Case Reports © 1990 S. Karger A G . Basel 0250-8095/90/0104-032 3$ 2.7 5/0
Am J Nephrol 1990;10:323-328
Membranous Nephropathy Associated with Giant Lymph Node Hyperplasia A Case Report with Histological and Ultrastructural Studies Giancarlo Ruggieria. Paola Barsottib, Giuseppe Coppolac, Cosimo Spinelli a, Alessandro Balduccia, Francesco Rosario Ventolaa, Gianna d ’Adamo'A. Marco Vincenzo Tatad, Vittorio Marinozzib 1 aServizio di Nefrologia c Dialisi e dDivisione di Chirurgia, Ospedale San Giacomo: '’Dipartimento di Biopatologia Umana, Università «La Sapienza»; ‘ Servizio di Anatomia Patologica, Ospedale San Giovanni, Roma, Italia
Key Words. Membranous nephropathy • Nephrotic syndrome ■Giant lymph node hyperplasia • Castleman’s disease Abstract. A young woman presented with nephrotic syndrome due to membranous nephropathy and a localized form of giant lymph node hyperplasia (Castleman’s disease) occurring as a large intra-abdominal mass. Five months after surgical removal of the mass, only mild proteinuria persisted. Twenty months later a second kidney biopsy showed a near-normal morphology. Six years later the patient was free of symptoms and had normal urinalysis. Reviewing the pertinent literature, it seems to be the first case of a biopsy-proven cure of membranous nephropathy in a patient with membranous nephropathy and Castleman’s disease.
Giant lymph node hyperplasia (GLNH) was first de scribed by Castleman et al. [1] in 1956 as a benign lym phoproliférative disorder, presenting as a solitary mass, the clinical manifestations of which mainly depend upon its localization and dimensions. Clinicopathologic classi fication [2] includes the more frequently occurring hya line-vascular (HV) type and the plasma cel! (PC) type which is often associated with systemic manifestations. Intermediate forms, sharing some aspects of both types, have also been reported. More recently a multicentric disease with histological features of GLNH but a more aggressive course was described [3, 4], Etiology, pathogenesis, and relationship between localized and multicentric forms of the disease are still being debated [5, 6]. 1 We wish to thank Dr. M. Peverini. who firstly studied the ab dominal mass, for her kind collaboration.
Renal involvement, in the form of proteinuria, uri nary sediment abnormalities, and/or renal function im pairment, has been reported (see table 1). Nevertheless, only very few histologically documented cases are avail able [7-10]. We describe a case of membranous nephropathy (MN) in a young female patient affected by a localized form of GLNH of HV type. After surgical excision of the mass, improvement of proteinuria was seen. The remis sion of the nephropathy was confirmed by a second renal biopsy and by a 6-year follow-up examination with neg ative urinalysis.
Case Report A 15-year-old woman with a > 1-year history of oedema, weight gain, and polyuria was admitted to the San Giacomo Hospital in December 1979. Physical examination revealed blood pressure 130/95 mm Hg, pitting ankle oedema, no peripheral lymphadenopathy: the spleen was palpable 2 cm below the costal margin. Initial
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Table 1. Renal involvement in Castleman’s disease Reference No.
n
Renal involvement
Castleman's disease form
type
Treatment
Outcome of renal disease
7
i
nephrotic syndrome; RB: minimal-change disease
L
HV
surgery
resolution
8
i
nephrotic syndrome; RB: membranous nephropathy
M
PC
none
not reported
15
i
proteinuria
M
HV
prednisone and cytotoxic drugs
renal failure
16
i
proteinuria, monoclonal gammopathy
M
PC
prednisone
not reported
17
i
nephrotic syndrome
L
HV
surgery and cytotoxic drugs
resolution
9
i
nephrotic syndrome; A: amyloidosis
L
PC
prednisone and cytotoxic drugs
renal failure
4
7/15
poorly defined renal abnormalities in 1 of 7; RB: no alteration on light microscopy
M
not reported
prednisone, prednisone and cytotoxic drugs, cytotoxic drugs, none
not reported
10
1/2
nephrotic syndrome, renal failure; RB: interstitial nephritis
M
HV
prednisone
improvement
18
1
heavy proteinuria
L
PC
surgery
resolution
19
1
heavy-chain proteinuria
M
mixed
prednisone and cytotoxic drugs
not reported
20
1
proteinuria
L
PC
radiation
resolution
21
6/16
proteinuria (3/6 hematuria, 2/6 renal failure)
M
PC or mixed
prednisone, prednisone and cytotoxic drugs, none
not reported
22
1
proteinuria, monoclonal gammopathy
M
PC
not reported
not reported
nephrotic syndrome; RB: (1) membranous nephropathy and (2) resolving glomerulonephritis
L
HV
surgery and cytotoxic drugs
resolution
This study 1
laboratory data were erythrocyte sedimentation rate 34 mm/h, total serum protein 50 g/1 (albumin 21, alpha-1 2.9, alpha-2 14, beta 8.2, gamma 3.9), IgG 3, IgA 0.6, IgM 1.8 g/1, cholesterol 7.7 mmol/l. triglycerides 3, haemoglobin 6.14 mmol/l, haematocrit 32%, iron serum content 8.4 mmol/l, white blood cell count 9,000/mm' with normal differential count, and platelets 300,000/mm5. Urinalysis showed proteinuria of 20 g/24 h with granular casts and red blood cells in urinary sediment. Normal or negative were blood urea nitro gen. serum creatinine, creatinine clearance, electrolytes, uricaemia. antistreptococcal antibodies, C3, C'4, direct and indirect Coombs tests, antinuclear antibodies, circulating immune complexes, hepati tis B surface antigen, fibrinogen, copper, and urinary light chains. Intravenous pyelography revealed no functional or morphologi cal renal abnormalities. Gastrointestinal X-ray showed compression of gastric body and antrum. An abdominal computerized tomogra phy scan confirmed the presence of a well-circumscribed intra abdominal soft-tissue mass which was considerably and homoge neously enhanced following intravenous infusion of contrast me dium. Radiological findings have already been reported (11],
An open needle kidney biopsy [12] performed in April 1980 established the diagnosis of MN. Two weeks later, excision of mesenteric mass and spleen (18 X 1 2 X 3 cm, 200 g) as well as a liver biopsy were performed. On histological examination the mesenteric mass was diagnosed as GLNH of the HV type. No significant alteration was detected at liver biopsy, and the spleen showed non-specific hyperplasia. One month later, heavy proteinuria and anaemia still persisted, and the patient started therapy with cyclophosphamide (125 mg daily) and indomethacin (150 mg daily) [13]. Re-evaluation of the patient in October 1980 revealed remission of the nephrotic syn drome with normalization of all laboratory data, but mild protein uria (1 g/24 h). Therapy was discontinued in November 1980. In June 1982, in view of persisting mild proteinuria (0.5 g/24 h), a second kidney biopsy showed mild glomerular abnormalities con sistent with resolution of the previous MN. From September 1982 proteinuna was constantly absent. In September 1988, 6 years later, the patient was completely free of symptoms and had normal labo ratory data.
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RB = Renal biopsy; A = autopsy; L - localized form; M = multicentric form. For explanation of the other abbreviations see text.
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Fig. 1. Mesenteric mass. The small lymphoid follicles are closely arranged. The interfollicular tissue contains numerous capillaries. Reticulin. X45.
Fig. 2. Mesenteric mass. This lymphoid follicle shows a large lymphocytic zone and a small germinal center containing hyaline material (harrowhcad). Note the radially penetrating capillary (ar rows). HE. X 112.
Fig. 3. Kidney, 1st biopsy. Periodic acid-silver methenamine staining of semithin sections shows diffuse thickening of the capil lary walls. Basement membrane projections are well recognizable on the epithelial side. X 1,175.
F'ig. 4. Kidney, 1st biopsy. In the fragment reprocessed for elec tron microscopy from paraffin-embedded block, epimembranous and intramembranous deposits are well demonstrated. Uranyl ace tate and lead citrate. X 17,000.
Pathological Findings Mesenteric Mass. Grossly the lesion appeared as a single, ovoid, well-capsulatcd mass ( 1 2 X 5 X 4 cm). On microscopic examina tion (fig. 1. 2), the lesion consisted of multiple lymphoid follicles with small germinal centers surrounded by numerous mature lym phocytes. The interfollicular tissue was characterized by prominenl vascular proliferation and contained a mixed cell population. The capillaries showed plump endothelial cells, and in some cases they
were surrounded by hyaline fibrous tissue. A number of lymphoid follicles appeared transfixed by radially penetrating capillaries. A few germinal centers contained hyaline substance. In the examined sections no lymphatic sinuses were recognized. The data were con sistent with GLNH of HV type. Kidney. At the first renal biopsy the glomeruli were characterized by diffuse thickening of the capillary wall without appreciable cell proliferation. Immunofluorescence studies demonstrated a granular
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Membranous Nephropathy and Giant Lymph Node Hyperplasia
Fig. 5. Kidney, 2nd biopsy. Irregular profiles on the epithelial side of the glomerular basement membrane arc focally seen. Peri odic acid-silver methenamine. X 470.
Fig. 6. Kidney, 2nd biopsy. On electron microscopy, the glomer ular capillary wall shows intramembranous and subendothelial elec tron-lucent areas containing granular, electron-dense material. Uranyl acetate and lead citrate. X 15.000.
positive reaction with antisera against IgG, C3, and, to a lesser extent, IgM; the staining was diffusely distributed on the glomerular capillary walls. The diagnosis of MN was established. Retrospective histochcmical and ultrastructural studies were performed on Eponembedded tissue fragments reprocessed from the paraffin block. Periodic acid-silver methenamine staining [ 14] of semilhin sections (fig. 3) and electron microscopic examination of ultrathin sections (fig. 4) showed epimembranous deposits and basement membrane projections, thus confirming the previous diagnosis. The second renal biopsy, obtained 2 years after surgery, had his tological and ultrastructural features consistent with the resolution of the previous MN: periodic acid-silver methenamine staining of semithin sections showed focal alterations of the subepilhelial as pect of the glomerular basement membranes (fig. 5). Electron micro scopic examination (fig. 6) demonstrated diffuse irregularities of the basement membranes, i.e., electron-lucent areas in the lamina densa and irregular thickening of the lamina rara interna, consistent with reabsorbed deposits in resolving MN. From the second renal biopsy, tissue for immunofluorescence analysis was not available.
proteinuria and/or haematuria or renal function impair ment. Nevertheless, histological studies of renal lesions were reported only in a very few cases, namely in an MN [8], an interstitial nephritis [10], and a case with only mini mal alterations at the light microscopic level [4] in patients with multicentric Castleman’s disease and amy loidosis (1 case) [9] and a minimal-change glomerulopa thy [7] associated with localized GLNH. The present case is the first report of a well-documented MN in a patient with the localized form of GLNH of the HV type. Although improvement of renal and other systemic symptoms after treatment of Castleman’s disease has already been reported [7, 10, 17, 18, 20], the resolution of the renal lesions has never been documented by a sec ond renal biopsy.ln the present case the resolution of the MN after surgical excision of the abdominal mass was proven at the ultrastructural level by the disappearance of the epimembranous deposits. The possibility of coincidental occurrence of MN and Castleman's disease cannot be ruled out: however, the assumption of a cause-effect link between the lymphopathy and the renal disease seems to be highly attractive. In the present case remission of the nephrotic syndrome was observed 5 months after surgery at the end of 4 months’ medical treatment; complete cure of the MN
Discussion Proteinuria or nephrotic syndrome in patients with localized GLNH has been occasionally reported (ta ble 1). Renal involvement, however, is a more frequent finding in the multicentric form of the disease, with prevalence in the PC-type cases, as shown in the series of Frizzera et al. [4] and Weisenburger et al. [21] which include 7 of 15 and 6 of 16 patients, respectively, with
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Membranous Nephropathy and Giant Lymph Node Hyperplasia
References 1 Castleman B. Iverson L, Mendez VP: Localized mediastinal lymph node hyperplasia resembling thymoma. Cancer 1956;9: 822-830. 2 Keller AR, Hocholzer L, Castleman B: Hyaline-vascular and plasma cell types of giant lymph node hyperplasia of the medi astinum and other locations. Cancer 1972;29:670-683. 3 Gaba AR, Stein RS, Sweet DL, Variakojis D: Multicentric giant lymph node hyperplasia. Am J Clin Pathol 1978;69:86-90. 4 Frizzera G, Massarelli G, Banks PM. Rosai J: A systemic lym phoproliférative disorder with morphologic features of Castleman’s disease. Pathological findings in 15 patients. Am J Surg Pathol 1983;7:211-231. 5 Diebold J: Mise au point: Hyperplasies réactionelles et pseudo lymphomes ganglionnaires avec hypergammaglobulinémie. Ann Pathol 1983;3:269-283. 6 Fizzcra G: Castleman’s disease. Hum Pathol 1985;16:202-205. 7 Humphreys SR. Holley KE. Smith LH, Mcllrath DC: Mesenteric angiofollicular lymph node hyperplasia (lymphoid hamartoma) with nephrotic syndrome. Mayo Clin Proc 1975;50:317-321. 8 Weisenburger DD: Membranous nephropathy: Its association with multicentric angiofollicular lymph node hyperplasia. Arch Pathol Lab Med 1979:103:591-594. 9 Pilon VA. Gomez LG. Butler JJ: Systemic amyloidosis associ ated with a benign mesenteric lymphoid mass. Am J Clin Pathol 1982;78:112-116. 10 Summerficld GP, Taylor W, Bellingham AJ, Goldsmith HJ: Hyaline-vascular variant of angiofollicular lymph node hyper plasia with systemic manifestations and response to corticoste roids. J Clin Pathol 1983;36:1005-1011.
11 Pincelli G, Falappa P, Danza FM: Mesenteric lymphoid hamar
toma. Diagn Imag 1981;50:321-324. 12 Ruggieri G. Tata MV, Ventola FR. Spinelli C, Balducci A. d’Ad-
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
amo G: A modified needle kidney biopsy: An open technique. Nephron 1985;41:367-368. Vanrenterghem Y, Roels L, Verberckmoes R, Michiesen P: Treatment of chronic glomerulonephritis with a combination of indomethacin and cyclophosphamide. Clin Nephrol 1975;4: 218-222. Marinozzi V, Faraggiana T: Impregnazione argentica ed ultramicrotomia nella diagnosi delle glomcrulonefriti. Pathologica 1980;72:1-26. Bartoli E, Massarelli G, Soggia G, Tanda F: Multicentric giant lymph node hyperplasia. A hyperimmune syndrome with a rap idly progressive course. Am J Clin Pathol 1980;73:423-426. Hineman VL, Phyliky RL. Banks PM: Angiofollicular lymph node hyperplasia and peripheral neuropathy. Association with monoclonal gammopathy. Mayo Clin Proc 1982;57:379-382. Karcher DS, Pearson CE, Butler WM, Hurwitz MA, Cassel PF: Giant lymph node hyperplasia involving the thymus with asso ciated nephrotic syndrome and myelofibrosis. Am J Clin Pathol 1982;77:100-104. Crook MJ, Shaheen KM, ManLee W: Giant lymph node hyper plasia associated with heavy proteinuria. NY State J Med 1984; 13:515-517. Urbano-Marquez A, Estruch R, Llebaria C, Pastor M. Rozman C: Generalized Castleman’s disease with urinary elimination of heavy chain fragments. Acta Haematol (Basel) 1984;71:400406. Stokes SH, Griffith RC, Thomas PRM: Angiofollicular lymph node hyperplasia (Castleman's disease) associated with vertebral destruction. Cancer 1985;56:876-879. Weisenburger DD, Nathwani BN, Winberg CD, Rappaport H: Multicentric angiofollicular lymph node hyperplasia: A clinicopathologic study of 16 cases. Hum Pathol 1985;16:162-172. Scully RE, Mark EJ, McNeely WF. McNeely BU: Case records of the Massachusetts General Hospital. Case 10-1987. N Engl J Med 1987;316:606-618. Noel LH, Zanetti M, Droz D, Barbanel C: Long-term prognosis of idiopathic membranous glomerulonephritis. Study of 116 untreated patients. Am J Med 1979;66:82-90. Donadio JV, Holley RE, Anderson CF. Taylor WF: Controlled trial of cyclophosphamide in idiopathic membranous nephropa thy. Kidney Ini 1974;6:431-439. Schena FP, Cameron JS: Treatment of proteinuric idiopathic glomerulonephritides in adults: A retrospective survey. Am J Med 1988:85:315-326. Wehrmann M, Bohole A, Bogenschutz O, Eissele R, Freislederer A. Ohlschlegel C. Schumm G, Batz C. Gartner HV: Long-term prognosis of chronic idiopathic membranous glomerulonephri tis. Clin Nephrol 1989;31:67-76. Ponticelli C, Zucchelli P, Imbasciati E, Cagnoli L, Pozzi C, Passerini P, Grassi C, Limido D. Pasquali S, Volpini T, Sasdelli M. Locatelli F: Controlled trial of mcthylprcdnisone and chloram bucil in idiopathic membranous nephropathy. N Engl J Med 1984;310:946-950. Ponticelli C, Zucchelli P. Passerini P. Cagnoli L. Cesana B. Pozzi C, Pasquali S, Imbasciati E, Grassi C, Redaelli B, Sasdelli M, Locatelli F: A randomized trial of methylprednisone and
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lesions was demonstrated 20 months later, and a 6-year follow-up examination was completely negative. In idio pathic MN, however, spontaneous remission requires a much longer time (mean 5.5 years) [23]; immunosup pressive drugs, if effective at all [24-26], need long-term therapy [ 13] or association with méthylprednisolone [27, 28] to induce stable remission; finally, complete disap pearance of MN morphologic lesions was not always seen in renal biopsies taken during clinical remission of the nephropathy [23, 29], In absence of antigen identification in the renal tis sue, the possible release of antigens responsible for the glomerular damage, as hypothesized in tumor-associated MN [30], cannot be excluded. Alternatively GLNH could also correspond to an altered immune response to endogenous or exogenous antigens. This mechanism has been suggested to explain MN associated with Hodgkin’s disease or other malignant lymphomas [30, 31]. Actual ly, the hypotesis of GLNH as a disreactive immunologi cal disorder [5, 6] and the similarity with lymph node changes seen in AIDS patients with systemic lymphadenopathy [32, 33] support this assumption.
29
30 31 32
Ruggicri/Barsotti/Coppola/Spinelli/Balducci/Vcntola/d’Adamo/Tata/Marinozzi
chlorambucil in idiopathic membranous nephropathy. N Engl J Med 1989;320:8-13. Rastogi SP. Hart-Mercer VJ, Kerr DNS: Idiopathic membra nous glomerulonephritis in adults: Remission following steroid therapy. Q J Med I969;38:335. Alpers CE, Cotran RS: Neoplasia and glomerular injury. Kidney Int 1986;30:465-473. Mallick NP, Short CD, Manos J: Clinical membranous nephrop athy. Nephron 1983;34:209-219. Baroni CD, Pezzella F, Stoppacciaro A, Mirolo M, Pescarmona E, Vitolo D, Cassano AM, Barsotti P, Nicoletti L, Ruco LP, Uccini S: Systemic lymphadenopathy (LAS) in intravenous drug abusers. Histology, immunohistochemistry and electron micros copy: Pathogenic correlations. Histopathology 1985;9:1275— 1293.
33 Lâchant NA, Sun NCJ, Leong LA, Oseas RS, Prince HE: Multicentric angiofoliicular lymph node hyperplasia (Castleman’s dis ease) followed by Kaposi’s sarcoma in two homosexual males with the acquired immunodeficiency syndrome (AIDS). Am J Clin Pathol 1985;83:27-33.
Received: April 3, 1989 Accepted: November 10, 1989 Giancarlo Ruggieri Servizio di Nefrologia e Dialisi Ospedale San Giacomo Via Canova, 29 1-00186 Roma (Italy)
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Am J Nephrol 1990;10:323-328
Membranous Nephropathy Associated with Giant Lymph Node Hyperplasia A Case Report with Histological and Ultrastructural Studies Giancarlo Ruggieria. Paola Barsottib, Giuseppe Coppolac, Cosimo Spinelli a, Alessandro Balduccia, Francesco Rosario Ventolaa, Gianna d ’Adamo'A. Marco Vincenzo Tatad, Vittorio Marinozzib 1 aServizio di Nefrologia c Dialisi e dDivisione di Chirurgia, Ospedale San Giacomo: '’Dipartimento di Biopatologia Umana, Università «La Sapienza»; ‘ Servizio di Anatomia Patologica, Ospedale San Giovanni, Roma, Italia
Key Words. Membranous nephropathy • Nephrotic syndrome ■Giant lymph node hyperplasia • Castleman’s disease Abstract. A young woman presented with nephrotic syndrome due to membranous nephropathy and a localized form of giant lymph node hyperplasia (Castleman’s disease) occurring as a large intra-abdominal mass. Five months after surgical removal of the mass, only mild proteinuria persisted. Twenty months later a second kidney biopsy showed a near-normal morphology. Six years later the patient was free of symptoms and had normal urinalysis. Reviewing the pertinent literature, it seems to be the first case of a biopsy-proven cure of membranous nephropathy in a patient with membranous nephropathy and Castleman’s disease.
Giant lymph node hyperplasia (GLNH) was first de scribed by Castleman et al. [1] in 1956 as a benign lym phoproliférative disorder, presenting as a solitary mass, the clinical manifestations of which mainly depend upon its localization and dimensions. Clinicopathologic classi fication [2] includes the more frequently occurring hya line-vascular (HV) type and the plasma cel! (PC) type which is often associated with systemic manifestations. Intermediate forms, sharing some aspects of both types, have also been reported. More recently a multicentric disease with histological features of GLNH but a more aggressive course was described [3, 4], Etiology, pathogenesis, and relationship between localized and multicentric forms of the disease are still being debated [5, 6]. 1 We wish to thank Dr. M. Peverini. who firstly studied the ab dominal mass, for her kind collaboration.
Renal involvement, in the form of proteinuria, uri nary sediment abnormalities, and/or renal function im pairment, has been reported (see table 1). Nevertheless, only very few histologically documented cases are avail able [7-10]. We describe a case of membranous nephropathy (MN) in a young female patient affected by a localized form of GLNH of HV type. After surgical excision of the mass, improvement of proteinuria was seen. The remis sion of the nephropathy was confirmed by a second renal biopsy and by a 6-year follow-up examination with neg ative urinalysis.
Case Report A 15-year-old woman with a > 1-year history of oedema, weight gain, and polyuria was admitted to the San Giacomo Hospital in December 1979. Physical examination revealed blood pressure 130/95 mm Hg, pitting ankle oedema, no peripheral lymphadenopathy: the spleen was palpable 2 cm below the costal margin. Initial
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Introduction
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Ruggieri/Barsotti/Coppola/Spinelli/Balducci/Ventola/d’Adamo/Tata/Marinozzi
Table 1. Renal involvement in Castleman’s disease Reference No.
n
Renal involvement
Castleman's disease form
type
Treatment
Outcome of renal disease
7
i
nephrotic syndrome; RB: minimal-change disease
L
HV
surgery
resolution
8
i
nephrotic syndrome; RB: membranous nephropathy
M
PC
none
not reported
15
i
proteinuria
M
HV
prednisone and cytotoxic drugs
renal failure
16
i
proteinuria, monoclonal gammopathy
M
PC
prednisone
not reported
17
i
nephrotic syndrome
L
HV
surgery and cytotoxic drugs
resolution
9
i
nephrotic syndrome; A: amyloidosis
L
PC
prednisone and cytotoxic drugs
renal failure
4
7/15
poorly defined renal abnormalities in 1 of 7; RB: no alteration on light microscopy
M
not reported
prednisone, prednisone and cytotoxic drugs, cytotoxic drugs, none
not reported
10
1/2
nephrotic syndrome, renal failure; RB: interstitial nephritis
M
HV
prednisone
improvement
18
1
heavy proteinuria
L
PC
surgery
resolution
19
1
heavy-chain proteinuria
M
mixed
prednisone and cytotoxic drugs
not reported
20
1
proteinuria
L
PC
radiation
resolution
21
6/16
proteinuria (3/6 hematuria, 2/6 renal failure)
M
PC or mixed
prednisone, prednisone and cytotoxic drugs, none
not reported
22
1
proteinuria, monoclonal gammopathy
M
PC
not reported
not reported
nephrotic syndrome; RB: (1) membranous nephropathy and (2) resolving glomerulonephritis
L
HV
surgery and cytotoxic drugs
resolution
This study 1
laboratory data were erythrocyte sedimentation rate 34 mm/h, total serum protein 50 g/1 (albumin 21, alpha-1 2.9, alpha-2 14, beta 8.2, gamma 3.9), IgG 3, IgA 0.6, IgM 1.8 g/1, cholesterol 7.7 mmol/l. triglycerides 3, haemoglobin 6.14 mmol/l, haematocrit 32%, iron serum content 8.4 mmol/l, white blood cell count 9,000/mm' with normal differential count, and platelets 300,000/mm5. Urinalysis showed proteinuria of 20 g/24 h with granular casts and red blood cells in urinary sediment. Normal or negative were blood urea nitro gen. serum creatinine, creatinine clearance, electrolytes, uricaemia. antistreptococcal antibodies, C3, C'4, direct and indirect Coombs tests, antinuclear antibodies, circulating immune complexes, hepati tis B surface antigen, fibrinogen, copper, and urinary light chains. Intravenous pyelography revealed no functional or morphologi cal renal abnormalities. Gastrointestinal X-ray showed compression of gastric body and antrum. An abdominal computerized tomogra phy scan confirmed the presence of a well-circumscribed intra abdominal soft-tissue mass which was considerably and homoge neously enhanced following intravenous infusion of contrast me dium. Radiological findings have already been reported (11],
An open needle kidney biopsy [12] performed in April 1980 established the diagnosis of MN. Two weeks later, excision of mesenteric mass and spleen (18 X 1 2 X 3 cm, 200 g) as well as a liver biopsy were performed. On histological examination the mesenteric mass was diagnosed as GLNH of the HV type. No significant alteration was detected at liver biopsy, and the spleen showed non-specific hyperplasia. One month later, heavy proteinuria and anaemia still persisted, and the patient started therapy with cyclophosphamide (125 mg daily) and indomethacin (150 mg daily) [13]. Re-evaluation of the patient in October 1980 revealed remission of the nephrotic syn drome with normalization of all laboratory data, but mild protein uria (1 g/24 h). Therapy was discontinued in November 1980. In June 1982, in view of persisting mild proteinuria (0.5 g/24 h), a second kidney biopsy showed mild glomerular abnormalities con sistent with resolution of the previous MN. From September 1982 proteinuna was constantly absent. In September 1988, 6 years later, the patient was completely free of symptoms and had normal labo ratory data.
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RB = Renal biopsy; A = autopsy; L - localized form; M = multicentric form. For explanation of the other abbreviations see text.
325
Fig. 1. Mesenteric mass. The small lymphoid follicles are closely arranged. The interfollicular tissue contains numerous capillaries. Reticulin. X45.
Fig. 2. Mesenteric mass. This lymphoid follicle shows a large lymphocytic zone and a small germinal center containing hyaline material (harrowhcad). Note the radially penetrating capillary (ar rows). HE. X 112.
Fig. 3. Kidney, 1st biopsy. Periodic acid-silver methenamine staining of semithin sections shows diffuse thickening of the capil lary walls. Basement membrane projections are well recognizable on the epithelial side. X 1,175.
F'ig. 4. Kidney, 1st biopsy. In the fragment reprocessed for elec tron microscopy from paraffin-embedded block, epimembranous and intramembranous deposits are well demonstrated. Uranyl ace tate and lead citrate. X 17,000.
Pathological Findings Mesenteric Mass. Grossly the lesion appeared as a single, ovoid, well-capsulatcd mass ( 1 2 X 5 X 4 cm). On microscopic examina tion (fig. 1. 2), the lesion consisted of multiple lymphoid follicles with small germinal centers surrounded by numerous mature lym phocytes. The interfollicular tissue was characterized by prominenl vascular proliferation and contained a mixed cell population. The capillaries showed plump endothelial cells, and in some cases they
were surrounded by hyaline fibrous tissue. A number of lymphoid follicles appeared transfixed by radially penetrating capillaries. A few germinal centers contained hyaline substance. In the examined sections no lymphatic sinuses were recognized. The data were con sistent with GLNH of HV type. Kidney. At the first renal biopsy the glomeruli were characterized by diffuse thickening of the capillary wall without appreciable cell proliferation. Immunofluorescence studies demonstrated a granular
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Membranous Nephropathy and Giant Lymph Node Hyperplasia
Fig. 5. Kidney, 2nd biopsy. Irregular profiles on the epithelial side of the glomerular basement membrane arc focally seen. Peri odic acid-silver methenamine. X 470.
Fig. 6. Kidney, 2nd biopsy. On electron microscopy, the glomer ular capillary wall shows intramembranous and subendothelial elec tron-lucent areas containing granular, electron-dense material. Uranyl acetate and lead citrate. X 15.000.
positive reaction with antisera against IgG, C3, and, to a lesser extent, IgM; the staining was diffusely distributed on the glomerular capillary walls. The diagnosis of MN was established. Retrospective histochcmical and ultrastructural studies were performed on Eponembedded tissue fragments reprocessed from the paraffin block. Periodic acid-silver methenamine staining [ 14] of semilhin sections (fig. 3) and electron microscopic examination of ultrathin sections (fig. 4) showed epimembranous deposits and basement membrane projections, thus confirming the previous diagnosis. The second renal biopsy, obtained 2 years after surgery, had his tological and ultrastructural features consistent with the resolution of the previous MN: periodic acid-silver methenamine staining of semithin sections showed focal alterations of the subepilhelial as pect of the glomerular basement membranes (fig. 5). Electron micro scopic examination (fig. 6) demonstrated diffuse irregularities of the basement membranes, i.e., electron-lucent areas in the lamina densa and irregular thickening of the lamina rara interna, consistent with reabsorbed deposits in resolving MN. From the second renal biopsy, tissue for immunofluorescence analysis was not available.
proteinuria and/or haematuria or renal function impair ment. Nevertheless, histological studies of renal lesions were reported only in a very few cases, namely in an MN [8], an interstitial nephritis [10], and a case with only mini mal alterations at the light microscopic level [4] in patients with multicentric Castleman’s disease and amy loidosis (1 case) [9] and a minimal-change glomerulopa thy [7] associated with localized GLNH. The present case is the first report of a well-documented MN in a patient with the localized form of GLNH of the HV type. Although improvement of renal and other systemic symptoms after treatment of Castleman’s disease has already been reported [7, 10, 17, 18, 20], the resolution of the renal lesions has never been documented by a sec ond renal biopsy.ln the present case the resolution of the MN after surgical excision of the abdominal mass was proven at the ultrastructural level by the disappearance of the epimembranous deposits. The possibility of coincidental occurrence of MN and Castleman's disease cannot be ruled out: however, the assumption of a cause-effect link between the lymphopathy and the renal disease seems to be highly attractive. In the present case remission of the nephrotic syndrome was observed 5 months after surgery at the end of 4 months’ medical treatment; complete cure of the MN
Discussion Proteinuria or nephrotic syndrome in patients with localized GLNH has been occasionally reported (ta ble 1). Renal involvement, however, is a more frequent finding in the multicentric form of the disease, with prevalence in the PC-type cases, as shown in the series of Frizzera et al. [4] and Weisenburger et al. [21] which include 7 of 15 and 6 of 16 patients, respectively, with
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References 1 Castleman B. Iverson L, Mendez VP: Localized mediastinal lymph node hyperplasia resembling thymoma. Cancer 1956;9: 822-830. 2 Keller AR, Hocholzer L, Castleman B: Hyaline-vascular and plasma cell types of giant lymph node hyperplasia of the medi astinum and other locations. Cancer 1972;29:670-683. 3 Gaba AR, Stein RS, Sweet DL, Variakojis D: Multicentric giant lymph node hyperplasia. Am J Clin Pathol 1978;69:86-90. 4 Frizzera G, Massarelli G, Banks PM. Rosai J: A systemic lym phoproliférative disorder with morphologic features of Castleman’s disease. Pathological findings in 15 patients. Am J Surg Pathol 1983;7:211-231. 5 Diebold J: Mise au point: Hyperplasies réactionelles et pseudo lymphomes ganglionnaires avec hypergammaglobulinémie. Ann Pathol 1983;3:269-283. 6 Fizzcra G: Castleman’s disease. Hum Pathol 1985;16:202-205. 7 Humphreys SR. Holley KE. Smith LH, Mcllrath DC: Mesenteric angiofollicular lymph node hyperplasia (lymphoid hamartoma) with nephrotic syndrome. Mayo Clin Proc 1975;50:317-321. 8 Weisenburger DD: Membranous nephropathy: Its association with multicentric angiofollicular lymph node hyperplasia. Arch Pathol Lab Med 1979:103:591-594. 9 Pilon VA. Gomez LG. Butler JJ: Systemic amyloidosis associ ated with a benign mesenteric lymphoid mass. Am J Clin Pathol 1982;78:112-116. 10 Summerficld GP, Taylor W, Bellingham AJ, Goldsmith HJ: Hyaline-vascular variant of angiofollicular lymph node hyper plasia with systemic manifestations and response to corticoste roids. J Clin Pathol 1983;36:1005-1011.
11 Pincelli G, Falappa P, Danza FM: Mesenteric lymphoid hamar
toma. Diagn Imag 1981;50:321-324. 12 Ruggieri G. Tata MV, Ventola FR. Spinelli C, Balducci A. d’Ad-
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amo G: A modified needle kidney biopsy: An open technique. Nephron 1985;41:367-368. Vanrenterghem Y, Roels L, Verberckmoes R, Michiesen P: Treatment of chronic glomerulonephritis with a combination of indomethacin and cyclophosphamide. Clin Nephrol 1975;4: 218-222. Marinozzi V, Faraggiana T: Impregnazione argentica ed ultramicrotomia nella diagnosi delle glomcrulonefriti. Pathologica 1980;72:1-26. Bartoli E, Massarelli G, Soggia G, Tanda F: Multicentric giant lymph node hyperplasia. A hyperimmune syndrome with a rap idly progressive course. Am J Clin Pathol 1980;73:423-426. Hineman VL, Phyliky RL. Banks PM: Angiofollicular lymph node hyperplasia and peripheral neuropathy. Association with monoclonal gammopathy. Mayo Clin Proc 1982;57:379-382. Karcher DS, Pearson CE, Butler WM, Hurwitz MA, Cassel PF: Giant lymph node hyperplasia involving the thymus with asso ciated nephrotic syndrome and myelofibrosis. Am J Clin Pathol 1982;77:100-104. Crook MJ, Shaheen KM, ManLee W: Giant lymph node hyper plasia associated with heavy proteinuria. NY State J Med 1984; 13:515-517. Urbano-Marquez A, Estruch R, Llebaria C, Pastor M. Rozman C: Generalized Castleman’s disease with urinary elimination of heavy chain fragments. Acta Haematol (Basel) 1984;71:400406. Stokes SH, Griffith RC, Thomas PRM: Angiofollicular lymph node hyperplasia (Castleman's disease) associated with vertebral destruction. Cancer 1985;56:876-879. Weisenburger DD, Nathwani BN, Winberg CD, Rappaport H: Multicentric angiofollicular lymph node hyperplasia: A clinicopathologic study of 16 cases. Hum Pathol 1985;16:162-172. Scully RE, Mark EJ, McNeely WF. McNeely BU: Case records of the Massachusetts General Hospital. Case 10-1987. N Engl J Med 1987;316:606-618. Noel LH, Zanetti M, Droz D, Barbanel C: Long-term prognosis of idiopathic membranous glomerulonephritis. Study of 116 untreated patients. Am J Med 1979;66:82-90. Donadio JV, Holley RE, Anderson CF. Taylor WF: Controlled trial of cyclophosphamide in idiopathic membranous nephropa thy. Kidney Ini 1974;6:431-439. Schena FP, Cameron JS: Treatment of proteinuric idiopathic glomerulonephritides in adults: A retrospective survey. Am J Med 1988:85:315-326. Wehrmann M, Bohole A, Bogenschutz O, Eissele R, Freislederer A. Ohlschlegel C. Schumm G, Batz C. Gartner HV: Long-term prognosis of chronic idiopathic membranous glomerulonephri tis. Clin Nephrol 1989;31:67-76. Ponticelli C, Zucchelli P, Imbasciati E, Cagnoli L, Pozzi C, Passerini P, Grassi C, Limido D. Pasquali S, Volpini T, Sasdelli M. Locatelli F: Controlled trial of mcthylprcdnisone and chloram bucil in idiopathic membranous nephropathy. N Engl J Med 1984;310:946-950. Ponticelli C, Zucchelli P. Passerini P. Cagnoli L. Cesana B. Pozzi C, Pasquali S, Imbasciati E, Grassi C, Redaelli B, Sasdelli M, Locatelli F: A randomized trial of methylprednisone and
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lesions was demonstrated 20 months later, and a 6-year follow-up examination was completely negative. In idio pathic MN, however, spontaneous remission requires a much longer time (mean 5.5 years) [23]; immunosup pressive drugs, if effective at all [24-26], need long-term therapy [ 13] or association with méthylprednisolone [27, 28] to induce stable remission; finally, complete disap pearance of MN morphologic lesions was not always seen in renal biopsies taken during clinical remission of the nephropathy [23, 29], In absence of antigen identification in the renal tis sue, the possible release of antigens responsible for the glomerular damage, as hypothesized in tumor-associated MN [30], cannot be excluded. Alternatively GLNH could also correspond to an altered immune response to endogenous or exogenous antigens. This mechanism has been suggested to explain MN associated with Hodgkin’s disease or other malignant lymphomas [30, 31]. Actual ly, the hypotesis of GLNH as a disreactive immunologi cal disorder [5, 6] and the similarity with lymph node changes seen in AIDS patients with systemic lymphadenopathy [32, 33] support this assumption.
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chlorambucil in idiopathic membranous nephropathy. N Engl J Med 1989;320:8-13. Rastogi SP. Hart-Mercer VJ, Kerr DNS: Idiopathic membra nous glomerulonephritis in adults: Remission following steroid therapy. Q J Med I969;38:335. Alpers CE, Cotran RS: Neoplasia and glomerular injury. Kidney Int 1986;30:465-473. Mallick NP, Short CD, Manos J: Clinical membranous nephrop athy. Nephron 1983;34:209-219. Baroni CD, Pezzella F, Stoppacciaro A, Mirolo M, Pescarmona E, Vitolo D, Cassano AM, Barsotti P, Nicoletti L, Ruco LP, Uccini S: Systemic lymphadenopathy (LAS) in intravenous drug abusers. Histology, immunohistochemistry and electron micros copy: Pathogenic correlations. Histopathology 1985;9:1275— 1293.
33 Lâchant NA, Sun NCJ, Leong LA, Oseas RS, Prince HE: Multicentric angiofoliicular lymph node hyperplasia (Castleman’s dis ease) followed by Kaposi’s sarcoma in two homosexual males with the acquired immunodeficiency syndrome (AIDS). Am J Clin Pathol 1985;83:27-33.
Received: April 3, 1989 Accepted: November 10, 1989 Giancarlo Ruggieri Servizio di Nefrologia e Dialisi Ospedale San Giacomo Via Canova, 29 1-00186 Roma (Italy)
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