Abstract
Multiple Endocrine Neoplasia type 1 (MEN1) is a rare syndrome caused by mutations in the MEN1 gene on chromosome 11. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumours (NET), pituitary tumours, adrenal adenomas and NET of the stomach, bronchus and thymus. The research in this
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thesis focusses on the long-term outcome of MEN1 related manifestations. Since the discovery of the MEN1 gene in 1997, presymptomatic genetic testing became available. In the research described in chapter 3 we show that patients with a genetic diagnosis had less manifestations at the end of follow-up and no MEN1 related malignancy or death, compared to patients with a clinical MEN1 diagnosis. Primary hyperparathyroidism is the most prevalent MEN1 manifestation and responsible for most MEN1 related surgeries. The optimal surgical strategy for MEN1 related pHPT is under debate. In chapter 4 we present the results of 52 patients who underwent primary surgery for MEN1 related pHPT. Of the patients who underwent less than subtotal parathyroidectomy (<SPTX), 90% had persistent/recurrent disease, this was 70% after SPTX and 17% after total parathyroidectomy (TPTX). After TPTX hypoparathyroidism lasting more than six months was seen in 67%, compared to 7% after SPTX. We performed a meta-analysis, showing that risk of persistence/recurrence was lowest after SPTX/TPTX, while risk of hypoparathyroidism was highest after TPTX. In chapter 5, we report the outcomes of 73 MEN1 patients with pHPT after their last parathyroidectomy. Risk of persistence/recurrence after the final surgery, based on the number of parathyroid glands removed, was 53% after <SPTX, 17% after SPTX and 19% after TPTX. The risk of hypoparathyroidism lasting ≥ six months was 24% after <SPTX, 39% after SPTX and 66% after TPTX. Median duration of hypoparathyroidism was 1.5 years, in 65% successful cessation of vitamin D/calcium was possible. After <SPTX, patients with nonsense or frameshift mutations in exons 2, 9, and 10 had a significantly lower risk of persistent/recurrent pHPT than patients with other mutations. Overall, for MEN1 related pHPT, SPTX seems to offer the best balance between risk of persistence/recurrence and risk of hypoparathyroidism. The most important determinants of survival in MEN1 are duodenopancreatic and thymus NETs. In chapter 7 we describe the occurrence and long-term outcome of thoracic NETs in the DMSG national MEN1 database (n=323). Thymus NETs occurred in 3.4% of patients, almost exclusively in males, with a 10-year survival of 25%. Lung NETs were identified in 42 patients (13.0%) with a 10-year survival of 71.1%. Tumour doubling time in males was 2.5 vs 5.5 years in females. In chapter 8 we describe the growth rate of small NF-pNETs. Average growth of the 115 included small NF-pNETs from 99 patients was slow (0.4 mm/y). Seventy percent of the tumours was stable and a subgroup of 30% was growing. No differences in clinical characteristics were identified between growing and stable tumours. Within the subgroup of growing tumours, germline missense mutations were significantly associated with accelerated growth compared with nonsense and frameshift mutations.
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