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

in Endocrine-Related Cancer
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  • 1 Departments of Surgical Oncology, GI Medical Oncology, and Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, Texas

Correspondence should be addressed to R F Gagel: rgagel@mdanderson.org

This paper is part of a thematic section on current knowledge and future research opportunities in hereditary endocrine tumours, as discussed at MEN2019: 16th International Workshop on Multiple Endocrine Neoplasia, 27–29 March 2019, Houston, TX, USA. This meeting was sponsored by Endocrine-Related Cancer.

The multiple endocrine neoplasia (MEN) workshops had their beginnings at Queen’s University in Kingston, Ontario in June 1984. This initial meeting brought clinicians and scientists together to focus on mapping the gene for multiple endocrine neoplasia type 2 (MEN2). These efforts culminated in the identification of the RET protooncogene as the causative gene a decade later. Over the next 35 years there were a total of 16 international workshops focused on the several MEN syndromes. Importantly, these workshops were instrumental in efforts to define the molecular basis for multiple endocrine neoplasia type 1 (MEN1), MEN2, von Hippel-Lindau disease (VHL), Carney Complex, hereditary pheochromocytoma and hyperparathyroidism. In this same spirit some 150 scientists and clinicians met at MD Anderson Cancer Center, 27–29 March 2019, for the 16th International Workshop on Multiple Endocrine Neoplasia (MEN2019). Appropriate to its location in a cancer centre, the workshop focused on important issues in the causation and treatment of malignant aspects of the MEN syndromes: medullary thyroid carcinoma, pancreatic neuroendocrine tumours, malignant pheochromocytoma and parathyroid carcinoma. Workshops at the meeting focused on a better understanding of how the identified molecular defects in these genetic syndromes lead to transformation, how to apply targeted kinase inhibitors and immunotherapy to treat these tumours and important clinical management issues. This issue of Endocrine-Related Cancer describes these discussions and recommendations.

Abstract

The multiple endocrine neoplasia (MEN) workshops had their beginnings at Queen’s University in Kingston, Ontario in June 1984. This initial meeting brought clinicians and scientists together to focus on mapping the gene for multiple endocrine neoplasia type 2 (MEN2). These efforts culminated in the identification of the RET protooncogene as the causative gene a decade later. Over the next 35 years there were a total of 16 international workshops focused on the several MEN syndromes. Importantly, these workshops were instrumental in efforts to define the molecular basis for multiple endocrine neoplasia type 1 (MEN1), MEN2, von Hippel-Lindau disease (VHL), Carney Complex, hereditary pheochromocytoma and hyperparathyroidism. In this same spirit some 150 scientists and clinicians met at MD Anderson Cancer Center, 27–29 March 2019, for the 16th International Workshop on Multiple Endocrine Neoplasia (MEN2019). Appropriate to its location in a cancer centre, the workshop focused on important issues in the causation and treatment of malignant aspects of the MEN syndromes: medullary thyroid carcinoma, pancreatic neuroendocrine tumours, malignant pheochromocytoma and parathyroid carcinoma. Workshops at the meeting focused on a better understanding of how the identified molecular defects in these genetic syndromes lead to transformation, how to apply targeted kinase inhibitors and immunotherapy to treat these tumours and important clinical management issues. This issue of Endocrine-Related Cancer describes these discussions and recommendations.

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.

Table 1

MEN workshops from 1984 to 2019.

YearLocationSponsoring institutionOrganizer(s)
1984Kingston, CanadaQueen’s UniversityCharles E Jackson

Nancy Simpson
1986Cambridge, UKJesus College, Cambridge UniversityBruce Ponder
1987Heidelberg, GermanyUniversity of HeidelbergKarin Frank-Raue

Friedhelm Raue
1991Houston, USABaylor College of MedicineGilbert Cote

Robert Gagel
1994Stockholm, SwedenKarolinska InstituteMagnus Nordensköld
1997Noordwijkerhout,

The Netherlands
Utrecht UniversityCornelius JM Lips
1999Gubbio, ItalyUniversity of FlorenceMaria-Luisa Brandi
2002Grand Rapids, USAVan Andel InstituteBin Teh
2004Bethesda, USANational Institutes of HealthSteven Marx

Constantine Stratakis
2006Marseille, FranceFrench Study Group of Endocrine TumorsPatricia Niccoli-Sire

Bernard Conte-Devoix
2008Delphi, GreeceAthens University &

Hellenic Endocrine Society
Maria Alevizaki

Constantine Stratakis
2010Gubbio, ItalyUniversity of FlorenceMaria-Luisa Brandi
2012Liege, BelgiumUniversity of LiegeAlbert Beckers
2014Vienna, AustriaUniversität WienBruno Niederle
2016Utrecht, The NetherlandsUtrecht UniversityGerloff Valk
2019Houston, USAUniversity of Texas MD Anderson Cancer CenterElizabeth Grubbs

Robert Gagel

Daniel Halperin

Steven Waguespack
2021aMarseille, FranceAix-Marseille UniversitéFrederic Castinetti

aMeeting in planning stages.

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).

Figure 1
Figure 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

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.

References

  • Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG & Libroia A 2001 Guidelines for diagnosis and therapy of MEN type 1 and type 2. Journal of Clinical Endocrinology and Metabolism 86 56585671. (https://doi.org/10.1210/jcem.86.12.8070)

    • Search Google Scholar
    • Export Citation
  • Carney JA, Gordon H, Carpenter PC, Shenoy BV & Gov LW 1985 The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine 64 270283.

    • Search Google Scholar
    • Export Citation
  • Crona J, Taieb D & Pacak K 2017 New perspectives on pheochromocytoma and paraganglioma: toward a molecular classification. Endocrine Reviews 38 489515. (https://doi.org/10.1210/er.2017-00062)

    • Search Google Scholar
    • Export Citation
  • Darling TN, Skarulis MC, Steinberg SM, Marx SJ, Spiegel AM & Turner M 1997 Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1. Archives of Dermatology 133 853857. (https://doi.org/10.1001/archderm.1997.03890430067009)

    • Search Google Scholar
    • Export Citation
  • Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P & Wells SA Jr 1993 Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Human Molecular Genetics 2 851856. (https://doi.org/10.1093/hmg/2.7.851)

    • Search Google Scholar
    • Export Citation
  • Gagel RF, Levy ML, Donovan DT, Alford BR, Wheeler T & Tschen JA 1989 Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Annals of Internal Medicine 111 802806. (https://doi.org/10.7326/0003-4819-111-10-802)

    • Search Google Scholar
    • Export Citation
  • Huntoon K, Oldfield EH & Lonser RR 2015 Dr. Arvid Lindau and discovery of von Hippel-Lindau disease. Journal of Neurosurgery 123 10931097. (https://doi.org/10.3171/2015.1.JNS131963)

    • Search Google Scholar
    • Export Citation
  • Jackson CE 1984 The First International Workshop on Multiple Endocrine Neoplasia Type 2 syndromes. Henry Ford Hospital Medical Journal 32 217218.

    • Search Google Scholar
    • Export Citation
  • Marx SJ & Goltzman D 2019 Evolution of our understanding of the hyperparathyroid syndromes: a historical perspective. Journal of Bone and Mineral Research 34 2237. (https://doi.org/10.1002/jbmr.3650)

    • Search Google Scholar
    • Export Citation
  • Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK & Papi L 1993 Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363 458460. (https://doi.org/10.1038/363458a0)

    • Search Google Scholar
    • Export Citation
  • Nordenskjöld M, Hamberger B & Öberg K 1995 Advances in multiple endocrine neoplasia type 1. Journal of Internal Medicine 238 232.

  • Ponder BA 1987 The second international workshop on multiple endocrine neoplasia type 2 syndromes. Henry Ford Hospital Medical Journal 35 9394.

    • Search Google Scholar
    • Export Citation
  • Rashid M, Khairi MR, Dexter RN, Burzynski NJ & Johnston CC Jr 1975 Mucosal neuroma, pheochromocytoma and medullary thyroid carcinoma: multiple endocrine neoplasia type 3. Medicine 54 89112. (https://doi.org/10.1097/00005792-197503000-00001)

    • Search Google Scholar
    • Export Citation
  • Sipple JH 1961 The association of pheochromocytoma with carcinoma of the thyroid gland. American Journal of Medicine 31 163166. (https://doi.org/10.1016/0002-9343(61)90234-0)

    • Search Google Scholar
    • Export Citation
  • Stratakis CA & Marx SJ 2004 Abstracts for the 9th International Workshop on Multiple Endocrine Neoplasia (lMEN 2004). Journal of Internal Medicine 255 696730. (https://doi.org/10.1111/j.1365-2796.2004.01343.x)

    • Search Google Scholar
    • Export Citation
  • Tatsi C & Stratakis CA 2019 The genetics of pituitary adenomas. Journal of Clinical Medicine 9 30. (https://doi.org/10.3390/jcm9010030)

  • Underdahl LO, Woolner LB & Black BM 1953 Multiple endocrine adenomas: report of 8 cases in which the parathyroids, pituitary and pancreatic islets were involved. Journal of Clinical Endocrinology and Metabolism 13 2047. (https://doi.org/10.1210/jcem-13-1-20)

    • Search Google Scholar
    • Export Citation
  • Wermer P 1954 Genetic aspects of adenomatosis of endocrine glands. American Journal of Medicine 16 363371. (https://doi.org/10.1016/0002-9343(54)90353-8)

    • Search Google Scholar
    • Export Citation
  • Williams ED & Pollock DJ 1966 Multiple mucosal neuromas with endocrine tumors: a syndrome allied to von Recklinghausen’s disease. Journal of Pathology and Bacteriology 91 7180. (https://doi.org/10.1002/path.1700910109)

    • Search Google Scholar
    • Export Citation

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    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.

  • Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG & Libroia A 2001 Guidelines for diagnosis and therapy of MEN type 1 and type 2. Journal of Clinical Endocrinology and Metabolism 86 56585671. (https://doi.org/10.1210/jcem.86.12.8070)

    • Search Google Scholar
    • Export Citation
  • Carney JA, Gordon H, Carpenter PC, Shenoy BV & Gov LW 1985 The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine 64 270283.

    • Search Google Scholar
    • Export Citation
  • Crona J, Taieb D & Pacak K 2017 New perspectives on pheochromocytoma and paraganglioma: toward a molecular classification. Endocrine Reviews 38 489515. (https://doi.org/10.1210/er.2017-00062)

    • Search Google Scholar
    • Export Citation
  • Darling TN, Skarulis MC, Steinberg SM, Marx SJ, Spiegel AM & Turner M 1997 Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1. Archives of Dermatology 133 853857. (https://doi.org/10.1001/archderm.1997.03890430067009)

    • Search Google Scholar
    • Export Citation
  • Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow P & Wells SA Jr 1993 Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Human Molecular Genetics 2 851856. (https://doi.org/10.1093/hmg/2.7.851)

    • Search Google Scholar
    • Export Citation
  • Gagel RF, Levy ML, Donovan DT, Alford BR, Wheeler T & Tschen JA 1989 Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Annals of Internal Medicine 111 802806. (https://doi.org/10.7326/0003-4819-111-10-802)

    • Search Google Scholar
    • Export Citation
  • Huntoon K, Oldfield EH & Lonser RR 2015 Dr. Arvid Lindau and discovery of von Hippel-Lindau disease. Journal of Neurosurgery 123 10931097. (https://doi.org/10.3171/2015.1.JNS131963)

    • Search Google Scholar
    • Export Citation
  • Jackson CE 1984 The First International Workshop on Multiple Endocrine Neoplasia Type 2 syndromes. Henry Ford Hospital Medical Journal 32 217218.

    • Search Google Scholar
    • Export Citation
  • Marx SJ & Goltzman D 2019 Evolution of our understanding of the hyperparathyroid syndromes: a historical perspective. Journal of Bone and Mineral Research 34 2237. (https://doi.org/10.1002/jbmr.3650)

    • Search Google Scholar
    • Export Citation
  • Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK & Papi L 1993 Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363 458460. (https://doi.org/10.1038/363458a0)

    • Search Google Scholar
    • Export Citation
  • Nordenskjöld M, Hamberger B & Öberg K 1995 Advances in multiple endocrine neoplasia type 1. Journal of Internal Medicine 238 232.

  • Ponder BA 1987 The second international workshop on multiple endocrine neoplasia type 2 syndromes. Henry Ford Hospital Medical Journal 35 9394.

    • Search Google Scholar
    • Export Citation
  • Rashid M, Khairi MR, Dexter RN, Burzynski NJ & Johnston CC Jr 1975 Mucosal neuroma, pheochromocytoma and medullary thyroid carcinoma: multiple endocrine neoplasia type 3. Medicine 54 89112. (https://doi.org/10.1097/00005792-197503000-00001)

    • Search Google Scholar
    • Export Citation
  • Sipple JH 1961 The association of pheochromocytoma with carcinoma of the thyroid gland. American Journal of Medicine 31 163166. (https://doi.org/10.1016/0002-9343(61)90234-0)

    • Search Google Scholar
    • Export Citation
  • Stratakis CA & Marx SJ 2004 Abstracts for the 9th International Workshop on Multiple Endocrine Neoplasia (lMEN 2004). Journal of Internal Medicine 255 696730. (https://doi.org/10.1111/j.1365-2796.2004.01343.x)

    • Search Google Scholar
    • Export Citation
  • Tatsi C & Stratakis CA 2019 The genetics of pituitary adenomas. Journal of Clinical Medicine 9 30. (https://doi.org/10.3390/jcm9010030)

  • Underdahl LO, Woolner LB & Black BM 1953 Multiple endocrine adenomas: report of 8 cases in which the parathyroids, pituitary and pancreatic islets were involved. Journal of Clinical Endocrinology and Metabolism 13 2047. (https://doi.org/10.1210/jcem-13-1-20)

    • Search Google Scholar
    • Export Citation
  • Wermer P 1954 Genetic aspects of adenomatosis of endocrine glands. American Journal of Medicine 16 363371. (https://doi.org/10.1016/0002-9343(54)90353-8)

    • Search Google Scholar
    • Export Citation
  • Williams ED & Pollock DJ 1966 Multiple mucosal neuromas with endocrine tumors: a syndrome allied to von Recklinghausen’s disease. Journal of Pathology and Bacteriology 91 7180. (https://doi.org/10.1002/path.1700910109)

    • Search Google Scholar
    • Export Citation