e206Ann R Coll Surg Engl 2012; 94: e206–e207
ONLINE CASE REPORT
Ann R Coll Surg Engl 2012; 94: e206–e207
Multiple endocrine neoplasia – Medullary thyroid cancer – Cushing’s syndrome
Accepted 7 February 2012; published online 4 September 2012
Greg Sadler, Consultant Endocrine Surgeon, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
T: +44 (0)1865 220 924; F: +44 (0)1865 220 925; E: firstname.lastname@example.org
MEN 2 syndrome masquerading as MEN 1
Tarek Ezzat1,2, Rajeev Paramesawaran1, Ben Phillips3, Greg Sadler1
1 Department of Endocrine Surgery, John Radcliffe Hospital, Oxford, UK
2 Department of Surgery, Alexandria University, Egypt
3 Department of Pathology, John Radcliffe Hospital, Oxford, UK
Patients with multiple endocrine neoplasia (MEN) type 2A develop medullary thyroid cancer, which is associated with poor
prognosis in its metastatic stage. Hyperparathyroidism is a common finding in both MEN 1 and 2. We report a 68-year-old
patient diagnosed clinically with MEN 1 based on the presence of hyperparathyroidism and pituitary Cushing’s disease with no
supporting genetic evidence. The hyperparathyroidism was later found to be part of MEN 2A with underlying metastatic medul-
lary thyroid cancer. We highlight the importance of genetic confirmation before a diagnosis of MEN 1 is made as other more
serious pathologies might be overlooked.
Multiple endocrine neoplasia (MEN) syndromes are rare
endocrine tumour syndromes. MEN 1 syndrome involves
primarily tumours of the parathyroid, pancreas and ante-
rior pituitary gland. Primary hyperparathyroidism, the ear-
liest and most frequent feature of MEN 1 syndrome, is also
present in 20–30% of patients with MEN 2A, in addition to
medullary thyroid cancer (MTC) and phaeochromocyto-
mas.1,2 Patients in the general population frequently have
abnormalities involving parathyroid hyperplasia and pitui-
tary adenoma. However, endocrinologists should be careful
diagnosing an MEN 1 phenotype based on these findings.
A 68-year-old man was referred with a diagnosis of MEN 1
phenotype (negative mutation) to treat associated hyperpar-
athyroidism. Both magnetic resonance imaging (MRI) and
sestamibi scintigraphy were concordant in localising a left
inferior parathyroid adenoma and the patient was listed for
The patient’s past medical history included diabetes and
Cushing’s syndrome diagnosed in 1990. An adrenal origin
to the Cushing’s syndrome was excluded due to elevated
adrenocorticotropic hormone responding to a corticotro-
pin releasing hormone test. Computed tomography (CT)
showed the presence of bilateral adrenal nodules and MRI
of the pituitary gland showed no evidence of a pituitary ad-
enoma but this was confirmed with inferior petrosal sinus
sampling. The patient had transphenoidal surgery to treat
his Cushing’s disease both in 1992 and 2006 but this was
unsuccessful. The pathology report showed an atypical ap-
pearance of a pituitary adenoma (Fig 1). Radiotherapy was
considered but this was withheld until after the parathyroid
surgery. He had chronic severe diarrhoea, investigated with
CT of the colon and colonoscopy, which proved to be nor-
The nodules of the adrenal glands remained stable on
serial MRI and CT with negative plasma metanephrines and
urinary catecholamines. Iobenguane and octreotide scans
were performed to investigate the adrenal glands. The oc-
treotide scan showed avid uptake in both adrenal glands
while the iobenguane scan showed uptake in the adrenal
glands with intense uptake in a left-sided thyroid nodule.
Clinical examination revealed a palpable lymph node in the
supraclavicular fossa. Needle cytology of the thyroid showed
evidence of neuroendocrine proliferation, suggesting the
possibility of MTC. Blood tests showed calcitonin levels of
27,000ng/l and carcinoembryonic antigen levels of 415μg/l.
Repeated 24-hour urinary tests showed elevated catecho-
lamines and metanephrines. Positron emission tomography
showed uptake in the left thyroid lobe and cervical lymph
nodes with left vocal cord palsy, in addition to uptake in both
adrenal glands, the liver and spine (Fig 2).
RET genetic analysis showed positive mutation of co-
don 634. The patient was started on phenoxybenzamine
and propranolol, and listed for a bilateral adrenalectomy.
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e207Ann R Coll Surg Engl 2012; 94: e206–e207
MEN 2 SYNDROME MASquERADING AS MEN 1
EzzAT PARAMESAWARAN PHilliPS SADlER
However, he developed airway difficulty and a decision to
perform an urgent thyroidectomy was made. A total thyroid-
ectomy with a left neck dissection was performed. Histology
of the thyroid showed MTC (Fig 3). As the patient was not
symptomatic with his phaeochromocytomas, the decision
was taken not to operate on the adrenal glands.
We report a rare case scenario of an MEN 2A syndrome
overlooked by a diagnosis of MEN 1 based on phenotype
with no supporting genetic abnormality. A phenotype diag-
nosis of MEN 1 based on parathyroid hyperplasia and pi-
tuitary adenoma alone might have serious consequences on
diagnosis and management. The failure to follow the natu-
ral history of the disease might produce confusing results.
This is in addition to the burden on the family members,
who would require genetic testing.3
Our patient had incurable MTC by the time a proper
diagnosis was made, with distant metastasis and locally
advanced disease compromising the airway. Unexplained
chronic persistent diarrhoea in the presence of hyper-
parathyroidism with suggestive evidence of MEN should
prompt a calcitonin measurement and exclusion of MTC.
More confusion was added by the asymptomatic phaeochro-
mocytoma, which is not infrequent in 30–50% of patients
with MEN 2A.4 In our patient, the decision to proceed with
thyroid surgery despite untreated phaeochromocytomas
was due to the rapid progression of the MTC with metastat-
ic lymph node disease in the central compartment compro-
mising the airway.
The importance of this diagnosis lies not only in manag-
ing the patient himself but in screening and treating other
family members. When the patient’s son was genetically
screened, he was found to carry the same genetic mutation.
A prophylactic thyroidectomy was then performed show-
ing evidence of MTC on histological examination; howev-
er, with no metastatic disease and hence associated with a
more favourable prognosis.
This case report highlights the importance of genetic testing
in diagnosis of MEN syndromes as solely clinical diagnosis
might lead to devastating consequences. Thyroid surgery
for MTC in the presence of phaeochromocytoma might be
attempted under certain circumstances to maintain a patent
airway. Nevertheless, this needs to be performed under close
monitoring with both alpha and beta receptor blockade.
1. Hai N, Aoki N, Shimatsu A et al. Clinical features of multiple endocrine
neoplasia type 1 (MEN1) phenocopy without germline MEN1 gene mutations:
analysis of 20 Japanese sporadic cases with MEN1. Clin Endocrinol (Oxf)
2000; 52: 509–518.
2. Schuffenecker i, Virally-Monod M, Brohet R et al. Risk and penetrance of
primary hyperparathyroidism in multiple endocrine neoplasia type 2A families
with mutations at codon 634 of the RET proto-oncogene. J Clin Endocrinol
Metab 1998; 83: 487–491.
3. Veldhuis JD, Norton JA, Wells SA et al. Surgical versus medical management
of multiple endocrine neoplasia (MEN) type i. J Clin Endocrinol Metab 1997;
4. Rodriguez JM, Balsalobre M, Ponce Jl et al. Pheochromocytoma in MEN 2A
syndrome. Study of 54 patients. World J Surg 2008; 32: 2,520–2,526.
Figure 1 Histological sections of the pituitary gland.
Unequivocal classical Cushing’s adenoma is not present.
The edge of one fragment is suspicious of the presence of
phenotypically distinct corticotropes (A). This population
of cells is positive for adrenocorticotropic hormone (B) and
negative for CAM 5.2 (C).
Figure 2 Computed tomography showed bilateral nodules
(A) with the left adrenal gland showing avid uptake on the
iobenguane scan in addition to liver deposits (B). Positron
emission tomography showed uptake in the left lobe of the
thyroid gland and cervical lymph nodes (C), segment V/Vi of the
liver (D) and a small deposit in the body of l3 (E).
Figure 3 Histological sections of medullary thyroid cancer.
Sections from the thyroid gland show a tumour composed of
nests of cells with neuroendocrine nuclear features associated
with foci of amyloid deposition (A), chromogranin (B) and
calcitonin (C) positivity.
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