HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: History of the multiple endocrine neoplasia workshops and overview of MEN2019

Overview

The multiple endocrine neoplasia syndromes are a varied group of disorders that include multiple endocrine neoplasia types 1 and 2 (MEN 1, MEN 2), von Hippel-Lindau (VHL) disease , Carney complex (CC), hereditary pheochromocytoma/paraganglioma, pituitary adenomas, and parathyroid tumours. The association of multiple endocrine neoplasms was first recognized after the publication of case reports and small series throughout the first half of the 20th century. However, it was not until the post-World War II explosion of biomedical research that these syndromes were better defined and categorized and their hereditary etiology elucidated. As each of these syndromes became better characterized, it also became clear that non-endocrine neoplastic manifestations occurred with some regularity. In 1953, Underdahl and colleagues (Underdahl et al. 1953) described eight cases of the syndrome we now know as MEN1, and Wermer and colleagues subsequently documented its autosomal dominant inheritance (Wermer 1954). In 1961, John Sipple identified a patient with thyroid cancer and pheochromocytoma and reviewed case reports from the literature providing the first clear description of MEN2A (Sipple 1961). E D Williams collated the clinical features of MEN 2B in 1966 (Williams & Pollock 1966). The ophthalmologic manifestations of von Hippel-Lindau disease were first reported by Eugen von Hippel, and the syndrome was more completely described by Arvid Lindau (Huntoon et al. 2015). Carney complex was first fully characterized by J Aiden Carney in 1985 (Carney et al. 1985), although earlier descriptions exist. Others have described the multiple heritable causes of primary hyperparathyroidism (Marx & Goltzman 2019), pituitary tumours (Tatsi & Stratakis 2019) and pheochromocytoma/paraganglioma (Crona et al. 2017).

Beginning in the 1960s, there was the confluence of hormone discovery and characterization of clinical and genetic information that permitted the development of the current classification of MEN syndromes. Several characteristics became clear. First, endocrine features dominated each of these clinical syndromes, but there were also non-endocrine manifestations. For example, the identification of angiofibromas, collagenomas, meningiomas, ependymomas, leiomyomas and lipomas in MEN 1 (Darling et al. 1997); mucosal neuromas, skeletal abnormalities, gastrointestinal disorders (Rashid et al. 1975), and cutaneous lichen amyloidosis in MEN2 (Gagel et al. 1989); and renal cell carcinoma, pancreatic/renal cysts, endolymphatic sac tumours, and reproductive system cystadenomas in VHL broadened the clinical features of these syndromes (Huntoon et al. 2015). It also became clear that, for each of these syndromes, there was a pattern of autosomal-dominant inheritance. Indeed, it was the opportunity to map these genes in well-characterized kindreds that led to the first MEN workshop in 1984.

Development of the MEN workshops

The first MEN workshop, with a singular focus on MEN2, was held at Queen’s University in Kingston, Ontario, a delightful lakefront city in southern Canada (Table 1). It was organized by two geneticists (Nancy E Simpson, PhD of Queen’s University and Charles E Jackson, MD of the Henry Ford Hospital) to bring together clinicians caring for MEN2 families and gene mappers (Jackson 1984). The major purpose of this workshop, attended by fewer than 50 participants, was to facilitate identification of the MEN2 gene. The meeting included a series of short lectures, but was dominated by workshops in which clinicians and geneticists assembled and discussed family trees of the kindreds with MEN 2. At its conclusion, a clear strategy for mapping the causative gene was outlined. The enthusiasm generated by this meeting led Bruce Ponder of Cambridge University to organize the second MEN meeting at Jesus College in Cambridge 2 years later (Ponder 1987). The close collaboration catalyzed by these meetings, together with execution of the strategy collectively generated, led to the identification of missense RET proto-oncogene mutations in MEN 2 in 1993 (Mulligan et al. 1993, Donis-Keller et al. 1993). This success led to subsequent meetings that focused not only on MEN2, but also on MEN1 and other hereditary endocrine tumour syndromes. For example, Magnus Nordensköld and his colleagues at the Karolinska Institute in Stockholm, Sweden, organized the 3rd MEN workshop in the Stockholm archipelago that included MEN 1 as a focus (Nordenskjöld et al. 1995). Each of the subsequent meetings focused on development of a better understanding of the causation of these syndromes and the integration of new information into the clinical management of affected families. One specific example is the 1999 Gubbio meeting, organized by Maria Luisa Brandi, where participants agreed upon strategies for the use of genetic testing in the clinical management of MEN syndromes, leading to another landmark publication that continues to guide clinical practice over 20 years later (Brandi et al. 2001). The best of these meetings were forward looking with the goal of using science to advance the field. An example is the 2004 MEN workshop in Bethesda, Maryland, sponsored by Steven Marx and Constantine Stratakis (Stratakis & Marx 2004), that drew upon the extensive resources of the United States National Institutes of Health to stimulate scientific discussions that applied new technology to the MEN syndromes.

With the accelerating pace of scientific progress, subsequent MEN meetings shifted their focus to the many questions that were being answered in the field, rather than those that still needed to be asked. While there has been much progress in identifying the causative germline DNA pathogenic variants, insight into how these genes transform the particular endocrine cell type is, in general, lacking. This lack of clarity regarding subsequent events in the transformation process has hindered development of therapeutic efforts for metastatic tumours, causing our field to lag behind many other areas of oncology. Additionally, the rarity and heterogeneity of this patient population yield specific challenges that require particularly focused and coordinated efforts among all stakeholders. It was therefore our goal for the 2019 Houston MEN meeting to reinvigorate the field by returning the focus to the unknown and restructuring it to emphasize robust discussion and foster international and multidisciplinary collaboration. We had three specific goals:

To accomplish these goals, approximately 40% of the meeting was specifically dedicated to working groups led by senior scientists and clinicians in the field. They were tasked with the goal of creating a roadmap for the future. Leaders were charged 9 months in advance to identify the key questions for each of the four malignant tumour types and how best to address them. This stimulated advance preparation, further focusing the discussion at the in-person MEN meeting. Following the meeting, the leaders were requested to collate the important and unresolved issues in their respective disease site and to formulate a set of goals and a 5-year plan for achieving these goals. A 5th working group that comprised genetic counseling experts in the field was also organized to focus on the challenges and opportunities in the management of patients and families affected by a hereditary endocrine neoplasia syndrome (Fig. 1).

Photograph of participants in the 16th International Workshop on Multiple Endocrine Neoplasia (MEN2019), 27–29 March 2019, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Citation: Endocrine-Related Cancer 27, 8; 10.1530/ERC-20-0201

• Download Figure
• Download figure as PowerPoint slide

View Full Size

Photograph of participants in the 16th International Workshop on Multiple Endocrine Neoplasia (MEN2019), 27–29 March 2019, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Citation: Endocrine-Related Cancer 27, 8; 10.1530/ERC-20-0201

• Download Figure
• Download figure as PowerPoint slide

Photograph of participants in the 16th International Workshop on Multiple Endocrine Neoplasia (MEN2019), 27–29 March 2019, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Citation: Endocrine-Related Cancer 27, 8; 10.1530/ERC-20-0201

• Download Figure
• Download figure as PowerPoint slide

This issue of Endocrine-Related Cancer includes manuscripts that summarize the disease-specific and genetic counseling working group discussions provide an update regarding current knowledge of the benign and malignant endocrine manifestations of the MEN syndromes, and outline opportunities for future research. Additional manuscripts in this special issue are focused on long-term follow-up of prophylactic thyroidectomy in the 1st family systematically screened for hereditary MTC, the genetics and clinical manifestations of familial-isolated pituitary adenomas and gigantism and the functional roles of AIP and GPR101 in pituitary tumorigenesis. As the chairs of the 2019 Houston meeting, we recognize that these proceedings could be used by scientific leaders in North and South America, Europe, Asia and Australasia to formulate national research strategies, and it is our intent that these forward-looking manuscripts will help to align investigators with national and international funding organizations so that research can proceed towards our vision of meaningfully improving the lives of patients with hereditary endocrine neoplasia syndromes. It is our hope that a spark of international and multidisciplinary collaboration on MEN research was ignited in Houston and that the pace of discovery will be accelerated as we look forward to Marseilles (MEN2021; https://www.worldmen2021.com) and beyond.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this editorial.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.