Nephropathology Slide Seminar: Case 2 European Congress of Pathology 30.8.2011

1. Nephropathology Slide Seminar: Case 2European Congress of Pathology 30.8.2011 Anne Raisanen-Sokolowski, MD, PhD Transplantation Laboratory Helsinki University Central Hospital Helsinki, Finland

2. 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

3. 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)

4. 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

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

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

13. 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: 14:2370-2378

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, 285-299

15. 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, 285-299

16. 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-1b and IL-6 stimulate VEGF production Dispenzieri: POEMS syndrome. Blood Reviews 2007: 21, 285-299

17. 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: 14:2370-2378

18. 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, 285-299

19. If we knew what we were doing it would not be called research A. Einstein Midnight Sun in Pyhatunturi, Lapland, July 14, 2011 at 23.28