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