Castle-POES disease Castle-POES disease successfully treated with successfully treated with RituximabRituximab

Nezam Torok , MD Nezam Torok , MD

PGY2PGY2

History : History :

A 42 year old African American Man A 42 year old African American Man CC : Back pain , for 1 week CC : Back pain , for 1 week

PMH : PMH : Nov 2008 : Pericardial Nov 2008 : Pericardial

effusioneffusion Dec 2008 : Suspecion Dec 2008 : Suspecion

of sarcoidosisof sarcoidosis

Social history Social history

Smoker Smoker 30 PPY 30 PPY sexual dysfunctionsexual dysfunction

Neurological : Motor function : power Neurological : Motor function : power 4/5 lower limb –leg flexor and extensors 4/5 lower limb –leg flexor and extensors as well as foot , bilaterally with as well as foot , bilaterally with diminished DTR and decreased diminished DTR and decreased sensation to touch , pain , and position , sensation to touch , pain , and position , otherwise negative .otherwise negative .

More lab tests : More lab tests :

HIV , HHV 8 negativeHIV , HHV 8 negative Normal or negative tests include Normal or negative tests include

: TFT , LH , FSH , : TFT , LH , FSH , testosterone ,ANA , ANCA , testosterone ,ANA , ANCA , ACE ,RF , SS-A , SS-B , C3, C4, ACE ,RF , SS-A , SS-B , C3, C4, Hep B , Hep C ,PSA, vit B12 , Hep B , Hep C ,PSA, vit B12 , APA .APA .

SPE : SPE : increase in IgG 1950increase in IgG 1950 mg/dL(normal 590-1540 mg/dL(normal 590-1540

mg/dL) mg/dL) mild increase in IgA mild increase in IgA 498 (normal 498 (normal

50-413mg/dL )50-413mg/dL ) serum immunofixation polyclonal serum immunofixation polyclonal

hypergammaglobulinemia with slightly excess hypergammaglobulinemia with slightly excess lambda chains , kappa chains 1040 mg/dL lambda chains , kappa chains 1040 mg/dL ( normal 539 -1320 mg/dL) , and ( normal 539 -1320 mg/dL) , and Lambda Lambda chains 690mg/dLchains 690mg/dL (normal 285-673mg/dL ) (normal 285-673mg/dL ) with kappa /lambda ratio of 1,5 .with kappa /lambda ratio of 1,5 .

Normal architecture

Effaced architecture of the LN in castlemans disease , HE stain 4 X

Normal architecture of LN

Atrophic germinal centers , HE stain 40X

Normal germinal center, containing larger lymphocytes undergoing activation

Atrophic germinal center and effaced architercture

Vascular proliferation ,10 X

Vascular proliferation 20 X

Vascular proliferation 40 X

interleukin 6 level: interleukin 6 level: 6 pg/ml (normal 6 pg/ml (normal 0-5pg/ml)0-5pg/ml)

plasmaplasma Vascular Endothelial Growth Vascular Endothelial Growth factor factor level (VEGF): 130 pg/ml level (VEGF): 130 pg/ml (normal 6-86 pg/ml) (normal 6-86 pg/ml)

normal interleukin 1.normal interleukin 1.

Summary of findings Summary of findings

Osteosclerotic lesionsOsteosclerotic lesions Neuropathy motor and sensory Neuropathy motor and sensory Skin changes Skin changes Lymphadenopathy Lymphadenopathy History of pericardial effusion History of pericardial effusion Castlemans disease Castlemans disease High IL-6 and VEGF High IL-6 and VEGF

Diagnosis is Diagnosis is

Multicentric Multicentric Castleman’s disease Castleman’s disease

with features of with features of POEMS syndrome POEMS syndrome

(Castle-POES)! (Castle-POES)!

Treatment Treatment

There is no standard treatment for this There is no standard treatment for this disorder and no randomized or quasi-disorder and no randomized or quasi-randomized controlled clinical trials of randomized controlled clinical trials of treatment for POEMS syndrome exist in treatment for POEMS syndrome exist in the available literature*the available literature*

* * Treatment for POEMS (polyneuropathy, organomegaly, Treatment for POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome. endocrinopathy, M-protein, and skin changes) syndrome. Kuwabara S; Dispenzieri A; Arimura K; Misawa S Kuwabara S; Dispenzieri A; Arimura K; Misawa S Cochrane Cochrane Database Syst Rev. 2008 Oct 8;(4):CD006828Database Syst Rev. 2008 Oct 8;(4):CD006828

How did we treat the How did we treat the patient patient

Rituximab Rituximab

375/m2 , weekly for 375/m2 , weekly for 4 weeks , then once 4 weeks , then once every 2-3 months every 2-3 months

How did the patient How did the patient respond respond

Remarkable improvement in muscle Remarkable improvement in muscle power , able to function again power , able to function again

Fatigue resolved Fatigue resolved Sexual function improved.Sexual function improved. Dec PET scan activity at the scerotic Dec PET scan activity at the scerotic

bone lesions bone lesions No lymphadenopathy No lymphadenopathy

BUT BUT

VEGF was still at the same level .VEGF was still at the same level . no change in skin lesions.no change in skin lesions. SPEP and immunofixation the same SPEP and immunofixation the same

pattern pattern

Investigational Investigational model model

differential scanning differential scanning calorimeter (DSC) calorimeter (DSC)

differential scanning differential scanning calorimeter (DSC calorimeter (DSC

Our Patient Control

The DST shows abnormal thermogram, The DST shows abnormal thermogram, which means there is abnomal molecular which means there is abnomal molecular species present in the serum of the serum species present in the serum of the serum sample that interact in a significant way with sample that interact in a significant way with one or more of the proteins in the serum one or more of the proteins in the serum

it is different from electrophoresis technique it is different from electrophoresis technique that are sensitive to size and charge that are sensitive to size and charge

What kind of protein , whats is the relation to What kind of protein , whats is the relation to immunofixation ?immunofixation ?

         “ “Thinking is more interesting than knowing, but less interesting than looking”.”.

References References BradwickBradwick PA, Zvaifler NJ, Gill GN, PA, Zvaifler NJ, Gill GN, et al. et al. Plasma celldyscrasia with Plasma celldyscrasia with

polyneuropathy, organomegaly,endocrinopathy, M protein and skin polyneuropathy, organomegaly,endocrinopathy, M protein and skin changes: the POEMSsyndrome. changes: the POEMSsyndrome. Medicine Medicine 1980; 1980; 5959: 311–322: 311–322

DispenzieriDispenzieri A, Kyle RA, Lacy MQ, et al. POEMS syndrome: definitions and A, Kyle RA, Lacy MQ, et al. POEMS syndrome: definitions and long-term outcome. Blood 2003;101:2496–506long-term outcome. Blood 2003;101:2496–506

NakanishiNakanishi T, Sobue I, Toyokura Y, et al. The Crow-Fukase syndrome: a T, Sobue I, Toyokura Y, et al. The Crow-Fukase syndrome: a study of 102 cases in Japan. Neurology 1984;study of 102 cases in Japan. Neurology 1984;34:712-20. 34:712-20.

ShikamaShikama N, Isono A, Otsuka Y, Terano T, Hirai A N, Isono A, Otsuka Y, Terano T, Hirai A.a case of POEMS .a case of POEMS syndrome with high concentration of IL-6 in pericardial fluid .syndrome with high concentration of IL-6 in pericardial fluid . J Intern J Intern Med. 2001 Aug;250(2):170-3Med. 2001 Aug;250(2):170-3

HashiguchiHashiguchi T, Arimura K, Matsumuro K, et al. Highly concentrated T, Arimura K, Matsumuro K, et al. Highly concentrated vascular endothelial growth factor in plateletsin Crow-Fukase syndrome. vascular endothelial growth factor in plateletsin Crow-Fukase syndrome. Muscle Nerve. 2000;23:1051-1056.Muscle Nerve. 2000;23:1051-1056.

SoubrierSoubrier M, Dubost JJ, Serre AF, et al. Growth factors in POEMS M, Dubost JJ, Serre AF, et al. Growth factors in POEMS syndrome: evidence for a marked increase in circulating vascular syndrome: evidence for a marked increase in circulating vascular endothelial growth factor. Arthritis Rheum. 1997;40:786-787endothelial growth factor. Arthritis Rheum. 1997;40:786-787

Joanne Shirine Allam, Cassie C. Kennedy, Timothy R. Aksamit and Joanne Shirine Allam, Cassie C. Kennedy, Timothy R. Aksamit and Angela Angela Dispenzieri Dispenzieri . Pulmonary Manifestations in Patients With POEMS Syndrome. . Pulmonary Manifestations in Patients With POEMS Syndrome. Chest Chest 2008;133;969-9742008;133;969-974