Survivin and XIAP expression in multiple pulmonal metastasesSurvivin and XIAP expression in multiple pulmonal metastasesfrom renal cell carcinoma (RCC) patients:from renal cell carcinoma (RCC) patients:

results of tissue micro array (TMA) studiesresults of tissue micro array (TMA) studiesP. SchneiderP. Schneider11, B. Baier, B. Baier22, O. Holotiuk , O. Holotiuk 33, M. Meinhard , M. Meinhard 44, A. Meye, A. Meye11 , A. Rolle , A. Rolle22, M.P. Wirth, M.P. Wirth11

http://urologie.uniklinikum-dresden.de

ptr.schneider@gmx.de

(1) Technical University of Dresden, Department of Urology, Dresden, Germany, (2) Coswig Specialised Hospital, Center for Pneumology and Thoracic Surgery, Department of Thoracic and Vascular Surgery, Coswig, Germany, (3) Group Practice for

Pathology Dresden, Dresden, Germany, (4) Technical University of Dresden, Institute of Pathology, Dresden, Germany

- this study firstly described the expression of Inhibitors of Apoptosis Protein (IAP) members in a great number of pulmonal ms from RCC

- (over)-expression of survivin and XIAP is higher than data known for primary RCC and normal kidney/lung- tissue

- marked intratumoral heterogeneity for survivin and XIAP

- in contrast to expression-score of patients, expression in single ms correlates with clinical parameters

ms should be counted as single tumors or groups of tumors with different expression levels could be a hint for repeatedly process of metastasis

- poorly differentiated tumors showed significant higher expression for both IAPs, higher expression of survivin correlates with increased levels of XIAP

- higher expression for XIAP correlates with poor survival

- low expression of survivin and XIAP is linked to higher number of ms and high expression leeds to extended time to ms-relapse

Conclusions

Introduction

- 3% of diagnosed tumors are renal origin, 50% of patients develop metastases (ms) 1

- frequent RCC ms-sites: 50-60% lung, 30-40% bone, 30-35% liver 2

- limited expression studies for pulmonal ms

- former described high expression of survivin and XIAP in RCC is linked with poor differentiation and lowered disease specific survival 3,4

References

(1) Janzen, N. K. et al. Urol Clin North Am 2003; 30(4): 843-52.

(2) Motzer, R. J. et al. N Engl J Med 1996; 335(12): 865-75.

(3) Parker, A. et al. Cancer 2006; 107(1): 37-45.

(4) Ramp, U., et al. Hum Pathol 2004; 35(8): 1022-8.

Survivin

- 89% of ms punches showed a typical cytoplasmatic staining for survivin (Fig.2)

- 71% of punches with lung tissue were negative

- ms were arranged in four groups by intensity and number of positive tumor cells (Tab.1)

- Survivin-groups showed significant correlations to following clinical parameters

- primary tumor N-stage (p<0.01)- primary tumor G-stage (p<0.01)- number of ms (p<0.01) (invers)- number of lymph node ms (p<0.05)- grading of ms (p<0.001)

- patients were divided into two groups according to survivin-status of corresponding ms

no significant correlations could be observed

Results I

Fig.2 Punch of RCC stained with anti-survivin

4x 40x

Tab.1 Arrangement of ms, allocation to groups

Fig.3 Kaplan-Meier-curves for disease-time (a), disease-free-intervall (b) and time to ms-relapse (c) with results of log-rank-test

XIAP

- 80% of ms punches showed characteristic cytoplasmatic staining for XIAP (Fig.5)

- 93% of lung punches showed no expression

- ms were divided into three groups by intensity and number of positive tumor cells (Tab.2)

- observed significant correlations between XIAP-groups and clinical parameters

- primary tumor T-stage (p<0.01) (invers)- primary tumor N-stage (p<0.001)- primary tumor G-stage (p<0.01)- number of ms (p<0.01) (invers)- grading of ms (p<0.001)- clinical staging (p<0.05) (invers)

- patients were arranged in three groups, according to XIAP-status of corresponding ms

Results II

4x 40x

Fig.4 Punch of RCC stained with anti-XIAP

Tab.2 Arrangement of ms, allocation to groups

Fig.5 Kaplan-Meier-curves for disease-time (a), disease-free-intervall (b) and time to ms-relapse (c) with result of log-rank-test

- Survivin expression correlates significantly with expression of XIAP (p<0.0001)

Results III

01

2

0

1

2

3

17 40

139

36 58 82

25

152522

28

23

XIAP

Survivin

Fig.6 Coherency between XIAP- and survivin-expression

Patients- 84 (52♂, 32♀) with clear cell RCC, age 43-82

- all with nephron-sparing or complete nephrectomy

- disease-time 5-376 month, disease-free-interval 0-348 month

Metastases- 606 ms, ranged from 1-64 per patient

- all resected with Nd:YAG-laser (precision resection)

Tissue micro arrays- 2 punches of every ms

- altogether 1201 ms-punches

- 118 punches from corresponding lung tissue

- arrayed on 9 blocks, first punch on outer ring, second at core, corresponding lung-tissue on separate field (Fig.1)

Immunohistochemistry

- 10 slides per TMA, 4µm thick

- slide 1 and 10 H&E stained, reviewed by pathologist

- staining with Vectastain ABC-AP Kit Universal

- XIAP: hILP/XIAP 610762, BD Biosciences, Heidelberg, BRD Vector Red AP Substrat Kit 1

- Survivin: human Survivin AF886, R&D Systems Inc., Minneapolis, MN, USA AP-New-Fuchsin

- evaluation with optical microscope

- score for: staining intensity (0=none, 1=weak, 2=medium, 3=strong) percent of positive cancer-cells (0, 5, 10, 20,…, 100)

Fig.1 Configuration of TMA (a), H&E stained 4µm slide (b), H&E stained punch (c)

Materials and methods

a b c

a b

c

a b

c

Abstract Nr:

Abstract Id:

no significant correlations could be observed