Preventive medicine of von Hippel–Lindau disease-associated pancreatic neuroendocrine tumors

Abstract

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; = 0.020; 80% vs 50% at 10 years; = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

Hemangioblastoma and von Hippel-Lindau disease: genetic background, spectrum of disease, and neurosurgical treatment

“…The spectrum of manifestations of the VHL disease comprises developmental changes with multiple pre-neoplastic lesions as well as cysts and tumors in various organs. Of these tumors, some are highly prone to become malignant and to settle local or distant metastases, in particular, clear cell renal cell carcinomas and pancreatic neuroendocrine tumors [ 18 , 19 ]. The risk for metastases of kidney and pancreas tumors is dependent on size (odds ratio 1.25 for each 1 cm increase, p < 0.001) [ 20 ].…”

Neuroendocrine Neoplasms of the Small Bowel and Pancreas

“…In line with the specific considerations for MEN1-associated PanNEN, PanNEN arising in the context of VHL disease are also subject to focussed strategies. In a multinational registry of over 2,000 patients, it was identified via multivariate prediction modelling that VHL-PanNEN should be considered for operated if their size approaches 2.8 cm in diameter [189]. A genotype-guided approach integrating genetic sequencing and tumour dimeter data have been advocated for directing risk stratification -in a study of 229 patients with pancreatic lesions in VHL, those with a missense mutation in VHL developed metastatic disease significantly more frequently and required surgical intervention more so than others, especially those with mutations in exon 3 [190].…”

Clinical diagnosis, treatment and screening of the VHL gene in three von Hippel‑Lindau disease pedigrees

“…Of the PNETs, 80-93% were <3.0 cm. The phenomena of tumor >3.0 cm, doubling time <500 days and codon 161 and 167 mutations at exon 3 were potentially malignant signs ( 3 , 38 , 39 ). In the present study, one patient (F3-II1, 66 years old) with PNETs required close monitoring for the possibility of malignancy, although no definite signs or symptoms were identified via clinical imaging.…”