Case Report Am J Nephrol 1992:12:466-470

Riyacl Said* Mesleh Tarawnehb Department of Medicine and Pathology, School of Medicine, Jordan University, Amman, Jordan

Membranoproliferative Glomerulonephritis Associated with Multicentric Angiofollicular Lymph Node Hyperplasia Case Report and Review of the Literature

Key Words

Membranoproliferative glomerulonephritis Nephrotic syndrome Angiofollicular lymph node hyperplasia Castleman’s disease

Abstract A 14-year-old boy presented with fever, anemia, hepatosplenomegaly, general­ ized lymphadenopathy and nephrotic syndrome. Lymph node biopsy showed angiofollicular lymph node hyperplasia (generalized Castleman’s disease) of the plasma cell type. Kidney biopsy showed membranoproliferative glomeru­ lonephritis type 1. Complete remission was achieved with corticosteroid treat­ ment and repeat kidney biopsy 22 months later showed complete resolution of the renal pathology. The association between membranoproliferative glomer­ ulonephritis and multicentric angiofollicular lymph node hyperplasia, plasma cell type, has not previously been reported.

usually presents as an isolated tumor mass, frequently asymptomatic, occasionally giving rise to symptoms due Angiofollicular lymph node hyperplasia (ALNH) was to mass effect and is characterized by small hyaline vascu­ first described as a distinct entity by Castleman et al. [ 1] lar follicles and interfollicular capillary proliferation. The in 1956 as a benign lymphoproliférative disorder, pre­ less common (9%) plasma cell type is characterized by senting as a localized solitary mass, most commonly large hyperplastic follicles with intervening sheets of involving the mediastinum. Since then, a number of cases plasma cells and typically has been associated with a num­ have been reported under various names and locations ber of systemic manifestations including fever, anemia, other than the mediastinum [2], This condition has many hyperglobulinemia, thrombocytosis, spenomegaly, abnor­ synonyms including angiomatous lymphoid hamartomas mal liver function and peripheral neuropathy [6-9]. More [3] and giant lymph node hyperplasia of the mediastinum recently, a mixed hyaline vascular and plasma cell type [4] , The etiology is not known but presumed to be infec­ lymph node hyperplasia has been reported [ 10]. Evidence of clinical renal involvement in ALNH has tious or inflammatory in origin, and the lymph node been previously reported and ranged from abnormal lesions always behave as a benign tumor [5]. Keller et al. [4] analyzed 81 cases and divided the lesions into two urine sediment to mild to moderate proteinuria, heavytypes based on definitive clinical and pathological crite­ chain proteinuria, abnormal kidney function and ne­ ria. The more common (91%) hyaline vascular type phrotic syndrome [11-15]. Only few of the nephrotic

Received: May 8.1992 Accepted: August 28. 1992

Riyad Said.MD. FACP Head, Division of Nephrology. Department of Medicine King Fahad National Guard Hospital PO Box 22490 Riyadh 11426 (Saudi Arabia)

© 1992 S. Karger AG. Basel 0250-8095/92/0126-0466 $2.75/0

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Introduction

Table 1. Renal histology in nephrotic syndrome associated with Castleman’s disease Reference

1 Humphreys et al. [15]

Renal histology

MC

Castleman’s disease

Treatment

Outcome

form

type

L

HV

surgery

resolution unknown

2 Weisenburger et al. [ 17]

MN

M

PC

none

3 Pilon et al. [20]

amyloidosis

L

PC

prednisone + cytotoxic drugs

death RF

4 Frizzera et al. [16]

MC

M

prednisone + cytotoxic drugs

unknown

5 Summerfield et al. [ 19]

interstitial nephritis

M

not reported HV

prednisone

improved

6 Ruggieri et al. [ 18]

MN

L

HV

surgery + cytotoxic drugs

resolution

7 Said et al. [current report]

MPGN

M

PC

prednisone

resolution

HV = Hyaline vascular; L = localized: M = multicentric; MC = minimal change; MN - membranous nephropathy; PC = plasma cell.

Case Report Our patient was a 14-year-old boy who was admitted to Jordan University Hospital for the first time in August 1984 with fever, fatigue and left upper abdominal pain of a few days' duration. He was found to have normocytic normochromic anemia, bilateral neck lymphadenopathy and hepatosplenomegaly. Lymph node biopsy was reported as nonspecific, reactive hyperplasia. Only supportive measures were given at that point in time. The patient was readmit­ ted in January 1987 with fever, fatigue, morning puffiness of the eyes and edema of the lower limbs, on and off for 3 weeks. Systemic review was noncontributory. Family history was negative for similar illness, renal disease, hypertension or diabetes. Physical examination revealed an ill-looking boy, pale, with mod­ erate puffiness of the eyes. Temperature was 38.6 °C, blood pressure 150/90 mm Hg. supine, pulse rate 88/min and regular. Generalized lymphadenopathy was present involving the neck, axillae, the supra­ clavicular and inguinal regions. The nodes were firm, of variable size, mobile and not tender. Both liver and spleen were enlarged. Moder­ ate ascites, presacral and lower limb edema were also present. Laboratory data showed the following: hemoglobin 8.8 g/dl. leu­ kocytes 10,600/mm3, platelets 485,000/mm3, reticulocyte count 3%. erythrocyte sedimentation rate (ESR) 65 mm/h, serum iron 116 ng/

ml with total iron-binding capacity of 210mg/dl. Blood film was unremarkable and both direct and indirect Coomb’s tests were nega­ tive. Serum urea nitrogen was 42 mg/dl, serum creatinine 1.7 mg/dl, fasting blood sugar 80 mg/dl. and the liver enzymes were normal. Urinalysis revealed 3+ albumin. 4-8 red blood cells per high-power field. 2-4 white blood cells per high-power field and 1 red cell cast was identified. Proteinuria 4.8 g/24 h was present but Bence-Jones proteins were negative. Total serum protein was 5.2 g/dl with albu­ min 2.5 g/dl. Serum protein electrophoresis showed hypergamma­ globulinemia. Antinuclear antibodies, antistreptolysin 0 titer, cryo­ globulins, rheumatoid factor and tests for hepatitis B surface antigen, toxoplasma and monospot were all negative. C3 was low, 60 mg/dl (normal 83-177), and C4 was normal (20 mg/dl). Chest X-ray was normal. Microscopic examination of the cervical and inguinal lymph node biopsy yielded ANLH, plasma cell type (fig. 1). Percutaneous kidney biopsy was done, and finally, laparotomy with splenectomy, liver biopsy and sampling of mesenteric lymph nodes was performed. The spleen showed nonspecific reactive hyperplasia of the cortex without plasmacytic infiltrate. Liver biopsy showed mild chronic triaditis. First Kidney Biopsy

On light-microscopic examination, a total of 20 glomeruli were seen. All showed marked capillary lobulation with thickening of the capillary membranes. In addition, pronounced accentuation of the mesangium and mesangial hyperccllularity with occasional polymor­ phonuclear cells were seen (fig. 2). The interstitium and the tubules were normal, and there was no evidence of vasculitis. Immunofluo­ rescence staining of the kidney biopsy was positive for IgG+ and C3++ in a granular pattern both in the mesangium and the capillary loops and negative for IgA and IgM. Electron-microscopic studies were not done. The impression was MPGN of type 1. The patient was treated with 60 mg of prednisone orally daily with excellent response. He became afebrile within a few days, pro­ teinuria decreased and complete remission of the nephrotic syn-

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patients have been biopsied, and various histological lesions have been described (table l). They ranged from minimal change [15, 16] to membranous nephropathy [17, 18], interstitial nephritis [19] and amyloidosis [20], The finding of membranoproliferative glomerulonephri­ tis (MPGN) in our nephrotic patient with ALNH (plasma cell type) is a new one, and to our knowledge, such an association has not been reported previously.

Fig. 2. First kidney biopsy: 4 glomeruli all showing hypercellularity, lobulation and irregular thickening of capillary wall. HE. X 100.

drome was achieved within 3 weeks. This was associated with a nor­ malization of the hemoglobin level and complete disappearance of the lymphadenopathy. Prednisone was gradually tapered and stopped after 12 weeks without any relapse. In November 1989, he was asymptomatic, normotensive, had no lymphadenopathy and a normal liver span. Laboratory data were as follows: hemoglobin 14.6 g/dl with ESR of 20mm/h, serum creatinine 0.8 mg/dl, total protein 7.5 g/dl and serum albumin 4.2 g/dl. C3 95 mg/dl and pro­ teinuria 120 mg/24 h. Repeat kidney biopsy 22 months later showed 8 glomeruli with minimal mesangial expansion otherwise normal cellularity and capillary basement membrane. Immunofluorescence staining was positive for C3+ and negative for IgA. IgG and IgM.

Discussion

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MPGN and ALNH

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Fig. 1. Cervical lymph node biopsy. HE. a Low-power view show­ ing follicles throughout the section with normal to large germinal centers. X25. bOne follicle showing large germinal center with peripheral cuff of mature lymphocytes. X 100. c lnterfolliclc tissue demonstrating sheets of plasma cells. X 200.

Nephrotic syndrome and other renal abnormalities have been described with various extrarenal malignancies [21]. Hodgkin’s disease and other lymphomas have been the most frequently reported tumors associated with ne­ phrotic syndrome [22], although other malignancies in­ cluding carcinoma of the lung, stomach and colon have been reported [23-25]. Similarly, nephrotic syndrome has been reported in association with giant lymph node hy­ perplasia, more frequently with the multicentric form of the disease. In 1975. Humphreys et al. [15] reported the first case of nephrotic syndrome associated with mesen­ teric angiofollicular lymph node hyperplasia of the hya­ line vascular type in an 18-year-old woman. Kidney biop­ sies showed minimal change disease, and complete remis­ sion of the nephrotic syndrome followed surgical removal of a benign mesenteric mass. Since then, several reports of

nephrotic syndrome in patients with ALNH have been reported (table 1). MPGN has not been reported prior to our case, neither with the localized nor with the multi­ centric form of ALNH. MPGN is a morphological entity and is associated with chronic primary, and usually progressive, glomerulo­ nephritis which occurs in older children and adults [26], In addition, the secondary forms of MPGN are most com­ monly associated with various immune complex, infec­ tious and neoplastic disorders. The pathogenesis of MPGN is incompletely understood. Both the primary and secondary forms are generally regarded as immune-com­ plex-mediated disorders [27], The significance of simultaneous occurrence of ALNH and MPGN in this patient is unclear. The possibility of a chance association must be considered. However, the assumption of a cause-effect link between these two con­ ditions is highly attractive, especially in view of the simul­ taneous improvement in this patient’s symptoms, the dis­ appearance of the lymph nodes, the remission of the nephrotic syndrome after splenectomy and prednisone treatment. In addition, ALNH is considered to be a mani­ festation of chronic antigenic stimulation due to an un­ known infectious or chronic inflammatory process [4], associated with an altered immune state [28], exhibiting a strong hyperimmune response to both endogenous or experimentally administered antigens [29. 30]. This al­ tered immune state may result in deposition of immune complexes and damage to the glomerular basement mem­ brane. Such mechanisms have been suggested to explain the pathogenesis of nephrotic syndrome associated with MPGN, Hodgkin's disease and other lymphomas. The treatment of choice for solitary ALNH is the surgi­ cal removal of the tumor which results in prompt resolu­

tion of the symptoms and laboratory abnormalities [4], Similarly, complete surgical resection of the tumor is usually followed by resulution of the systemic manifestions in the multicentric ALNH. though when the lymphadenopathy is more generalized, resection becomes diffi­ cult or even impossible. In such cases, corticosteorids offer an effective alternative treatment in the multicentric form of ALNH. as has been documented by Summerfield et al. [31] who treated 2 patients with ALNH of the hya­ line vascular type with steroids and obtained an excellent response to treatment in both. Similarly, our patient showed a dramatic response to corticosteroid therapy, and both the systemic manifestations and the lymphadenopathy improved with treatment. Our patient continued to be in a long-lasting remission up to 22 months after splenectomy and corticosteroid treatment. Couch et al. [32] also reported a case of thrombotic thrombocytopenic purpura in association with a localized mediastinal ALNH treated with prednisolone combined with multiple plasmapheresis and exchange transfusions. After 2 epi­ sodes of relapse, the patient eventually entered a stable remission. In summary, we present a young male patient with multicentric ALNH, plasma cell type, and nephrotic syn­ drome with biopsy-proven MPGN. Excellent response to steroid treatment and splenectomy was achieved. The association between MPGN and ANLH has not been pre­ viously reported. Acknowledgement The authors with to thank Professor Miltiadis Stefadouros for reviewing the manuscript and Mrs. Theresa Taylor for secretarial assistance.

References 5 Anagonstou D. Hamson CV: Angiofollicular lymph node hyperplasia. J Clin Pathol 1972: 25:306-311. 6 Boxer LA. Boxer GL. Flair RC. Engstrom PF. Brown GS: Angiomatous lymphoid hamarto­ mas associated with chronic anemia, hypoferremia and hypergammaglobulinemia. J Pcdiatr 1972;81:66-70. 7 Yu GS. Carson JW: Giant lymph node hyper­ plasia, plasma cell type, of the mediastinum with peripheral neuropathy. Am J Clin Pathol 1976;66:46-53.

8 Frizzera G. Peterson BA. Bayrd ED. Goldman A: A systemic lymphoproliférative disorder with morphological features of Castleman’s disease: Clinical findings and dinicopathological correlation in 15 patients. J Clin Oncol 1985:3:1202-1216. 9 Frigert JM. Sweet DL. Coleman M. et al: Multicentric angiofollicular lymph node hyperpla­ sia with peripheral neuropathy, pseudotumor cerebri, IgA dysproteinemia and thrombocyto­ sis in women: A distinct syndrome. Ann Intern Med 1990:113:362-367. ’

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1 Castleman B. Iverson K. Menendez VP: Local­ ized mediastinal lymph node hyperplasia re­ sembling thymoma. Cancer 1956:9:822—830. 2 Rosai J. Levine GD: Tumors of thymus: Atlas of tumor pathology, Washington. Armed Forces Institute of Pathology. 1976, pp 213219. 3 Tung KSK, McCormack LJ: Angiomatous lym­ phoid hamartoma. Cancer 1967:20:525-536. 4 Keller AR. Hocholzer L, Castleman B: Hyaline vascular and plasma cell types of giant lymph node hyperplasia of the mediastinum and other locations. Cancer 1972;29:670-683.

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18 Ruggieri G. Barsotti P. Coppola G. et al: Mem­ branous nephropathy associated with giant lymph node hyperplasia. Am J Nephrol 1990: 10:323-328. 19 Summerfield GP, Taylor W. Bellingham AJ, Goldsmith HJ: Hyaline vascular variant of an­ giofollicular lymph node hyperplasia with sys­ temic manifestation and response to corticoste­ roids. J Clin Pathol 1983:36:1005-1011. 20 Pilon VA, Gomez LG, Butler JJ: Systemic amyloidosis associated with a benign mesen­ teric lymphoid mass. Am J Clin Pathol 1982; 78:112-116. 21 Kiely JM, Wagoner RD. Holley KE: Renal complications of lymphoma. Ann Intern Med 1969:71:1159-1175. 22 Plager J, Stutzman L: Acute nephrotic syn­ drome as a manifestation of active Hodgkin’s disease. Am J Med 1971;50:56-66. 23 Cagliano RG, Costanzi JJ. Beathard GA, ct al: The nephrotic syndrome associated with neo­ plasia: An unusual paraneoplastic syndrome: Report of a case and review of the literature. Am J Med 1976;60:1026-1031. 24 Lee JC, Yamanchi H. Hopper J: The associa­ tion of cancer and nephrotic syndrome. Ann Intern Med 1966;64:41-51. 25 Cantrell EG: Nephrotic syndrome cured by removal of gastric carcinoma. Br Med J 1969:2: 739-740. 26 Donadio JV Jr: Membranoproliferative glo­ merulonephritis: in Schrier RW. Gottschalk CW (cds): Disease o f the Kidney, ed 4. Boston, Little. Brown, 1988. pp 2035-2060.

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27 Donadio JV Jr: Membranoproliferative glo­ merulonephritis: in Jacobson H. Striker G, Klahr S (eds): The Principles and Practices of Nephrology, ed I. Philadelphia, Decker, 1991, pp 299-302. 28 Ballow M, Park BH. Dupont B. ct al: Benign giant lymphoid hyperplasia of the mediasti­ num with associated abnormalities o f the im­ mune system. J Pediatr 1974:84:418-420. 29 Bartoli E. Massarelli G, Soggia G, Tanda F: Multicentric giant lymph node hyperplasia: A hyperimmune syndrome with rapidly progres­ sive course. Am J Clin Pathol 1980:73:423— 426. 30 Langevoort HL: Histophysiology of antibody response: Histogenesis of the plasma cell reac­ tion in rabbit spleen. Lab Invest 1963:12:106— 118. 31 Summerfield GP, Taylor W. Bellingham AJ. Goldsmith HJ: Hyaline vascular variant of an­ giofollicular lymph node hyperplasia with sys­ temic manifestation and response to steroid. J Clin Pathol 1983:36:1005-1011. 32 Couch WD: Giant lymph node hyperplasia as­ sociated with thrombotic thrombocytopenic purpura. Am J Clin Pathol 1980:74:340-344.

MPGN and ALNH

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10 Garcia San Miguel J, Rozman C, Palacin A, Nomdeden B: Mesenteric hyaline plasma cell lymph node hyperplasia with amyloid deposits. Arch Intern Med 1981:141:261-263. 11 Weiscnburger DD, Nathwani BN, Winberg CD. Rappaport H: Multicentric angiofollicular lymph node hyperplasia: A clinicopathological study of 16 cases. Human Pathol 1985:16:162— 192. 12 Frizzera G: Castleman's disease. Human Pa­ thol 1985;16:202-205. 13 Crook MJ. Shaheen KM, Manlee W: Giant lymph node hyperplasia associated with heavy proteinuria. NY State J Med 1980:13:515517. 14 Urbano-Marquez A, Estruch R. Grau JM, Llebaria C, Pastor M. Rozman C: Generalized Castleman’s disease with urinary elimination of heavy chain fragments. Acta Haematol (Ba­ sel) 1984;71:400-406. 15 Humphreys SR. Holley KE. Smith LH. Mcllrath DC: Mesenteric angiofollicular lymph node hyperplasia (lymphoid hamartoma) with nephrotic svndrome. Mavo Clin Proc 1975:50: 317-321. 16 Frizzera G. Massarelli G. Banks PM. Rosai J: A systemic lymphoproliférative disorder with morphological features of Castleman's disease: Pathological findings in 15 patients. Am J Surg Pathol 1983;3:269-283. 17 Wcisenburger D: Membranous nephropathy: Its association with multicentric angiofollicular lymph node hyperplasia. Arch Pathol Lab Med 1979:103:591-594.

Membranoproliferative glomerulonephritis associated with multicentric angiofollicular lymph node hyperplasia. Case report and review of the literature.

A 14-year-old boy presented with fever, anemia, hepatosplenomegaly, generalized lymphadenopathy and nephrotic syndrome. Lymph node biopsy showed angio...
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