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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
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
intermediate1 pt
low/very low6 pts
This series
• 6/9 pts(5 low risk, 1 high risk)
4 pts
2 pts
This series: pts with multifocal disease
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 3 100%
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 7 100%
Kramer et al. World J Gastroenterol 2007 1 100%
Kang et al. Am J Surg Pathol 2007 5 100%
“The presence of multiple GIST in NF1 might reflect a distinct rate-limiting step in oncogenesiscompared with sporadic GIST. While a broad spectrumof inactivating genetic mechanism might lead tosuppression 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”
8 pts: WT
1 pt (gastric + duodenal GIST): PDGFRA exon 18 (D842V) mutation in the gastric GIST; WT in the duodenal GIST
This series: molecular genetics
PDGFRA
G A G W C A T C A
D842V in exon 18 of PDGFRAImmunohistochemistry
D842V affecting the A-loop of PDGFRA
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 3 KIT delWK557-558 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 3 None
Lee et al. Dig Dis Sci. 2006 1 None
Andersson et al. Am J Surg Pathol. 2005 12 None
Miettinen et al. Am J Surg Pathol. 2006 15 None
Steward et al. J Med Genet. 2007 2 None
Kinoshita et al. J Pathol. 2004 7 None
Kang et al. Am J Surg Pathol. 2007 5 None
KIT & PDGFRA mutations
KIT/PDGFRA
KIT/PDGFRA
1 pt: pheochromocytoma
1 pt: pheochromocytoma + ampullary neuroendrocrine tumor
This series: pts with NET
neuroendocrine tumourpheocromocitoma
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 1 Somatostatinoma
Kramer et al. Z Gastroenterol, 2005 1 Duodenum neuroendocrine carcinoma
Lisewski et al. Int Semin Surg Oncol, 2006 1 Bilateral pheocromocytoma
Kramer et al. World J Gastroenterol, 2007 1 Bilateral pheocromocytoma
Erem et al. J Endocrinol Investigation, 2007 1 Pheocromocytoma
Bumming et al. Scand J Gastroenterol, 2006 1 Pheocromocytoma
Mussi et al. Clin Cancer Res, 2008 2 Pheocromocytoma Somatostatinoma
Juergens et al. AJR, 2006 1 Duodenal somatostatinoma
Suzuki et al. J Gastroenterol, 2004 1 Somatostatinoma
Masanobu et al. J Gastroenterol, 2002 1 Somatostatinoma
GIST and NET in NF1
SUV 5
SUV 4.5
SUV 4.7
SUV 3.8
Study Patients FDG uptake
(SUV max)Ferner et al. Ann Oncol, 2008 105
(80 PN, 29 MPNST, 5 AN)
Range 3.9-7.7; 1.3-1.8
Fisher et al. J Neurooncol, 2008 13 pts
(19 PN)
Range 0.9-4 (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 13 pts
(12 PN, 13 MPNST)
Range 1.8-12.3; 0.5-1.8
Solomon et al. Clin Nucl Med, 2001 1 pt No correlation
Ferner et al. J Neurol Neurosurg Psychiatry, 2000
18 pts
(23 PN)
Range 2.7-8.4; 0.56-3.3
overlap 2.7-3.3
PET in NF1
SUV level predicts outcomein NF1 pts with MPNSTs
SUV cut-off value = 3 No correlation with
histological grading
FDG PET distinguishesMPNSTs from benign neurogenic tumours with 100% sensivity and 83% specificity at an SUV cut-off value = 1.8
Significant difference betweenmean SUV of malignant andbenign tumours
Overlap with SUVmax = 2.5-3.5 lesions should be reviewedclinically
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
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
This series: prognosis
GIST in NF1: prognosis
Author Patients Median follow-upMiettinen 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 surgeryMedian FU 2 yrs
Yantiss et al. Mod Pathol 2005 3 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
This series:1 pt treated preoperatively
baseline + 4 w
This series: secondary resistance
D820N cKit ex 17
A G A A T r A T T
1 pt (ileal GIST): Kit exon 17 (D820N) mutation in metastatic lesions;WT in primary tumour
immunohistochemistry
cKIT
Mussi et al. Clin Cancer Res 2008:14 July 15
AntiTK activity
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
elena.fumagalli@istitutotumori.mi.it