Surgical Oncology 9 (2000) 111}118

Multiple endocrine neoplasia type 2B * genetic basis and

clinical expression
N.C. Lee , J.A. Norton
*
Department of Surgery, University of California, San Francisco, CA 94143, USA

Department of Surgery, San Francisco Veterans Awairs Medical Center, San Francisco, CA 94121, USA

Abstract

Multiple endocrine neoplasia (MEN) type 2B is a heritable endocrine disorder characterized by medullary thyroid carcinoma
(MTC), pheochromocytoma, multiple mucosal neuromas, and a marfanoid habitus. Intestinal ganglioneuromatosis, corneal nerve
thickening and skeletal abnormalities are also often present. The disease is inherited in an autosomal dominant fashion and is caused
by a single mutation in the RET proto-oncogene, with a methionine to threonine substitution at codon 918. The MTC in MEN 2B
presents at an earlier age and tends to be more aggressive than the MTC in MEN 2A. It is multicentric and bilateral and occurs as
young as age 3, with early lymph node metastases. Pheochromocytoma is also often bilateral but is rarely malignant. If pheoch-
romocytoma is detected, adrenalectomy should precede thyroidectomy to avoid intraoperative catecholamine crisis. Patients at risk
for MEN 2B should undergo genetic screening in infancy. Total thyroidectomy should be performed on all patients positive for RET
mutations even prior to the onset of clinical symptoms.  2001 Published by Elsevier Science Ltd.

Keywords: Multiple endocrine neoplasia type 2B; RET proto-oncogene; Medullary thyroid carcinoma; Pheochromocytoma; Mucosal neuroma
syndrome

Multiple endocrine neoplasia (MEN) type 2B belongs Chong et al. to distinguish it from Sipple syndrome (now
to a family of heritable endocrine diseases that includes called MEN 2A) [9].
MEN 1, MEN 2A, and familial medullary thyroid carci- Both MEN 2A and 2B share the presence of medullary
noma (FMTC) (Table 1). The "rst description of tumors thyroid carcinoma and pheochromocytoma. MEN 2B
arising in multiple endocrine organs was in 1903 by is further distinguished by a characteristic pheno-
Erdheim [1]. Fifty years later, Wermer reported the type that includes multiple mucosal neuromas, intestinal
familial occurrence of adenomas in the pituitary, para- ganglioneuromatosis, a marfanoid habitus, and mus-
thyroids, and pancreatic islet cells, now known as MEN culoskeletal and ophthalmic abnormalities. Hyper-
1 [2]. In 1959, Hazard et al. "rst recognized medullary parathyroidism, which occurs in up to 30% of MEN 2A
thyroid carcinoma as a distinct tumor [3]. Sipple "rst patients, is not found in MEN 2B [10]. Familial
described the association of medullary thyroid cancer, medullary thyroid cancer is de"ned by the presence of
pheochromocytoma and parathyroid adenoma in 1961 medullary thyroid cancer in four or more family
[4], and the syndrome was later termed `multiple members without the associated endocrine abnormalities
endocrine neoplasia type 2a by Steiner et al. [5]. The seen in MEN 2A and 2B [11].
association between medullary thyroid carcinoma, Ninety percent of the cases of MEN 2 are of the MEN
pheochromocytoma, and multiple mucosal neuromas 2A subtype [12]. While MEN 2B is less common, it
was described by Williams and Pollock in 1966 and appears at an earlier age and tends to be more aggressive
con"rmed by others including Gorlin and Schimke than MEN 2A [13]. The average age of onset is in the
[6}8]. This syndrome was named MEN 2B in 1975 by second to third decade of life for MEN 2A, but patients
with MEN 2B present in the "rst to second decade of life
[14]. Patients with MEN 2B also tend to have a poorer
* Corresponding author at Department of Surgery, San Francisco prognosis than patients with MEN 2A or FMTC [15].
Veterans Administration Hospital, San Francisco, CA 94121, USA.
Fax: #1-415-750-2181. Whereas 80% of MEN 2A cases are caused by genetic
E-mail addresses: [email protected] (N.C. Lee), janortn@ inheritance, 50% of MEN 2B cases are due to de novo
itsa.ucsf.edu (J.A. Norton). mutations [16]. This statistic re#ects that on average,

0960-7404/01/$ - see front matter  2001 Published by Elsevier Science Ltd.

PII: S 0 9 6 0 - 7 4 0 4 ( 0 0 ) 0 0 0 3 8 - 4
112 N.C. Lee, J.A. Norton / Surgical Oncology 9 (2000) 111}118

MEN 2B patients are less likely to reproduce because signalling for cell growth and di!erentiation of tissues
they die of their disease at an earlier age. derived from neural crest cells, such as the C cells of the
MEN 2B demonstrates an autosomal dominant pat- thyroid, the adrenal medulla, the parathyroid gland, and
tern of inheritance. There is essentially complete penetr- the enteric autonomic nerve plexus [23]. Loss of RET
ance of the genetic defect, but with variable expressivity, function prevents renal organogenesis and enteric neuron
as not all patients manifest all the characteristics of the formation in mice [24].
syndrome [17]. Although there is an equal sex distribu- In MEN 2A, 2B, and FMTC, mutations in the RET
tion in inherited cases, Carlson et al. have shown that 25 gene lead to activation of the gene [25]. Therefore, only
of 25 sporadic cases of MEN 2B were formed from a single copy of the gene need be mutated in order to
mutations on the paternally derived chromosome, sug- cause disease. Over 95% of MEN 2B cases are caused by
gesting that a RET allele may be more susceptible to a single point mutation in the intracellular tyrosine
mutation when inherited from the father [16]. kinase domain of the RET gene, with a substitution of
MEN 2A, 2B, and FMTC are all caused by defects in threonine for methionine at codon 918 in exon 16
the RET proto-oncogene. The RET (rearranged during [26}28]. This MEN 2B mutation induces medullary
transfection) proto-oncogene was "rst cloned as a chim- thyroid carcinoma in transgenic mice [29]. This speci"c
eric oncogene during a classic NIH3T3 transformation mutation is also found in sporadic cases of MEN 2B and
assay [18]. The gene is located on chromosome 10q11.2 is associated with a poor prognosis [30,31]. There have
and consists of 21 exons spanning 55 kb [19,20]. The also been a few reported cases of MEN 2B with a muta-
extracellular domain consists of a cysteine-rich region tion in codon 883, with a substitution of phenylalanine
close to the cellular membrane and a more distal cad- for alanine [32,33]. In contrast, there are several di!erent
herin-like domain. Beyond a transmembrane portion mutations causing MEN 2A and FMTC, which are
there is an intracellular portion with two tyrosine kinase located in the cysteine-rich extracellular domain. Muta-
domains [21]. The RET gene encodes a cell surface tions within one of "ve cysteine codons are found in
glycoprotein which is a member of the receptor tyrosine 85}95% of patients with MEN-2A and FMTC, including
kinase family. Binding of the RET ligand, glial-derived mutations at codons 609, 611, 618, and 620 in exon
neurotropic factor, causes dimerization and activation 10 and codon 634 in exon 11 of the RET gene (Fig. 1)
of the receptor [22]. The RET gene is important in [34].

Table 1
Clinical and genetic characteristics of the multiple endocrine neoplasias

MEN 1 MEN 2A MEN 2B FMTC

Age of onset 20}30 20}30 0}20 40}50

Clinical Parathyroid hyperplasia Medullary thyroid carcinoma Medullary thyroid carcinoma Medullary thyroid carcinoma
features Pancreatic islet cell tumors Pheochromocytoma Pheochromocytoma
Anterior pituitary tumors Parathyroid hyperplasia Mucosal neuromas
Marfanoid habitus
Inheritance Autosomal dominant Autosomal dominant Autosomal dominant Autosomal dominant
A!ected gene menin tumor suppressor gene RET proto-oncogene RET proto-oncogene RET proto-oncogene
Chromosome 11q13 10q11.2 10q11.2 10q11.2
Codons 609, 611, 618, 620, 634 918 609, 611, 618, 620, 768, 883

MEN, multiple endocrine neoplasia; FMTC, familial medullary thyroid carcinoma.

Fig. 1. Schematic diagram of the RET proto-oncogene receptor tyrosine kinase protein. Substitution mutations in one of "ve cysteine residues in
exons 10 and 11 in the extracellular domain lead to multiple endocrine neoplasia (MEN) 2A and familial medullary thyroid carcinoma (FMTC).
Mutations in codons 768 and 883 in exons 13 and 14 of the intracellular tyrosine kinase 1 region are associated with FMTC alone. Methionine to
threonine mutation in codon 918 in exon 16 of the intracellular tyrosine kinase 2 region results in MEN 2B.
 N.C. Lee, J.A. Norton / Surgical Oncology 9 (2000) 111}118 113

Fig. 2. The characteristic phenotype of MEN 2B include mucosal neuromas present on the lips and anterior third of the tongue.

Fig. 3. Slit lamp examination in the same patient reveals corneal nerve hypertrophy.

Patients with MEN-2B have a striking phenotypic Intestinal involvement is a prominent feature of MEN
appearance which includes mucosal neuromas and mus- 2B, and is usually present early in life before the endo-
culoskeletal abnormalities [35]. Patients have mucosal crine neoplasms are manifest. Most patients describe
neuromas on the anterior third of the tongue, buccal constipation since early infancy. Other features include
mucosa, lips, and inner eyelids (Fig. 2). These neuromas abdominal pain and cramping, projectile vomiting, diver-
contribute to a facies marked by thickened irregular lips ticulosis and megacolon in severe cases. In adulthood
and thickened, sometimes everted eyelids. The patients either constipation or diarrhea is usually present. The
exhibit a marfanoid habitus with a tall and slender build, diarrhea is thought to be due to the release of humoral
long limbs and high arched palate, and a long thin face factors such as calcitonin by the hyperplastic C-cells
with prognathism. Bony abnormalities are present such [37]. Intestinal ganglioneuromatosis is present anywhere
as pectus excavatum, pes cavus, talipes equinovarus, slip- from the oral mucosa to the rectum (Fig. 4). Pathological
ped capital femoral epiphysis, kyphosis, scoliosis, and specimens demonstrate hypertrophy and disorganization
increased joint laxity. Ocular manifestations such as cor- of the myenteric plexus and proliferation of ganglions.
neal nerve hypertrophy on slit lamp examination may The ganglioneuromatosis causes defective peristalsis
also be seen [36] (Fig. 3). and poor contractility [38]. Patients with intestinal
114 N.C. Lee, J.A. Norton / Surgical Oncology 9 (2000) 111}118

Fig. 4. Intestinal ganglioneuromatosis is present in nearly all MEN 2B patients, with nodular neuromas present on the mucosal surfaces of the bowel.

Fig. 5. Medullary thyroid carcinoma is usually multicentric and bilateral, and is located at the junction of the upper and middle 1/3 of the thyroid
lobes, where the greatest concentration of C-cells is present.

ganglioneuromatosis exhibit similar symptoms to course, with earlier metastasis and a poorer prognosis
patients with Hirschsprung's disease. Interestingly, compared to MEN 2A and FMTC [13]. Metastases
Hirschsprung's disease has also been linked to defects in appear "rst in the regional cervical or mediastinal lymph
the RET gene. While RET mutations in MEN lead to nodes, followed by distant metastases in the liver, lungs,
activating gain-of-function mutations which lead to un- and bone [17]. The mean age at diagnosis of MTC was
controlled cellular proliferation, the mutations causing 20 years in MEN 2B, as compared to 25 years in MEN
Hirschprung's disease instead cause loss of function and 2A, 29 years in FMTC, and 47 years in sporadic cases
absence of intestinal ganglia [39,40]. [42]. The medullary thyroid carcinoma in MEN is
Essentially, all MEN 2B patients develop medullary almost always multicentric and bilateral, whereas spor-
thyroid cancer, which is a tumor of calcitonin-secreting adic cases of MTC are usually unilateral [15]. C-cells are
parafollicular C cells [41]. Patients with MEN 2B who located primarily in the superior poles of the thyroid, at
are not diagnosed based on the typical phenotype usually the junction of the upper and middle thirds, and the
present "rst with a neck mass due to the medullary medullary thyroid tumors develop here as whitish brown,
thyroid carcinoma. Medullary thyroid cancer presents at well-circumscribed nodules [17] (Fig. 5). C-cell hyper-
an earlier age in MEN 2B and follows a more virulent plasia is thought to be a precursor of MTC, and has been
 N.C. Lee, J.A. Norton / Surgical Oncology 9 (2000) 111}118 115

documented in MEN 2B patients as young as 3 months genetic result for RET mutations had MTC in 3 of
[43]. Fine-needle aspiration biopsies typically show 7 patients (43%) and C-cell hyperplasia in 4 of 7 (57%)
characteristic changes for MTC including multinuclea- [50]. Wells et al. performed genetic testing on 58 kindred
tion, amyloid, and calci"cations as well as trabecular, members at risk for MEN 2A and found that 21 had
alveolar, and spindle cell patterns of tumor growth, and inherited a RET mutation. Of these, 18 underwent
can be con"rmed by staining for calcitonin [44]. thyroidectomy and all were found to have C-cell hyper-
Patients with C-cell hyperplasia or MTC have elev- plasia. Nine had microscopic MTC and 5 had macro-
ations in plasma calcitonin levels due to secretion of scopic MTC [51]. These and other studies demonstrate
calcitonin by the C-cells. A serum calcitonin level greater that genetic screening for RET mutations allows thyroid-
than 1000 pg/ml associated with an elevated carcinoem- ectomy to be performed at an earlier stage of disease than
bryonic antigen con"rms the diagnosis [15]. Provocative relying on clinical symptoms or standard biochemical
tests with calcium and pentagastrin are used to detect tests.
tumors when the plasma calcitonin is normal. The cal- Pheochromocytoma is present in 50% of patients with
citonin level is measured before and 1}3 and 5 min after MEN 2B, and presents at a median age of 28 [45]. Unlike
intravenous infusion of 2 mg/kg/min calcium gluconate sporadic pheochromocytoma, greater than half have
and 0.5
g/kg/5 s pentagastrin [45]. However, this test is bilateral tumors. Only about 10% are malignant, and are
associated with unpleasant side e!ects such as diarrhea, rarely extra-adrenal. Hyperplasia of the adrenal medulla
abdominal cramping, #ushing, and vomiting. The test is found as a precursor to pheochromocytoma. Symp-
may also be associated with both false-positive and toms and signs include diaphoresis, headache, anxiety,
false-negative results, which decreases its utility for palpitations, and hypertension, although some patients
screening. With the development of direct genetic testing are asymptomatic [52].
for RET mutations, the provocative test is now reserved Diagnosis is made through a combination of bio-
for detecting persistent or recurrent MTC after total chemical tests and radiologic studies. Traditionally,
thyroidectomy [14]. Direct testing of peripheral biochemical tests rely on a 24-h urinary collection to
leukocytes for RET mutations requires only a single measure urinary noreprinephrine and epinephrine, meta-
blood sample and is highly accurate and speci"c. Muta- nephrines, and vanillylmandelic acid, as well as plasma
tions of the RET gene are detected using PCR ampli"ca- norepinephrine and epinephrine. However, these tests
tion and analysis of restriction endonuclease digestion of have had problems with low sensitivity and speci"city
RET fragments or by direct DNA sequencing [46]. Since [53]. Recently, measurements of plasma normetaneph-
MTC is almost always bilateral in MEN, pre-operative rine and metanephrine have been shown to be more
radiologic studies are not usually needed, but CT, MRI sensitive and speci"c for detecting pheochromocytoma in
and somatostatin receptor scintigraphy can be used to MEN 2 and von Hippel Lindau disease [54]. All patients
localize recurrences or metastases [47]. with MEN 2 had high plasma concentrations of meta-
MTC is resistant to radiation and chemotherapy; nephrine, whereas the patients with von Hippel Lindau
thus surgical resection o!ers the only chance for disease had elevations of normetanephrine alone. The
cure. The standard for MTC is to perform total thyroid- sensitivity of the plasma normetanephrine and meta-
ectomy with central neck lymph node dissection [42]. nephrine was 97% compared to 47}74% for the other
Patients with MEN 2A have a 30% risk of developing biochemical tests, and had a speci"city of 96%. CT, MRI,
hyperparathyroidism and so the parathyroids are usually and meta-iodobenzylguanidine (MIBG) scintigraphy are
removed, with autotransplantation to the forearm. used to localize the tumor [55]. Sensitivity of combined
Unlike MEN 2A, patients with MEN 2B are not at risk CT and MRI was 87% with a speci"city of 100%
for hyperparathyroidism and the parathyroid glands can and diagnostic accuracy of 89%. MIBG scintigraphy had
be grafted onto the sternocleidomastoid [15]. Early diag- a sensitivity of 92%, speci"city of 17% and diagnostic
nosis of MTC is essential given the highly aggressive accuracy of 77%. MIBG scintigraphy is sensitive, but has
nature and metastatic potential of the disease. Genetic a lower speci"city in distinguishing between medullary
testing should be performed by age 5 for patients at risk hyperplasia and small pheochromocytomas. CT or MRI
for MEN 2A, and even as early as 1 year for patients should be performed "rst, and MIBG scintigraphy re-
at risk for MEN 2B. Prophylactic thyroidectomy should served for patients with clinically or biochemically sus-
be performed once a RET mutation is detected, and can pected tumor not localized by CT or MRI.
be done even in infancy [48]. Thyroidectomy for MTC in Patients diagnosed with pheochromocytoma should
the setting of MEN 2B has been performed on patients as undergo adrenalectomy. Because of the lower risk of
young as 7 months [49]. In a study of MEN 2 patients malignancy of pheochromocytoma, some have favored
undergoing thyroidectomy based on the clinical or bio- unilateral adrenalectomy when only one adrenal gland is
chemical indications, MTC was found in 45 of 46 patients a!ected, to avoid the risk of Addisonian crisis and de-
(98%) and C-cell hyperplasia in one patient. Those pendence on exogenous steroid replacement with bilat-
patients who had thyroidectomy based on a positive eral adrenalectomy [52]. Others advocate initial bilateral
116 N.C. Lee, J.A. Norton / Surgical Oncology 9 (2000) 111}118

total adrenalectomy given the high incidence of bilateral screening for RET mutations enables thyroidectomy to
disease at the cellular level, which would eliminate the be performed at an earlier stage of disease, which should
possibility of future catecholamine crisis or metastases improve the prognosis for this aggressive form of endo-
[56]. Laparoscopic adrenalectomy has been performed crine disease.
for pheochromocytoma, including bilateral and partial
adrenalectomy, with no di!erence in intraoperative
hemodynamics or morbidity compared to open adrenalec-
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