REVIEW

Hereditary medullary thyroid carcinoma: the managementdilemma

Ping Zhou • Jian Liu • Shao-Wen Cheng •

Bing Wang • Rong Yang • Ling Peng

Published online: 20 December 2011

� Springer Science+Business Media B.V. 2011

Abstract Hereditary medullary thyroid carcinoma (hered-

itary MTC) is a rare malignancy, accounting for 25–30% of

all MTC. It occurs as part of multiple endocrine neoplasia

type 2 (MEN 2). Autosomal dominant gain-of-function

mutations in the RET proto-oncogene is the cause of the

disease, in which the common mutations are codons 609,

611, 618, 620, 630, 634 and 918. In recent years, the spec-

trum of RET gene mutations has changed. The classical

mutations reduced, whereas the less aggressive mutations

increased. Hereditary MTC is a time-dependent disease.

Stages of the disorder at diagnosis can significantly influence

survival rates. Based on the genotype–phenotype, RET

mutations have been classified into four risk levels by

American Thyroid Association (ATA) at 2009. The classi-

fication system guides the hereditary MTC management,

including risk assessment, biochemical screenings and

surgical intervention. Though the application of genetic

testing and codon-specific phenotypes in hereditary MTC

diagnosis is effective with high accuracy, there are some

difficulties in implementing RET gene testing as a routine for

MTC diagnosis. And most of carriers with RET mutations

did not undergo thyroidectomy at the age recommended by

the ATA guidelines. The aim of the study is to review the

hereditary MTC and discuss the management dilemma.

Keywords Hereditary medullary thyroid carcinoma �RET proto-oncogene � Mutation � Management �Prophylactic thyroidectomy

Abbreviations

RET Rearranged during transfection

Hereditary MTC Hereditary medullary thyroid

carcinoma

MEN 2 Multiple endocrine neoplasia type 2

ATA American Thyroid Association

MTC Medullary thyroid carcinoma

CCH C-cell hyperplasia

Pheo Pheochromocytoma

HPT Hyperparathyroidism

FMTC Familial MTC

VUS Variant of unknown significance

HSCR Hirschsprung disease

Introduction

Medullary thyroid carcinoma (MTC) is a rare form of

thyroid cancer which originates from calcitonin-producing

parafollicular C cells, accounting for 3–8% of all thyroid

cancer [1]. In 1959, Hazard first distinguished MTC from

other poor differentiated or anaplastic forms of thyroid

Ping Zhou and Jian Liu contributed equally to this work.

P. Zhou � B. Wang � R. Yang

Department of Surgical Oncology, The First Affiliated Hospital,

School of Medicine, Zhejiang University, 79 Qingchun Road,

Hangzhou 310003, Zhejiang Province, China

J. Liu (&)

Department of Surgical Oncology, Hangzhou Hospital of

Traditional Chinese Medicine, 453 Stadium Road, Hangzhou

310007, Zhejiang Province, China

e-mail: liujiancsw@163.com

S.-W. Cheng

Trauma Center, The Affiliated Hospital of Hainan Medical

College, 31 Long Hua Road, Haikou 571100, China

L. Peng

Department of Medical Oncology, The First Affiliated Hospital,

School of Medicine, Zhejiang University, 79 Qingchun Road,

Hangzhou 310003, Zhejiang Province, China

123

Familial Cancer (2012) 11:157–165

DOI 10.1007/s10689-011-9501-7

carcinoma. And C-cell hyperplasia (CCH) is the preneo-

plastic lesion [2, 3]. MTC can be divided into sporadic

(75%) and hereditary (25%) types [4]. Hereditary MTC is a

core feature of multiple endocrine neoplasia type 2 (MEN

2), an autosomal dominant inherited cancer syndrome.

Three distinct clinical subtypes of MEN 2 have been

characterized: (i) MEN 2A, by MTC ([90%) in combina-

tion with pheochromocytoma (Pheo) (10–50%) and

hyperparathyroidism (HPT) (10–25%), (ii) MEN 2B, by

MTC associated with Pheo, multiple mucosal neuromas

and marfanoid habitus, (iii) familial MTC (FMTC), by

MTC with a very low incidence of other endocrinopathies.

Because mutations (codons 768 and 804) of FMTC partly

overlap with MEN 2A, FMTC is now considered to be a

clinical variant of MEN 2A rather than a distinct entity [5].

RET genetic screening

RET gene mutations

RET proto-oncogene change or mutation is the cause of

hereditary MTC. In 1993 and 1994, three intense investi-

gations proved the association of RET gene mutations with

hereditary MTC [6–8]. The RET gene is localized to

10q11.2 encoding a tyrosine kinase receptor that influences

cell proliferation, differentiation, migration and apoptosis.

The receptor is mainly expressed in neural crest-derived

tissues, such as C-cells of the thyroid, adrenal medullary

cells, colonic ganglia cells and parathyroid cells.

RET mutations are heterozygous and missense sequence

changes in exons 5, 8, 10, 11 and 13–16. The web of ARUP

Scientific Resource for Research and Education offers full

RET proto-oncogene sequence analysis and sets up the

publicly available and searchable MEN2 RET database.

The database records all RET sequence variants related

with MEN2 syndromes and concerned clinical information.

In the database, RET sequence changes are divided into

four classifications: ‘‘Pathogenic’’ mutation, ‘‘Benign’’

polymorphism, VUS (variant of unknown significance) and

HSCR (Hirschsprung disease) variant. The ‘‘Pathogenic’’

mutation, a deleterious germline RET sequence change,

can cause MEN2 and segregate with the MEN2 disease

symptoms within a family (Table 1) [9].

Studies have shown that more than 98% of MEN 2A,

95% of MEN 2B and 85% of FMTC have RET mutations

(Fig. 1). And codons 609, 611, 618, 620, 630 and 634 are

the common mutations of MEN 2A and FMTC, in which

the most common mutation is the codon 634, accounting

for 80–85% of MEN2A and 25–35% of FMTC [5]. In

addition, codon 533 mutation in exon 8 has also been

related to MEN2A and FMTC, but is rare [10, 11]. 95% of

MEN2B have codon 918 mutation, and the remaining 5%

of patients carry codon 883 mutation or two-hit mutations

of 804 with 805, 806 or 904 [12–15].

However, the spectrum of RET gene mutations has

changed in recent years. Compared with previous RET

mutation spectrum, Frank-Raue et al. [16–18] reported the

number of classical mutation at codon 634 (level 2, higher

risk of aggressive MTC) reduced, whereas the less aggres-

sive mutations and exons 13–15 mutations (level 1, high risk

of aggressive MTC) increased, especially at codons 790, 791

and 804 (Fig. 2). A study of Frank-Raue showed level 1

mutations were diagnosed in 38.9% of families, and level 2

and 3 mutations were screened in 54.4 and 5.6% of families

[19]. At the same time, some rare (codon 631) and de novo

mutations (codons 292 and 881) have emerged [20, 21].

Kalliopi et al. [22] reported two de novo mutations (the

2458C[T mutation and the transition from I590 to G608)

associated with MEN2. Perhaps, the change can be explained

by the extension (5, 8, and 13–16 exons) of RET sequence

analysis for the gene testing and the missed diagnosis of less

aggressive cases before [23]. In addition, the difference of

ethnical origins and different mutation sites studied in vari-

ous studies also influence the mutation spectrum.

Nevertheless, it has been unclear the prevalence of

specific RET mutations in distinct regions. And no com-

prehensive data has been obtained to clarify the familial

prevalence and RET mutations distribution on a national or

international level. The study of German RET mutations

families revealed the most frequent RET amino acid sub-

stitution was Cys634Arg (21%), followed by Met918Thr

(15%) and Cys634Tyr (9%) [23]. Collecting the data of

356 RET mutations families from Germany, France, Italy,

Poland and Czech Republic, Machens et al. [24] reported

the germline mutations in continental Europe mainly

involved codon 634 (41.0%), followed by codons 804

(11.8%) and 918 (9.6%). However, compared with Euro-

pean researches, the study of Italy showed the most fre-

quent RET amino acid substitution was Val804Met

(19.6%), followed by Cys634Arg (13.6%). And a higher

prevalence of Val804Met and Ser891Ala mutations, a

lower prevalence of Leu790Phe and Tyr791Phe mutations,

and an unexpected higher prevalence of FMTC (57.6%)

with respect to other MEN 2 syndromes (34% of MEN 2A

and 6.8% of MEN 2B) also were observed [25].

The significance and dilemma of RET genetic analysis

RET genetic analysis is a safe and accurate measure of

hereditary MTC diagnosis. Before RET genetic analysis,

the first-degree relatives of hereditary MTC patients who

have a 50% chance of inheriting the predisposing genes

had to undergo repeated biochemical screenings in order to

preclude the disorder. But because of the ambiguous results

of biochemical screenings, the disorder used to be missed,

158 P. Zhou et al.

123

or misdiagnosed, or diagnosed at an advanced stage. After

the application of genetic screening, the disease can be

diagnosed at the early stage and the result of genetic

analysis is more reliable than biochemical screenings.

Genetic testing permits identification of at-risk individuals,

more effective and timely screenings and early surgical

intervention. Meanwhile, Gene testing may make muta-

tion-negative family members avoid the unpleasant and

costly biochemical examinations.

The 2009 ATA guidelines recommended the first-degree

relatives of MEN2A and FMTC to perform genetic analysis

before 5 years old, while as soon as possible and within the

first year of life for the first-degree relatives of MEN 2B

[26]. Otherwise, it has to be discussed that germline

mutations were screened in 4–10% of apparently sporadic

MTC, which emphasized the significance of molecular

testing in order to characterize the MTC as sporadic or

hereditary [27–29].

Though DNA-based predictive testing is 100% accurate

and is considered to be the standard diagnosis for all

first-degree pre-symptomatic relatives, there are some

difficulties in implementing RET gene testing in the whole

family. From the patients’ perspective, there is a loss of

privacy and a feeling of discrimination, which prevent the

proband from informing their relatives about the hereditary

disease.

ATA genotype–phenotype classification

Particular mutations correlate with special phenotypes.

Based on the genetype–phenotype, RET mutations have

been stratified into four risk levels (level A, B, C and D) by

American Thyroid Association (ATA) at 2009 [26]

(Table 1). Level D mutations, the typical MEN2B char-

acterized by the youngest onset age of MTC and the

highest risk of MTC metastasis and mortality, include

codon 883 mutations in exon 15 and codon 918 mutations

in exon 16. And dual mutations, codons 804/805, 804/806

and 804/904 mutations are also ascribed to the level. Level

C mutations, the classical MEN2A characterized by the

higher risk of aggressive MTC, involve codon 634

Table 1 Genotype–phenotype correlations and the MTC and ATA risk levels for hereditary MTC

Exon Mutation ATA

risk level

MTC

risk level

MEN2 phenotype Youngest age at first diagnosis References

MTC Pheo HPT

5 V292 M – – MEN2A 44 – – [21]

8 C515S A – Unclassified 35 – – [47]

8 532 duplication A – FMTC 19 – – [35]

8 G533C A 1 MEN2A/FMTC 21 34 – [9, 48]

10 C609R/G/Y/S/F B 2 MEN2A/FMTC/Unclassified 5? 19 38 [9, 16]

10 C611S/R/G/Y/F/W B 2 MEN2A/FMTC/Unclassified 6 30 40 [9, 49]

10 C618S/R/G/Y/F/W B 2 MEN2A/FMTC/Unclassified 7 19 41 [7, 9]

10 C620S/R/G/Y/F/W B 2 MEN2A/FMTC/Unclassified 5 19 – [7, 9]

11 C630R/Y/F B 2 MEN2A/FMTC/Unclassified 1 – 32 [9, 38]

11 D631Y B – MEN2A 22 – – [20]

11 C634S/R/G/Y/F/L/W C 2 MEN2A/FMTC/Unclassified 1.1 5 10 [9]

11 635insertion ELCR;T636P A – MEN2A – – – [9]

11 637 duplication – – MEN2A 56 – – [50]

11 K666E A 1 MEN2A/Unclassified 12 35 – [9, 51]

13 E768D A 1 MEN2A/FMTC/Unclassified 9 59 – [9]

13 Q781R – – Unclassified 71 – – [51]

13 L790F A 1 MEN2A/FMTC 9 28 – [9, 52]

13 Y791F A 1 MEN2A/FMTC 5 38 38 [9, 53]

14 V804 M/L A 1 MEN2A/FMTC/Unclassified 6? 28 9 [9, 54]

15 A883T/F D 3 MEN2B/Unclassified 10? – – [55]

15 S891A A 1 MEN2A/FMTC 13 46 17 [9, 56]

16 R912P A 2 Unclassified 14 – – [57]

16 M918T D – MEN2B 0.17 12 – [9, 43]

ATA American thyroid association, Risk from aggressive MTC: level D is highest risk

Risk from aggressive MTC from the Seventh International Workshop on MEN (2): Level 1, high risk; level 2, higher risk; level 3, highest risk

Hereditary medullary thyroid carcinoma 159

123

mutation in exon 11. Level B mutations, mostly MEN 2A

and minority FMTC, are at intermediate risk of aggressive

MTC and mainly include codons 609, 611, 618 and 620

mutations in exons 10. Level A mutations, predominately

FMTC and minority MEN2A, have the lowest risk of

aggressive MTC and mainly involve codons 768, 790 and

791 mutations in exon 13, codon 804 mutations in exon 14

and codon 891 mutations in exon 15 [26]. Studies have

shown patients of level B or A mutations have CCH rather

than MTC before the second decade of life and present

MTC with a less aggressive process [30].

Risk-factors influencing prognosis

The main factors influencing survival rates are disease stages

of the disorder (primary tumor size, regional lymph nodes

metastasis and distant metastasis) and age at diagnosis.

Disease staging

Disease stages significantly influence survival rates of the

disorder. An epidemiological and population-based study of

1252 MTC patients showed that patients with tumors confined

to the thyroid gland had a 10-year survival rate of 95.6%, those

with lymph nodes metastasis had an overall survival rate of

75.5% and with distant metastasis only 40% [31].

The presence of palpable thyroid nodules influences the

prognosis and is associated with persistent or recurrent

disease after surgical procedure. On the contrary, the dis-

ease without palpable thyroid nodules has a better prog-

nosis. Lau et al. [32] analyzed 22 patients who had codon

634 mutation and underwent prophylactic total thyroidec-

tomy, and the result showed five of six patients had normal

postoperative ultrasound and no patient presented recur-

rence of hereditary MTC after a median follow-up of

49 months (range, 13–128 months). Another study on 41

individuals younger than 25 years old from 17 independent

MEN2A kindred showed all of asymptomatic patients (20

individuals) were all disease-free after a follow-up of

4.4 ± 1.4 years, whereas 47.6% of symptomatic patients

(21 individuals) had persistent disease (follow-up of

12.0 ± 5.9 years) [33]. Similarly, children identified as

RET mutations carriers by DNA analysis had no evidence

of persistent or recurrent MTC in five or more years after

total thyroidectomy [33–35]. Otherwise, the histological

Fig. 2 Changes in the RET mutational spectrum through years.

a 1996, b 2003, c 2010, Un. Unknown

Fig. 1 The common codons mutations of the RET gene associated

with hereditary MTC (FMTC, MEN2A, MEN2B)

160 P. Zhou et al.

123

differences between the symptomatic and asymptomatic

patients were also obvious. In the asymptomatic group, the

histology was either isolated CCH or CCH associated with

MTC. In the symptomatic group, multifocal MTC without

CCH was detected. Then, palpable thyroid nodule is an

independent predictor of recurrent or persistent hereditary

MTC, patients with small foci may have a greater chance

of surgical cure than the large one. And if thyroidectomy is

performed at asymptomatic age, the disease can be curable

[36–38].

Lymph node metastasis is a poor prognostic factor of

hereditary MTC, which greatly influence the prognosis.

Though lymph node metastasis was uncommon in young

children with MEN2A, the youngest patient with lymph

node metastasis was 5 years old [33, 36]. Data analysis

showed patients with lymph node metastasis at diagnosis

were incurable by surgical intervention. And lymph node

metastasis was also associated with decreased 10-year

overall survival [39].

Age

Hereditary MTC is an age-related disease [3]. The age at

diagnosis greatly influences survival rates. Patients

younger than 40 years at diagnosis have a 5- and 10-years

disease-specific survival rate of 95 and 75%, respectively,

compared with 65 and 50% for those older than 40 years

[1]. The risk of tumor-related death increases by 5.2% for

each additional year of age. And the prognosis is especially

poor in patients older than 65 years [31].

Clinical symptoms and histological progression from

CCH to MTC are age-dependent. The mean age of CCH and

node-negative MTC at diagnosis are 8.3 years and 10.2

years among patients with extracellular-domain mutations

(exons 10 and 11), and 11.2 years and 16.6 years among

patients with intracellular-domain mutations (exons 13, 14

and 15) [3]. And the age from primary tumor of MTC to

lymph node metastasis is 10 years in exons 13, 14 and 15,

21 years in exon 10, 5 years in exons 11 and 2.7 years in

MEN2B. And the age from primary tumor to distant

metastasis is 56 years in exons 13, 14 and 15, 22 years in

exon 10, 15 years in exon 11 and 5 years in MEN2B [40].

Penetrance of RET mutations is also age-dependent.

Penetrance in exon 10 is 4% by age 10 years, 25% by age

25 years and 80% by age 50 years [41]. And penetrance of

both exons 10 and 11 mutations reach 80% by age 50 years

and almost 100% by age 70 years [42].

Prophylactic thyroidectomy

Given the penetrance of RET mutations is almost 100%, all

carriers should undergo prophylactic thyroidectomy. The

timing and extent of prophylactic thyroidectomy depend on

the ATA risk levels (Fig. 3). For the level D mutations,

MTC may be present in infancy and lymph nodal metas-

tasis may become apparent in childhood, and thus pro-

phylactic thyroidectomy with central node dissection

should be enforced as soon as possible and within the first

year of life. Among the level C mutations, the typical onset

age of MTC is the third or fourth year and then total thy-

roidectomy with or without central node dissection should

be enforced before the fifth year of life. Because subjects

with the level B or A mutations rarely advent MTC before

the second decade of life and tend to have a less aggressive

course of MTC, the recommended age of prophylactic

thyroidectomy is more controversial. Some practitioners

believed that the surgical intervention can be delayed

beyond age 5 years if basal and stimulated serum calcito-

nin and annual cervical ultrasound starting by 5 years of

age are normal [26, 30, 43]. Though there is enough evi-

dence to support prophylactic thyroidectomy before

5 years old in patients with codon 634 mutation, the

decision of prophylactic thyroidectomy in carriers with the

level A or B mutations still depends on personal experience

and the surgical intervention has to be individualized until

more data are available [26].

Taking into account risk-factors of hereditary MTC and

penetrance of RET mutations, RET gene carriers should

undergo timely prophylactic thyroidectomy before the

neoplastic transformation from CCH to MTC.

The dilemma of prophylactic thyroidectomy

The gold therapeutic standard of hereditary MTC is total

thyroidectomy. If found RET mutations, patients should

undergo total thyroidectomy before the neoplastic trans-

formation from CCH to MTC. But because of the surgical

complications (vocal cord paresis and hypocalcaemia) and

long-term drug compliance, few carriers accepted the

prophylactic intervention, especially young children

(Table 2). Lau et al. [32] reported 14% of hypocalcaemia

after total thyroidectomy in 22 carriers with codon 634

mutation. And Bergenfelz et al. [44] reported 3.9% and

4.4% of vocal cord paresis and hypocalcaemia, respec-

tively. In addition, owing to the influence of gene pene-

trance, some individuals with RET mutations had normal

glands in the adult or even later. For these reasons, some

RET mutations carriers are unwilling to undergo thyroid-

ectomy without clear evidence of MTC.

In order to lessen the surgical complications, many cli-

nicians think prophylactic thyroidectomy should be oper-

ated by specialists with a high level of thyroidectomy

experience. And specialist standards for prophylactic thy-

roidectomy should be defined and specified. Expertise of

approved centers should also be regulated and documented.

Hereditary medullary thyroid carcinoma 161

123

Hereditary MTC management

Management diagram

The application of RET proto-oncogene mutations, geno-

type–phenotype classification and prophylactic thyroidec-

tomy creates a new paradigm for hereditary MTC

management. And the present studies and follow-up data

support the application of ‘codon-directed’ guidelines for

hereditary MTC management [45]. Individuals with a per-

sonal history of MTC, a family history of MEN 2 and the

preneoplastic lesion CCH should accept the germline RET

gene testing. When a proband is found, the genetic coun-

seling, molecular diagnosis and risk assessment should be

provided to the proband. And all first-agree relatives of the

proband should undergo the genetic screening of the same

mutation. Testing negative members are at low risk of

developing hereditary MTC and can avoid the unpleasant

and costly biochemical screenings. Positive members are at

high risk of developing hereditary MTC (dependent on gene

involved) and should accept the genotype-informed sur-

veillance and prophylactic thyroidectomy.

Management dilemma

Unfortunately, despite of the emphasis on early diagnosis

and timely thyroidectomy, there has still no obvious

improvement toward earlier diagnosis and survival rates.

On the one hand, the timing of thyroidectomy in hereditary

MTC patients is relatively late because of the late

Fig. 3 Algorithm for the

diagnosis, follow up and

management of patients with

hereditary MTC

Table 2 The studies of prophylactic thyroidectomy for RET mutations carriers

Study (reference) RET mutations No. of carriers, age No. of carriers

not underwent PrThy

Management measures

Romei, 2011 [58] Not indicated 20, not indicated 20 Clinical and biochemical assessment yearly

Qi, 2011 [59] p.V292M/R67H/R982C 6, 19–70 years old 4 Two carriers await thyroidectomy

Two carriers are being followed up

Jung, 2010 [60] C618S 2, 12–37 years old 2 Refusing further biochemical investigation

Allen, 2009 [46] C618S 4, not indicated 4 Not indicated

Calva, 2009 [61] C609Y 14, not indicated 7 Not indicated

PrThy prophylactic thyroidectomy

Carriers, was defined as having no evidence or clinical suspicion of the disease at the time of the diagnosis

‘‘Management measures’’ are for carriers not underwent PrThy

162 P. Zhou et al.

123

diagnosis, the old age in work-up and time-consuming

decision-making. On the other hand, gene carriers are

reluctant to undergo prophylactic thyroidectomy owing to

the surgical complications and long-term drug compliance.

From the current literature, we conclude that there are

still some difficulties in hereditary MTC management [46].

First of all, some regions can not get RET gene mutations

testing. Secondly, inquiry and RET gene testing of the

apparently sporadic MTC kindred are not complete. And

clinicians are not fully aware of the signification of RET

mutations for hereditary MTC diagnosis and treatment.

Otherwise, most of carriers described in current studies did

not accept prophylactic thyroidectomy at the age recom-

mended by the ATA guidelines and the follow-up of pro-

phylactic surgery is not long enough.

Conclusion

Identification of RET gene mutations heralds the era of

evidence-based molecular diagnosis, gene-informed risk

assessment and preventative therapy. The application of

genetic testing and codon-specific phenotypes in hereditary

MTC diagnosis is safe and accurate, and provides the basis

for individualized risk evaluation and prophylactic thy-

roidectomy of carriers. The present studies and follow-up

data support the application of ‘codon-directed’ guidelines

for the hereditary MTC management. Therefore, the 2009

ATA guidelines of hereditary MTC management should be

strictly enforced in clinic. At the same time, concerted

efforts from the international collaboration are needed to

strengthen the signification of RET gene testing for

hereditary MTC diagnosis and treatment. And further

studies and more data are needed to observe the long-term

survival. Hopefully, the management paradigm of heredi-

tary MTC will be better carried out in clinic.

Acknowledgments We are deeply appreciative of our mentors and

friends for guide and help, including Zhi-Min Ma, Wen-He Zhao,

Wei-Bing Wang and Xin-Xing Duan. And we thank the following

institutions which provided valuable information: Department of

Surgical oncology and Pathology of the first affiliated hospital of

Zhejiang university school of medicine.

Conflict of interest There are no conflicts of interest.

References

1. Clark OH, Kebebew E, Ituarte PHG, Siperstein AE, Duh QY

(2000) Medullary thyroid carcinoma—clinical characteristics,

treatment, prognostic factors, and a comparison of staging sys-

tems. Cancer 88(5):1139–1148

2. Hazard JB, Hawk WA, Crile G Jr (1959) Medullary (solid) car-

cinoma of the thyroid; a clinicopathologic entity. J Clin Endo-

crinol Metab 19(1):152–161

3. Machens A, Niccoli-Sire P, Hoegel J, Frank-Raue K, van

Vroonhoven TJ, Roeher HD, Wahl RA, Lamesch P, Raue F,

Conte-Devolx B, Dralle H (2003) Early malignant progression of

hereditary medullary thyroid cancer. N Engl J Med 349(16):

1517–1525. doi:10.1056/NEJMoa012915

4. Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E,

Feuer EJ, Thun MJ (2004) Cancer statistics, 2004. CA Cancer J

Clin 54(1):8–29

5. Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF,

van Amstel HK, Lips CJ, Nishisho I, Takai SI, Marsh DJ, Rob-

inson BG, Frank-Raue K, Raue F, Xue F, Noll WW, Romei C,

Pacini F, Fink M, Niederle B, Zedenius J, Nordenskjold M,

Komminoth P, Hendy GN, Mulligan LM et al (1996) The rela-

tionship between specific RET proto-oncogene mutations and

disease phenotype in multiple endocrine neoplasia type 2. Inter-

national RET mutation consortium analysis. JAMA 276(19):

1575–1579

6. Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner

E, Love DR, Mole SE, Moore JK, Papi L et al (1993) Germ-line

mutations of the RET proto-oncogene in multiple endocrine

neoplasia type 2A. Nature 363(6428):458–460. doi:10.1038/3634

58a0

7. Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lair-

more TC, Howe JR, Moley JF, Goodfellow P, Wells SA Jr (1993)

Mutations in the RET proto-oncogene are associated with MEN

2A and FMTC. Hum Mol Genet 2(7):851–856

8. Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder

MA, Gardner E, Scheumann GF, Jackson CE, Tunnacliffe A et al

(1994) Point mutation within the tyrosine kinase domain of the

RET proto-oncogene in multiple endocrine neoplasia type 2B and

related sporadic tumours. Hum Mol Genet 3(2):237–241

9. Margraf RL, Crockett DK, Krautscheid PM, Seamons R, Cald-

eron FR, Wittwer CT, Mao R (2009) Multiple endocrine neo-

plasia type 2 RET protooncogene database: repository of MEN2-

associated RET sequence variation and reference for genotype/

phenotype correlations. Hum Mutat 30(4):548–556. doi:10.1002/

humu.20928

10. Peppa M, Boutati E, Kamakari S, Pikounis V, Peros G, Pana-

yiotides IG, Economopoulos T, Raptis SA, Hadjidakis D (2008)

Multiple endocrine neoplasia type 2A in two families with the

familial medullary thyroid carcinoma associated G533C mutation

of the RET proto-oncogene. Eur J Endocrinol 159(6):767–771.

doi:10.1530/eje-08-0476

11. Kaldrymides P, Mytakidis N, Anagnostopoulos T, Vassiliou M,

Tertipi A, Zahariou M, Rampias T, Koutsodontis G, Konstanto-

poulou I, Ladopoulou A, Bei T, Yannoukakos D (2006) A rare

RET gene exon 8 mutation is found in two Greek kindreds with

familial medullary thyroid carcinoma: implications for screening.

Clin Endocrinol (Oxf) 64(5):561–566. doi:10.1111/j.1365-2265.

2006.02509.x

12. Gimm O, Marsh DJ, Andrew SD, Frilling A, Dahia PL, Mulligan

LM, Zajac JD, Robinson BG, Eng C (1997) Germline dinucleo-

tide mutation in codon 883 of the RET proto-oncogene in mul-

tiple endocrine neoplasia type 2B without codon 918 mutation.

J Clin Endocrinol Metab 82(11):3902–3904

13. Cranston AN, Carniti C, Oakhill K, Radzio-Andzelm E, Stone

EA, McCallion AS, Hodgson S, Clarke S, Mondellini P, Leyland

J, Pierotti MA, Whittaker J, Taylor SS, Bongarzone I, Ponder BA

(2006) RET is constitutively activated by novel tandem mutations

that alter the active site resulting in multiple endocrine neoplasia

type 2B. Cancer Res 66(20):10179–10187. doi:10.1158/0008-

5472.can-06-0884

14. Miyauchi A, Futami H, Hai N, Yokozawa T, Kuma K, Aoki N,

Kosugi S, Sugano K, Yamaguchi K (1999) Two germline mis-

sense mutations at codons 804 and 806 of the RET proto-onco-

gene in the same allele in a patient with multiple endocrine

Hereditary medullary thyroid carcinoma 163

123

neoplasia type 2B without codon 918 mutation. Jpn J Cancer Res

90(1):1–5

15. Iwashita T, Murakami H, Kurokawa K, Kawai K, Miyauchi A,

Futami H, Qiao S, Ichihara M, Takahashi M (2000) A two-hit

model for development of multiple endocrine neoplasia type 2B

by RET mutations. Biochem Biophys Res Commun 268(3):

804–808. doi:10.1006/bbrc.2000.2227

16. Frank-Raue K, Hoppner W, Frilling A, Kotzerke J, Dralle H,

Haase R, Mann K, Seif F, Kirchner R, Rendl J, Deckart HF, Ritter

MM, Hampel R, Klempa J, Scholz GH, Raue F (1996) Mutations

of the ret protooncogene in German multiple endocrine neoplasia

families: relation between genotype and phenotype. German

Medullary Thyroid Carcinoma Study Group. J Clin Endocrinol

Metab 81(5):1780–1783

17. Yip L, Cote GJ, Shapiro SE, Ayers GD, Herzog CE, Sellin RV,

Sherman SI, Gagel RF, Lee JE, Evans DB (2003) Multiple

endocrine neoplasia type 2: evaluation of the genotype-phenotype

relationship. Arch Surg 138(4):409–416. doi:10.1001/archsurg.

138.4.409 discussion 416

18. Frank-Raue K, Rondot S, Raue F (2010) Molecular genetics and

phenomics of RET mutations: impact on prognosis of MTC. Mol

Cell Endocrinol 322(1–2):2–7. doi:10.1016/j.mce.2010.01.012

19. Frank-Raue K, Rondot S, Schulze E, Raue F (2007) Change in

the spectrum of RET mutations diagnosed between 1994 and

2006. Clin Lab 53(5–6):273–282

20. Frank-Raue K, Dohring J, Scheumann G, Rondot S, Lorenz A,

Schulze E, Dralle H, Raue F, Leidig-Bruckner G (2010) New

mutations in the RET protooncogene-L881 V—associated with

medullary thyroid carcinoma and -R770Q—in a patient with

mixed medullar/follicular thyroid tumour. Exp Clin Endocrinol

Diabetes 118(8):550–553. doi:10.1055/s-0029-1241851

21. Castellone MD, Verrienti A, Magendra Rao D, Sponziello M,

Fabbro D, Muthu M, Durante C, Maranghi M, Damante G, Piz-

zolitto S, Costante G, Russo D, Santoro M, Filetti S (2010) A

novel de novo germ-line V292 M mutation in the extracellular

region of RET in a patient with phaeochromocytoma and med-

ullary thyroid carcinoma: functional characterization. Clin

Endocrinol (Oxf) 73(4):529–534. doi:10.1111/j.1365-2265.2009.

03757.x

22. Pazaitou-Panayiotou K, Giatzakis C, Koutsodontis G, Vratimos

A, Chrisoulidou A, Konstantinidis T, Kamakari S (2010) Iden-

tification of two novel mutations in the RET proto-oncogene in

the same family. Thyroid 20(4):401–406. doi:10.1089/thy.2009.

0262

23. Machens A, Dralle H (2008) Familial prevalence and age of RET

germline mutations: implications for screening. Clin Endocrinol

(Oxf) 69(1):81–87. doi:10.1111/j.1365-2265.2007.03153.x

24. Machens A, Lorenz K, Dralle H (2009) Constitutive RET tyro-

sine kinase activation in hereditary medullary thyroid cancer:

clinical opportunities. J Intern Med 266(1):114–125. doi:10.1111/

j.1365-2796.2009.02113.x

25. Romei C, Mariotti S, Fugazzola L, Taccaliti A, Pacini F, Opocher

G, Mian C, Castellano M, degli Uberti E, Ceccherini I, Cremonini

N, Seregni E, Orlandi F, Ferolla P, Puxeddu E, Giorgino F, Colao

A, Loli P, Bondi F, Cosci B, Bottici V, Cappai A, Pinna G,

Persani L, Verga U, Boscaro M, Castagna MG, Cappelli C, Za-

telli MC, Faggiano A, Francia G, Brandi ML, Falchetti A,

Pinchera A, Elisei R (2010) Multiple endocrine neoplasia type 2

syndromes (MEN 2): results from the ItaMEN network analysis

on the prevalence of different genotypes and phenotypes. Eur J

Endocrinol 163(2):301–308. doi:10.1530/eje-10-0333

26. Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H,

Moley JF, Pacini F, Ringel MD, Schlumberger M, Wells SA Jr

(2009) Medullary thyroid cancer: management guidelines of the

American Thyroid Association. Thyroid 19(6):565–612. doi:

10.1089/thy.2008.0403

27. Bugalho MJ, Domingues R, Santos JR, Catarino AL, Sobrinho L

(2007) Mutation analysis of the RET proto-oncogene and early

thyroidectomy: results of a Portuguese cancer centre. Surgery

141(1):90–95. doi:10.1016/j.surg.2006.03.025

28. Wiench M, Wygoda Z, Gubala E, Wloch J, Lisowska K, Kras-

sowski J, Scieglinska D, Fiszer-Kierzkowska A, Lange D, Kula

D, Zeman M, Roskosz J, Kukulska A, Krawczyk Z, Jarzab B

(2001) Estimation of risk of inherited medullary thyroid carci-

noma in apparent sporadic patients. J Clin Oncol 19(5):

1374–1380

29. Elisei R, Romei C, Cosci B, Agate L, Bottici V, Molinaro E,

Sculli M, Miccoli P, Basolo F, Grasso L, Pacini F, Pinchera A

(2007) RET genetic screening in patients with medullary thyroid

cancer and their relatives: experience with 807 individuals at one

center. J Clin Endocr Metab 92(12):4725–4729. doi:10.1210/Jc.

2007-1005

30. Allen SM, Bodenner D, Suen JY, Richter GT (2009) Diagnostic

and surgical dilemmas in hereditary medullary thyroid carci-

noma. Laryngoscope 119(7):1303–1311. doi:10.1002/lary.20299

31. Roman S, Lin R, Sosa JA (2006) Prognosis of medullary thyroid

carcinoma—demographic, clinical, and pathologic predictors of

survival in 1252 cases. Cancer 107(9):2134–2142. doi:10.1002/

Cncr.22244

32. Lau GS, Lang BH, Lo CY, Tso A, Garcia-Barcelo MM, Tam PK,

Lam KS (2009) Prophylactic thyroidectomy in ethnic Chinese

patients with multiple endocrine neoplasia type 2A syndrome

after the introduction of genetic testing. Hong Kong Med J 15(5):

326–331

33. Punales MK, da Rocha AP, Meotti C, Gross JL, Maia AL (2008)

Clinical and oncological features of children and young adults

with multiple endocrine neoplasia type 2A. Thyroid 18(12):

1261–1268. doi:10.1089/thy.2007.0414

34. Spinelli C, Di Giacomo M, Costanzo S, Elisei R, Miccoli P

(2010) Role of RET codonic mutations in the surgical manage-

ment of medullary thyroid carcinoma in pediatric age multiple

endocrine neoplasm type 2 syndromes. J Pediatr Surg

45(8):1610–1616. doi:10.1016/j.jpedsurg.2010.03.019

35. Frank-Raue K, Buhr H, Dralle H, Klar E, Senninger N, Weber T,

Rondot S, Hoppner W, Raue F (2006) Long-term outcome in 46

gene carriers of hereditary medullary thyroid carcinoma after

prophylactic thyroidectomy: impact of individual RET genotype.

Eur J Endocrinol 155(2):229–236. doi:10.1530/eje.1.0221636. Skinner MA, Moley JA, Dilley WG, Owzar K, Debenedetti MK,

Wells SA Jr (2005) Prophylactic thyroidectomy in multiple

endocrine neoplasia type 2A. N Engl J Med 353(11):1105–1113.

doi:10.1056/NEJMoa043999

37. Schellhaas E, Konig C, Frank-Raue K, Buhr HJ, Hotz HG (2009)

Long-term outcome of ‘‘prophylactic therapy’’ for familial

medullary thyroid cancer. Surgery 146(5):906–912. doi:10.1016/

j.surg.2009.06.007

38. Ukkat J, Gimm O, Brauckhoff M, Bilkenroth U, Dralle H (2004)

Single center experience in primary surgery for medullary thyroid

carcinoma. World J Surg 28(12):1271–1274. doi:10.1007/

s00268-004-7608-9

39. Raval MV, Sturgeon C, Bentrem DJ, Elaraj DM, Stewart AK,

Winchester DJ, Ko CY, Reynolds M (2010) Influence of lymph

node metastases on survival in pediatric medullary thyroid can-

cer. J Pediatr Surg 45(10):1947–1954. doi:10.1016/j.jpedsurg.

2010.06.013

40. Baumgartner-Parzer SM, Lang R, Wagner L, Heinze G, Niederle

B, Kaserer K, Waldhausl W, Vierhapper H (2005) Polymor-

phisms in exon 13 and intron 14 of the RET protooncogene:

genetic modifiers of medullary thyroid carcinoma? J Clin Endo-

crinol Metab 90(11):6232–6236. doi:10.1210/jc.2005-1278

41. Frank-Raue K, Rybicki LA, Erlic Z, Schweizer H, Winter A,

Milos I, Toledo SP, Toledo RA, Tavares MR, Alevizaki M, Mian

164 P. Zhou et al.

123

C, Siggelkow H, Hufner M, Wohllk N, Opocher G, Dvorakova S,

Bendlova B, Czetwertynska M, Skasko E, Barontini M, Sanso G,

Vorlander C, Maia AL, Patocs A, Links TP, de Groot JW, Ker-

stens MN, Valk GD, Miehle K, Musholt TJ, Biarnes J, Damja-

novic S, Muresan M, Wuster C, Fassnacht M, Peczkowska M,

Fauth C, Golcher H, Walter MA, Pichl J, Raue F, Eng C, Neu-

mann HP (2011) Risk profiles and penetrance estimations in

multiple endocrine neoplasia type 2A caused by germline RET

mutations located in exon 10. Hum Mutat 32(1):51–58. doi:

10.1002/humu.21385

42. Milos IN, Frank-Raue K, Wohllk N, Maia AL, Pusiol E, Patocs

A, Robledo M, Biarnes J, Barontini M, Links TP, de Groot JW,

Dvorakova S, Peczkowska M, Rybicki LA, Sullivan M, Raue F,

Zosin I, Eng C, Neumann HP (2008) Age-related neoplastic risk

profiles and penetrance estimations in multiple endocrine neo-

plasia type 2A caused by germ line RET Cys634Trp (TGC [TGG) mutation. Endocr Relat Cancer 15(4):1035–1041. doi:

10.1677/erc-08-0105

43. Raue F, Frank-Raue K (2010) Update multiple endocrine neo-

plasia type 2. Fam Cancer 9(3):449–457. doi:10.1007/s10689-

010-9320-2

44. Bergenfelz A, Jansson S, Kristoffersson A, Martensson H, Re-

ihner E, Wallin G, Lausen I (2008) Complications to thyroid

surgery: results as reported in a database from a multicenter audit

comprising 3,660 patients. Langenbecks Arch Surg 393(5):

667–673. doi:10.1007/s00423-008-0366-7

45. Grubbs EG, Waguespack SG, Rich TA, Xing Y, Ying AK, Evans

DB, Lee JE, Perrier ND (2010) Do the recent American Thyroid

Association (ATA) Guidelines accurately guide the timing of

prophylactic thyroidectomy in MEN2A? Surgery 148(6):

1302–1309. doi:10.1016/j.surg.2010.09.020 Discussion 1309–1310

46. Richter GT, Allen SM, Bodenner D, Suen JY (2009) Diagnostic

and surgical Dilemmas in hereditary medullary thyroid carci-

noma. Laryngoscope 119(7):1303–1311. doi:10.1002/Lary.20299

47. Fazioli F, Piccinini G, Appolloni G, Bacchiocchi R, Palmonella

G, Recchioni R, Pierpaoli E, Silvetti F, Scarpelli M, Bruglia M,

Melillo RM, Santoro M, Boscaro M, Taccaliti A (2008) A new

germline point mutation in Ret exon 8 (cys515ser) in a family

with medullary thyroid carcinoma. Thyroid 18(7):775–782. doi:

10.1089/thy.2007.0365

48. Da Silva AM, Maciel RM, Da Silva MR, Toledo SR, De Carv-

alho MB, Cerutti JM (2003) A novel germ-line point mutation in

RET exon 8 (Gly(533)Cys) in a large kindred with familial

medullary thyroid carcinoma. J Clin Endocrinol Metab

88(11):5438–5443

49. Mulligan LM, Eng C, Healey CS, Clayton D, Kwok JB, Gardner

E, Ponder MA, Frilling A, Jackson CE, Lehnert H et al (1994)

Specific mutations of the RET proto-oncogene are related to

disease phenotype in MEN 2A and FMTC. Nat Genet 6(1):70–74.

doi:10.1038/ng0194-70

50. Hoppner W, Dralle H, Brabant G (1998) Duplication of 9 base

pairs in the critical cysteine-rich domain of the RET proto-

oncogene causes multiple endocrine neoplasia type 2A. Hum

Mutat Suppl 1:S128–S130

51. Maschek W, Pichler R, Rieger R, Weinhausel A, Berg J (2002) A

new identified germline mutation of the RET proto-oncogene

responsible for familial medullary thyroid carcinoma in co-exis-

tence with a hyperfunctioning autonomous nodule. Clin Endo-

crinol (Oxf) 56(6):823

52. Jindrichova S, Vcelak J, Vlcek P, Neradilova M, Nemec J,

Bendlova B (2004) Screening of six risk exons of the RET proto-

oncogene in families with medullary thyroid carcinoma in the

Czech Republic. J Endocrinol 183(2):257–265. doi:10.1677/joe.

1.05838

53. Berndt I, Reuter M, Saller B, Frank-Raue K, Groth P, Grussen-

dorf M, Raue F, Ritter MM, Hoppner W (1998) A new hot spot

for mutations in the ret protooncogene causing familial medullary

thyroid carcinoma and multiple endocrine neoplasia type 2A.

J Clin Endocrinol Metab 83(3):770–774

54. Fink M, Weinhusel A, Niederle B, Haas OA (1996) Distinction

between sporadic and hereditary medullary thyroid carcinoma

(MTC) by mutation analysis of the RET proto-oncogene. Study

Group Multiple Endocrine Neoplasia Austria (SMENA). Int J

Cancer 69(4):312–316. doi:10.1002/(sici)1097-0215(19960822)

69:4\312:aid-ijc13[3.0.co;2-7

55. Smith DP, Houghton C, Ponder BA (1997) Germline mutation of

RET codon 883 in two cases of de novo MEN 2B. Oncogene

15(10):1213–1217. doi:10.1038/sj.onc.1201481

56. Hofstra RM, Fattoruso O, Quadro L, Wu Y, Libroia A, Verga U,

Colantuoni V, Buys CH (1997) A novel point mutation in the

intracellular domain of the ret protooncogene in a family with

medullary thyroid carcinoma. J Clin Endocrinol Metab 82(12):

4176–4178

57. Jimenez C, Dang GT, Schultz PN, El-Naggar A, Shapiro S,

Barnes EA, Evans DB, Vassilopoulou-Sellin R, Gagel RF, Cote

GJ, Hoff AO (2004) A novel point mutation of the RET proto-

oncogene involving the second intracellular tyrosine kinase

domain in a family with medullary thyroid carcinoma. J Clin

Endocrinol Metab 89(7):3521–3526. doi:10.1210/jc.2004-0073

58. Romei C, Cosci B, Renzini G, Bottici V, Molinaro E, Agate L,

Passannanti P, Viola D, Biagini A, Basolo F, Ugolini C, Mate-

razzi G, Pinchera A, Vitti P, Elisei R (2011) RET genetic

screening of sporadic medullary thyroid cancer (MTC) allows the

preclinical diagnosis of unsuspected gene carriers and the iden-

tification of a relevant percentage of hidden familial MTC

(FMTC). Clin Endocrinol (Oxf) 74(2):241–247. doi:10.1111/

j.1365-2265.2010.03900.x

59. Zhang XN, Qi XP, Ma JM, Du ZF, Ying RB, Fei J, Jin HY, Han

JS, Wang JQ, Chen XL, Chen CY, Liu WT, Lu JJ, Zhang JG

(2011) RET germline mutations identified by exome sequencing

in a Chinese multiple endocrine neoplasia type 2A/familial

medullary Thyroid carcinoma family. PLoS One 6(5). doi:

10.1371/journal.pone.0020353

60. Park H, Jung J, Uchino S, Lee Y (2010) A Korean family of

familial medullary thyroid cancer with Cys618Ser RET germline

mutation. J Korean Med Sci 25(2):226–229. doi:10.3346/jkms.

2010.25.2.226

61. Calva D, O’Dorisio TM, Sue O’Dorisio M, Lal G, Sugg S,

Weigel RJ, Howe JR (2009) When is prophylactic thyroidectomy

indicated for patients with the RET codon 609 mutation? Ann

Surg Oncol 16(8):2237–2244. doi:10.1245/s10434-009-0524-3

Hereditary medullary thyroid carcinoma 165

123