Molecular Analyses in Endocrine Pathology
Dr. George Kontogeorgos
Dr. Robert Yoshiyuki Osamura
Dr. Jennifer Hunt
Section 4 -
De Novo Mulitiple Endocrine Neoplasia 2B
Robert Yoshiyuki Osamura
Tokai University School of Medicine
| Diagnosis: ||de novo mulitiple endocrine neoplasia 2B |
Bilateral adrenal pheochromocytoms
Medullary thyroid carcinoma(MTC)
A 31 year-old male was admitted to the hospital because of noncardiogenic pulmonary edema. He lacked
marfanoid habitus but thickened lips and tongue neuroma were present. Chroniic constipation had been
present since childhood, and the patent had a two-year history of untreated hypertension. Non-caciogenic
pulmonary edema and toxic megacolon were noted, and the abdominal CT scan revealed bilateral adrenal
tumors. Ultrasonograph of the thyroid showed two mass lesions. Intubation and mechanical ventilation
were performed because of severe hypoxemia. Endocrinological examinations showed high levels of serum
and urinary fractionaed catecholamines, serum calcitonin, serum carcinoembryouic antigen(CEA), and serum
intact parathyroid hormone. High catecholamine level was thought to be the cause of pulmonary edema.
RET gene analysis showed a codon 918 mutation in exon 16 resulting in an ATG(methionine) to
ACG(threonine) substitution, but analysis of the patient's parent's showed the wild type. Therefore, the
patient was diagnosed as having de novo MEN2B. He underwent laparoscopic bilateral adrenalectomy.
However, the values of serum calcitonin and CEA did not return to normal ranges. Micrometastases were
Bilateral adrenal pheochromocytomas
Medullary carcinoma of thyroid(MCT)
Molecular Endocrine Pathology
Genetic and molecular analysis(germline mutation)
RET gene analysis on genomic DNA from the blood cells
Germline mutation:heterozygous point mutation, ATG to ACG
Resulting in substitution of methionine by threonine at codon 918 in exon 16
RET gene analysis on somatic DNA from the paraffin sections(somatic mutation)
From bilateral pheochromocytomas and MCT
Showed the same point mutation at codon 918
Multiple endocrine neoplasia type 2
MEN2 is an autosomal dominant inherited cancer syndrome. Predisposition to MEN2 is caused by germline
mutations of the RET proto-oncogene on chromosome 10q11.2. There are three clinically distinct forms of
MEN2 syndrome-MEN2A,familial medullary thyroid carcinoma(FMTC), and MEN2B. In all of these subtypes,
medullary thyroid carcinoma(MTC)is a key. MEN2A is the most common subtype of MEN2. Clinical features
of the MEN2A syndrome include MTC,and/or C-cell hyperplasia(CCH) in almost all affected individuals,
pheochromocytoma(approximately 50%) and hyperparathyroidism(HPT(15-30%). MEN2B is the most aggressive of
the MEN2 variants and accounts for approximately 5% of all cases of MEN2. MEN2B is similar to MEN2A but
is characterized by the earlier onset of the disease and by developmental abonormalities. In FMTC, the
third form of MEN2, MTC is the only clinical feature. Introduced in recent years and still developing
genetic testingof individuals at highest hereditary risk of MEN2 syndrome holds the possibility of early
detection and improved treatment and prognosis.
Brauckhoff et al.(2004) reported 21 cases of of ME2B syndrome due to codon 918T mutation of the RET
protooncongene. More than 50% of patients with typical MEN2B have a de novo M918T germline mutation.
Mean age at MEN2B diagnosis was 14.2years (range 1-31 years).. All patients had MTC. Severe intestinal
manifestation occurred more aften in the group of early onset. They suggested an additional pathological
process in the younger subgroup reinforcing the very high transforming in vitro activity of the M918T RET
Elder et al. reported the higher frequency of various syndrome in pheochromocytomas and suggested
revision of the "10% rule tumors". Firstly, a larger proportion of these tumors are today discovered in
normotensive patients during imaging carried out for other reasons than suspicion of pheochromocytoma.
Secondly, although the differential diagnosis between malignant and benign tumors remains a challenge,
the risk of malignancy well exceeds the classical 10% in patients with extra-adrenal disease, and/or
carriers of germ-line SDHB mutations. Finally, up to a third of patients carry a germ-line mutation in a
gene predisposing to pheochromocytoma and/or paraganglioma. Identification of a constitutional mutation
in RET, VHL, SDHD, or SDHB has implications for clinical screening and follow-up for both the patient and
for relatives at risk who can be identified by screening for the same mutation. Genetic testing in
apparently sporadic cases is therefore regarded as beneficial, especially in patients diagnosed before 50
years of age, and in patients with bilateral, multifocal, malignant and/or extra-adrenal disease.
Massoll and Mazzaferri emphasized that all patients who have MTC should be tested for RET mutations,
including putative sporadic cases. He concluded MTC cases should be tested for MEN type1, Germline
Schlling et al. examined the mutation of codon 918 in the blood samples(germline mutation) and in the
tumor tissue embedded in FFPE blocks(somatic mutation). They showed that in the sporadic medullary
thyroid carcinoma 918 mutation patients followed more aggressive development of distant metastases during
follow-up with decreased metastses-free survival. In their series, 918mt patients had a significantly
lower survival rate than 918we pteitns. These data show that the RET colon 918 mutation has a pgognostic
impact on patients with sporadic MTC whch may influence follow-up treatment.
- Peczkowska M and Januszewicz A.;Mutiple endocrine neoplasia type 2. Familial Cancer 4:25-36, 2005.
- Brauckhoff M.et al. Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation:clinical manifestation and course in early and late onset disease. World J Surg 28:1305-11, Epub 2004.
- Elder EE,Elder G,Larsson C.:Pheochromocytoma and functioning paraganglioma syndrome:no longer the 10% tumor. J Sug Oncol 89:193-201,2005.
- Massoll N.Mazzaferri EL.:Diagnosis and management of medullary thyroid carcinoma. Clin Lab Med 24:49-83,2004.
- Schilling T. et al. Prognostic value of codon 918(ATG-ACG) RET proto-oncogene mutatations in sporadic medullary thyroid carcinoma. Int J Caner 95:62-66, 2001.
- Jindrichova S et al. Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. J Endocrinol 183:257-265.