Nephropathology Slide Seminar: Case 2 European Congress of Pathology Anne Raisanen-Sokolowski, MD, PhD Transplantation Laboratory Helsinki University Central Hospital Helsinki, Finland

Patient data 1 53 years old, previously healthy male One year ago vision began to worsen, diagnosed and treated as iritis Thereafter fever (ad 39°C) and malaise for 6 months. He suffered malfunction of intestine, edema in the lower extremities and muscle weakness, loss of appetite, weight loss

Patient data 2 The patient presented with:  tingling in finger tips and polyneuropathy by ENMG  hepatosplenomegalia Ultrasound: several focal defects in liver, suspicion of metastasis Biopsy: necrosis -> suspicion of Tbc -> treatment started -> laboratory findings negative Ascites  Hypogonadism (low testosterone)

Patient data 3 The patient presented with:  paraproteinemia in plasma (kappa light chain, 3-10 g/l) crista biopsy 10% plasma cells  hematuria (>20 erytrocytes/hpf)  proteinuria (dU-Prot 0,32-0,42 g/day, P-Alb 27 g/l, Crea 103 mmol/l)  Cachexia Kidney biopsy taken

Immunofluoresence study Performed in frozen sections IgG, IgA, IgM, C3, C1q, fibrinogen, kappa and lambda were negative

Biopsy findings Glomeruli  lobular and mesangial proliferation  GBM duplication, mesangial interposition  no immune deposit (IF and EM negative) Tubuli and vessels  unremarkable

Diagnosis Membranoproliferative glomerulonephritis associated with POEMS syndrome  Polyneuropathy  Organomegaly (hepatosplenomegaly)  Endocrinopathy (hypogonadism)  M-component (kappa light chain) in plasma  Skin lesions (none) Nakamoto et al: A spectrum of clinicopathological features of nephropathy associated with POEMS syndrome. NDT 1999: 14:

POEMS syndrome 1 POEMS syndrome is a rare paraneoplastic syndrome secondary to plasma cell dyscrasia  Usually lambda light chain (95%) Incidence peaks in 5th and 6th decade of life, unlike multiple myeloma (7-8th) Dispenzieri: POEMS syndrome. Blood Reviews 2007: 21,

POEMS syndrome 2 Complex pathogenesis: elevation of proangiogenic and proinflammatory cytokines are hallmarks of this disorder Patients with POEMS have elevated VEGF levels in plasma, serum, ascites and cerebrospinal fluid Dispenzieri: POEMS syndrome. Blood Reviews 2007: 21,

POEMS syndrome 3 VEGF is the dominant driving cytokine  Targets endothelial cells and induces an increase in vascular permeability  Important in angiogenesis and osteogenesis  VEGF is expressed by osteoblasts, in bone tissue, macrophages, tumor cells (including plasma cells), megakaryocytes and platelets  IL-1  and IL-6 stimulate VEGF production Dispenzieri: POEMS syndrome. Blood Reviews 2007: 21,

Pathological features of POEMS nephropathy Glomerular enlargement Cell proliferation and swelling Mesangial loosening and mesangiolysis Microaneurysms Nodular-like lesions Infiltration of plasma cells and mononuclear cells Tubular atrophy and interstitial fibrosis Acute tubular necrosis No immune deposits Nakamoto et al: A spectrum of clinicopathological features of nephropathy associated with POEMS syndrome. NDT 1999: 14:

Treatment No randomized, controlled trials in POEMS Radiation therapy, chemotherapy, corticosteroids, anti-VEGF mAb (Bevacizumab, Avestin) and stem cell transplantation Case Patient received cyclic chemotherapy- corticosteroids-Bevacizumab treatment for 11 months, remission -> autologous stem cell transplantation 3/2011 ->5/2011 in remission Dispenzieri: POEMS syndrome. Blood Reviews 2007: 21,

Midnight Sun in Pyhatunturi, Lapland, July 14, 2011 at If we knew what we were doing it would not be called research A. Einstein