Diagnosis and follow-up of MEN1 : Results from the DutchMEN1 study group

Abstract

Multiple Endocrine Neoplasia type1 (MEN1) is a rare autosomal inherited disorder, characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumors (dpNET), and pituitary tumors (PIT). Other tumors associated with MEN1 are lung NET, thymic NET, adrenal adenomas, and even some solid tumors such as breast cancer. MEN1 significantly impacts life-expectancy and quality of life in those affected. On average MEN1 patients have a 27 years decreased life-expectancy.

Over recent decades, the follow-up and treatment of MEN1 patients has greatly improved. Still, many controversies over diagnosis, follow-up and treatment of MEN1 remain. Because of the low prevalence of MEN1, these controversies seemed difficult to investigate. In the Netherlands, care for MEN1 patients is densely centralized in eight university medical centers taking care for over 90% of MEN1 patients. The DutchMEN1 study group is an unique collaboration to improve care for MEN1 patients. The DutchMEN1 study groups database comprises longitudinal follow-up of all MEN1 patients treated in the university medical centers, enabling studies for the evidence based care for MEN1 patients.

The current thesis focuses on the diagnosis and follow-up of MEN1 patients. Currently, diagnosis of MEN1 can be established by genetic testing or clinically by the presence of at least two out of three major manifestations (pHPFT, dpNET, and PIT). Patients meeting clinical criteria, without a MEN1 mutation in genetic analysis are also referred to as 'phenocopies'. Phenocopies turned out to have a completely different clinical course, only very seldomly developed a third or other associated MEN1 manifestation, and had a significantly higher life-expectancy. Further we investigated when to test patients with endocrine tumors for a MEN1 mutation. The current guidelines seem too strict and this can therefore result in a delayed diagnosis of MEN1. The age limit for the testing of patients with parathyroid adenoma of 30 years turned out to be used too strictly as a cut-off. In addition, clinicians should especially have a high index of suspicion for MEN1 if the family history of patients is positive for NETs.

Follow-up in MEN1 is aimed at early detection of MEN1 associated manifestation and is performed by biochemical and radiological screening. In part two of this thesis we investigated the efficacy of the screening program in early detection of MEN1 manifestations. Biochemical tumor markers for dpNET performed poor and their use should no longer be advised for this purpose. Despite thoracic screening and early surgery premature death because of thymic NETs remains high. Given the low prevalence and incidence of thymic NETs a discussion should be started regarding the number of patients to be screened to prevent one premature death because of a thymic NET. A similar discussion should be started with regard to the frequency of follow-up CT scans. The need for early surgical interventions for MEN1 related lung NETs, given the now found relatively indolent course, should also be reconsidered. With regard to MEN1 related pituitary tumors we found that these tumors did not have a more aggressive behavior than their sporadic counterparts which was suggested in previous studies. Therefore, pituitary tumors in MEN1 patients can be followed and treated using the same guidelines as sporadically occurring pituitary tumors.