1. GASTROINTESTINAL STROMAL TUMORS (GIST)
IN NEUROFIBROMATOSIS 1 (NF1) PATIENTS:
A CLINICOPATHOLOGIC ANALYSIS
OF NINE CASES
Elena Fumagalli,
Paola Coco, Elena Palassini, Palma Dileo, 
Rossella Bertulli, Paolo G. Casali
Istituto Nazionale Tumori
Milan, Italy

2. This series 5 females : 4 males Median age 51 yrs (range 36-59)
Localized disease in all cases, with multiple lesions in 6 pts
Site:
stomach and duodenum 1pt
duodenum 2 pts
jejunum 1 pt
ileum 4 pts
other 1 pt
Risk stratification:
high 2 pts
intermediate 1 pt
low/very low 6 pts

3. This series: pts with multifocal disease
(5 low risk, 1 high risk)
2 pts
4 pts

4. Multifocal disease Study Patients Multifocality
Yantiss et al. Mod Pathol 2005 3
100%
Takazawa et al. Am J Surg Pathol 2005 8
90%
Mussi et al. Clin Cancer Res 2008 28
43%
Maertens et al. Hum Mol Genet 2006
Andersson et al. Am J Surg Pathol 2005 11
91%
Miettinen et al. Am J Surg Pathol 2006 45
62%
Kinoshita et al. J Pathol 2004 7
Kramer et al. World J Gastroenterol 2007 1
Kang et al. Am J Surg Pathol 2007 5

5. “The presence of multiple GIST in NF1 might reflect
a distinct rate-limiting step in oncogenesis
compared with sporadic GIST. While a broad spectrum
of inactivating genetic mechanism might lead to
suppression of the wild type NF1 allele and GIST
formation in NF1 pts, only a limited set of specific
activating mutations in KIT/PDGFRA will result in
sporadic GIST”

6. This series: molecular genetics
8 pts: WT
1 pt (gastric + duodenal GIST):
PDGFRA exon 18 (D842V) mutation in the gastric GIST; WT in the duodenal GIST

7. affecting the A-loop of PDGFRA
Immunohistochemistry
D842V in exon 18 of PDGFRA
G A G W C A T C A
PDGFRA
D842V
affecting the A-loop of PDGFRA

8. KIT & PDGFRA mutations Study Patients Mutations
Takazawa et al. Am J Surg Pathol. 2005 9
KIT L558L, P627L ex11, I653T ex13; PDGFRA P589S ex12, R822S
Yantiss et al. Mod Pathol. 2005 3
KIT V559D ex11 in 3 tumors →1 pt
Cheng et al. Dig Dis Sci. 2004
KIT delWK ex11 in 1 pt
Mussi et al. Clin Cancer Res.2008 25
KIT delV560 ex11,dupl A502_Y503 ex9; PDGFRA D842V ex18
Maertens et al. Hum Mol Genet. 2006
None
Lee et al. Dig Dis Sci. 2006 1
Andersson et al. Am J Surg Pathol. 2005 12
Miettinen et al. Am J Surg Pathol. 2006 15
Steward et al. J Med Genet. 2007 2
Kinoshita et al. J Pathol. 2004 7
Kang et al. Am J Surg Pathol. 2007 5

9. KIT/PDGFRA
KIT/PDGFRA

10. This series: pts with NET
1 pt: pheochromocytoma
+ ampullary neuroendrocrine tumor
pheocromocitoma
neuroendocrine tumour

11. GIST and NET in NF1 Study Patients NET
Karatzas et al. Eur J Surg Oncol, 2000 1
Somatostatinoma
Andersson et al. Am J Surg Pathol, 2005 4
Pheocromocytoma
Usui et al. J Gastroenterol,2002
Kramer et al. Z Gastroenterol, 2005
Duodenum neuroendocrine carcinoma
Lisewski et al. Int Semin Surg Oncol, 2006
Bilateral pheocromocytoma
Kramer et al. World J Gastroenterol, 2007
Erem et al. J Endocrinol Investigation, 2007
Bumming et al. Scand J Gastroenterol, 2006
Mussi et al. Clin Cancer Res, 2008 2
Pheocromocytoma Somatostatinoma
Juergens et al. AJR, 2006
Duodenal somatostatinoma
Suzuki et al. J Gastroenterol, 2004
Masanobu et al. J Gastroenterol, 2002

12. SUV 5

13. SUV 4.5
SUV 4.7

14. SUV 3.8

16. PET in NF1 Study Patients FDG uptake (SUV max)
Ferner et al. Ann Oncol, 2008
105
(80 PN, 29 MPNST, 5 AN)
Range ;
Fisher et al. J Neurooncol, 2008
13 pts
(19 PN)
Range (median 1.5)
Brinkman et al. W J Sur, 2007
1 pt
(20 PN)
No correlation
Bredella et al. AJR, 2007
45 pts
(24 MPNST, 26 PN)
Range 8.5+/-0.63; 1.5+/-0.37
Brenner et al. Eur J Nucl Med Mol Imaging, 2006
16 pts
SUV<3; SUV>3
Correlation with outcome
Cardona et al. Eur J Sur Oncol, 2003
(12 PN, 13 MPNST)
Range ;
Solomon et al. Clin Nucl Med, 2001
Ferner et al. J Neurol Neurosurg Psychiatry, 2000
18 pts
(23 PN)
Range ;
overlap

17. FDG PET distinguishes
MPNSTs
from benign neurogenic tumours
with 100% sensivity
and 83% specificity
at an SUV cut-off value = 1.8
SUV level predicts outcome
in NF1 pts with MPNSTs
SUV cut-off value = 3
No correlation with
histological grading

18. FDG PET and PET TC is Significant difference between
mean SUV of malignant and
benign tumours
Overlap with SUVmax =
 lesions should be reviewed
clinically
Time for measuring SUV 240 min
FDG PET and PET TC is
sensitive and specific
for MPNST in NF1 pts
Research with different tracers to predict tumour grade

20. This series: prognosis
8 pts: alive and well
median follow-up = 23 months (range = 6-97 months)
1 pt: metastatic disease (baseline: >5 cm; >10/50 HPF)
 death after progression to Imatinib

21. GIST in NF1: prognosis Author Patients Median follow-up
Miettinen et al. Am J Surg Pathol 2006 45
Median FU 13.6 yrs 20 pts alive
Mussi et al. Clin Cancer Res 2008 28
5 yrs disease specif survival 54.3% (median not reached); event free survival 43.9% (median 48 mos)
Median FU (metastaic GIST): 33 mos
Maertens et al. Hum Mol Genet 2006 3
No metastases, 1 pt died due to complications after surgery
Median FU 2 yrs
Yantiss et al. Mod Pathol 2005
1 pt died due to metastases: KIT V559D ex11 in 3 tumors
Andersson et al. Am J Surg Pathol 2005 15
Median FU 3 yrs 6 pts alive

22. This series: 1 pt treated preoperatively
baseline
+ 4 w

23. This series: secondary resistance
1 pt (ileal GIST):
Kit exon 17 (D820N) mutation in metastatic lesions;
WT in primary tumour
D820N cKit ex 17
immunohistochemistry
A G A A T r A T T
cKIT
Mussi et al. Clin Cancer Res 2008:14 July 15

24. AntiTK activity

25. Conclusions
Only anecdotal cases of GIST have been reported in NF1, though in the face of a 5-10% risk of developing the disease in this syndrome
WT are predominant, but KIT/PDGFRA mutations are occasionally present (both to KIT and PDGFRA)
NET may be concurrent, in the face of a 1% risk of these diseases in NF1
Prognosis of WT GIST in NF1, although multifocal, is good, but may be worse for KIT/PDGFRA-mutated GIST
AntiTK are often ineffective, but responses have been occasionally reported (and secondary resistance may arise)
GIST in NF1 are often positive on PET scan, but specificity may be problematic against other lesions, including neurofibromas