SPECIAL FEATURE

Review

Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma: An Update

Samuel A. Wells, Jr, Furio Pacini, Bruce G. Robinson, and Massimo Santoro

Cancer Genetics Branch (S.A.W.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20814; Section of Endocrinology and Metabolism (F.P.), Department of Internal Medicine, Endocrinology, and Metabolism, and Biochemistry, University of Siena, 53100 Siena, Italy; University of Sydney School of Medicine (B.R.), The University of Sydney, Sydney, New South Wales 2065, Australia; and Dipartimento di Downloaded from https://academic.oup.com/jcem/article/98/8/3149/2833379 by guest on 29 September 2021 Medicina Molecolare e Biotecnologie Mediche (M.S.), Universita’ di Napoli “Federico II”, Edificio 19, Torre Biologica, Via S. Pansini 5, 80131, Napoli, Italy

Context: Over the last decade, our knowledge of the multiple endocrine neoplasia (MEN) type 2 syndromes MEN2A and MEN2B and familial medullary thyroid carcinoma (FMTC) has expanded greatly. In this manuscript, we summarize how recent discoveries have enhanced our understand- ing of the molecular basis of these diseases and led to improvements in the diagnosis and man- agement of affected patients.

Evidence Acquisition: We reviewed the English literature through PubMed from 2000 to the present, using the search terms medullary thyroid carcinoma, multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma, RET proto-oncogene, and calcitonin.

Evidence Synthesis: Over 70 RET mutations are known to cause MEN2A, MEN2B, or FMTC, and recent findings from studies of large kindreds with these syndromes have clouded the relationship between genotype and phenotype, primarily because of the varied clinical presentation of different families with the same RET mutation. This clinical variability has also confounded decisions about the timing of prophylactic thyroidectomy for MTC, the dominant endocrinopathy associated with these syndromes. A distinct advance has been the demonstration through phase II and phase III clinical trials that molecular targeted therapeutics are effective in the treatment of patients with locally advanced or metastatic MTC.

Conclusions: The effective management of patients with MEN2A, MEN2A, and FMTC depends on an understanding of the variable behavior of disease expression in patients with a specific RET mutation. Information gained from molecular testing, biochemical analysis, and clinical evaluation is important in providing effective management of patients with either early or advanced-stage MTC. (J Clin Endocrinol Metab 98: 3149–3164, 2013)

ince the seventh International Workshop published or somatic activating RET mutations that either alone S the Consensus Guidelines for the Diagnosis and or in association with a second RET mutation, charac- Therapy of Multiple Endocrine Neoplasia types 1 and 2 terize modified phenotypes (2–4). There have been ad- over a decade ago, there has been a marked expansion ditional studies addressing the indications and timing of in our knowledge of the basic and clinical aspects of prophylactic thyroidectomy in family members who these syndromes (1). This is particularly true of multiple have inherited a mutated RET allele. Also, completed endocrine neoplasia (MEN) type 2A, MEN2B, and fa- phase II and phase III clinical trials of molecular tar- milial medullary thyroid carcinoma (FMTC), where ex- geted therapeutics (MTTs) have shown efficacy in pa- tensive studies of large families, often from national tients with advanced (MTC), a disease stage for which consortia, have led to the identification of new germline there has been no effective therapy.

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: CCH, C-cell hyperplasia; CEA, carcinoembryonic antigen; CLA, cutaneous Printed in U.S.A. lichen amyloidosis; FMTC, familial medullary thyroid carcinoma; HD, Hirschsprung’s dis- Copyright © 2013 by The Endocrine Society ease; MEN, multiple endocrine neoplasia; MTC, medullary thyroid carcinoma; MTT, mo- Received January 22, 2013. Accepted May 30, 2013. lecular targeted therapeutic; RET, rearranged during transfection. First Published Online June 6, 2013

doi: 10.1210/jc.2013-1204 J Clin Endocrinol Metab, August 2013, 98(8):3149–3164 jcem.endojournals.org 3149 3150 Wells, Jr et al Hereditary Medullary Thyroid Carcinoma J Clin Endocrinol Metab, August 2013, 98(8):3149–3164

The RET proto-oncogene comprises 21 ex- ons and is located on chromosome 10 (10q11.2). Homologs of RET are present in higher and lower vertebrates, as well as in Drosophilia melanogaster (12, 13). RET en- codes a single-pass transmembrane receptor of the tyrosine kinase family of proteins, and at several stages of development, it is expressed in cells derived from the branchial arches (para- thyroids), from the neural crest (the brain,

parasympathetic and sympathetic ganglia, thy- Downloaded from https://academic.oup.com/jcem/article/98/8/3149/2833379 by guest on 29 September 2021 roid C-cells, adrenal medulla, and enteric gan- glia), and from the urogenital system (14). RET is the integral component of a tripartite cell- surface complex including a member of the gli- al-derived neurotrophic factor (GDNF) family ligands (GFL) (Figure 1), to which it binds in conjunction with its cognate glycosylphos- phatidylinositol-linked GDNF family ␣ recep- tors (GFR␣ 1–4). Ligand binding, requiring calcium ions chelated to the RET extracellular domain, induces dimerization and phosphor- ylation of the RET receptor with downstream activation of several signal transduction path- ways (15) (Figure 1). In MEN2A, MEN2B, and FMTC, the mutations are activating, unlike most other hereditary cancer syndromes, which are associated with DNA mismatch re- pair genes or inactivation of tumor suppressor genes. The recent discovery that somatic Figure 1. The RET protein. Abbreviations: ART, artemin; CLD, cadherin-like HRAS, KRAS, and NRAS mutations occur in domains; CRD, cysteine-rich domain; GDNF, glial-derived neurotrophic factor; GFL, approximately 10% to 45% of sporadic ␣ ␣ glial-derived neurotrophic factor family ligands; GFR (1–4), GDNF family MTCs, and are almost always mutually exclu- receptors; Ki, kinase insert region; NTN, neuturin; PSP, persephin; SP, signal peptide; TK, tyrosine kinase domain; TM, transmembrane domain. The position of major RET sive with somatic RET mutations, suggests an phosphorylation sites (Y905, Y1015, and Y1062) are marked, as are other important alternate molecular pathway for the phosphorylation sites and signaling pathways. development of this malignancy (16, 17). A re- cent exomic sequencing study demonstrated Recently, several professional groups have published ad- that besides RET and rarely RAS, no other gene is com- ditional guidelines defining the management of patients with monly targeted by point mutations in MTC (18). MTC or neuroendocrine tumors (5–7). Accordingly, our Approximately 50% of patients with familial Hirsch- purpose is not to develop another set of guidelines, or to sprung’s disease (HD) have RET mutations, and chromo- revise existing guidelines, but to provide an overview of the somal translocations that activate RET occur in approx- current knowledge of the MEN2 syndromes and FMTC. imately 30% of patients with papillary thyroid carcinoma and less often in patients with lung cancer and chronic myelomonocytic leukemia (19–22). The Molecular Genetic Basis of MEN2A, MEN2B, and FMTC Clinical Manifestations of MEN2A, MEN2B, Each of the MEN2 syndromes and FMTC is inherited in and FMTC an autosomal dominant pattern and is caused by muta- tions in the RET (rearranged during transfection) proto- MEN type 2A oncogene (8–11). Over 1000 kindreds with these endo- MEN2A (OMIM 171400) accounts for 80% of hered- crinopathies have been identified throughout the world. itary MTC syndromes. Virtually all patients develop doi: 10.1210/jc.2013-1204 jcem.endojournals.org 3151

MTC, up to 50% develop pheochromocytomas, and up to is made after MTC in 50% of cases, concurrently with 30% develop hyperparathyroidism depending on the RET MTC in 40% of cases, and before MTC in 10% of cases. codon mutation (23). Patients with MEN2A may also de- The tumors are almost always benign and confined to the velop cutaneous lichen amyloidosis (CLA), HD, or rarely adrenal gland. In 65% of cases, they are multicentric and prominent corneal nerves (24). Despite the facts that RET bilateral. Patients with unilateral pheochromocytomas is highly expressed in human fetal kidney during morpho- usually develop a contralateral pheochromocytoma within genesis and that ret-knockout mice (retϪ/Ϫ) display renal 10 years (31). agenesis or severe dysgenesis, there are few reports of gen- There is significant morbidity and mortality associated itourinary abnormalities in patients with MEN2A, with an undiagnosed pheochromocytoma; thus, in pa- MEN2B, or FMTC (25, 26). tients with known MEN2A or MEN2B, it is critical to rule

MTC accounts for approximately 5% of all thyroid out this tumor before interventional procedures. Before Downloaded from https://academic.oup.com/jcem/article/98/8/3149/2833379 by guest on 29 September 2021 cancers and occurs either sporadically (75% of cases) or in the introduction of biochemical and genetic testing, pheo- a hereditary pattern. The MTC arises from the neural chromocytoma, not MTC, was the most common cause of crest-derived C-cells and up to 50 C-cells per low-power death in patients with MEN2A. The deaths were com- field are present in the normal adult thyroid gland (27). In monly associated with surgical procedures or childbirth the early stage of pathogenesis these cells proliferate, as (23, 32). After the introduction of biochemical and genetic C-cell hyperplasia (CCH), the only histological manifes- screening in families with hereditary MTC, deaths due to tation of incipient disease. The so-called secondary CCH, pheochromocytoma markedly decreased. occurring in association with diseases such as hyperpara- Patients suspected of having a pheochromocytoma thyroidism, hypergastrinemia, and renal insufficiency, or should have measurement of plasma-free or urinary-frac- after the administration of certain drugs, is not a prema- tionated metanephrines or both (33, 34). Computed to- lignant condition (28). The maximum C-cell surface area mography scanning and magnetic resonance imaging are in the adult thyroid gland is twice as high in men as used to localize pheochromocytomas. The sensitivity women (29). The C-cells secrete the 32–amino-acid (90%–100%) and specificity (70%–80%) are similar for polypeptide calcitonin and the glycoprotein carcinoem- the 2 procedures (35, 36). bryonic antigen (CEA), which serve as excellent tumor Excepting very unusual circumstances, a pheochro- markers for MTC. The serum calcitonin level, both in mocytoma should be resected before the MTC if both the basal state and after iv administration of the secre- are present. Preoperative preparation is with ␣-adren- tagogues calcium or pentagastrin is higher in men com- ergic blockade and if necessary ␤-adrenergic blockade. pared with women, almost certainly a reflection of the Unilateral adrenalectomy is indicated in patients with a gender difference in C-cell mass. single pheochromocytoma, because there is a significant Unlike sporadic MTC, which presents as a solitary uni- incidence of Addisonian crisis associated with bilateral lateral thyroid nodule, hereditary MTC is multicentric and adrenalectomy (31, 37). In patients with bilateral pheo- occupies the upper and middle portions of each thyroid chromocytomas, both adrenals are resected under corti- lobe. The tumor remains confined to the thyroid gland for costeroid coverage preoperatively and continuously post- a variable period of time before spreading to the regional operatively. The standard procedure is laparoscopic lymph nodes and subsequently to the liver, lung, bone, and adrenalectomy (38, 39). Because of the substantial mor- brain. Histologically, 20% of the tumors have a predom- bidity and occasional mortality associated with bilateral inantly cellular growth pattern, 40% have a fibrous pat- adrenalectomy for pheochromocytoma surgeons have ex- tern with more than half of the cellular component re- plored procedures such as subtotal adrenalectomy to pre- placed by a calcified acellular stroma, and the remaining serve adrenocortical function (40). Although the concept 40% display an intermediate pattern with neoplastic nests of preserving adrenal cortical function in this clinical set- of cells separated by bands of fibrous tissue. The stroma is ting has merit, there has been a limited experience with the composed primarily of full-length calcitonin, which has procedure and there are few reports of long-term fol- staining properties similar to amyloid (30). There is a low-up in treated patients (40, 41). graded progression in tumor histology with a cellular Hyperparathyroidism develops in 20% to 30% of pa- growth pattern developing early and progressing to inter- tients with MEN2A. The mean age of onset is 36 years mediate and fibrous patterns as the MTC ages. (42). In most cases, hyperparathyroidism is diagnosed Pheochromocytomas develop in approximately 50% concurrently with MTC, being the first manifestation of of patients with MEN2A and MEN2B, the clinical pre- the syndrome in less than 5% of cases. The hypercalcemia sentation and behavior being similar in the 2 syndromes. is usually mild, and 85% of patients are asymptomatic The mean age of presentation is 36 years, and the diagnosis (43). The size of the parathyroid glands may vary greatly 3152 Wells, Jr et al Hereditary Medullary Thyroid Carcinoma J Clin Endocrinol Metab, August 2013, 98(8):3149–3164 with from 1 to 4 being enlarged. Histologically, the en- (enlarged corneal nerves, conjunctivitis sicca, and the larged parathyroid glands contain multiple hyperplastic inability to cry tears), musculoskeletal manifestations nodules in a pattern best defined as pseudonodular hy- (bowing of the extremities and slipped capital femoral perplasia (44). During thyroidectomy for MTC, the sur- epiphysis), and generalized ganglioneuromatosis. Over geon often finds 1 or more enlarged parathyroid glands 90% of patients have gastrointestinal symptoms char- even though the patient is asymptomatic and normocal- acterized by abdominal pain, constipation, and alter- cemic. There is no single satisfactory operation for hyper- natively diarrhea, bloating, and megacolon. The gas- parathyroidism in MEN2A, the options being subtotal trointestinal symptoms are particularly evident in parathyroidectomy with preservation of a small remnant children and young adults and may require a surgical of one gland or total parathyroidectomy with heterotopic procedure to relieve symptoms (54, 55). autotransplantation (45, 46). It is important that clinicians who first see children with Downloaded from https://academic.oup.com/jcem/article/98/8/3149/2833379 by guest on 29 September 2021 CLA occurs in approximately 10% of families with MEN2B recognize the characteristic signs and symptoms MEN2A. The skin lesions are particularly evident in the associated with the syndrome, because the MTC is highly scapular region of the back corresponding to dermatomes aggressive in this setting and there is a narrow window T2 to T6. The inciting lesion appears to be notalgia par- during which thyroidectomy may be curative (56–59). In esthetica, a sensory neuropathy involving the dorsal spinal approximately 50% of MEN2B cases, a de novo germline nerves. Secondary changes characterized by the deposition RET mutation gives rise to the disease. Newborns are at a of amyloid result from pruritus and repetitive scratching. particular disadvantage in this setting, because their par- The CLA may be present at a young age and before the ents appear normal, and the disease is unexpected. In one onset of clinically evident MTC, thus serving as a precur- series of 21 patients with sporadic MEN2B, the mean age sor for the syndrome (47, 48). at diagnosis was 14.2 years (60). Even in the most advan- HD can occur in patients with MEN2A and FMTC and tageous setting where thyroidectomy is performed in the is characterized by the failure of neural crest cells to mi- neonatal period, the outcome is often dismal (61). In pa- grate, proliferate, and differentiate into submucosal tients with de novo MEN2B, the mutated allele arises from (Meissner), myenteric (Auerbach), and deep submucosal the father. This is also true of the 10% of cases of de novo (Henle’s) enteric plexuses. Several genes have been impli- MEN2A (62, 63). cated in HD, the major ones being RET and endothelin receptor B (EDNRB). (49) Whereas EDNRB mutations Familial MTC are present in approximately 5% of patients with HD, FMTC (OMIM 155240) accounts for 15% of heredi- RET mutations are found in 15% to 20% of sporadic tary MTCs. This entity is characterized by the presence of cases and 50% of familial cases (50). HD occurs in ap- only MTC, which has a late age of onset and a less ag- proximately 7% of patients with MEN2A and FMTC (4). gressive clinical course compared with MEN2A and Conversely, 2% to 5% of patients with HD have heredi- MEN2B (64). As defined in the “Guidelines for Diagnosis tary MTC (51, 52). The RET mutations associated with and Therapy of MEN Type 1and Type 2” (1), a diagnosis HD disable the activation or expression of RET, resulting of FMTC would apply to kindreds with more than 10 in loss-of-function in contrast to the RET mutations as- carriers, multiple carriers, or affected members over the sociated with MEN2A, MEN2B, and FMTC, which in- age of 50 and an adequate medical history to exclude the duce constitutive activation and gain-of-function. The presence of pheochromocytoma and hyperparathyroid- generally accepted explanation for the concurrence of HD ism, especially in older subjects (1). These criteria are more and MEN2A or FMTC is that a dual effect is induced by rigorous than those set forth by the International RET the associated RET mutations, which through constitutive Mutation Consortium Analysis, which defined FMTC as activation, are sufficient to trigger neoplastic transforma- a kindred with a minimum of 4 family members with MTC tion of the thyroid C-cells and adrenal chromaffin cells yet, and no objective evidence of pheochromocytoma or hy- because of impaired expression of the RET protein at the perparathyroidism (65). cell surface, are insufficient to generate a trophic response in the precursor neurons (53). Genotype-Phenotype Correlations in MEN type 2B MEN2A, MEN2B, and FMTC MEN2B (OMIM 162300) accounts for 5% of heredi- tary MTCs. Patients with MEN2B also develop pheochro- Clinical studies have provided an important framework mocytomas and a definitive phenotype characterized by for understanding the relationship of genotype to pheno- typical facies, a marfanoid habitus, ocular abnormalities type, especially in MEN2A. For example, in 95% of pa- doi: 10.1210/jc.2013-1204 jcem.endojournals.org 3153 tients with MEN2A, RET mutations occur in codons 609, evident that many kindreds first designated as FMTC, 611, 618, and 620 in exon 10 or in codon 634 in exon11. with longer follow-up, or upon study of other kindreds The presence of any germline mutation at codon 634 is with the same mutation, are found to have MEN2A. This highly associated with the development of hyperparathy- situation is exemplified by a 6-generation Brazilian kin- roidism and also pheochromocytoma, the frequency of the dred of 229 family members, 76 of whom had MTC due latter depending on the RET codon mutation: 609 (4%), to a G533C mutation but no evidence of pheochromocy- 611 (0%), 618 (22%), 620 (9%), and 634 (50%) (66). The toma or hyperparathyroidism (77). The family appeared presence of CLA in MEN2A is almost always associated to have FMTC; however, it was subsequently reported with a C634 RET codon mutation; however, it has also that a 62-year-old member of this kindred developed a been reported in a subject with a V804M germline mu- pheochromocytoma (78). Furthermore, 2 Greek families tation (65, 67). The HD associated with MEN2A almost with the G533C mutation were reported to have MTC and Downloaded from https://academic.oup.com/jcem/article/98/8/3149/2833379 by guest on 29 September 2021 always involves the cysteine codons in exon 10, includ- pheochromocytoma, thus clarifying that this RET muta- ing 609 (15%), 611 (5%), 618 (30%), and 620 (50%) tion is associated with MEN2A (79, 80). (68, 69). The matter of nomenclature has been further compli- The large majority of patients with MEN2B have mu- cated as various investigators have used FMTC to define tations in exon 16 (M918T) and less often exon 15 families, most commonly those with the noncysteine RET (A883F). The clinical behavior of the MTC appears to be mutations in codons 768, 790, 791, or 804, who predom- less aggressive in patients with the A883F mutation, com- inantly manifest MTC and have a much lower frequency pared with those with a M918T mutation, and despite the of pheochromocytoma or hyperparathyroidism (5, 81– generally poor prognosis, rare long-term cures after early 83). If these broader criteria were followed, the incidence thyroidectomy have been reported (59, 70, 71). Patients of FMTC would comprise 30% to 60% of patients with with rare double RET mutations involving codon V804M hereditary MTC. and either codon Y806C, S904C, or E805K present with Thus, a clear definition of FMTC is needed. Consider- atypical MEN2B, characterized by MTC with a late age of ing the rigid criteria proposed by the “Guidelines for Di- onset and varying aggressiveness (72–74). agnosis and Therapy of MEN Type 1and Type 2” (1), The most common FMTC mutations affect extracellu- there are at present only 3 documented families that would lar cysteine codons in RET exon 10, or intracellular RET be classified as FMTC (Supplemental Table 1) (1, 84–86). codons other than A883 and M918. One solution is to retain the definition of FMTC with The reported RET germline point mutations and their the strict criteria originally proposed, realizing that after associated clinical phenotypes are shown in Figure 2, and long-term follow-up, a family suspected of having FMTC the list of all reported RET mutations, deletions, inser- may develop hyperparathyroidism or pheochromocy- tions, duplications, homozygous mutations, and multiple toma and be reclassified as MEN2A (1). A second alter- codon mutations associated with MEN2A, MEN2B, and native is to expand the definition of FMTC to include FMTC are listed in Supplemental Table 1 (published on families with certain RET mutations who have late-onset The Endocrine Society’s Journals Online web site at MTC with the infrequent occurrence of pheochromocy- http://jcem.endojournals.org). toma or hyperparathyroidism. A third alternative is to Early reports evaluating the association between geno- discard the term FMTC and classify all patients with he- type and phenotype occurred at a time when many RET reditary MTC, other than those with MEN2B, as MEN2A mutations causing hereditary MTC were yet to be discov- and designate them by a specific RET mutation, for ex- ered (65, 75, 76). It was expected that as a larger number ample MEN2A_RET C634R (87). With this option, there of families were studied, the relationship between geno- would be two MEN2 syndromes, with approximately type and phenotype would become clearer; however, in 95% classified as MEN2A, which would be a remarkably many ways, the opposite has happened. It has become heterogeneous group with over 70 different RET muta- apparent that different families with MEN2A due to the tions in families that express MTC, pheochromocytomas, same RET mutation often have significant variability in and hyperparathyroidism over a wide range of frequen- the clinical expression of disease and aggressiveness of the cies, times of onset, and clinical behavior. This would not MTC. This is presumably due to coexpression of disease- address the issue of a number of small families, or single modifying alleles. individuals, many with rare germline RET mutations, who Although the original criteria defining MEN2A and defy classification. MEN2B have remained unchanged, there has been a par- All considered, it seems reasonable to retain the term ticular problem with FMTC, where already there are 2 sets FMTC and include within it 1) families with a RET germ- of criteria defining the syndrome (1, 65). It has become line mutations who meet the original strict criteria for 3154 Wells, Jr et al Hereditary Medullary Thyroid Carcinoma J Clin Endocrinol Metab, August 2013, 98(8):3149–3164 Downloaded from https://academic.oup.com/jcem/article/98/8/3149/2833379 by guest on 29 September 2021

Figure 2. The RET gene, the RET protein, and RET point mutations associated with MEN2A, MEN2B, and FMTC. RET gene structure with coding exons numbered 1 to 20 is shown as the central figure in gray. Alternative splicing in exon 19 generates 2 alternative mRNAs, coding for RET-51 (1114 residues) when exon 19 is spliced to exon 20 or RET-9 (1072 residues) when exon 19 remains unspliced. Moreover, alternative splicing to another exon (exon 21) causes the synthesis of the C-terminal part of another less abundant RET isoform, RET-43. In this figure, only RET-51 is represented, whereas RET-9, RET-43, and the alternative exon 21 are not. The RET protein is represented on the left in blue and red. Amino acid residues, numbered 1 to 1114, are shown to the left of the figure. The extracellular RET domain (with the signal peptide [SP], 4 cadherin-like domains [CLD1–4], and a cysteine-rich domain [CRD]), the transmembrane domain (TM), and the intracellular tyrosine kinase domain (TK) are represented. The RET TK is split into 2 subdomains (TK1 and TK2) by an insert region (Ki). The positions of reported RET point mutations associated with MEN2A, MEN2B, and FMTC are shown to the right of the RET gene. The mutations causing MEN2A and MEN2B are shown in black, whereas the mutations for FMTC are shown in red. An asterisk denotes homozygous mutations. Some of the reported RET mutations have no function studies demonstrating that the specific mutation is a bona fide gain-of-function mutation. Not included in Figure 2 are reports of deletions, insertions, duplications, or multiple mutations. This information, as well as references for each point mutation or genetic alteration, is includedin Supplemental Table 1. [Modified from Figure 5 in J. W. de Groot et al: RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors. Endocr Rev. 2006;27:535–560 (163), with permission. © The Endocrine Society.] doi: 10.1210/jc.2013-1204 jcem.endojournals.org 3155

FMTC (1), 2) small families (at least 2 generations, with at In many European centers, it is standard practice to least 2 but fewer than 10 RET gene carriers) with MTC but measure serum calcitonin levels in patients presenting with no pheochromocytoma or hyperparathyroidism, or 3) nodular goiters to exclude MTC, although this has not small families or single individuals with 2 or fewer mem- become common practice in the United States or Australia bers with MTC in a single generation without pheochro- (92–95). mocytoma or hyperparathyroidism. According to this classification, the reported families or Direct DNA analysis for mutations in the RET single individuals with only MTC, and associated specific proto-oncogene RET germline mutations, are listed in Supplemental Table Approximately 98% of index patients with MEN2 and 1. It is important to note that to designate a family with a FMTC have an identifiable RET mutation (81, 96). Figure specific RET germline mutation, eg, C611F, as FMTC, 2 lists the currently known RET point mutations (within Downloaded from https://academic.oup.com/jcem/article/98/8/3149/2833379 by guest on 29 September 2021 there must be no other reported family with this specific exons) documented in hereditary MTC. Unlike the char- acteristic mutations in exons 10, 11, 15, and 16 associated mutation that has either a pheochromocytoma or with MEN2A and MEN2B, little is known about the mode hyperparathyroidism. of activation of extracellular mutations in RET exons 5 Although this modified nomenclature may add clarity and 8 (97–100). Also, the mechanisms by which intracel- to the disease phenotypes and genotypes, clinical investi- lular codon mutations in exons 13 and 14, and less com- gators still need to be aware of the substantial variability monly non-MEN2B mutations in exons 15 and 16, acti- in the clinical expression of disease within MEN2A and vate RET are unclear, although in the latter case, it has FMTC families. This is especially relevant in patients con- been suggested that they disrupt the autoinhibited dimer sidered for prophylactic thyroidectomy. conformation of wild-type RET, thereby enabling RET kinase (101). In families with a known germline RET mutation, test- The Diagnosis of Hereditary and Sporadic ing of family members at risk is relatively easy because a MTC targeted approach can be focused on the specific codon Serum calcitonin housing the mutation. In new families with hereditary MTC where the RET status is unknown, the usual strategy Formerly, measurement of serum calcitonin levels, es- for testing family members at direct risk is to sequence the pecially after the iv administration of the provocative most commonly affected exons and, if negative, to extend secretagogues calcium or pentagastrin, or a combination sequencing to additional exons. If no RET mutation is of the two, served as the primary method for screening found, it may be necessary to sequence the entire coding family members at risk for hereditary MTC (88). Since the region of the gene. As the extent of sequencing increases, introduction of direct DNA analysis for detecting RET so does the cost. Gene sequencing technology, however, is mutations, the determination of serum calcitonin levels is becoming cheaper, and clinicians may find that rather rarely used alone for the early diagnosis of hereditary than a tiered approach, it may be more practical in new MTC; however, in some clinics, it is the basis for timing families with hereditary MTC to sequence the entire RET prophylactic thyroidectomy in family members who have coding region, because this would allow the detection of inherited a mutated RET allele. The preferred assays for not only uncommon RET mutations but also double mu- quantitating serum calcitonin are 2-site, 2-step, chemilu- tations, deletions, and insertions. minescent, immunometric assays that are highly specific One cannot overemphasize the importance of direct for monomeric calcitonin. With these assays, the risks of DNA sequencing to detect RET mutations in kindred a hook effect, or cross-reactivity with other peptides or members at risk for hereditary MTC. There are 69 labo- byproducts of inflammatory or infectious reactions are ratories internationally that perform direct DNA analysis minimal (89–91). The reference values for basal serum for RET mutations (102). The large majority of them se- calcitonin levels are Ͻ10 pg/mL for males and Ͻ5pg/mL quence selected exons (most commonly 10, 11, 13, 14, 15, for females. The reference values for children are more and 16, and in some laboratories, exon 8) or the entire varied, especially in neonates, where they can be as high as coding region. Prenatal diagnosis is offered in some 40 pg/mL (89). The normal range of basal and stimulated laboratories. serum calcitonin levels may vary from laboratory to lab- Approximately, 3% to 7% percent of patients with pre- oratory; thus, for serial measurements of calcitonin, it is sumed sporadic MTC actually have hereditary MTC; best that clinicians use the same laboratory with its estab- thus, it is important to test for germline RET mutations in lished reference range. new patients with MTC regardless of their family history 3156 Wells, Jr et al Hereditary Medullary Thyroid Carcinoma J Clin Endocrinol Metab, August 2013, 98(8):3149–3164

(103, 104). Genetic counselors and physicians are respon- the organ at risk, 4) excellent replacement therapy for the sible for providing information to patients regarding the function of the removed organ, and 5) a reliable method clinical expression of hereditary MTC, the patterns of in- for determining whether the operative procedure has been heritance, the role of genetic testing, and available thera- curative. Few hereditary malignancies meet all of these peutic options. The physician has a duty to warn the pa- criteria; fortunately, MEN2A, MEN2B, and FMTC meet tient that family members may be at foreseeable harm each of them. (105, 106). Also, adult patients, or parents of minors, Direct DNA analysis of family members at risk for he- should inform family members at risk that they should be reditary MTC can detect those who have inherited a mu- tested. The issue of an affected subject’s reluctance to pro- tated RET allele, and they can be offered thyroidectomy vide information to family members or to prevent minors before the development of MTC or while it is still confined at risk from having genetic testing is a more difficult issue, to the thyroid gland. In many cases, the procedure is not Downloaded from https://academic.oup.com/jcem/article/98/8/3149/2833379 by guest on 29 September 2021 which is conflicted by recent provisions inherent in the prophylactic, because CCH, with or without small foci of Health Insurance Portability and Accountability Act MTC, may be present in the resected gland. Nevertheless, (HIPAA) (105). prophylactic or early thyroidectomy in patients found to have a mutated RET allele characteristic of hereditary MTC can be preventative or curative and has become stan- Management of Medullary Thyroid dard management throughout the world. Carcinoma in Patients With MEN2A, A major consideration is the age at which to perform MEN2B, and FMTC thyroidectomy. Several professional groups have devel- oped guidelines for the timing of thyroidectomy, all of The strongest predictor of survival in patients with MTC, which are based on the perceived clinical behavior of the whether hereditary or sporadic, is stage of disease at di- specific RET mutation causing hereditary MTC (Table 1) agnosis. In a population-based study the 10-year disease- (1, 5–7). specific survival exceeded 90% in patients with localized With some RET mutations, the course of action is disease; however, it decreased to 78% and 40%, respec- straightforward. For example, in patients with MEN2B tively, in patients with regional or distant metastases (107). and an M918T or A883F RET mutation, the MTC is Only 10% of patients with metastases to cervical nodes are highly aggressive and thyroidectomy should be performed cured by thyroidectomy and extensive lymph node dissection as soon as the diagnosis is established, even in the first (108–110). The postoperative serum calcitonin falls within months of life. Also, most patients with MEN2A have the normal range in 60% of patients with node-negative mutations in RET codon 634 and even though malignant disease but in only 10% of patients with node-positive transformation can occur as early as 1 year of age, in- disease (108). The prognosis is excellent in patients who volvement of regional lymph nodes rarely occurs before 11 have a preoperative serum calcitonin less than 150 pg/ years of age (2, 112). Most clinicians agree that in this mL, an MTC smaller than 1 cm, and no lymph node setting, the thyroid gland should be removed at or before metastases (108). The 10-year survival approaches 5 years of age, and to decrease the risk of hypoparathy- 100% in patients with undetectable basal and stimu- roidism, a central compartment lymph node dissection is lated calcitonin levels after initial thyroidectomy (111). unnecessary (112). In patients with tumor confined to the thyroid gland, Excepting these 2 examples, the task is more challeng- the standard operation is total thyroidectomy with resec- ing considering the large number of RET mutations iden- tion of lymph nodes in the central zone of the neck, an area tified in subjects with MEN2A and FMTC (Supplemental bounded by the hyoid superiorly, the sternal notch infe- Table 1). It is important that the treating physician study riorly, and the carotid arteries laterally. The neck dissec- the pattern of disease presentation in a new family, as- tion is more extensive in patients with evident cervical suming that it is of sufficient size to yield meaningful in- lymph node metastases. formation. Even in large kindreds, the pattern of disease presentation may not become evident until evaluation of Prophylactic thyroidectomy several family members, and even then it may vary with In patients with hereditary cancer, several criteria reports of other kindreds with the same RET mutation. should be met when considering removal of an organ des- For example, in previous studies of kindreds with MEN2A tined to become malignant. There should be 1) near-com- caused by mutations in RET codon C609S, there were no plete penetrance of the mutated gene, 2) a reliable method reported cases of pheochromocytoma (1, 65). Over the of detecting family members who have inherited a mutated last decade, however, not only has there been documen- allele, 3) minimal morbidity associated with removal of tation of pheochromocytomas in families with this muta- doi: 10.1210/jc.2013-1204 jcem.endojournals.org 3157

Table 1. Guidelines for Timing Prophylactic Thyroidectomy in Hereditary MTC Downloaded from https://academic.oup.com/jcem/article/98/8/3149/2833379 by guest on 29 September 2021

tion but in one kindred, pheochromocytoma was the dom- jects with a given RET germline mutation, some investi- inant endocrinopathy, there being no clinically evident gators have based the timing on the level of basal or MTC (113–115). Furthermore, the age of CCH or MTC stimulated serum calcitonin (120). This approach is con- onset in the youngest patient varied from 9 years in one troversial, however, because there are reports of subjects kindred to 48 years in another, and in all but 1 kindred, the at risk for hereditary MTC with elevated calcitonin levels, age of MTC onset in the youngest patient was above 20 whose thyroidectomy specimens showed no CCH or MTC years (116). In some reports of kindreds with the V804L and subsequent RET mutation analysis was negative RET mutation, there was low penetrance of MTC, (121–123). At present, there are no accepted guidelines for whereas in other kindreds with the same mutation, or the V804M mutation, the MTC was more aggressive (117– the use of basal or stimulated calcitonin levels to determine 119). MEN2A kindreds such as these, and they are not the timing of thyroidectomy in subjects at risk for hered- unusual, present a conundrum and a challenge for clini- itary MTC. The issue is of great importance, however, and cians when considering timing of thyroidectomy. rigorous guidelines need to be defined, especially for cli- Realizing the difficulty of determining the age when nicians who choose a watchful waiting approach for sub- prophylactic thyroidectomy should be performed in sub- jects who have inherited a certain mutated RET allele. 3158 Wells, Jr et al Hereditary Medullary Thyroid Carcinoma J Clin Endocrinol Metab, August 2013, 98(8):3149–3164

Physicians caring for families with hereditary MTC CEA increases progressively, whereas the calcitonin does must consider the risks associated with thyroidectomy not. This suggests cellular dedifferentiation, a hypothesis performed at a very young age, compared with the risks supported by immunohistochemistry studies of CCH, associated with delaying the procedure, possibly losing MTC confined to the thyroid gland, and metastatic MTC patients to follow-up, or finding at thyroidectomy that the (127, 128). MTC has spread beyond the thyroid gland (118, 124). If during the postoperative period the serum calcitonin level increases above 150 to 200 pg/mL, a total body com- The operative procedure puted tomography scan is indicated. Patients who develop In patients with MEN2B regardless of age, and patients metastases to regional lymph nodes but have no distant with MEN2A and FMTC who are above 8 years of age, a metastases are candidates for resection of the recurrent total thyroidectomy with resection of lymph nodes in the tumor. There have been several reports of repeat surgery Downloaded from https://academic.oup.com/jcem/article/98/8/3149/2833379 by guest on 29 September 2021 central compartment of the neck is indicated. In patients for MTC, but to date, there are no randomized trials com- with MEN2A or FMTC who are less than 5 years of age, paring repeat neck surgery to either watchful waiting or with no enlarged cervical lymph nodes, total thyroidec- other therapies. Compartmental dissection was originally tomy alone is the preferred procedure. Regardless of the thought to be curative in approximately 30% of patients operative approach, care must be taken to protect the (129). Recent studies, however, have shown that the se- parathyroid glands, the recurrent laryngeal nerves, and rum calcitonin falls within the normal range postopera- the external branch of the superior laryngeal nerves. Gen- tively in one-third of patients, yet surgical cure, indicated erally, the results of prophylactic thyroidectomy in this by undetectable serum calcitonin levels after pentagastrin clinical setting have been very satisfactory. The European or calcium stimulation is rare (129–131). Some single-arm Multiple Endocrine Neoplasia Study Group evaluated studies suggest that external beam radiotherapy adminis- 207 patients from 145 kindreds with MEN2A, MEN2B, tered postoperatively decreases the incidence of locore- and FMTC. In patients with RET codon 634 mutations, gional disease; however, it has not improved overall sur- malignant transformation was present as early as 1 year of vival (132, 133). age and the cumulative age-related risk of MTC increased progressively with age, but there was no evidence of lymph Complications of hormonal excess from MTC node metastases before 14 years of age (2). In another Approximately 30% of patients with MTC develop di- study of 50 patients with MEN2A followed for a mini- arrhea, and it is more common in patients with high levels mum of 5 years after prophylactic thyroidectomy, no of serum calcitonin (134). Mild diarrhea can be managed lymph node metastases were present in children less than with loperamide or codeine; however, severe diarrhea is 11 years of age. In 44 children, the serum calcitonin was more difficult to control. Tumor debulking or selective undetectable after stimulation with combined calcium and pentagastrin infusion; however, 3 children developed per- arterial chemoembolization may provide benefit in se- manent hypoparathyroidism, emphasizing the risk of per- lected cases (135, 136). forming a central lymph node dissection below 5 years of The development of Cushing’s syndrome due to inap- age (112). propriate ACTH secretion occurs in less than 3% of pa- tients with MTC (137). The treatment is resection of the Postoperative evaluation primary tumor, or in patients with metastases, the admin- Patients should be evaluated within 6 months postop- istration of adrenal enzyme inhibitors such as ketocona- eratively by physical examination and determination of zole, metyrapone, aminoglutethimide, mitotane, etomi- serum levels of calcitonin and CEA. If the serum levels of date, or more recently, mifepristone (138). In many cases tumor markers remain undetectable or within the normal bilateral adrenalectomy is necessary to control the excess range for 5 years, there is no need for additional studies, glucocorticoid production. The prognosis is poor because and patients can be followed at yearly intervals. A reliable most patients die within a year of the diagnosis. indicator of the rate of MTC progression is the doubling time of serum calcitonin or CEA. A calcitonin doubling The management of distant metastases time between 6 months and 2 years is associated with 5- The development of distant metastases from MTC is an and 10-year survival rates of 92% and 37%, whereas a ominous sign because survival after discovery is 51% at 1 calcitonin doubling time less than 6 months is associated year, 26% at 5 years, and 10% at 10 years (111, 139). In with 5- and 10-year survival rates of 25% and 8%, re- patients with an indolent rate of progression, local treat- spectively (125, 126). The serum levels of calcitonin and ment of distant metastases, either by surgical resection, CEA are strongly correlated; however, in some cases, the chemical ablation, or radiotherapy, depending on the an- doi: 10.1210/jc.2013-1204 jcem.endojournals.org 3159

Table 2. Clinical Trials With MTT in Patients with MTC

No. Stable PFS, Drug (Ref.) Study Patients PR, % Disease, % mo Axitinib (151) Phase II 11 18 27a NA Motesanib (152) Phase II 91 2 48b 12 Sorafenib (153) Phase II 16 6.3 87.5a 17.9 Sunitinib (162) Phase II 6 50 NA NA Vandetanib (161) Phase II 30 20 53b 27.9c Vandetanib (100 mg/d) (154) Phase II 19 16 53b NA Cabozantinib (155) Phase II 37 29 41b NA Vandetanib (300 mg/d) (159) Phase III 231/100 0.46 (HR) 0.46 (ORR) 30.5c c

Cabozantinib (160) Phase III 219/111 0.28 (HR) 0.28 (ORR) 11.2 Downloaded from https://academic.oup.com/jcem/article/98/8/3149/2833379 by guest on 29 September 2021 Imatinib (156) Phase II 15 0 27b 0 Imatinib (157) Phase II 9 0 56a 0 Sorafenib plus Tipifarnib (158) Phase II 13 38 31b 17 Abbreviations: HR, hazard ratio comparing progression-free survival in treated compared with placebo control patients; NA, not available; ORR, overall response rate; PFS, progression-free survival; PR, partial response Response Evaluation Criteria in Solid Tumors, (RECIST). a Ͼ4 mo. b Ͼ6 mo. c Estimated PFS in months. atomical site involved, may provide benefit for variable vated, leading to immortalization of the cell. The protein periods of time. tyrosine kinases were recognized as vulnerable therapeutic targets and attracted the interest of clinical oncologists as Systemic therapy for metastatic MTC well as the pharmaceutical industry. The first example that Single-agent or combination chemotherapy has yielded an MTT had efficacy was documented in a randomized short-term responses in the range of 10% to 20% in pa- trial of patients with chronic myeloid leukemia (CML) tients with advanced MTC. Until recently, doxorubicin comparing the tyrosine kinase inhibitor imatinib with in- was the only drug approved by the U.S. Food and Drug terferon alfa plus cytarabine. The results with imatinib Administration (FDA) for the treatment of patients with were far superior to those with interferon alfa plus cytar- advanced MTC, and it is still used for this indication today abine, and at 60 months, 96% of 362 patients still on but much less frequently as frontline therapy (140, 141). imatinib experienced a complete cytogenetic response Other therapeutic agents, ranging from angiogenesis (148). This trial was a major landmark in cancer care and inhibitors and epigenetic-modulating agents to selective created great enthusiasm and cautious expectation that COX-2 inhibitors, have been relatively ineffective in pa- novel MTTs would show similar efficacy in patients with tients with differentiated thyroid carcinoma, and there is other liquid and solid tumors, where the initiating onco- little or no experience in phase II trials of patients with genic event was known and druggable. Although clinical MTC (142–144). Various immunotherapeutic regimens trials of MTTs in patients with solid organ malignancies have been evaluated in patients with advanced MTC, in- has not replicated the striking success achieved with ima- cluding 2 trials of dendritic cells, pulsed with either cal- tinib in CML, some drugs have been effective with signif- citonin and CEA or tumor lysate. Responses were vari- able, but partial remissions were noted in 4 of 17 patients icant improvement in progression-free survival or overall in the 2 trials (145, 146). Pretargeted radioimmuno- survival (149, 150). therapy with bispecific monoclonal 131I antibody against Currently, there are over 20 published phase II or phase CEA has shown promise in early clinical studies but has III clinical trials of MTTs in patients with locally advanced not yet been studied in prospective randomized phase III or metastatic thyroid cancer. Twelve of these document trials (147). The lack of effective systemic therapeutic the efficacy of various MTTs in patients with MTC (Table agents has been a major problem for physicians and their 2) (151–162). Although not all MTTs have shown activ- patients. ity, most have with confirmed partial remissions ranging In the normal state, external growth factors transmit from 2% to 50%. Two of the compounds, vandetanib and signals within the cell through a series of reactions that cabozantinib, have been evaluated in prospective, ran- transfer phosphate from ATP to tyrosine residues in poly- domized, double-blind phase III clinical trials, and each peptides. The reactions are catalyzed by protein tyrosine demonstrated significantly improved progression-free kinases, which when mutated become constitutively acti- survival compared with placebo. Recently, the FDA ap- 3160 Wells, Jr et al Hereditary Medullary Thyroid Carcinoma J Clin Endocrinol Metab, August 2013, 98(8):3149–3164 proved the 2 compounds for treatment of patients with 2. Machens A, Niccoli-Sire P, Hoegel J, et al. Early malignant pro- advanced MTC (159, 160). Virtually all MTTs are asso- gression of hereditary medullary thyroid cancer. N Engl J Med. 2003;349:1517–1525. ciated with toxicities, which in some cases lead to dose 3. Paszko Z, Sromek M, Czetwertynska M, et al. 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