Wilms

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Wilms tumour gene 1 (WT1) is a new prognostic
marker in high grade uterine sarcoma

• A. Coosemans, B. Van Calster, L. Verbist,
  Ph. Moerman, I. Vergote, S.W. Van Gool, F. Amant

Laboratory of Experimental Gynaecology and
Immunology, UZ Gasthuisberg, Katholieke
Universiteit Leuven, Belgium Department of
Electric Engineering (ESAT), Katholieke
Universiteit Leuven, Belgium Department of human
pathology, UZ Gasthuisberg, Katholieke
Universiteit Leuven, Belgium
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Background (1)

• WT1 Wilms tumour gene 1
• located on 11p13
• 1990 discovered in Wilms tumour (paediatric
  kidney cancer)
• Complex molecular function transcription and
  translation on DNA and RNA level
• Role
• Embryogenic role in development of urogenital
  system, central nervous system, heart, blood
• Adult life role in carcinogenesis
  overexpression of wild type in several
  haematological and solid malignancies
• Depending on the type of tumour behaviour as a
  oncogene or supressor gene

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Background (2)

• Uterine sarcoma
• Rare type of uterine tumour
• 4 subtypes
• Carcinosarcoma (CS), leiomyosarcoma (LMS),
  undifferentiated sarcoma (US) high grade
• Endometrial stromal sarcoma (ESS) low grade
• Poor prognosis 5 year survival
• Stage I-II 50
• Stage III-IV 10
• Surgery is the corner stone - no clear benefits
  from adjuvant therapy in early stages
  shortlasting therapeutic options in advanced
  stages

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Background (3)

• WT1 and uterine sarcoma

IHC IHC IHC IHC IHC RT-PCR RT-PCR RT-PCR RT-PCR
CS ESS LMS US AS LMS CS ESS US
Agoff, 2001 9/10
Dupont, 2004 7/10
Sumathi, 2004 13/14
Sotobori, 2006 5/5
Coosemans, 2007 12/27 7/15 29/38 4/7 6/6 4/4 6/6 3/4
Soslow, 2008 6/7
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Materials and methods (1)

• 54 women with high grade uterine sarcoma
• Follow up of at least 12 months

No. of patients n () No. of patients n ()
Age Tumoural size
lt52 yrs 10 (18,5) lt5cm 8 (15)
52 yrs 44 (81,5) 5cm 32 (59)
Sarcoma subtype unknown 14 (26)
LMS 20 (37) Recurrent disease
CS 27 (50) No 14 (26)
US 7 (13) Yes 40 (74)
Stage Death
I 22 (41) No 18 (33)
II 6 (11) Yes 36 (67)
III 12 (22)
IV 14 (26)
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Materials and methods (2)

• IMMUNOHISTOCHEMISTRY
• WT1 immunohistochemistry on 1 slide of each
  tumour (monoclonal mouse anti-human Wilms
  Tumor 1 clone 6F-H2 (DAKO))
• STATISTICAL ANALYSIS
• Survival curves by Kaplan Meier
• Univariate and multivariate analysis by Cox
  regression analysis

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Materials and methods (3)

• 1984-2008 26 studies on prognosis in uterine
  sarcoma, including multivariate analysis in more
  than 40 patients
• Most frequently studied parameters
• Stage 24 studies
• Age 23 studies
• Grade 15 studies
• Subtype 11 studies
• Menopauzal status 10 studies
• Size 9 studies
• Mitotic index 8 studies
• Adjuvant therapy 6 studies

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Results (1)
WT1 positive tumors 34 (63) WT1 negative tumors 20 (37) WT1 positive tumors 34 (63) WT1 negative tumors 20 (37)
Age Tumoral size
lt52 yrs 6 (18) 4 (20) lt5cm 5 (15) 3 (15)
52 yrs 28 (82) 16 (80) 5cm 22 (65) 10 (50)
Sarcoma subtype unknown 7 (21) 7 (35)
LMS 16 (47) 4 (20) Recurrent disease
CS 14 (41) 13 (65) No 6 (18) 12 (60)
US 4 (12) 3 (15) Yes 28 (82) 8 (40)
Stage Death
I 10 (29) 12 (60) No 7 (21) 9 (45)
II-IV 24 (71) 8 (40) Yes 27 (79) 11 (55)
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Results (2) univariate analysis
Kaplan Meier survival curves
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Results (3) univariate analysis
LR p0,0058
LR p lt0,0001
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Results (4) multivariate analysis
Variable Hazard ratio 95 CI on HR LR P-value
WT1 status 2.381 1.151-4.926 0.019
Stage 2.953 1.294-6.739 0.010
Age 1.053 0.775-1.430 0.742
Sarcoma subtype
CS vs US 0.486 0.147-1.609 0.442
LMS vs US 0.743 0.255-2.166 0.442
Size 1.775 0.484-6.517 0.385
PFS
Variable Hazard ratio 95 CI on HR LR P-value
WT1 status 2.990 1.286-6.950 0.011
Stage 4.995 1.882-13.26 0.001
Age 1.194 0.845-1.687 0.315
Sarcoma subtype
CS vs US 0.272 0.075-0.980 0.100
LMS vs US 0.325 0.104-1.014 0.100
Size 1.493 0.368-6.054 0.572
OS
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Conclusion

• WT1 independently worsens the prognosis of
  uterine sarcoma
• The stronger the WT1 expression, the worse the
  prognosis
• Similar observations have been made in breast
  carcinoma (Miyoshi, 2002), leukaemia (Inoue,
  1994) and hepatocellular carcinoma (Sera, 2008)