Clinical and genetic analysis of patients with pancreatic neuroendocrine tumors associated with von Hippel-Lindau disease.
BACKGROUND
Patients with von Hippel-Lindau disease (VHL) may develop pancreatic neuroendocrine tumors (PNETs), which can behave in a malignant fashion. We prospectively evaluated size criteria for resection of lesions and the role of genotype/phenotype analysis of germline VHL mutations in predicting clinical course.


METHODS
From December 1988 through December 1999 we screened 389 patients with VHL. The diagnosis of PNET was made by pathologic analysis of tissues or by radiographic appearance. Germline mutations were determined by quantitative Southern blotting, fluorescence in situ hybridization and complete gene sequencing.


RESULTS
Forty-four patients with PNETs have been identified; 25 have undergone surgical resection, 5 had metastatic disease, and 14 are being monitored. No patient who has undergone resection based on tumor size criteria has developed metastases. Patients with PNETs were more likely to have missense mutations (58%), and 4 of 5 patients (80%) with metastatic disease had mutations in exon 3 compared with 18 of 39 (46%) patients without metastatic disease.


CONCLUSIONS
Imaging for detection and surgical resection based on size criteria have resulted in the successful management of VHL patients with PNETs. Analysis of germline mutations may help identify patients at risk for PNET and which patients may benefit from surgical intervention.
Libutti
S K
SK
Surgical Metabolism Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Choyke
P L
PL
Alexander
H R
HR
Glenn
G
G
Bartlett
D L
DL
Zbar
B
B
Lubensky
I
I
McKee
S A
SA
Maher
E R
ER
Linehan
W M
WM
Walther
M M
MM
D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D008025:Ligases; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000150:complications / Q000235:genetics / Q000601:surgery*; D010190:Pancreatic Neoplasms / Q000150:complications / Q000235:genetics / Q000601:surgery*; D011446:Prospective Studies; D011506:Proteins / Q000235:genetics; D014057:Tomography, X-Ray Computed; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease / Q000150:complications / Q000235:genetics / Q000601:surgery*
D011506:Proteins; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D008025:Ligases; C497446:VHL protein, human