ANGIOIMMUNOBLASTIC LYMPHADENOPATHY WITH RETINITIS AND DRUG RELATED EXACERBATIONS A Clinicopathological Case Study H. JOACHIM DEEG, MD, JACK W. SINGER, MD, AND THOMAS W. HUANG, MD, PHD A patient with angioimmunoblastic lymphadenopathy with dysproteinemia was followed over a three year period from diagnosis to death. He presented with arthralgias, uveitis and respiratory insufficiency and developed hyper- uricemic renal failure upon institution of treatment. Aggressive combination chemotherapy was required to reverse progressive thrombocytopenia and pulmonary involvement. A complete remission was achieved twice. There was a striking temporal relationship between the administration of antibiotics or allopurinol and exacerbations of the disease. Hypocomplementemia and transient evidence of vasculitis suggested the presence of immunecomplexes. Serial lymph node biopsies showed the progression of this disorder from a pleomorphic immunoblastic proliferation to a lymphocyte-depleted, fibrotic process, in parallel with a decline from hyper- to hypogammaglobulinemia. This case illustrates the broad clinical spectrum of angioimmunoblastic lymphadenopathy with dysproteinemia and suggests that aggressive treatment is necessary in selected patients. Cancer 44:1745- 1750, 1979. MMUNOBLASTIC LYMPHADENOPATHY'~ or an- I gioimmunoblastic lymphadenopathy with dy~proteinemia~ is a lymphoma-like disorder, characterized by diffuse proliferation of im- munoblasts, plasma cells, lymphocytes, histio- cytic cells and small blood vessels with promi- nent endothelium associated with inter- cellular deposition of acidophilic material. The main organs involved are lymph nodes, spleen, bone marrow, liver, but the clinical spectrum is broad. We report here on a patient followed for three years.* His case is remarkable for his presentation with uveitis, arthritis, and hyper- uricemia with renal failure, the presence of cryoglobulinemia, and multisystem involve- ment. He had an extended chemotherapy- induced remission and drug-related exacer- From the Division of Oncology, Departments of Medicine and Pathology, University of Washington, and the Veterans Administration Hospital, Seattle, Washington. Supported by Grant Numbers CA 05231 and CA 18029, awarded by the National Cancer Institute, DHEW. Drs. Singer and Huang are supported in part by the Medical Research Service of the Veterans Administration. Dr. Deeg is a Fellow of the Leukemia Society of America. Address for reprints: H. Joachim Deeg, MD, Division of Oncology, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98104. * This case was previously reported in abstract form.' Accepted for publication November 8, 1978. bations. Progressive histologic changes were documented on sequential lymph node biopsies. CASE REPORT A 61-year-old white male with no past medical problems presented in September 1973 with generalized symmetrical polyarthritis. The latex fixation reaction was negative, and he became asymptomatic on indomethacin. One month later a right posterior uveitis and vasculitis with retinal hemorrhage were diagnosed, which promptly improved with prednisone. In December 1973 the uveitis recurred and prednisone was given again. In mid-February 1974 the patient developed dyspnea, fatigue, weight loss and low grade fever one week after discontinuation of prednisone. His dyspnea progressed and abdominal distension, splenomegaly, generalized lymphadenopathy and a faint maculopapular rash appeared. His chest radiograph showed perihilar interstitial infiltrates (Fig. 1). The arterial PO, was 70 mm Hg. Skin tests for purified protein derivative (PPD) and mumps were negative. The direct Coombs test was positive with anti-I specificity. The total protein was 7.8 g/dl with 45.3% polyclonal gamma- globulin. Bence Jones protein was not detectable (further results in Table 1). A right axillary lymph node biopsy was diagnostic for angioimmunoblastic lymphadenopathy (Fig. 2). Bone marrow (BM) aspirate and biopsy were normal. As the patient 0008-543X/79/1100/1745 $0.80 0 American Cancer Society 1745
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ANGIOIMMUNOBLASTIC LYMPHADENOPATHY W I T H RETINITIS AND DRUG RELATED EXACERBATIONS
A Clinicopathological Case Study
H. JOACHIM DEEG, MD, JACK W. SINGER, MD, AND THOMAS W. HUANG, MD, PHD
A patient with angioimmunoblastic lymphadenopathy with dysproteinemia was followed over a three year period from diagnosis to death. He presented with arthralgias, uveitis and respiratory insufficiency and developed hyper- uricemic renal failure upon institution of treatment. Aggressive combination chemotherapy was required to reverse progressive thrombocytopenia and pulmonary involvement. A complete remission was achieved twice. There was a striking temporal relationship between the administration of antibiotics or allopurinol and exacerbations of the disease. Hypocomplementemia and transient evidence of vasculitis suggested the presence of immunecomplexes. Serial lymph node biopsies showed the progression of this disorder from a pleomorphic immunoblastic proliferation to a lymphocyte-depleted, fibrotic process, in parallel with a decline from hyper- to hypogammaglobulinemia. This case illustrates the broad clinical spectrum of angioimmunoblastic lymphadenopathy with dysproteinemia and suggests that aggressive treatment is necessary in selected patients.
Cancer 44:1745- 1750, 1979.
MMUNOBLASTIC LYMPHADENOPATHY'~ or an- I gioimmunoblastic lymphadenopathy with dy~proteinemia~ is a lymphoma-like disorder, characterized by diffuse proliferation of im- munoblasts, plasma cells, lymphocytes, histio- cytic cells and small blood vessels with promi- nent endothelium associated with inter- cellular deposition of acidophilic material. The main organs involved are lymph nodes, spleen, bone marrow, liver, but the clinical spectrum is broad.
We report here on a patient followed for three years.* His case is remarkable for his presentation with uveitis, arthritis, and hyper- uricemia with renal failure, the presence of cryoglobulinemia, and multisystem involve- ment. He had an extended chemotherapy- induced remission and drug-related exacer-
From the Division of Oncology, Departments of Medicine and Pathology, University of Washington, and the Veterans Administration Hospital, Seattle, Washington.
Supported by Grant Numbers CA 05231 and CA 18029, awarded by the National Cancer Institute, DHEW. Drs. Singer and Huang are supported in part by the Medical Research Service of the Veterans Administration. Dr. Deeg is a Fellow of the Leukemia Society of America.
Address for reprints: H. Joachim Deeg, MD, Division of Oncology, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Seattle, WA 98104.
* This case was previously reported in abstract form.' Accepted for publication November 8, 1978.
bations. Progressive histologic changes were documented on sequential lymph node biopsies.
CASE REPORT
A 61-year-old white male with no past medical problems presented in September 1973 with generalized symmetrical polyarthritis. The latex fixation reaction was negative, and he became asymptomatic on indomethacin. One month later a right posterior uveitis and vasculitis with retinal hemorrhage were diagnosed, which promptly improved with prednisone. In December 1973 the uveitis recurred and prednisone was given again.
In mid-February 1974 the patient developed dyspnea, fatigue, weight loss and low grade fever one week after discontinuation of prednisone. His dyspnea progressed and abdominal distension, splenomegaly, generalized lymphadenopathy and a faint maculopapular rash appeared. His chest radiograph showed perihilar interstitial infiltrates (Fig. 1). The arterial PO, was 70 mm Hg. Skin tests for purified protein derivative (PPD) and mumps were negative. The direct Coombs test was positive with anti-I specificity. The total protein was 7.8 g/dl with 45.3% polyclonal gamma- globulin. Bence Jones protein was not detectable (further results in Table 1). A right axillary lymph node biopsy was diagnostic for angioimmunoblastic lymphadenopathy (Fig. 2). Bone marrow (BM) aspirate and biopsy were normal. As the patient
0008-543X/79/1100/1745 $0.80 0 American Cancer Society
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1746 CANCER Nouember 1979 Vol. 44
deteriorated clinically, cyclophosphamide was started on March 2, 1974, 200 mg/day iv for three doses. He developed renal failure and was trans- ferred to the University Hospital.
Upon admission on March 7, 1974 he was hypo- tensive. A pericardial friction rub and S4 gallop were heard. Hepatomegaly and ascites were pres- ent. Chest x-ray showed perihilar infiltrates, cardiomegaly and pleural effusions. A pericardial effusion was demonstrated by echocardiogram. Atypical lymphocytes with clefted nuclei, plasma- cytoid cells and rouleaux-formation were noted on peripheral smear. Cryoglobulin measured 0.2%. A repeat BM examination was consistent with an “immunoblastic disorder.” A review of the lymph node biopsy by consultant pathologists (including Dr. H. Rappaport’s laboratory) confirmed the
FIG. 1. Chest radiograph from February 1974 shows mediastinal widening, hilar prominence and increased interstitial mark- ings in both lung fields. Pericardial effusion was documented by echocardiography. A pulmonary artery catheter is in place (H & E, x 12401.
diagnosis of angioimmunoblastic lymphadenop- athy with dysproteinemia (AILD). Cyclophospha- mide, vincristine, prednisone (CVP) and allopuri- no1 were given.* Pleural effusions persisted, some vasculitic-purpuric lesions over both legs cleared, and his renal failure resolved.
In June 1974 mild retinitis with vasculitis was noted. He was fully active and in complete clinical remission by September 1974 after eight courses of CVP (Table 1 ) . Skin testing after discontinuation of therapy showed no reaction to dermatophytin, streptokinase/streptodornase, PPD and mumps as well as dinitrochlorobenzene (DNCB). Persistent arthalgias were controlled with choline salicylate. In March 1975 a 1 x 3 cm lymph node was felt in his left axilla and a liver-spleen scan showed mild enlargement of both organs. In May a single
FIG. 2. The architec- ture of the lymph node is completely effaced by a pleomorphic in- filtrate composed of iin- munoblasts, lympho- cytes, and plasma cells. Vascular proliferation is also evident (H & E, x 1240).
No. 5 IMMUNOBLASTIC LYMPHADENOPATHY * Deeg et al. 1747
TABLE 1. Clinical and Laboratory Parameters in Relation to Therapy in a Patient with AILD Followed over 3 Years
lY74 1975 1976 Feb Mdrch April Sepl. March May Feb. April Ma) June Aug. Nov Dec. -
The Temporal Relationship of Exacerbation5 of the Disease to the Administration of Antihiotics and Allopurinol is shotin above. (1 = elevated, 1 =decreased, + = presence of symptom or abnormal finding-, - = absent
or normal; N = normal value; T =Tetracycline, C = Cloxacillin, G = Genta- micin, M = Mechicillin, A = Ampicillin. D = Dicloxacillin, CA = Carbenicil- lio, CE = Cefazulin, Al = Allopurinol. CXR = chest radiograph).
enlarged femoral lymph node was biopsied (Fig. 3). dicloxacillin. Early in February hepatospleno- The histology was similar to the previous biopsy, megaly and mediastinal widening developed along and no treatment was given. with fatigue, fever and cervical lymphadenopathy.
In January 1976 a skin infection was treated with Immunoglobulins were decreased and the ANA
FIG. 3. The lymph node findings are simi- lar to Fig. 2. Additional findings include the presence of clusters of mature histiocytes ( H & E, ~ 1 2 4 0 ) .
1748 CANCER November 1979 VOl. 44
was positive at a titer of 1 : 10. A lymph node biopsy revealed complete effacement of the lymph node architecture by angioimmunoblastic lymphad- enopathy. The imrnunoblasts and lymphocytes were relatively depleted (see Fig. 4).
He improved on prednisone, but continued to have night sweats; rnethotrexate (MTX), 15 mg/m2 of body surface area intravenously every other week was added, and he became asymptomatic. In June, after taking ampicillin (for 4 days) for a rhinitis, he was readmitted with lymphadenop- athy and hepato-splenomegaly. MTX was stopped and CVP started again, inducing a complete response by September 1976.
In November he received ampicillin for a root canal treatment. He was admitted to the hospital the following day with high fever, conjunctivitis and diffuse lymphadenopathy. Left-sided pleuritic chest pain and a maculopapular rash developed. All cultures remained negative. A skin biopsy showed perivascular infiltrates with round cells and histiocytes. CVP was continued. Pancytopenia and areas of necrosis were seen on a BM aspirate. Nucleated RBC and immature rnyeloid cells ap- peared on peripheral smear and the LDH rose. Broad spectrum antibiotics and prednisone were given again as the patient appeared to be septic; his renal function deteriorated. Another BM aspiration showed mainly histiocytes and some lymphocytes. He developed massive splenomegaly and could not be supported with platelets. Doxoru- bicin (30 mg/m2 iv, one dose) and procarbazine (150 mglday orally for 4 days) were started. H e developed abdominal pain and a repeat liver spleen scan suggested splenic infarcts. Serum amylase was normal. Ascitic fluid contained 3.1 g of protein/dl
FIG. 4. There is a relative depletion of im- munoblasts, lympho- cytes, and plasma cells and concomitant in- crease in mature histio- cytes (H & E, X 1240).
and no white cells. A repeat BM examination showed an increased amount of fibrous tissue, and no definite necrosis. Promyelocytes were present on peripheral smear. Antibiotics were continued but he developed increasing dyspnea and pain in his left chest and flank and died on December 30, 1976.
Postmortem Examination There were multiple microscopic abscesses in
lungs, heart, liver and spleen, containing gram- positive cocci; cultures grew Staphylococcus aureus. Death was presumably due to Staphylococcal sepsis. All lymph nodes disclosed diffuse effacement of normal architecture by a fibrohistiocytic and small vascular proliferation. Abundant eosinophilic deposits were present. Lymphocytes were mark- edly depleted and immunoblasts were rare. Oc- casional polymorphonuclear leukocytes were scat- tered throughout (Fig. 5). Similar changes were seen in lungs, liver (weighing 3,000 g) and spleen (1,500 g). About half the bone marrow was re- placed by the same process. Meticulous examina- tion failed to reveal any evidence of immuno- blastic sarcoma.
Other findings included multiple infarcts and extramedullary hemopoiesis in the spleen and acute tubular necrosis of the kidneys.
DISCUSSION
T h i s pa t ien t manifested many of t h e features of immunoblastic lymphadenop- athy" or angioimmunoblastic lymphadenop- athy with d y s p r ~ t e i n e r n i a . ~ , ~ Al though pul-
No. 5 IMMUNOBLASTIC LYMPHADENOPATHY . Deeg et al. 1749
FIG. 5. Lymph nodes at autopsy reveal de- pletion of immunore- active cells and histio- cytes. There is fibro- blast proliferation and deposition of collagen (H & E, ~ 1 2 4 0 ) .
monary involvement has been mentioned in the initial ~ e r i e s , ~ . ' ~ and in some other re- p o r t ~ , ~ , ' ~ this complication, being symp- tomatic, has been emphasized only re-
T o our knowledge no patient has been re- ported with AILD associated with uveitis. Frizzera et aL7 excluded cases showing vas- culitis or necrosis; the remainder of the findings and lymph node histology in this patient however fit entirely the description of AILD. Vasculitis has also been described in some other reports'2,1E; a histological con- firmation in our case is lacking. The comple- ment component C3 was low on two deter- minations, which has been described be- fore,lfiJ8 as well as cryoglobulinemia.i3~16~1s Immunecomplexes were not studied. Whereas the latex fixation test was consistently nega- tive, the ANA was positive during an exacer- bation of our patient's disease. The similarity of AILD to collagen-vascular disease, mainly systemic lupus erythematosus has been stressed in the l i t e r a t ~ r e , ~ ~ ' ~ " ~ * ' ~ but we did not find a report of positive ANA. There was no histological support for the diagnosis of disseminated lupus, in particular not in kidneys or spleen in our patient at the time of autopsy.
A striking feature of this case was the occurrence of fever, skin rash, lymphadenop- athy and hepatosplenomegaly following the administration of antibiotics, and allopurinol.
cently.E,9,11,18.20
Only mild e~sinophi l ia~*~' was observed once. The possibility of antigens, mainly drugs, triggering this disorder, has been discussed by many authors7*10~12*16,18 and suggests a com- parison to the syndrome caused by anti- con~ulsants. '~ Severely impaired skin test reactivity has been found repeatedly,4,7,1fi suggesting a T-cell d e f e ~ t . ~
Serial lymph node biopsies (Figs. 2-5) show the progression of the disease. An active pleomorphic proliferation of lymphocytes, immunoblasts and plasma cells was present initially, at a time when the patient had also hypergammaglobulinemia. The following bi- opsy shows an increase of mature histiocytes and a tendency of these cells to form clusters; there is a concomitant decrease of lympho- cytes, plasma cells and immunoblasts and less vascular proliferation. The next two biopsies show marked depletion of lympho- cytes and immunoblasts along with fibroblast p r o l i f e r a t i ~ n , ~ ~ ' ~ ~ ' ~ collagen fibers, eosinophils and eosinophilic deposits. The patient was then hypogammaglobulinemic. The promi- nent lymphocyte depletion shows similarities with the graft-versus-host rea~t ion ' ,~ , '~; this cellular depletion and sclerosis have been observed regardless of previous therapy.14
Death from infection is in agreement with the l i t e r a t ~ r e . ~ * ' ~ . ' ~ Very careful treatment with immunosuppressive agents or no treat- ment at all has been r e c ~ m m e n d e d . " ~ * ' ~ ~ ' ~ Our
1750 CANCER Nouember 1979 Vol. 44
patient however failed to respond to predni- sone or methotrexate alone. Furthermore- initially and late in his course -life-threatening pulmonary disease, systemic symptoms and progressive thrombocytopenia required an aggressive approach. He is comparable in this regard to group 2 in the description by Frizzera et aL7 An enlarging spleen late in his course was assumed to be due to transforma- tion of AILD into immunoblastic sarcoma.
Localized immunoblastic sarcoma has been described.1° No invasive diagnostic pro- cedures could be performed (because of thrombocytopenia and lack of increments following platelet transfusions), and addi- tional chemotherapy was given.
This case iliustrates the broad spectrum of immunoblastic lymphadenopathy and stresses the need for aggressive chemotherapy in selected patients.
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