Nephrol. Dial. Transplant.-2001-Curioni-1475-8

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					Nephrol Dial Transplant (2001) 16: 1475±1478

Case Report

Castleman's disease with nephrotic syndrome, amyloidosis and
autoimmune manifestations

Simona Curioni1,2, Marco D'Amico1,5, Rita Quartagno3, Stefania Martino1,3,
Giacomo Dell'Antonio4 and Daniele Cusi1

 Chair of Nephrology and Graduate School of Nephrology, University of Milan, 2Division of Nephrology,
S. Carlo Borromeo Hospital, 3Division of Nephrology, Dialysis and Hypertension, S. Raffaele Hospital,
 Department of Pathology, S. Raffaele Hospital, Milan, and 5Division of Nephrology, A. Manzoni Hospital,
Lecco, Italy

Keywords: AA amyloidosis; autoimmune manifesta-                     of the AA type, and a plethora of autoimmune
tions; Castleman's disease (hyaline±vascular type);                 manifestations: uveitis, deep venous thrombosis, anti-
nephrotic syndrome; uveitis; venous thrombosis                      cardiolipin antibody positivity, pyoderma gangreno-
                                                                    sum, epididymitis, and sacroiliitis.

Castleman's disease (also called giant lymph-node
hyperplasia or angiofollicular lymph-node hyper-                    A 39-year-old male patient of Tunisian origin was
plasia) is a highly heterogeneous clinico-pathological              admitted to our unit in 1999 because of abdominal
entity belonging to the lympho-proliferative disorders.             pain, nephrotic syndrome, and latero-cervical lympho-
Originally described in 1956 by Castleman and                       adenopathy.
co-workers w1x as a large, benign, unique asymptomatic                 The patient's past medical history had begun 7 years
mass of mediastinal lymph nodes, it was shown in                    earlier. In 1992, he sought medical attention for recur-
subsequent reports to include extra-mediastinal and                 rent ulceration in the lower limbs. At that time a skin
multicentric forms w2x.                                             biopsy was performed in a dermatology unit and
   Two histological patterns of lymph nodes were                    showed pyoderma gangrenosum.
described: the hyaline±vascular and plasma-cell types.                 Two years later (1994) he began reporting recurrent
The former is more common (80±90%), and is char-                    abdominal pain crises, and during one of these he
acterized by the proliferation of capillary vessels in              underwent appendectomy (the results of the histo-
germinal centres of lymphatic folliculi, which assume               logical examination are not available). The operation
a hyaline aspect. It is classically reported to have                was complicated by thrombosis of the inferior vena
mono-localization, often mediastinal, and a benign                  cava and did not provide any relief to the patient's
course after removal of the mass. The plasma-cell                   abdominal complaints. In the same year the patient
variant is less frequent (10±20%) and presents hyper-               noticed the appearance of a left latero-cervical mass,
plastic follicles interspersed by sheets of plasma cells.           but no further investigations were undertaken.
It is often multi-centric and usually associated with                  From 1995 the patient's clinical picture became
systemic manifestations of in¯ammatory disease. The                 complicated by uveitis, epididymitis, arthralgias,
prognosis is worse, with infections and progression to              chronic lumbar back pain, recurrent diarrhoea,
lymphoma as the major causes of death. Mixed or                     proctorragia, weight loss (the exact chronology could
transitional forms have also been described w2x.                    not be documented by the patient), and led to his
   We report here an unusual case of Castleman's                    admission to a department of internal medicine (1997).
disease of the hyaline±vascular type with multi-centric             On that occasion, proteinuria (2 guday), and positivity
localization (cervical, mediastinal, abdominal), charac-            for anti-cardiolipin IgG (52.8 Uuml) and anti-hepatitis
terized by nephrotic syndrome, systemic amyloidosis                 C virus (HCV) antibodies (HCV-RNA was negative)
                                                                    were found. Multiple left latero-cervical lymph nodes
                                                                    were documented by ultrasound examination, in addi-
Correspondence and offprint requests to: Simona Curioni MD,         tion to the node that had been present since 1994,
Division of Nephrology, S. Carlo Borromeo Hospital, via Pio II 3,   and was about 5 cm in diameter. The biopsy of a
I-20153 Milan, Italy.                                               minor lymph node showed diffuse histiocytosis, focal

#   2001 European Renal Association±European Dialysis and Transplant Association
1476                                                                                                             S. Curioni et al.

amyloid, and no granulomas. A bone marrow biopsy
was normal. Chronic in¯ammatory bowel diseases were
excluded by colonoscopy and small-bowel enema. The
attending physicians diagnosed an anti-phospholipid
antibody syndrome and the patient was treated with
oral anticoagulants and corticosteroids. The latter
were spontaneously withdrawn by the patient about
1 year later.
   No history of chronic fever or familial amyloidosis
was reported.
   On admission to our unit (1999), the clinical picture
was dominated by severe abdominal pain and overt
nephrotic syndrome with normal renal function
(proteinuria ranged from 3 to 7 guday, with electro-
phoretic pattern of glomerular, partially selective
proteinuria; proteinaemia was 3.62 gudl, albuminaemia
30.6%, and creatinine clearance 127 mlumin).               Fig. 1. Details of the cervical lymph node, with follicular hyperplasia
   Physical examination showed orthostatic hypo-           and hyalinized vessels with amyloid deposits (Congo red, white light,
tension, 3q pre-tibial pitting oedema, super®cial          original magni®cation 3 200).
cava±cava venous reticulum on the abdomen, a left
latero-cervical mobile mass of about 5 cm, and skin
dyschromia of the lower limbs. The abdomen had no          focal deposits of amyloid (Figure 1). The patient
signs of peritonitis.                                      underwent a renal biopsy, resulting in a diagnosis of
   The abdominal investigation by ultrasound and           amyloidosis with intense glomerular and interstitial
colour Doppler, computed tomography (CT) and               vessel involvement. The potassium permanganate pre-
angio-NMR con®rmed the already identi®ed inferior          treatment abolition of Congo red staining, the absence
vena cava thrombosis, excluded other surgical patho-       of k and l deposits on immuno¯uorescence, and
logy, and revealed multiple mesenteric and para-           the positive immunostaining with anti-human amyloid
aortic±caval lymph nodes of approximately 1 cm in          A component antibody (Dakopatts, Denmark) con-
diameter. Another lymph node of about 1 cm was             ®rmed the diagnosis of renal amyloid of the AA
shown by thoracic CT at the right pulmonary hilus.         secondary type (Figure 2), which was also found in
   The laboratory data showed normal white blood           multiple intestinal biopsies.
cell count (6300uml), microcytic anaemia (haemoglobin         Because of the history of arthralgias and back pain,
9.5 gudl, mean cell volume 72 ¯ with normal haemo-         X-rays were performed on pelvis, spine, and main
globin electrophoresis), normal reticulocyte count         joints, and showed bilateral sacroiliitis.
(60 3 106ul), reduced iron stores (serum iron 30 mgudl,       The patient was treated with colchicine (1 mguday),
serum ferritin 25 mguml, total iron binding capacity       indomethacin (75 mguday), diuretics, and a 2-month
1.08 gul), increased in¯ammatory indices (C-reactive       corticosteroid course (prednisone 1 mgukguday, which
protein 40 mgul, erythrocyte sedimentation rate            was later tapered off and stopped because of the
64 mmu1st h, IL-6 23 pguml); normal liver enzymes,         occurrence of severe left lower-limb phlebitis).
serum b2 microglobulin (2.31 ngul) and circulating            Three months later, the patient's general conditions
angiotensin-converting enzyme levels (50 Uul). No          were ameliorated, abdominal and back pain were
monoclonal components were found in serum or urine.        reduced, nephrotic syndrome had partially remitted
Serology for autoimmunity was negative (ANA, ENA,          (proteinuria was 2.12 guday, proteinaemia 5.23 gudl,
rheumatoid factor, anti ds-DNA, SS-A, SS-B, anti-Sm,       and albuminaemia 38.8%), and in¯ammatory indices
anti-RNP, anti-Scl70 autoantibodies, C3, C4, immu-         were reduced (C-reactive protein was 5 mgul, and IL-6
noglobulin dosage, cryoglobulins, ANCA). In parti-         12 pguml). Anaemia also had improved (haemoglobin
cular, positivity for antiphospholipid antibodies was      11.2 gudl).
not con®rmed (lupus-like anticoagulant was negative,
anti-cardiolipin IgG was 8 Uuml, anti-cardiolipin IgM
was 3 Uuml).
   Serology for infections was negative, including         Discussion
human immunode®ciency virus (HIV), and HCV (both
HCV antibodies and HCV-RNA). IgG antibodies were           Since its initial description, Castleman's disease has
positive only for cytomegalovirus (CMV), Epstein±          been rede®ned from a localized tumour-like mass of
Barr virus (EBV), and Toxoplasma. A PPD skin test          lymphoid tissue, considered to be hamartomatous, to
was non-reactive. Tests for BK in the sputum and           a systemic disease with general manifestations and
parasites in the stool were also negative.                 multiple organ involvement. The localized forms are
   The largest cervical mass of 5 cm was surgically        often mediastinal, asymptomatic, and associated with
removed and histological examination revealed              the hyaline±vascular histological pattern. Multicentric
Castleman's disease of the hyaline±vascular type with      forms often have an aggressive and relapsing course,
Castleman's disease with nephrotic syndrome and amyloidosis                                                               1477

                                                                     autoimmune diseases (systemic lupus erythematosus,
                                                                     POEMS syndrome, etc.) w2x. When this patient came
                                                                     under our observation, anti-HCV antibodies were no
                                                                     longer present (both HCV antibodies and HCV-RNA
                                                                     were negative) and other infections, including HIV,
                                                                     were ruled out. The autoantibody pattern and the
                                                                     clinical picture did not point to any primary auto-
                                                                     immune disease. Moreover, the cervical mass, from
                                                                     which Castleman's disease was subsequently dia-
                                                                     gnosed, had appeared before many of the organ com-
                                                                     plications, reinforcing our hypothesis that Castleman's
                                                                     disease was responsible for triggering the in¯ammatory
                                                                     response with consequent autoimmune organ mani-
                                                                     festations and secondary AA-amyloid deposition,
                                                                     which in turn was responsible for the nephrotic syn-
                                                                     drome, the gastrointestinal disorders, and orthostatic
                                                                        Systemic amyloidosis is a very rare complication
                                                                     of Castleman's disease. Only 17 cases have been
                                                                     described, and only nine of these had nephrotic syn-
                                                                     drome caused by documented renal amyloidosis w3x.
                                                                     All were of the plasma cell or mixed histological
                                                                     pattern. Other reported forms of renal involvement in
                                                                     Castleman's disease are rare and heterogeneous, and
                                                                     include minimal-change disease, membranous GN,
                                                                     membranoproliferative GN, mesangial proliferative
                                                                     GN, and interstitial nephritis w4x.
                                                                        Recent studies have demonstrated an association
                                                                     of Castleman's disease with excess production of the
                                                                     cytokine IL-6 w4x. IL-6 is a pleiotrophic cytokine
                                                                     produced by several cell types, including activated
                                                                     monocytes, B cells, endothelial cells, ®broblasts, and
                                                                     mesangial cells. It has a panoply of biological effects,
Fig. 2. Glomeruli with large amyloid deposits, demonstrated (a) by   including a major regulatory effect on acute-phase
intense staining for Congo red and (b) by anti-human amyloid A       response in humans. Large amounts of IL-6 were
component (original magni®cation 3 200).                             shown to be produced at the germinal centres of hyper-
                                                                     plastic lymph nodes from patients with Castleman's
                                                                     disease, and clinical improvement was observed along
                                                                     with decreases in IL-6 levels after the removal of the
and are usually associated with the plasma cell pattern              involved lymph nodes w4x or treatment with anti-IL-6
and with systemic manifestations.                                    antibodies w5x. Corticosteroid therapy has also been
    Our case is unusual in that the hyaline±vascular                 shown to reduce IL-6 levels.
histological pattern was observed in a patient with                     Accordingly, our patient had increased IL-6 levels
documented multi-station lymph-node involvement                      (23 pguml) on admission to our unit. Three months
(the major being cervical, the others mediastinal and                after the excision of the largest lymph node mass and
abdominal) and an impressive concomitant chronic                     the initiation of therapy (steroids, colchicine, and
in¯ammatory state. In fact, beyond the general and                   indomethacin), IL-6 decreased to near normal values
previously described in¯ammatory signs (malaise,                     (12 pguml) and the clinical picture ameliorated (partial
weight loss, anaemia, increased in¯ammatory indices),                remission of the nephrotic syndrome, lessening of
the patient's clinical history was characterized by a                abdominal and back pain, improvement of anaemia,
plethora of autoimmune manifestations, including                     and reduction of in¯ammatory indices).
pyoderma gangrenosum, uveitis, epididymitis, sacroi-                    The treatment of Castleman's disease and the
liitis, and positive anticardiolipin antibodies (which               possible reversal of both amyloidosis and the nephrotic
were not re-con®rmed, probably due to the previous                   syndrome are controversial issues, based essentially on
corticosteroid treatment).                                           case reports, since controlled clinical studies are lack-
    As currently understood, Castleman's disease is                  ing because of the rarity of the disease. In some reports
considered to be a heterogeneous entity related to                   on monocentric forms, it was shown that the surgical
conditions of immune deregulation. In this respect, it is            removal of the lymph node mass was curative w6,7x
interesting that various disorders of the immune                     and led to the regression of the nephrotic syndrome
system may be characterized by Castleman-like histo-                 and of amyloidosis, as detected by abdominal fat
logical changes, such as infections (HIV) and primary                aspiration biopsy w6x. However, a recent report,
1478                                                                                                                S. Curioni et al.

although con®rming the regression of the nephrotic               References
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Acknowledgements. This work was supported in part by Ministero       of unicentric and multicentric Castleman's disease: a report
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                                                                 Received for publication: 4.11.00
                                                                 Accepted in revised form: 9.1.01

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