in the nerve and very partial in each nerve trunk. The amyelinic nerves seemed normal and the Schwann cells were not modified. The conjunctive structure of the nerve was morphologically intact and no fibrillar material suggesting amyloid could be found. There was no inflammatory infiltrate. The wall of some small arteries however, was thickened by an "onion bulb" proliferation of basal membranes which included cytoplasmic ramifications of endothelial cells (Fig. 7). Fresh longitudinally cut fragments of the same nerve trunk were studied with the usual two-layer immunofluorescent technique. Fluorescein-conjugated anti IgG and anti IgM antiserums stained the preparations in a nonspecific way and only a diffuse basal fluorescence was observed. In contrast, application of the fluorescein-conjugated anti IgA antiserum revealed intense staining of the perineurium and of the central portion of the nerve (Fig. 8). No specific labelling was obtained with any of the antiserums when tested on fragments of peripheral nerve trunks of three controls with osteolytic myelomas (two IgG myelomas, one IgA myeloma), but without clinical or electrical signs of polyneuropathy.
Therapy andfollow-up The patient was treated with a daily dose of cyclophosphamide (100 mg per os) and high doses of vitamin B complex. This therapy was continued from May 1974 to J u n e 1976 with gradual and marked improvement of the sensorimotor polyneuropathy. In May 1975, after one year of therapy, the motor nerve conduction velocities became subnormal and, a motor response was again elicited in the anterior tibial nerves. The radiological control showed no variations in size and aspect of the previous lesions, nor the development of any other ones. Although the patient experienced a clear improvement in his clinical state, chemotherapy did not appear to modit) the serum levels either of CT or of immunoglobulins [Table 1] while repeated immunoelectrophoresis of serum proteins showed the abnormal IgA spike throughout the clinical course.
DISCUSSION This unusual observation raises many questions but we shall discuss the two major ones only: the osteosclerotic myeloma and the myelomatous polyneuropathies.
Osteosclerotic M~eloma with Polyneuropathy and Ectopic Secretion of Calcitonin
135
]"ix. 1.
Radiograph oj eervicalspine revealing homogeneousosteocondensationsat the level of." (a ) C3 vertebral body,, (b ) C7 posterior apoplo,~is and left pediele. Fig. 2. Microscopic section qJ'lymph node showing striking infiltration by plasma cells at varying stages of maturity;. Inset: detail of large and binuclealed plasma cells ( H . E . 100 and 400 x ). Fig. 3. Mieros'copic sectionj}om C7 osteosclerotic posterior apophysis demon.strating thickened bony trabeculae and reduced marrow spaees ( H . E . 60 x ).
~.4.
Transverse ~eclion oj nerve demonstrating a normal population of large, medium and small myelinated and unmyelinated axons. ( Toluidine blue: 480 x . )
136
j. j. Rousseau et
al.
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