25 2 Endocrine-Related A Machens et al. Advances in risk-oriented 25:2 T41–T52 Cancer surgery for MEN2 THEMATIC REVIEW Advances in risk-oriented surgery for multiple endocrine neoplasia type 2 Andreas Machens1 and Henning Dralle2 1Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany 2Department of General, Visceral and Transplantation Surgery, Section of Endocrine Surgery, University of Duisburg-Essen, Essen, Germany Correspondence should be addressed to A Machens: [email protected] This paper is part of a thematic review section on 25 Years of RET and MEN2. The guest editors for this section were Lois Mulligan and Frank Weber. Abstract Genetic association studies hinge on definite clinical case definitions of the disease of Key Words interest. This is why more penetrant mutations were overrepresented in early multiple f biochemical screening endocrine neoplasia type 2 (MEN2) studies, whereas less penetrant mutations went f DNA-based screening underrepresented. Enrichment of genetic association studies with advanced disease f RET proto-oncogene may produce a flawed understanding of disease evolution, precipitating far-reaching f gene test surgical strategies like bilateral total adrenalectomy and 4-gland parathyroidectomy in f gene carrier MEN2. The insight into the natural course of the disease gleaned over the past 25 years f multiple endocrine caused a paradigm shift in MEN2: from the removal of target organs at the expense of neoplasia type 2A greater operative morbidity to close biochemical surveillance and targeted resection of adrenal tumors and hyperplastic parathyroid glands. The lead time provided by early identification of asymptomatic MEN2 carriers under biochemical surveillance delimits a ‘window of opportunity’, within which (i) pre-emptive total thyroidectomy alone is adequate, circumventing morbidity attendant to central node dissection; (ii) subtotal ‘tissue-sparing’ adrenalectomy is sufficient, trading the risk of steroid dependency for the risk of a second pheochromocytoma in the adrenal remnant and (iii) parathyroidectomy is limited to enlarged glands, trading the risk of postoperative hypoparathyroidism for the risk of leaving behind hyperactive parathyroid glands. Future research should delineate further the mutation-specific, age-dependent penetrance of pheochromocytoma and primary hyperparathyroidism to refine the risk-oriented approach to MEN2. The sweeping changes in the management of MEN2 since the new millenium hold the hope that death and major morbidity from this uncommon disease can be eliminated in our Endocrine-Related Cancer lifetime. (2018) 25, T41–T52 Introduction More than fifty years ago, the medical community It is now commonly referred to as multiple endocrine witnessed the birth of a new hereditary endocrine neoplasia type 2 or MEN2, especially when complemented syndrome encompassing medullary thyroid cancer (MTC) by primary hyperparathyroidism. This achievement and pheochromocytoma: ‘Sipple syndrome’, named after was brought about by a combination of astute clinical the author of this seminal description (Sipple 1961). observation (Sipple 1961, Williams 1965) coupled with http://erc.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/ERC-17-0202 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 01:35:28AM via free access 10.1530/ERC-17-0202 Endocrine-Related A Machens et al. Advances in risk-oriented 25:2 T42 Cancer surgery for MEN2 advances in immunohistochemistry and hormonal an individual’s genetic predisposition to MEN2, was assay technology. superior to biochemical screening for subclinical disease Before that landmark event, individuals operated on (Lips et al. 1994, Wells et al. 1994, Learoyd et al. 1997, for MTC would be misdiagnosed with papillary, follicular Dralle et al. 1998). Because genetic association studies are or undifferentiated thyroid cancer. Some individuals used critically dependent on definite clinical case definitions to succumb to acute cardiovascular or cerebrovascular of the disease of interest, more penetrant RET mutations events, typically during childbirth masquerading as were overrepresented in early MEN2 studies (Fig. 1; Eng eclampsia or on invasive procedures, which in hindsight et al. 1996, Frank-Raue et al. 2010, Machens et al. 2013a), were ascribed to adrenergic hormonal excess from occult including the International MEN2 Consortium analysis pheochromocytoma (Lips et al. 1981). ‘Sipple syndrome’, (Eng et al. 1996): or MEN2A, came to attention in 1961 because it is • Highest risk mutations in codon 918 (classic MEN2B; a ‘noisy’ syndrome with as many patients initially American Thyroid Association/ATA HST) (Wells et al. identified based on the presence of hypercalcemia or 2015); pheochromocytoma as MTC, facilitating its recognition • High-risk mutations in codon 634 (classic MEN2A; ATA (Grubbs & Gagel 2015). Although most patients with H) (Wells et al. 2015). fully penetrant MEN2 were ascertained quickly as having MEN2, patients featuring just one of the three Initially underrepresented went moderate-risk mutations syndromic constituents continued to be misdiagnosed in codons 609, 611, 618, 620 and 630 (‘incomplete’ with ‘sporadic’ disease. MEN2A; ATA MOD), whereas the weaker moderate-risk The molecular era for MEN2 was ushered in with mutations in codons 768, 790, 804 and 891 (‘familial the discovery of RET (rearranged during transfection) as MTC’/FMTC; ATA MOD) were missed altogether. These the susceptibility gene on chromosome 10q11.2 in 1993 weaker mutations were subsequently reported in (Donis-Keller et al. 1993, Mulligan et al. 1993). It became 1995–1998 (Bolino et al. 1995, Eng et al. 1995, Hofstra immediately apparent that DNA-based screening, revealing et al. 1997, Berndt et al. 1998). Prevalence of Highest, High and Moderate Risk Mutations in MEN 2 Genotype ATA risk Prevalence of RET Mutations Amino acid category CLD1 substitutions (Wells et al. Eng et al. Frank-Raue et al. Machens et al. 1996 2010 2013 CLD2 per codon 2015) (440 families) (110 families) (317 families) Cadherine- like domains CLD3 Exon 10 20% 19% 26% CLD4 C609R/G/F/S/Y MOD C611R/G/F/S/W/Y (88 families) (21 families) moderate (83 families) C618R/G/F/S/Y Cysteine-rich C620R/G/F/S/W/Y CRD (cysteine domain codons) Exon 11 C630R/F/S/Y 43% 38% TM Transmembrane H Exon 11 62% (47 families) JM C634R/G/F/S/W/Y high (119 families) (271 families) Exon 13 TK 1 E768D MOD L790F moderate Intracellular Exon 14 (non-cysteine 27% tyrosine V804L/M 34% codons) kinase (6 families) 1% (85 families) Exon 15 (37 families) TK 2 S891A 17% Exon 16 HST (75 families) 9% M918T highest 5% (5 families) (30 families) tail Figure 1 Prevalence of highest, high- and moderate-risk mutations in MEN2. http://erc.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/ERC-17-0202 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 01:35:28AM via free access Endocrine-Related A Machens et al. Advances in risk-oriented 25:2 T43 Cancer surgery for MEN2 The enrichment of genetic association studies with Mere review articles were excluded from review. To avoid individuals who manifest advanced disease (multifocal duplication, earlier reports from groups that updated disease with involvement of multiple glands) is a previously published information in a subsequent, more methodological limitation (‘selection bias’), which is comprehensive report were not considered. Pertinent unavoidable when the susceptibility gene is unknown. publications were reviewed further, and data elements Less well appreciated are the clinical ramifications of were extracted as appropriate in structured format. such enrichment for hereditary conditions like MEN2 in which every thyroid C-cell, adrenal medullary cell and Case definitions of MEN2 components parathyroid chief cell has inherited the predisposition to MTC, pheochromocytoma or pseudonodular A diagnosis of medullary thyroid carcinoma typically parathyroid hyperplasia (Eng et al. 1996, Machens et al. required tumor extension beyond the basement 2003). These theoretical considerations, supported by membrane, demonstration of lymphatic or vascular histopathological evidence of diffuse multifocal disease in invasion or both. multiple glands in MEN2 (Lips et al. 1978) and fueled by Pheochromocytoma typically was diagnosed in reports about clusters of fatal outcome in certain MEN2 the presence of raised plasma-free metanephrines and families (Lips et al. 1981), resulted in fairly extensive normetanephrines, or 24-h urine metanephrines and initial surgical strategies for pre-emption, in particular normetanephrines, supported by histopathological bilateral total adrenalectomy (Lips et al. 1981) and confirmation of the biochemical diagnosis on the 4-gland parathyroidectomy with or without autografting adrenal specimens. of parathyroid slivers to the sternocleidomastoid muscle A diagnosis of primary hyperparathyroidism was or the brachioradial muscle of the nondominant forearm based on the evidence of hypercalcemia, typically in the (Yoshida et al. 2009, Moley et al. 2015). presence of increased parathyroid hormone levels. Twenty-five years after the advent of the genomic epoch for MEN2, it may be pertinent to take stock of Results the wealth of genomic and outcome data accrued. This review article endeavors to gauge mutation-specific Transformation