British Journal of Emmatology, 1979,43, 149-1 50.
Short Communication ANGIO-IMMUNOBLASTIC LYMPHADENOPATHY WITH LUPUS ERYTHEMATOSUS CELLS It has been proposed that angio-immunoblastic lymphadenopathy is a non-neoplastic hyperimmune state with excess B-cell proliferation (Lukes & Tindle, 1975). More recently an associated defect of T-cell regulation has been suggested (Rudders & De Lellio, 1977). The condition is manifest clinically by hepatosplenomegaly, dysproteinaemia, often of a polyclonal nature, and generalized lymphadenopathy (Frizzera et al, 1974). There is often a Coombs positive haemolytic anaemia and a non-specific picture of night sweats, weight loss and skin rash. Histologically the disease is characterized by an immunoblastic proliferation accompanied by arborizing blood vessels and amorphous interstitial eosinophilic deposits as seen on haematoxylin and eosin staining. W e describe here a case of immunoblastic lymphadenopathy which is of special interest owing to the hitherto unreported association with lupus erythematosus cells. A 58-year-old man presented with a 4-week history of increasing lassitude, intermittent fever, night sweats, weight loss and confusion. There was no past history of significant illness or of exposure to toxic substances. He was anaemic with petechial haemorrhages in the oral mucous membranes and on the limbs. There was generalized lymphadenopathy and hepatosplenomegaly with wasting of the limbs and distal muscle weakness. A peripheral neuropathy was confirmed by absent deep tendon reflexes and impaired pin-prick and light touch sensation below the knees. Laboratory investigation revealed a dysproteinaemia with polyclonal elevation of the IgG and IgM fractions. Repeated LE cell preparations were positive (Fig lc) but the DNA binding percentage was normal. The C3 fraction of serum complement was reduced, with the C4 fraction at the lower limit of normal. Rheumatoid factor was detected a t a titre of 1/160. Toxoplasma dye test titre was 1/64 but toxoplasma specific IgM was not detected. Viral studies were negative. No Bence Jones protein was detected in the urine. Bone marrow aspiration and trephine biopsies revealed diffuse infiltration of the marrow by plasmacytoid cells and mature plasma cells with reduction of the other haemopoietic elements. Histology of a cervical lymph node showed effacement of the normal architecture by proliferating blood vessels, lymphocytes, plasmacytoid cells, plasma cells and large immunoblasts (Fig 1), the features being typical of angio-immunoblastic lymphadenopathy. Treatment with high dose steroids was commenced and he was given red cell and platelet support. Regression of the lymphadenopathy and hepatosplenomegaly occurred but an autoimmune haemolytic anaemia developed, which responded to azathioprine. Steroids were subsequently withdrawn and he remained in remission for 3 weeks, taking azathioprine 100 mg/d. Serum immunoglobulin levels fell to within the normal range. Bone marrow depresCorrespondence:Dr B. A . Gusterson, Unit of Human Cancer Biology, Ludwig Institute for Cancer Research (London Branch), Royal Marsden Hospital, Sutton, Surrey SM2 SPT. 0007-1048/79/0900-0149$02.00 01979 Blackwell Scientific Publications
149
150
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sion then developed and in spite of steroid, antibiotic and blood support, he finally died with a perforation of the bowel and a chest infection. At autopsy there was universal depletion of lymphoid tissue with absence of recognizable follicles in the lymph nodes and a residuum of lymphocytic vascular cuffing in the spleen. Lymphoid tissue in the jejunum and ileum showed a similar depletion with multiple sites of ulceration and perforation of the jejunum at one site. There was no histological evidence of systemic lupus erythematosus or of lymphoma in any of the tissues examined. Sections of the lungs confirmed the presence of a confluent bronchopneumonia. Angio-immunoblastic lymphadenopathy is a very unusual disease in that its presentation and course is very much like a lymphoma but the serological changes are those seen in a collagen disorder (Budman et al, 1978).The association of angio-immunoblastic lymphadenopathy with both autoimmune phenomena (Watanabe, 1977; Wechsler & Stavridges, 1977)and lymphomas (Fisher et al, 1977; Yataganas et al, 1977) is well documented and it may be appropriate to consider this clinico-pathological entity as part of a broad spectrum of conditions that are a result of chronic antigenic stimulation. The presence of LE cells in this case is yet another possible manifestation of the loss of normal T-cell function and although no specific stimulus could be identified it is most likely that many different stimuli can provoke a mixed B and T cell response resulting in a hyperimmune state with features similar to those described. O n the basis of current knowledge it would appear sensible to include angio-immunoblastic lymphadenopathy along with rheumatoid arthritis, SLE and lymphoma among the group of conditions that have recently been described by Wyburn-Mason (1979) as different manifestations of the same underlying disturbance, i.e. chronic antigenic stimulation.
Unit of Human Cancer Biology, Ludwig Institute for Cancer Research (London Branch), Royal Marsden Hospital, Sutton, Surrey S M 2 5PT
B. A . GUSTERSON
Institute of Cancer Research, Department of Medicine, Royal Marsden Hospital, Sutton, Surrey S M 2 5PX
B. M. FlTZHARRIS
REFERENCES BUDMAN, D.R., KOZINER,B., CUNNINGHAM-RUN- munoblastic lymphadenopathy.AmericanJournul o j DLES, C., FILIPPA,D. & GOOD,R.A. (1978) IgA Clinical Pathology, 68, 518-521. deficiency associated with angio-immunoblastic WATANABE, H. (1977) Association of immunoblastic lymphadenopathy. N e w England Journal of Medilymphadenopathy and Hashimoto’s thyroiditis. cine, 298, 1204. Annuls of Internal Medicine, 87,62-64. FISHER,R.I., JAFFE, E.S., BRAYLAN, R.C., ANDERSON, WECHSLER, H.L. & STAVRIDES, A. (1977) Immunoblastic lymphadenopathy with purpura and cryoglobuJ.C.& TAN,H.K. (1976) Immunoblastic lymphalinaemia. Archives ofDermatology, 113,636441. denopathy. American Journal of Medicine, 61, 533-559. WYBURN-MASON, R. (1979) SLEand lymphoma. LanFRIZZERA,G . , MORAN, E.M. & RAPPAPORT, H. (1974) cet, i, 156. Angio-immunoblastic lymphadenopathy with YATAGANAS, X., PA PA D I M ~~R C., I OU PANGALIS, , G., LOUKOPAUOS,D., FESSAS,P. & PAPACHARALAMdysproteinaemia. Lancet. i, 1070-1073. POUS, N. (1977) Angio-immunoblastic lymphaLUKES, R.J. & TINDLE, B.H. (1975) Immunoblastic denopathy terminating as Hodgkin’s . disease. lymphadenopathy. N e w England Journal of Medicine, 292, 1-8. Cancer, 39,2183-2189. RUDDERS,R.A. & DE LELLIO,R.A.R. (1977) Im-
Short Communication ANGIO-IMMUNOBLASTIC LYMPHADENOPATHY WITH LUPUS ERYTHEMATOSUS CELLS It has been proposed that angio-immunoblastic lymphadenopathy is a non-neoplastic hyperimmune state with excess B-cell proliferation (Lukes & Tindle, 1975). More recently an associated defect of T-cell regulation has been suggested (Rudders & De Lellio, 1977). The condition is manifest clinically by hepatosplenomegaly, dysproteinaemia, often of a polyclonal nature, and generalized lymphadenopathy (Frizzera et al, 1974). There is often a Coombs positive haemolytic anaemia and a non-specific picture of night sweats, weight loss and skin rash. Histologically the disease is characterized by an immunoblastic proliferation accompanied by arborizing blood vessels and amorphous interstitial eosinophilic deposits as seen on haematoxylin and eosin staining. W e describe here a case of immunoblastic lymphadenopathy which is of special interest owing to the hitherto unreported association with lupus erythematosus cells. A 58-year-old man presented with a 4-week history of increasing lassitude, intermittent fever, night sweats, weight loss and confusion. There was no past history of significant illness or of exposure to toxic substances. He was anaemic with petechial haemorrhages in the oral mucous membranes and on the limbs. There was generalized lymphadenopathy and hepatosplenomegaly with wasting of the limbs and distal muscle weakness. A peripheral neuropathy was confirmed by absent deep tendon reflexes and impaired pin-prick and light touch sensation below the knees. Laboratory investigation revealed a dysproteinaemia with polyclonal elevation of the IgG and IgM fractions. Repeated LE cell preparations were positive (Fig lc) but the DNA binding percentage was normal. The C3 fraction of serum complement was reduced, with the C4 fraction at the lower limit of normal. Rheumatoid factor was detected a t a titre of 1/160. Toxoplasma dye test titre was 1/64 but toxoplasma specific IgM was not detected. Viral studies were negative. No Bence Jones protein was detected in the urine. Bone marrow aspiration and trephine biopsies revealed diffuse infiltration of the marrow by plasmacytoid cells and mature plasma cells with reduction of the other haemopoietic elements. Histology of a cervical lymph node showed effacement of the normal architecture by proliferating blood vessels, lymphocytes, plasmacytoid cells, plasma cells and large immunoblasts (Fig 1), the features being typical of angio-immunoblastic lymphadenopathy. Treatment with high dose steroids was commenced and he was given red cell and platelet support. Regression of the lymphadenopathy and hepatosplenomegaly occurred but an autoimmune haemolytic anaemia developed, which responded to azathioprine. Steroids were subsequently withdrawn and he remained in remission for 3 weeks, taking azathioprine 100 mg/d. Serum immunoglobulin levels fell to within the normal range. Bone marrow depresCorrespondence:Dr B. A . Gusterson, Unit of Human Cancer Biology, Ludwig Institute for Cancer Research (London Branch), Royal Marsden Hospital, Sutton, Surrey SM2 SPT. 0007-1048/79/0900-0149$02.00 01979 Blackwell Scientific Publications
149
150
B . A . Gusterson and B. M . Fitzharris
sion then developed and in spite of steroid, antibiotic and blood support, he finally died with a perforation of the bowel and a chest infection. At autopsy there was universal depletion of lymphoid tissue with absence of recognizable follicles in the lymph nodes and a residuum of lymphocytic vascular cuffing in the spleen. Lymphoid tissue in the jejunum and ileum showed a similar depletion with multiple sites of ulceration and perforation of the jejunum at one site. There was no histological evidence of systemic lupus erythematosus or of lymphoma in any of the tissues examined. Sections of the lungs confirmed the presence of a confluent bronchopneumonia. Angio-immunoblastic lymphadenopathy is a very unusual disease in that its presentation and course is very much like a lymphoma but the serological changes are those seen in a collagen disorder (Budman et al, 1978).The association of angio-immunoblastic lymphadenopathy with both autoimmune phenomena (Watanabe, 1977; Wechsler & Stavridges, 1977)and lymphomas (Fisher et al, 1977; Yataganas et al, 1977) is well documented and it may be appropriate to consider this clinico-pathological entity as part of a broad spectrum of conditions that are a result of chronic antigenic stimulation. The presence of LE cells in this case is yet another possible manifestation of the loss of normal T-cell function and although no specific stimulus could be identified it is most likely that many different stimuli can provoke a mixed B and T cell response resulting in a hyperimmune state with features similar to those described. O n the basis of current knowledge it would appear sensible to include angio-immunoblastic lymphadenopathy along with rheumatoid arthritis, SLE and lymphoma among the group of conditions that have recently been described by Wyburn-Mason (1979) as different manifestations of the same underlying disturbance, i.e. chronic antigenic stimulation.
Unit of Human Cancer Biology, Ludwig Institute for Cancer Research (London Branch), Royal Marsden Hospital, Sutton, Surrey S M 2 5PT
B. A . GUSTERSON
Institute of Cancer Research, Department of Medicine, Royal Marsden Hospital, Sutton, Surrey S M 2 5PX
B. M. FlTZHARRIS
REFERENCES BUDMAN, D.R., KOZINER,B., CUNNINGHAM-RUN- munoblastic lymphadenopathy.AmericanJournul o j DLES, C., FILIPPA,D. & GOOD,R.A. (1978) IgA Clinical Pathology, 68, 518-521. deficiency associated with angio-immunoblastic WATANABE, H. (1977) Association of immunoblastic lymphadenopathy. N e w England Journal of Medilymphadenopathy and Hashimoto’s thyroiditis. cine, 298, 1204. Annuls of Internal Medicine, 87,62-64. FISHER,R.I., JAFFE, E.S., BRAYLAN, R.C., ANDERSON, WECHSLER, H.L. & STAVRIDES, A. (1977) Immunoblastic lymphadenopathy with purpura and cryoglobuJ.C.& TAN,H.K. (1976) Immunoblastic lymphalinaemia. Archives ofDermatology, 113,636441. denopathy. American Journal of Medicine, 61, 533-559. WYBURN-MASON, R. (1979) SLEand lymphoma. LanFRIZZERA,G . , MORAN, E.M. & RAPPAPORT, H. (1974) cet, i, 156. Angio-immunoblastic lymphadenopathy with YATAGANAS, X., PA PA D I M ~~R C., I OU PANGALIS, , G., LOUKOPAUOS,D., FESSAS,P. & PAPACHARALAMdysproteinaemia. Lancet. i, 1070-1073. POUS, N. (1977) Angio-immunoblastic lymphaLUKES, R.J. & TINDLE, B.H. (1975) Immunoblastic denopathy terminating as Hodgkin’s . disease. lymphadenopathy. N e w England Journal of Medicine, 292, 1-8. Cancer, 39,2183-2189. RUDDERS,R.A. & DE LELLIO,R.A.R. (1977) Im-
