neoplasia endocrina múltiple

Multiple Endocrine Neoplasia Type 2 and FamilialMedullary 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, Maryland20814; 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 ofMedicine (B.R.), The University of Sydney, Sydney, New South Wales 2065, Australia; and Dipartimento diMedicina Molecolare e Biotecnologie Mediche (M.S.), Universita di Napoli Federico II, Edificio 19, TorreBiologica, Via S. Pansini 5, 80131, Napoli, Italy

Context: Over the last decade, our knowledge of the multiple endocrine neoplasia (MEN) type 2syndromes MEN2A and MEN2B and familial medullary thyroid carcinoma (FMTC) has expandedgreatly. 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 thepresent, using the search termsmedullary thyroid carcinoma,multiple endocrine neoplasia type 2,familial medullary thyroid carcinoma, RET proto-oncogene, and calcitonin.

Evidence Synthesis:Over 70 RETmutations are known to causeMEN2A,MEN2B, or FMTC, and recentfindings from studies of large kindreds with these syndromes have clouded the relationship betweengenotype and phenotype, primarily because of the varied clinical presentation of different familieswith the same RETmutation. This clinical variability has also confounded decisions about the timing ofprophylactic thyroidectomy for MTC, the dominant endocrinopathy associated with these syndromes. Adistinct advance has been the demonstration through phase II and phase III clinical trials that moleculartargeted therapeutics are effective in the treatment of patientswith locally advanced ormetastaticMTC.

Conclusions: The effective management of patients with MEN2A, MEN2A, and FMTC depends onan understanding of the variable behavior of disease expression in patients with a specific RETmutation. Informationgained frommolecular testing, biochemical analysis, and clinical evaluationis important in providing effective management of patients with either early or advanced-stageMTC. (J Clin Endocrinol Metab 98: 31493164, 2013)

Since the seventh International Workshop publishedthe Consensus Guidelines for the Diagnosis andTherapy ofMultiple Endocrine Neoplasia types 1 and 2over a decade ago, there has been a marked expansionin our knowledge of the basic and clinical aspects ofthese syndromes (1). This is particularly true ofmultipleendocrine neoplasia (MEN) type 2A, MEN2B, and fa-milial medullary thyroid carcinoma (FMTC), where ex-tensive studies of large families, often from nationalconsortia, have led to the identification of new germline

or somatic activating RET mutations that either aloneor in association with a second RET mutation, charac-terize modified phenotypes (24). There have been ad-ditional studies addressing the indications and timing ofprophylactic thyroidectomy in family members whohave inherited a mutated RET allele. Also, completedphase II and phase III clinical trials of molecular tar-geted therapeutics (MTTs) have shown efficacy in pa-tients with advanced (MTC), a disease stage for whichthere has been no effective therapy.

ISSN Print 0021-972X ISSN Online 1945-7197Printed in U.S.A.Copyright 2013 by The Endocrine SocietyReceived January 22, 2013. Accepted May 30, 2013.First Published Online June 6, 2013

Abbreviations: CCH, C-cell hyperplasia; CEA, carcinoembryonic antigen; CLA, cutaneouslichen amyloidosis; FMTC, familial medullary thyroid carcinoma; HD, Hirschsprungs dis-ease; MEN, multiple endocrine neoplasia; MTC, medullary thyroid carcinoma; MTT, mo-lecular targeted therapeutic; RET, rearranged during transfection.

S P E C I A L F E A T U R E

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doi: 10.1210/jc.2013-1204 J Clin Endocrinol Metab, August 2013, 98(8):31493164 jcem.endojournals.org 3149

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Recently, several professional groups have published ad-ditional guidelines defining themanagementof patientswithMTC or neuroendocrine tumors (57). Accordingly, ourpurpose is not to develop another set of guidelines, or torevise existing guidelines, but to provide an overview of thecurrent knowledge of the MEN2 syndromes and FMTC.

The Molecular Genetic Basis of MEN2A,MEN2B, and FMTC

Each of the MEN2 syndromes and FMTC is inherited inan autosomal dominant pattern and is caused by muta-tions in the RET (rearranged during transfection) proto-oncogene (811). Over 1000 kindreds with these endo-crinopathies have been identified throughout the world.

The RET proto-oncogene comprises 21 ex-ons and is located on chromosome 10(10q11.2). Homologs of RET are present inhigher and lower vertebrates, as well as inDrosophilia melanogaster (12, 13). RET en-codes a single-pass transmembrane receptor ofthe tyrosine kinase family of proteins, and atseveral stages of development, it is expressed incells derived from the branchial arches (para-thyroids), from the neural crest (the brain,parasympathetic and sympathetic ganglia, thy-roid C-cells, adrenal medulla, and enteric gan-glia), and from theurogenital system (14).RETis the integral component of a tripartite cell-surface complex including amember of the gli-al-derived neurotrophic factor (GDNF) familyligands (GFL) (Figure 1), to which it binds inconjunction with its cognate glycosylphos-phatidylinositol-linked GDNF family recep-tors (GFR 14). Ligand binding, requiringcalcium ions chelated to the RET extracellulardomain, induces dimerization and phosphor-ylation of the RET receptor with downstreamactivation of several signal transduction path-ways (15) (Figure1). InMEN2A,MEN2B, andFMTC, the mutations are activating, unlikemost other hereditary cancer syndromes,which are associated with DNA mismatch re-pair genes or inactivation of tumor suppressorgenes. The recent discovery that somaticHRAS, KRAS, and NRAS mutations occur inapproximately 10% to 45% of sporadicMTCs, and are almost always mutually exclu-sive with somatic RETmutations, suggests animportant alternatemolecular pathway for thedevelopment of this malignancy (16, 17). A re-cent exomic sequencing study demonstrated

that besides RET and rarely RAS, no other gene is com-monly targeted by point mutations in MTC (18).

Approximately 50% of patients with familial Hirsch-sprungs disease (HD) haveRETmutations, and chromo-somal translocations that activate RET occur in approx-imately 30%of patients with papillary thyroid carcinomaand less often in patients with lung cancer and chronicmyelomonocytic leukemia (1922).

Clinical Manifestations of MEN2A, MEN2B,and FMTC

MEN type 2AMEN2A (OMIM 171400) accounts for 80% of hered-

itary MTC syndromes. Virtually all patients develop

Figure 1. The RET protein. Abbreviations: ART, artemin; CLD, cadherin-likedomains; CRD, cysteine-rich domain; GDNF, glial-derived neurotrophic factor; GFL,glial-derived neurotrophic factor family ligands; GFR (14), GDNF family receptors; Ki, kinase insert region; NTN, neuturin; PSP, persephin; SP, signal peptide;TK, tyrosine kinase domain; TM, transmembrane domain. The position of major RETphosphorylation sites (Y905, Y1015, and Y1062) are marked, as are otherphosphorylation sites and signaling pathways.

3150 Wells, Jr et al Hereditary Medullary Thyroid Carcinoma J Clin Endocrinol Metab, August 2013, 98(8):31493164


MTC, up to 50%develop pheochromocytomas, and up to30%develophyperparathyroidismdependingon theRETcodon mutation (23). Patients withMEN2Amay also de-velop cutaneous lichen amyloidosis (CLA), HD, or rarelyprominent corneal nerves (24). Despite the facts that RETis highly expressed in human fetal kidney during morpho-genesis and that ret-knockout mice (ret/) display renalagenesis or severe dysgenesis, there are few reports of gen-itourinary abnormalities in patients with MEN2A,MEN2B, or FMTC (25, 26).

MTC accounts for approximately 5% of all thyroidcancers and occurs either sporadically (75%of cases) or ina hereditary pattern. The MTC arises from the neuralcrest-derived C-cells and up to 50 C-cells per low-powerfield are present in the normal adult thyroid gland (27). Inthe early stage of pathogenesis these cells proliferate, asC-cell hyperplasia (CCH), the only histological manifes-tation of incipient disease. The so-called secondary CCH,occurring in association with diseases such as hyperpara-thyroidism, hypergastrinemia, and renal insufficiency, orafter the administration of certain drugs, is not a prema-lignant condition (28). The maximum C-cell surface areain the adult thyroid gland is twice as high in men aswomen (29). The C-cells secrete the 32amino-acidpolypeptide calcitonin and the glycoprotein carcinoem-bryonic antigen (CEA), which serve as excellent tumormarkers for MTC. The serum calcitonin level, both inthe basal state and after iv administration of the secre-tagogues calcium or pentagastrin is higher in men com-pared with women, almost certainly a reflection of thegender difference in C-cell mass.

Unlike sporadicMTC,which presents as a solitary uni-lateral thyroidnodule, hereditaryMTCismulticentric andoccupies the upper and middle portions of each thyroidlobe. The tumor remains confined to the thyroid gland fora variable period of time before spreading to the regionallymphnodes and subsequently to the liver, lung, bone, andbrain. Histologically, 20% of the tumors have a predom-inantly cellular growth pattern, 40% have a fibrous pat-tern with more than half of the cellular component re-placed by a calcified acellular stroma, and the remaining40%display an intermediate patternwith neoplastic nestsof cells separated by bands of fibrous tissue. The stroma iscomposed primarily of full-length calcitonin, which hasstaining properties similar to amyloid (30). There is agraded progression in tumor histology with a cellulargrowth pattern developing early and progressing to inter-mediate and fibrous patterns as the MTC ages.

Pheochromocytomas develop in approximately 50%of patients with MEN2A and MEN2B, the clinical pre-sentation and behavior being similar in the 2 syndromes.Themeanageofpresentation is36years, and thediagnosis

is made after MTC in 50% of cases, concurrently withMTC in 40% of cases, and before MTC in 10% of cases.The tumors are almost always benign and confined to theadrenal gland. In 65% of cases, they are multicentric andbilateral. Patients with unilateral pheochromocytomasusually develop a contralateral pheochromocytoma within10 years (31).

There is significant morbidity andmortality associatedwith an undiagnosed pheochromocytoma; thus, in pa-tientswith knownMEN2AorMEN2B, it is critical to ruleout this tumor before interventional procedures. Beforethe introduction of biochemical and genetic testing, pheo-chromocytoma, notMTC,was themost common cause ofdeath in patients with MEN2A. The deaths were com-monly associated with surgical procedures or childbirth(23, 32).After the introductionof biochemical and geneticscreening in families with hereditary MTC, deaths due topheochromocytoma markedly decreased.

Patients suspected of having a pheochromocytomashould have measurement of plasma-free or urinary-frac-tionated metanephrines or both (33, 34). Computed to-mography scanning and magnetic resonance imaging areused to localize pheochromocytomas. The sensitivity(90%100%) and specificity (70%80%) are similar forthe 2 procedures (35, 36).

Excepting very unusual circumstances, a pheochro-mocytoma should be resected before the MTC if bothare present. Preoperative preparation is with -adren-ergic blockade and if necessary -adrenergic blockade.Unilateral adrenalectomy is indicated in patients with asingle pheochromocytoma, because there is a significantincidence of Addisonian crisis associated with bilateraladrenalectomy (31, 37). In patients with bilateral pheo-chromocytomas, both adrenals are resected under corti-costeroid coverage preoperatively and continuously post-operatively. The standard procedure is laparoscopicadrenalectomy (38, 39). Because of the substantial mor-bidity and occasional mortality associated with bilateraladrenalectomy for pheochromocytoma surgeons have ex-plored procedures such as subtotal adrenalectomy to pre-serve adrenocortical function (40). Although the conceptof preserving adrenal cortical function in this clinical set-ting hasmerit, there has been a limited experiencewith theprocedure and there are few reports of long-term fol-low-up in treated patients (40, 41).

Hyperparathyroidism develops in 20% to 30% of pa-tients with MEN2A. The mean age of onset is 36 years(42). In most cases, hyperparathyroidism is diagnosedconcurrently with MTC, being the first manifestation ofthe syndrome in less than 5%of cases. The hypercalcemiais usually mild, and 85% of patients are asymptomatic(43). The size of the parathyroid glands may vary greatly

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with from 1 to 4 being enlarged. Histologically, the en-larged parathyroid glands contain multiple hyperplasticnodules in a pattern best defined as pseudonodular hy-perplasia (44). During thyroidectomy for MTC, the sur-geon often finds 1 or more enlarged parathyroid glandseven though the patient is asymptomatic and normocal-cemic. There is no single satisfactory operation for hyper-parathyroidism in MEN2A, the options being subtotalparathyroidectomy with preservation of a small remnantof one gland or total parathyroidectomy with heterotopicautotransplantation (45, 46).

CLA occurs in approximately 10% of families withMEN2A. The skin lesions are particularly evident in thescapular region of the back corresponding to dermatomesT2 to T6. The inciting lesion appears to be notalgia par-esthetica, a sensory neuropathy involving the dorsal spinalnerves. Secondary changes characterizedby thedepositionof amyloid result from pruritus and repetitive scratching.The CLA may be present at a young age and before theonset of clinically evident MTC, thus serving as a precur-sor for the syndrome (47, 48).

HD can occur in patientswithMEN2Aand FMTCandis characterized by the failure of neural crest cells to mi-grate, proliferate, and differentiate into submucosal(Meissner), myenteric (Auerbach), and deep submucosal(Henles) enteric plexuses. Several genes have been impli-cated in HD, the major ones being RET and endothelinreceptor B (EDNRB). (49) Whereas EDNRB mutationsare present in approximately 5% of patients with HD,RET mutations are found in 15% to 20% of sporadiccases and 50% of familial cases (50). HD occurs in ap-proximately 7%of patients withMEN2A and FMTC (4).Conversely, 2% to 5% of patients with HD have heredi-tary MTC (51, 52). The RET mutations associated withHD disable the activation or expression ofRET, resultingin loss-of-function in contrast to the RET mutations as-sociated with MEN2A, MEN2B, and FMTC, which in-duce constitutive activation and gain-of-function. Thegenerally accepted explanation for the concurrence ofHDand MEN2A or FMTC is that a dual effect is induced bytheassociatedRETmutations,which throughconstitutiveactivation, are sufficient to trigger neoplastic transforma-tionof the thyroidC-cells andadrenal chromaffin cells yet,because of impaired expression of the RET protein at thecell surface, are insufficient to generate a trophic responsein the precursor neurons (53).

MEN type 2BMEN2B (OMIM 162300) accounts for 5% of heredi-

taryMTCs. PatientswithMEN2Balso develop pheochro-mocytomas and a definitive phenotype characterized bytypical facies, a marfanoid habitus, ocular abnormalities

(enlarged corneal nerves, conjunctivitis sicca, and theinability to cry tears), musculoskeletal manifestations(bowing of the extremities and slipped capital femoralepiphysis), and generalized ganglioneuromatosis. Over90% of patients have gastrointestinal symptoms char-acterized by abdominal pain, constipation, and alter-natively diarrhea, bloating, and megacolon. The gas-trointestinal symptoms are particularly evident inchildren and young adults and may require a surgicalprocedure to relieve symptoms (54, 55).

It is important that clinicianswho first see childrenwithMEN2B recognize the characteristic signs and symptomsassociated with the syndrome, because theMTC is highlyaggressive in this setting and there is a narrow windowduring which thyroidectomy may be curative (5659). Inapproximately 50% ofMEN2B cases, a de novo germlineRETmutation gives rise to the disease. Newborns are at aparticular disadvantage in this setting, because their par-ents appear normal, and the disease is unexpected. In oneseries of 21 patients with sporadic MEN2B, the mean ageat diagnosis was 14.2 years (60). Even in the most advan-tageous setting where thyroidectomy is performed in theneonatal period, the outcome is often dismal (61). In pa-tientswithdenovoMEN2B, themutated allele arises fromthe father. This is also true of the 10% of cases of de novoMEN2A (62, 63).

Familial MTCFMTC (OMIM 155240) accounts for 15% of heredi-

taryMTCs. This entity is characterized by the presence ofonly MTC, which has a late age of onset and a less ag-gressive clinical course compared with MEN2A andMEN2B (64). As defined in the Guidelines for Diagnosisand Therapy ofMEN Type 1and Type 2 (1), a diagnosisof FMTC would apply to kindreds with more than 10carriers, multiple carriers, or affected members over theage of 50 and an adequate medical history to exclude thepresence of pheochromocytoma and hyperparathyroid-ism, especially in older subjects (1). These criteria aremorerigorous than those set forth by the International RETMutation Consortium Analysis, which defined FMTC asakindredwith aminimumof4 familymemberswithMTCand no objective evidence of pheochromocytoma or hy-perparathyroidism (65).

Genotype-Phenotype Correlations inMEN2A, MEN2B, and FMTC

Clinical studies have provided an important frameworkfor understanding the relationship of genotype to pheno-type, especially in MEN2A. For example, in 95% of pa-



tients withMEN2A,RETmutations occur in codons 609,611, 618, and 620 in exon 10 or in codon 634 in exon11.The presence of any germline mutation at codon 634 ishighly associated with the development of hyperparathy-roidismandalsopheochromocytoma, the frequencyof thelatter depending on the RET codon mutation: 609 (4%),611 (0%), 618 (22%), 620 (9%), and634 (50%) (66).Thepresence of CLA inMEN2A is almost always associatedwith a C634 RET codon mutation; however, it has alsobeen reported in a subject with a V804M germline mu-tation (65, 67). TheHDassociatedwithMEN2Aalmostalways involves the cysteine codons in exon 10, includ-ing 609 (15%), 611 (5%), 618 (30%), and 620 (50%)(68, 69).

The large majority of patients with MEN2B have mu-tations in exon 16 (M918T) and less often exon 15(A883F). The clinical behavior of the MTC appears to beless aggressive in patients with the A883Fmutation, com-paredwith those with aM918Tmutation, and despite thegenerally poor prognosis, rare long-term cures after earlythyroidectomy have been reported (59, 70, 71). Patientswith rare doubleRETmutations involving codonV804Mand either codon Y806C, S904C, or E805K present withatypicalMEN2B, characterized byMTCwith a late age ofonset and varying aggressiveness (7274).

The most common FMTCmutations affect extracellu-lar cysteine codons in RET exon 10, or intracellular RETcodons other than A883 and M918.

The reported RET germline point mutations and theirassociated clinical phenotypes are shown in Figure 2, andthe list of all reported RET mutations, deletions, inser-tions, duplications, homozygous mutations, and multiplecodon mutations associated with MEN2A, MEN2B, andFMTC are listed in Supplemental Table 1 (published onThe Endocrine Societys Journals Online web site athttp://jcem.endojournals.org).

Early reports evaluating the association between geno-type and phenotype occurred at a time when many RETmutations causing hereditaryMTCwere yet to be discov-ered (65, 75, 76). It was expected that as a larger numberof families were studied, the relationship between geno-type and phenotype would become clearer; however, inmany ways, the opposite has happened. It has becomeapparent that different families with MEN2A due to thesame RET mutation often have significant variability inthe clinical expression of disease and aggressiveness of theMTC. This is presumably due to coexpression of disease-modifying alleles.

Although the original criteria defining MEN2A andMEN2B have remained unchanged, there has been a par-ticular problemwithFMTC,where already there are 2 setsof criteria defining the syndrome (1, 65). It has become

evident that many kindreds first designated as FMTC,with longer follow-up, or upon study of other kindredswith the same mutation, are found to haveMEN2A. Thissituation is exemplified by a 6-generation Brazilian kin-dred of 229 family members, 76 of whom had MTC dueto a G533C mutation but no evidence of pheochromocy-toma or hyperparathyroidism (77). The family appearedto have FMTC; however, it was subsequently reportedthat a 62-year-old member of this kindred developed apheochromocytoma (78). Furthermore, 2 Greek familieswith theG533Cmutationwere reported tohaveMTCandpheochromocytoma, thus clarifying that this RET muta-tion is associated with MEN2A (79, 80).

The matter of nomenclature has been further compli-cated as various investigators have used FMTC to definefamilies, most commonly those with the noncysteineRETmutations in codons 768, 790, 791, or 804, who predom-inantly manifest MTC and have a much lower frequencyof pheochromocytoma or hyperparathyroidism (5, 8183). If these broader criteria were followed, the incidenceof FMTC would comprise 30% to 60% of patients withhereditary MTC.

Thus, a clear definition of FMTC is needed. Consider-ing the rigid criteria proposed by the Guidelines for Di-agnosis and Therapy of MEN Type 1and Type 2 (1),there are at present only 3documented families thatwouldbe classified as FMTC (Supplemental Table 1) (1, 8486).

One solution is to retain the definition of FMTC withthe strict criteria originally proposed, realizing that afterlong-term follow-up, a family suspected of having FMTCmay develop hyperparathyroidism or pheochromocy-toma and be reclassified as MEN2A (1). A second alter-native is to expand the definition of FMTC to includefamilies with certain RETmutations who have late-onsetMTC with the infrequent occurrence of pheochromocy-toma or hyperparathyroidism. A third alternative is todiscard the term FMTC and classify all patients with he-reditaryMTC, other than thosewithMEN2B, asMEN2Aand designate them by a specific RET mutation, for ex-ampleMEN2A_RETC634R (87).With this option, therewould be two MEN2 syndromes, with approximately95% classified asMEN2A, which would be a remarkablyheterogeneous group with over 70 different RET muta-tions in families that expressMTC, pheochromocytomas,and hyperparathyroidism over a wide range of frequen-cies, times of onset, and clinical behavior. This would notaddress the issue of a number of small families, or singleindividuals,manywith raregermlineRETmutations,whodefy classification.

All considered, it seems reasonable to retain the termFMTC and include within it 1) families with aRET germ-line mutations who meet the original strict criteria for



Figure 2. The RET gene, the RET protein, and RET point mutations associated with MEN2A, MEN2B, and FMTC. RET gene structure with codingexons 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 toanother 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 isrepresented, 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 acidresidues, numbered 1 to 1114, are shown to the left of the figure. The extracellular RET domain (with the signal peptide [SP], 4 cadherin-likedomains [CLD14], and a cysteine-rich domain [CRD]), the transmembrane domain (TM), and the intracellular tyrosine kinase domain (TK) arerepresented. The RET TK is split into 2 subdomains (TK1 and TK2) by an insert region (Ki). The positions of reported RET point mutations associatedwith MEN2A, MEN2B, and FMTC are shown to the right of the RET gene. The mutations causing MEN2A and MEN2B are shown in black, whereasthe mutations for FMTC are shown in red. An asterisk denotes homozygous mutations. Some of the reported RET mutations have no functionstudies 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 included inSupplemental Table 1. [Modified from Figure 5 in J. W. de Groot et al: RET as a diagnostic and therapeutic target in sporadic and hereditaryendocrine tumors. Endocr Rev. 2006;27:535560 (163), with permission. The Endocrine Society.]



FMTC (1), 2) small families (at least 2 generations,with atleast 2but fewer than10RETgene carriers)withMTCbutno pheochromocytoma or hyperparathyroidism, or 3)small families or single individuals with 2 or fewer mem-bers with MTC in a single generation without pheochro-mocytoma or hyperparathyroidism.

According to this classification, the reported families orsingle individuals with onlyMTC, and associated specificRET germlinemutations, are listed in Supplemental Table1. It is important to note that to designate a family with aspecific RET germline mutation, eg, C611F, as FMTC,there must be no other reported family with this specificmutation that has either a pheochromocytoma orhyperparathyroidism.

Although this modified nomenclature may add clarityto the disease phenotypes and genotypes, clinical investi-gators still need to be aware of the substantial variabilityin the clinical expression of disease within MEN2A andFMTC families. This is especially relevant in patients con-sidered for prophylactic thyroidectomy.

The Diagnosis of Hereditary and SporadicMTC

Serum calcitoninFormerly, measurement of serum calcitonin levels, es-

pecially after the iv administration of the provocativesecretagogues calcium or pentagastrin, or a combinationof the two, served as the primary method for screeningfamilymembers at risk for hereditaryMTC (88). Since theintroduction of direct DNA analysis for detecting RETmutations, the determination of serum calcitonin levels israrely used alone for the early diagnosis of hereditaryMTC; however, in some clinics, it is the basis for timingprophylactic thyroidectomy in family members who haveinherited a mutated RET allele. The preferred assays forquantitating serum calcitonin are 2-site, 2-step, chemilu-minescent, immunometric assays that are highly specificfor monomeric calcitonin. With these assays, the risks ofa hook effect, or cross-reactivity with other peptides orbyproducts of inflammatory or infectious reactions areminimal (8991). The reference values for basal serumcalcitonin levels are 10 pg/mL for males and 5pg/mLfor females. The reference values for children are morevaried, especially in neonates, where they can be as high as40 pg/mL (89). The normal range of basal and stimulatedserum calcitonin levels may vary from laboratory to lab-oratory; thus, for serial measurements of calcitonin, it isbest that clinicians use the same laboratory with its estab-lished reference range.

In many European centers, it is standard practice tomeasure serumcalcitonin levels inpatientspresentingwithnodular goiters to exclude MTC, although this has notbecome common practice in the United States or Australia(9295).

Direct DNA analysis for mutations in the RETproto-oncogene

Approximately 98%of index patients withMEN2 andFMTChave an identifiableRETmutation (81, 96). Figure2 lists the currently known RET point mutations (withinexons) documented in hereditary MTC. Unlike the char-acteristicmutations in exons 10, 11, 15, and 16 associatedwithMEN2AandMEN2B, little is knownabout themodeof activation of extracellular mutations in RET exons 5and 8 (97100). Also, the mechanisms by which intracel-lular codon mutations in exons 13 and 14, and less com-monly non-MEN2B mutations in exons 15 and 16, acti-vate RET are unclear, although in the latter case, it hasbeen suggested that they disrupt the autoinhibited dimerconformation of wild-type RET, thereby enabling RETkinase (101).

In families with a known germlineRETmutation, test-ing of family members at risk is relatively easy because atargeted approach can be focused on the specific codonhousing the mutation. In new families with hereditaryMTCwhere theRET status is unknown, theusual strategyfor testing family members at direct risk is to sequence themost commonly affected exons and, if negative, to extendsequencing to additional exons. If no RET mutation isfound, it may be necessary to sequence the entire codingregion of the gene. As the extent of sequencing increases,so does the cost. Gene sequencing technology, however, isbecoming cheaper, and clinicians may find that ratherthan a tiered approach, it may be more practical in newfamilies with hereditaryMTC to sequence the entireRETcoding region, because this would allow the detection ofnot only uncommon RETmutations but also double mu-tations, deletions, and insertions.

One cannot overemphasize the importance of directDNA sequencing to detect RET mutations in kindredmembers at risk for hereditary MTC. There are 69 labo-ratories internationally that perform direct DNA analysisfor RET mutations (102). The large majority of them se-quence selected exons (most commonly 10, 11, 13, 14, 15,and 16, and in some laboratories, exon 8) or the entirecoding region. Prenatal diagnosis is offered in somelaboratories.

Approximately, 3%to7%percent of patientswithpre-sumed sporadic MTC actually have hereditary MTC;thus, it is important to test for germlineRETmutations innew patients with MTC regardless of their family history



(103, 104). Genetic counselors and physicians are respon-sible for providing information to patients regarding theclinical expression of hereditary MTC, the patterns of in-heritance, the role of genetic testing, and available thera-peutic options. The physician has a duty to warn the pa-tient that family members may be at foreseeable harm(105, 106). Also, adult patients, or parents of minors,should inform family members at risk that they should betested. The issue of an affected subjects reluctance to pro-vide information to family members or to prevent minorsat risk from having genetic testing is a more difficult issue,which is conflicted by recent provisions inherent in theHealth Insurance Portability and Accountability Act(HIPAA) (105).

Management of Medullary ThyroidCarcinoma in Patients With MEN2A,MEN2B, and FMTC

The strongest predictor of survival in patients withMTC,whether hereditary or sporadic, is stage of disease at di-agnosis. In a population-based study the 10-year disease-specific survival exceeded 90% in patients with localizeddisease; however, it decreased to 78% and 40%, respec-tively, in patients with regional or distant metastases (107).Only 10% of patients with metastases to cervical nodes arecuredbythyroidectomyandextensive lymphnodedissection(108110). The postoperative serum calcitonin falls withinthe normal range in 60% of patients with node-negativedisease but in only 10% of patients with node-positivedisease (108). The prognosis is excellent in patients whohave a preoperative serum calcitonin less than 150 pg/mL, an MTC smaller than 1 cm, and no lymph nodemetastases (108). The 10-year survival approaches100% in patients with undetectable basal and stimu-lated calcitonin levels after initial thyroidectomy (111).

In patients with tumor confined to the thyroid gland,the standard operation is total thyroidectomy with resec-tion of lymphnodes in the central zone of the neck, an areabounded by the hyoid superiorly, the sternal notch infe-riorly, and the carotid arteries laterally. The neck dissec-tion is more extensive in patients with evident cervicallymph node metastases.

Prophylactic thyroidectomyIn patients with hereditary cancer, several criteria

should be met when considering removal of an organ des-tined to become malignant. There should be 1) near-com-plete penetrance of the mutated gene, 2) a reliable methodofdetecting familymemberswhohave inheritedamutatedallele, 3) minimal morbidity associated with removal of

the organ at risk, 4) excellent replacement therapy for thefunction of the removed organ, and 5) a reliable methodfor determiningwhether the operative procedure has beencurative. Few hereditary malignancies meet all of thesecriteria; fortunately, MEN2A, MEN2B, and FMTC meeteach of them.

Direct DNA analysis of family members at risk for he-reditary MTC can detect those who have inherited a mu-tated RET allele, and they can be offered thyroidectomybefore the development ofMTCorwhile it is still confinedto the thyroid gland. In many cases, the procedure is notprophylactic, because CCH, with or without small foci ofMTC, may be present in the resected gland. Nevertheless,prophylactic or early thyroidectomy in patients found tohave a mutated RET allele characteristic of hereditaryMTCcanbepreventativeor curative andhasbecome stan-dard management throughout the world.

A major consideration is the age at which to performthyroidectomy. Several professional groups have devel-oped guidelines for the timing of thyroidectomy, all ofwhich are based on the perceived clinical behavior of thespecificRETmutation causing hereditaryMTC (Table 1)(1, 57).

With some RET mutations, the course of action isstraightforward. For example, in patients with MEN2Band an M918T or A883F RET mutation, the MTC ishighly aggressive and thyroidectomy should be performedas soon as the diagnosis is established, even in the firstmonths of life. Also, most patients with MEN2A havemutations in RET codon 634 and even though malignanttransformation can occur as early as 1 year of age, in-volvementof regional lymphnodes rarelyoccursbefore11years of age (2, 112). Most clinicians agree that in thissetting, the thyroid gland should be removed at or before5 years of age, and to decrease the risk of hypoparathy-roidism, a central compartment lymph node dissection isunnecessary (112).

Excepting these 2 examples, the task is more challeng-ing considering the large number of RETmutations iden-tified in subjects withMEN2A and FMTC (SupplementalTable 1). It is important that the treating physician studythe pattern of disease presentation in a new family, as-suming that it is of sufficient size to yield meaningful in-formation. Even in large kindreds, the pattern of diseasepresentation may not become evident until evaluation ofseveral family members, and even then it may vary withreports of other kindreds with the same RET mutation.For example, in previous studies of kindredswithMEN2Acaused by mutations in RET codon C609S, there were noreported cases of pheochromocytoma (1, 65). Over thelast decade, however, not only has there been documen-tation of pheochromocytomas in families with this muta-



tionbut in onekindred, pheochromocytomawas the dom-inant endocrinopathy, there being no clinically evidentMTC (113115). Furthermore, the age of CCH or MTConset in the youngest patient varied from 9 years in onekindred to48years in another, and in all but 1kindred, theage of MTC onset in the youngest patient was above 20years (116). In some reports of kindreds with the V804LRET mutation, there was low penetrance of MTC,whereas in other kindreds with the same mutation, or theV804M mutation, the MTC was more aggressive (117119). MEN2A kindreds such as these, and they are notunusual, present a conundrum and a challenge for clini-cians when considering timing of thyroidectomy.

Realizing the difficulty of determining the age whenprophylactic thyroidectomy should be performed in sub-

jects with a given RET germline mutation, some investi-gators have based the timing on the level of basal orstimulated serum calcitonin (120). This approach is con-troversial, however, because there are reports of subjectsat risk for hereditaryMTCwith elevated calcitonin levels,whose thyroidectomyspecimens showednoCCHorMTCand subsequent RET mutation analysis was negative(121123).At present, there are noaccepted guidelines fortheuseofbasal or stimulated calcitonin levels todeterminethe timing of thyroidectomy in subjects at risk for hered-itaryMTC.The issue is of great importance, however, andrigorous guidelines need to be defined, especially for cli-nicians who choose a watchful waiting approach for sub-jects who have inherited a certain mutated RET allele.

Table 1. Guidelines for Timing Prophylactic Thyroidectomy in Hereditary MTC



Physicians caring for families with hereditary MTCmust consider the risks associated with thyroidectomyperformed at a very young age, compared with the risksassociated with delaying the procedure, possibly losingpatients to follow-up, or finding at thyroidectomy that theMTC has spread beyond the thyroid gland (118, 124).

The operative procedureIn patientswithMEN2B regardless of age, and patients

withMEN2A and FMTCwho are above 8 years of age, atotal thyroidectomy with resection of lymph nodes in thecentral compartment of the neck is indicated. In patientswith MEN2A or FMTC who are less than 5 years of age,with no enlarged cervical lymph nodes, total thyroidec-tomy alone is the preferred procedure. Regardless of theoperative approach, care must be taken to protect theparathyroid glands, the recurrent laryngeal nerves, andthe external branch of the superior laryngeal nerves. Gen-erally, the results of prophylactic thyroidectomy in thisclinical setting have been very satisfactory. The EuropeanMultiple Endocrine Neoplasia Study Group evaluated207 patients from 145 kindreds with MEN2A, MEN2B,and FMTC. In patients with RET codon 634 mutations,malignant transformationwas present as early as 1 year ofage and the cumulative age-related risk ofMTC increasedprogressivelywith age, but therewasno evidenceof lymphnode metastases before 14 years of age (2). In anotherstudy of 50 patients with MEN2A followed for a mini-mum of 5 years after prophylactic thyroidectomy, nolymph node metastases were present in children less than11 years of age. In 44 children, the serum calcitonin wasundetectable after stimulationwith combined calciumandpentagastrin infusion; however, 3 children developed per-manent hypoparathyroidism, emphasizing the risk of per-forming a central lymph node dissection below 5 years ofage (112).

Postoperative evaluationPatients should be evaluated within 6 months postop-

eratively by physical examination and determination ofserum levels of calcitonin and CEA. If the serum levels oftumor markers remain undetectable or within the normalrange for 5 years, there is no need for additional studies,and patients can be followed at yearly intervals. A reliableindicator of the rate of MTC progression is the doublingtime of serum calcitonin or CEA. A calcitonin doublingtime between 6 months and 2 years is associated with 5-and 10-year survival rates of 92% and 37%, whereas acalcitonin doubling time less than 6 months is associatedwith 5- and 10-year survival rates of 25% and 8%, re-spectively (125, 126). The serum levels of calcitonin andCEA are strongly correlated; however, in some cases, the

CEA increases progressively, whereas the calcitonin doesnot. This suggests cellular dedifferentiation, a hypothesissupported by immunohistochemistry studies of CCH,MTC confined to the thyroid gland, and metastatic MTC(127, 128).

If during the postoperative period the serum calcitoninlevel increases above 150 to 200 pg/mL, a total body com-puted tomography scan is indicated. Patientswho developmetastases to regional lymph nodes but have no distantmetastases are candidates for resection of the recurrenttumor. There have been several reports of repeat surgeryforMTC, but to date, there are no randomized trials com-paring repeat neck surgery to either watchful waiting orother therapies. Compartmental dissection was originallythought to be curative in approximately 30% of patients(129). Recent studies, however, have shown that the se-rum calcitonin falls within the normal range postopera-tively in one-third of patients, yet surgical cure, indicatedby undetectable serum calcitonin levels after pentagastrinor calciumstimulation is rare (129131). Some single-armstudies suggest that external beam radiotherapy adminis-tered postoperatively decreases the incidence of locore-gional disease; however, it has not improved overall sur-vival (132, 133).

Complications of hormonal excess from MTCApproximately 30% of patients withMTC develop di-

arrhea, and it is more common in patients with high levelsof serum calcitonin (134). Mild diarrhea can be managedwith loperamide or codeine; however, severe diarrhea ismore difficult to control. Tumor debulking or selectivearterial chemoembolization may provide benefit in se-lected cases (135, 136).

The development of Cushings syndrome due to inap-propriate ACTH secretion occurs in less than 3% of pa-tients with MTC (137). The treatment is resection of theprimary tumor, or in patients with metastases, the admin-istration of adrenal enzyme inhibitors such as ketocona-zole, metyrapone, aminoglutethimide, mitotane, etomi-date, or more recently, mifepristone (138). In many casesbilateral adrenalectomy is necessary to control the excessglucocorticoid production. The prognosis is poor becausemost patients die within a year of the diagnosis.

The management of distant metastasesThe development of distantmetastases fromMTC is an

ominous sign because survival after discovery is 51% at 1year, 26% at 5 years, and 10% at 10 years (111, 139). Inpatients with an indolent rate of progression, local treat-ment of distant metastases, either by surgical resection,chemical ablation, or radiotherapy, depending on the an-



atomical site involved, may provide benefit for variableperiods of time.

Systemic therapy for metastatic MTCSingle-agent or combination chemotherapy has yielded

short-term responses in the range of 10% to 20% in pa-tients with advanced MTC. Until recently, doxorubicinwas the only drug approved by the U.S. Food and DrugAdministration (FDA) for the treatment of patients withadvancedMTC, and it is still used for this indication todaybut much less frequently as frontline therapy (140, 141).

Other therapeutic agents, ranging from angiogenesisinhibitors and epigenetic-modulating agents to selectiveCOX-2 inhibitors, have been relatively ineffective in pa-tients with differentiated thyroid carcinoma, and there islittle or no experience in phase II trials of patients withMTC (142144). Various immunotherapeutic regimenshave been evaluated in patients with advanced MTC, in-cluding 2 trials of dendritic cells, pulsed with either cal-citonin and CEA or tumor lysate. Responses were vari-able, but partial remissions were noted in 4 of 17 patientsin the 2 trials (145, 146). Pretargeted radioimmuno-therapy with bispecific monoclonal 131I antibody againstCEA has shown promise in early clinical studies but hasnot yet been studied in prospective randomized phase IIItrials (147). The lack of effective systemic therapeuticagents has been a major problem for physicians and theirpatients.

In the normal state, external growth factors transmitsignals within the cell through a series of reactions thattransfer phosphate fromATP to tyrosine residues in poly-peptides. The reactions are catalyzed by protein tyrosinekinases, which when mutated become constitutively acti-

vated, leading to immortalization of the cell. The proteintyrosinekinaseswere recognizedas vulnerable therapeutictargets and attracted the interest of clinical oncologists aswell as thepharmaceutical industry.The first example thatan MTT had efficacy was documented in a randomizedtrial of patients with chronic myeloid leukemia (CML)comparing the tyrosine kinase inhibitor imatinib with in-terferon alfa plus cytarabine. The results with imatinibwere far superior to those with interferon alfa plus cytar-abine, and at 60 months, 96% of 362 patients still onimatinib experienced a complete cytogenetic response(148). This trial was a major landmark in cancer care andcreated great enthusiasm and cautious expectation thatnovel MTTs would show similar efficacy in patients withother liquid and solid tumors, where the initiating onco-genic event was known and druggable. Although clinicaltrials of MTTs in patients with solid organ malignancieshas not replicated the striking success achieved with ima-tinib in CML, some drugs have been effective with signif-icant improvement in progression-free survival or overallsurvival (149, 150).

Currently, there are over 20 published phase II or phaseIII clinical trials ofMTTs in patientswith locally advancedor metastatic thyroid cancer. Twelve of these documentthe efficacy of variousMTTs in patientswithMTC (Table2) (151162). Although not all MTTs have shown activ-ity, most have with confirmed partial remissions rangingfrom2%to50%.Twoof the compounds, vandetanib andcabozantinib, have been evaluated in prospective, ran-domized, double-blind phase III clinical trials, and eachdemonstrated significantly improved progression-freesurvival compared with placebo. Recently, the FDA ap-

Table 2. Clinical Trials With MTT in Patients with MTC

Drug (Ref.) StudyNo.Patients PR, %

StableDisease, %

PFS,mo

Axitinib (151) Phase II 11 18 27a NAMotesanib (152) Phase II 91 2 48b 12Sorafenib (153) Phase II 16 6.3 87.5a 17.9Sunitinib (162) Phase II 6 50 NA NAVandetanib (161) Phase II 30 20 53b 27.9c

Vandetanib (100 mg/d) (154) Phase II 19 16 53b NACabozantinib (155) Phase II 37 29 41b NAVandetanib (300 mg/d) (159) Phase III 231/100 0.46 (HR) 0.46 (ORR) 30.5c

Cabozantinib (160) Phase III 219/111 0.28 (HR) 0.28 (ORR) 11.2c

Imatinib (156) Phase II 15 0 27b 0Imatinib (157) Phase II 9 0 56a 0Sorafenib 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 4 mo.b 6 mo.c Estimated PFS in months.



proved the 2 compounds for treatment of patients withadvanced MTC (159, 160). Virtually all MTTs are asso-ciated with toxicities, which in some cases lead to dosereductions or even cessation of therapy. Currently, treat-ment with MTTs has reached a plateau in patients withadvanced MTC and improved therapeutic efficacy willcome only through the development of drugs that bindthe mutated kinase with greater specificity or the designof combinatorial therapeutic regimens that improve ef-ficacy while impeding drug resistance.

Unfortunately, in trials of MTTs for advanced MTC,clinical responses have been characterized by partial, notcomplete, remissions, and in time, resistance to the drugdevelops and the tumorprogresses.Clinical trials ofMTTshave not required the collection of tumor tissue from par-ticipating patients; thus, associated correlative studies arelacking and mechanisms of resistance remain unknown.Preclinical studies and the molecular analysis of tumortissues from patients with a range of other tumors haveshown that mechanisms of resistance to MTTs are mul-tifactorial, often complex, andmostly lineage-specific. In-formation from these studies has been critical to the de-velopment of second- and third-generation MTTs andmost importantly in the design of effective combinatorialtherapeutic regimens.

With the remarkable and continuing advances in bio-technology, the amount of genomic information availableto clinical investigators and the practicing endocrine on-cologist will increase at a rapid pace. In the age of per-sonalized medicine, the development of a new class ofmolecular targeted therapeutics holds great promise forpatients with advancedmalignancies, and especially thosewith hereditary cancer syndromes.

Acknowledgments

Address all correspondence and requests for reprints to: SamuelA. Wells, Jr, MD, Cancer Genetics Branch, National CancerInstitute, National Institutes of Health, Building 37, Room10106A, 37ConventDrive, Bethesda,Maryland 20814. E-mail:[email protected].

Disclosure Summary: B.G.R. has served on advisory boardsfor AstraZeneca, Eisai, and Bayer. M.S. has received researchsupport from AstraZeneca and Roche and participated in a col-laborative study with Ariad. F.P. and S.A.W. have nothing todeclare.

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