198
ably close to the doses used in medical practice. As long as we remain ignorant of possible in-vivo effect on D.N.A. of ultrasound at medical doses, care should be taken when using sonication medicine, and uncontrolled peaks of high intensity should be avoided. Medical Genetics, Free University of Brussels, Faculty of Medicine, 97 rue aux Laines, 1000 Brussels, Belgium.
H. GALPERIN-LEMAITRE
Gynaecology and Obstetric Clinic, Brugmann University Hospital, Brussels.
S. LEVI
Crozer-Chester Medical Center,
IMMUNOBLASTIC LYMPHADENOPATHY ASSOCIATED WITH PHENYTOIN
(DIPHENYLHYDANTOIN) SIR,-Lukes and Tindle1 noted a frequent association of im-
lymphadenopathy (I.L.) with drug treatment, incase, diphenylhydantoin (’Dilantin’). Since there is a possibility that this lymphoproliferative process may be induced by chronic antigenic or drug stimulation, recognition of potentially provocative agents is important. We, too, have seen a patient who developed 1.L. while taking dilantin. A 78-year-old Black woman complained of fatigue and night
munoblastic
cluding,
in
one
She had arteriosclerotic cardiovascular disease and a seizure disorder requiring dilantin anticonvulsant therapy. Massive diffuse lymphadenopathy and hepatosplenomegaly were prominent physical findings. Her condition deteriorated rapidly over several weeks, despite stopping dilantin. Laboratory investigations showed: haemoglobin 10 g/dl; white blood-cell count 15 850 per mm3, with a predominance of reactive lymphocytes, plasmacytoid lymphocytes, and immunoblastic cells; platelet-count 72 000 per mm3; uric-acid 22 mg/dl; serum-protein electrophoresis 9.4 g/dl gammaglobulin, with a broad-based biclonal peak; quantitative immunoglobulin analysis showing two monoclonal proteins of kappa IgG’ and kappa IgA type (protein analysis performed by Dr Bias Frangione); direct Coombs test weakly positive; cryoglobulins and cryofibrinogen negative; Venereal Disease Research Laboratories and fluorescent-treponemal-antibody tests positive ; heterophile antibodies 1/28; positive rheumatoid factor; cold agglutinins 1/128. Lymph-node biopsy showed the angioimmunoblastic proliferation characteristic of i.L. Our diagnosis and slides were kindly reviewed and confirmed by Dr Henry Rappaport. Bonemarrow revealed lymphoproliferation consistent with i.L. This rapidly progressing and disabling disease was not influenced by discontinuing dilantin for 2 weeks, but physical findings and results of laboratory tests began to improve a few days after starting chemotherapy (cyclophosphamide, vincristine, prednisone) and were nearly normal after 2 months of observation and treatment. Prophylactic penicillin was also given because of serological evidence of syphilis. The patient died unexpectedly, apparently of her cerebrovascular disease, 2 months after starting treatment and 1 month after obtaining a clinical remission of her 1.L. At necropsy, I.L. was not apparent on external examination but was manifested by prominent lymph-node involvement, with abundant fibrosis and interstitial eosinophilic material, depletion of normal cells, and proliferation of vessels and plasmacytoid cells. Bone-marrow and spleen contained minor changes possibly related to 1.L. Cause of death was not established but was most likely related to her severe cardiovascular disease. No evidence of syphilis was found. This case illustrates’ the clinicopathological features of !.L. in a patient taking dilantin anticonvulsant medication. This association of dilantin with I.L. will undoubtedly be found more often in the future now that the characteristic features of i.L. are well described.2-4 The importance of remaining sweats.
Lukes, R: J., Tindle, B. H. New Engl. J. Med. 1975, 292, 1. Frizzera, G., Moran, E. M., Rappaport, H. Lancet, 1974, i, 1070. 3. Nomanbhoy, Y. T., Prager, P. R. ibid, 1974, ii, 409. 4. Horne, C. H. W., Fraser, R. A., Petric, J. C. ibid, p. 291.
1. 2.
of this association resides in the possibility of reversing I.L. by removal of the offending drug and starting chemotherapy early in the course of the lymphoproliferation. Until the cause and pathogenesis of I.L. are better understood, it will be important to continue reporting all drugs and antigens found associated with this disorder. aware
Department of Hematology-Oncology, Pathology, Chester, Pennsylvania, 19013, U.S.A.
MELVYN J. LAPES RAYMOND J. VIVACQUA KRISTINA ANTONIADES
CHROMOSOME ABNORMALITIES IN ANGIOIMMUNOBLASTIC LYMPHADENOPATHY SIR,-Angioimmunoblastic lymphadenopathy (A.LL.) has only lately become recognised as a distinct clinical and histological entity.’-3 Histologically the process is thought to be benign. However, Lukes and Tindle2 pointed to its potential transformation into malignant immunoblastic sarcoma. We studied the chromosome constitution of lymph-node-derived cells of 2 patients with this disease and found considerable anomalies in both cases. Case 1.- This 32-year-old man was found to have right cervical lymphadenopathy in April, 1975. In July, 1975, he presented with generalised lymphadenopathy, hepatosplenomegaly, fever (38.5-39.5"C), skin rash, eosinophilia (13%), and hypergammaglobulinaemia (immunoglobulins 5.33 g/dl, with an increase of IgM, IgG, and IgA). Lymph-node histology in July revealed non-specific lymphadenitis, but in August and November changes compatible with A.I.L. were seen. Chromosome analysis of 89 metaphases of lymph-nodederived cells in November, 1975, showed 19 hyperdiploid and 3 pseudodiploid. 11of the hyperdiploid metaphases had the karyotype 47, XY, +3. 2 others were 47, XY, +3, -9, +21 and 48, XY, +3, +8, +9, - 20, respectively. 5 other metaphases with 47 chromosomes, 1 with 49 chromosomes, and the pseudodiploid metaphases lacked a consistent pattern. Except for a brief period of prednisone therapy in June, 1975, the patient has had no treatment so far. CASE2.—A.I.L. was diagnosed in this 45-year-old man in September, 1974. Generalised lymphadenopathy developed in July, 1974, and on admission he was found to have hepatosplenomegaly, fever (38°C), a
history of weight-loss
and skin
allergy against
various substances,
eosinophilia (9%), and hyperglobulinmniia (immunoglobulins 1.6 edl, with an increase in M, G, and A components). Lymph-node histology in September and December, 1974, and March, 1975, indicated A.I.L. The chromosome constitution of lymph-node cells (direct preparation) was analysed in September and December, 1974, and the results, being almost identical, were pooled. Of 75 metaphases studied, 50 were hyperdiploid and 11 pseudodiploid. 8 of the pseudodiploid metaphases had a Bq+. 35 of the hyperdiploid metaphases had the karyotype 47,XY,Bq+,+lC, and 15 were 47,XY,+1C. No chromosome banding could be achieved. The chromosome constitution of phytohaemagglutinin-stimulated peripheral-blood lymphocytes was normal. At the time of lymph-node biopsies the patient was untreated. Since April, 1975, he has required prednisone therapy.
These are the only 2 patients with A.I.L. so far seen in our clinic. Both patients had chromosomally abnormal clones in the lymphatic tissue. Clones of cells carrying acquired chromosomal anomalies almost always indicate malignant growth, and our findings therefore cast some doubt on the notion that A.I.L. is a benign disease. They support the view of Lukes and Tindle2 that A.I.L. may be a "prelymphoma". Longitudinal studies will be necessary to determine whether or not all patients with A.I.L. have chromosome anomalies and whether those with anomalies are more likely to develop truly malignant
lymphomas.
D. K. H. is
supported by the Deutsche Forschungsgemeinschaft.
Medical University Clinic
(Tumour Research), Hufelandstrasse 55, 43 Essen 1.
D. K. HOSSFELD K. HÖFFKEN C. G. SCHMIDT
Josef Hospital, Mülheimerstrasse 83, 42 Oberhausen, Germany.
H. DIEDRICHS
1. Frizzera, G., Moran, E. M., Rappaport, H. Lancet, 1974, i, 1070. 2. Lukes, R. J., Tindle, B. H. New Engl. J. Med. 1975, 292,1. 3. Radaszkiewicz, T., Lennert, K. Dt. med. Wschr. 1975, 100, 1157.
ably close to the doses used in medical practice. As long as we remain ignorant of possible in-vivo effect on D.N.A. of ultrasound at medical doses, care should be taken when using sonication medicine, and uncontrolled peaks of high intensity should be avoided. Medical Genetics, Free University of Brussels, Faculty of Medicine, 97 rue aux Laines, 1000 Brussels, Belgium.
H. GALPERIN-LEMAITRE
Gynaecology and Obstetric Clinic, Brugmann University Hospital, Brussels.
S. LEVI
Crozer-Chester Medical Center,
IMMUNOBLASTIC LYMPHADENOPATHY ASSOCIATED WITH PHENYTOIN
(DIPHENYLHYDANTOIN) SIR,-Lukes and Tindle1 noted a frequent association of im-
lymphadenopathy (I.L.) with drug treatment, incase, diphenylhydantoin (’Dilantin’). Since there is a possibility that this lymphoproliferative process may be induced by chronic antigenic or drug stimulation, recognition of potentially provocative agents is important. We, too, have seen a patient who developed 1.L. while taking dilantin. A 78-year-old Black woman complained of fatigue and night
munoblastic
cluding,
in
one
She had arteriosclerotic cardiovascular disease and a seizure disorder requiring dilantin anticonvulsant therapy. Massive diffuse lymphadenopathy and hepatosplenomegaly were prominent physical findings. Her condition deteriorated rapidly over several weeks, despite stopping dilantin. Laboratory investigations showed: haemoglobin 10 g/dl; white blood-cell count 15 850 per mm3, with a predominance of reactive lymphocytes, plasmacytoid lymphocytes, and immunoblastic cells; platelet-count 72 000 per mm3; uric-acid 22 mg/dl; serum-protein electrophoresis 9.4 g/dl gammaglobulin, with a broad-based biclonal peak; quantitative immunoglobulin analysis showing two monoclonal proteins of kappa IgG’ and kappa IgA type (protein analysis performed by Dr Bias Frangione); direct Coombs test weakly positive; cryoglobulins and cryofibrinogen negative; Venereal Disease Research Laboratories and fluorescent-treponemal-antibody tests positive ; heterophile antibodies 1/28; positive rheumatoid factor; cold agglutinins 1/128. Lymph-node biopsy showed the angioimmunoblastic proliferation characteristic of i.L. Our diagnosis and slides were kindly reviewed and confirmed by Dr Henry Rappaport. Bonemarrow revealed lymphoproliferation consistent with i.L. This rapidly progressing and disabling disease was not influenced by discontinuing dilantin for 2 weeks, but physical findings and results of laboratory tests began to improve a few days after starting chemotherapy (cyclophosphamide, vincristine, prednisone) and were nearly normal after 2 months of observation and treatment. Prophylactic penicillin was also given because of serological evidence of syphilis. The patient died unexpectedly, apparently of her cerebrovascular disease, 2 months after starting treatment and 1 month after obtaining a clinical remission of her 1.L. At necropsy, I.L. was not apparent on external examination but was manifested by prominent lymph-node involvement, with abundant fibrosis and interstitial eosinophilic material, depletion of normal cells, and proliferation of vessels and plasmacytoid cells. Bone-marrow and spleen contained minor changes possibly related to 1.L. Cause of death was not established but was most likely related to her severe cardiovascular disease. No evidence of syphilis was found. This case illustrates’ the clinicopathological features of !.L. in a patient taking dilantin anticonvulsant medication. This association of dilantin with I.L. will undoubtedly be found more often in the future now that the characteristic features of i.L. are well described.2-4 The importance of remaining sweats.
Lukes, R: J., Tindle, B. H. New Engl. J. Med. 1975, 292, 1. Frizzera, G., Moran, E. M., Rappaport, H. Lancet, 1974, i, 1070. 3. Nomanbhoy, Y. T., Prager, P. R. ibid, 1974, ii, 409. 4. Horne, C. H. W., Fraser, R. A., Petric, J. C. ibid, p. 291.
1. 2.
of this association resides in the possibility of reversing I.L. by removal of the offending drug and starting chemotherapy early in the course of the lymphoproliferation. Until the cause and pathogenesis of I.L. are better understood, it will be important to continue reporting all drugs and antigens found associated with this disorder. aware
Department of Hematology-Oncology, Pathology, Chester, Pennsylvania, 19013, U.S.A.
MELVYN J. LAPES RAYMOND J. VIVACQUA KRISTINA ANTONIADES
CHROMOSOME ABNORMALITIES IN ANGIOIMMUNOBLASTIC LYMPHADENOPATHY SIR,-Angioimmunoblastic lymphadenopathy (A.LL.) has only lately become recognised as a distinct clinical and histological entity.’-3 Histologically the process is thought to be benign. However, Lukes and Tindle2 pointed to its potential transformation into malignant immunoblastic sarcoma. We studied the chromosome constitution of lymph-node-derived cells of 2 patients with this disease and found considerable anomalies in both cases. Case 1.- This 32-year-old man was found to have right cervical lymphadenopathy in April, 1975. In July, 1975, he presented with generalised lymphadenopathy, hepatosplenomegaly, fever (38.5-39.5"C), skin rash, eosinophilia (13%), and hypergammaglobulinaemia (immunoglobulins 5.33 g/dl, with an increase of IgM, IgG, and IgA). Lymph-node histology in July revealed non-specific lymphadenitis, but in August and November changes compatible with A.I.L. were seen. Chromosome analysis of 89 metaphases of lymph-nodederived cells in November, 1975, showed 19 hyperdiploid and 3 pseudodiploid. 11of the hyperdiploid metaphases had the karyotype 47, XY, +3. 2 others were 47, XY, +3, -9, +21 and 48, XY, +3, +8, +9, - 20, respectively. 5 other metaphases with 47 chromosomes, 1 with 49 chromosomes, and the pseudodiploid metaphases lacked a consistent pattern. Except for a brief period of prednisone therapy in June, 1975, the patient has had no treatment so far. CASE2.—A.I.L. was diagnosed in this 45-year-old man in September, 1974. Generalised lymphadenopathy developed in July, 1974, and on admission he was found to have hepatosplenomegaly, fever (38°C), a
history of weight-loss
and skin
allergy against
various substances,
eosinophilia (9%), and hyperglobulinmniia (immunoglobulins 1.6 edl, with an increase in M, G, and A components). Lymph-node histology in September and December, 1974, and March, 1975, indicated A.I.L. The chromosome constitution of lymph-node cells (direct preparation) was analysed in September and December, 1974, and the results, being almost identical, were pooled. Of 75 metaphases studied, 50 were hyperdiploid and 11 pseudodiploid. 8 of the pseudodiploid metaphases had a Bq+. 35 of the hyperdiploid metaphases had the karyotype 47,XY,Bq+,+lC, and 15 were 47,XY,+1C. No chromosome banding could be achieved. The chromosome constitution of phytohaemagglutinin-stimulated peripheral-blood lymphocytes was normal. At the time of lymph-node biopsies the patient was untreated. Since April, 1975, he has required prednisone therapy.
These are the only 2 patients with A.I.L. so far seen in our clinic. Both patients had chromosomally abnormal clones in the lymphatic tissue. Clones of cells carrying acquired chromosomal anomalies almost always indicate malignant growth, and our findings therefore cast some doubt on the notion that A.I.L. is a benign disease. They support the view of Lukes and Tindle2 that A.I.L. may be a "prelymphoma". Longitudinal studies will be necessary to determine whether or not all patients with A.I.L. have chromosome anomalies and whether those with anomalies are more likely to develop truly malignant
lymphomas.
D. K. H. is
supported by the Deutsche Forschungsgemeinschaft.
Medical University Clinic
(Tumour Research), Hufelandstrasse 55, 43 Essen 1.
D. K. HOSSFELD K. HÖFFKEN C. G. SCHMIDT
Josef Hospital, Mülheimerstrasse 83, 42 Oberhausen, Germany.
H. DIEDRICHS
1. Frizzera, G., Moran, E. M., Rappaport, H. Lancet, 1974, i, 1070. 2. Lukes, R. J., Tindle, B. H. New Engl. J. Med. 1975, 292,1. 3. Radaszkiewicz, T., Lennert, K. Dt. med. Wschr. 1975, 100, 1157.
