Tumour genetics and the

endocrine surgeon
Mr Fausto Palazzo MS FRCS
Department of Endocrine Surgery
Hammersmith Hospital
Samantha
 Des

Samantha
Brian’s story

•51 year old male

• left flank pain
• heart rate 70, BP 130/80
• large, tender abdominal mass
• urinary catecholamines &
metanephrines raised
 Brian’s story
• Necrotic phaeochromocytoma
•Adrenalectomy
Raised calcitonin:
• Thyroidectomy
• 6mm MTC & C-cell hyerplasia
• 3/9 +ve central lymph nodes
•Hyperparathyroidism
• 2 adenomas
Complex medical
history cancers seen
in the US.
Before 1959, thought
to be a variant of
anaplastic thyroid
carcinoma with
amyloid stroma.
Medullary thyroid
carcinoma comprises
approximately 5-9%
of thyroid
 Brian’s Genetic testing

• Mutation G to T (substitution) in exon

14 codon 804 identified on chromosome
10: MEN-2A

Exons 10, 11, 16 of the RET

protooncogene
Family tree
MEN 2
Germline mutations RET proto-oncogene
responsible for
 MEN 2A
 MEN 2B

 FMTC

RET encodes a trans-membrane growth

neurotrophic receptor with tyrosine kinase activity
MEN 2
MEN 2A Gain of function mutations within codons
specifying cysteine residues in the extracellular
FMTC
ligand binding domain of the RET gene product

MEN 2B Intracellular tyrosine kinase domain

Phenotype
MEN 2A
 medullary thyroid carcinoma
 hyperparathyroidism

 Phaeochromocytoma

MEN 2B
 medullary thyroid carcinoma (earlier onset & aggressive)
 phaeochromocytoma

 mucosal lesions
MEN 2B

MTC
Phaeochromocytoma
Marfanoid habitus
Tongue/lip neuromas
MEN 1
Autosomal dominant
MEN 1 gene: Chromosome 11 (long arm)
Encodes tumour suppressor gene: MENIN
Defect in MENIN
 pHPT (90%+)
 Pancreatic endocrine tumours (50%+)
 Pituitary tumours (30%+)
 (adrenocortical cancers, foregut carcinoids, follicular thyroid
cancers, multiple cutaneous lipomas, angiofibromas etc)
Treatment issues in MEN 2A
Thyroid
 timing of surgery
 extent of thyroid and lymph node surgery

Parathyroids
 extent of parathyroid surgery
Adrenals
 extent and nature of adrenal surgery
 Treatment of medullary thyroid Ca

“a surgeon’s disease”
• aggressive cancer
• C-cells do not concentrate iodine
• chemotherapy, radiation not
consistently effective
When? genotype-phenotype correlation
634, 618
 early onset, high risk
 surgery at diagnosis (before 5 years)

790, 620, 611

 later onset, medium risk
 surgery in childhood

768, 804
 late onset, low risk
 surgery in adolescence
How extensive should surgery be?

Total thyroidectomy
Lymph node dissection?
 Depends on whether
 pre-clinical disease
 no clinical node involvement

 clinically involved nodes

 In presence of clinically evident disease

Majority of nodes
initially involved in
MTC lie in the
paratracheal area
node classification (selective dissection)
 Dralle classification
1a & 1b
central compartment
2&3
lateral compartments
4a & 4b
anterior mediastinum
 Level VI dissection

Trachea

Oesophagus

Recurrent
nerve
 perithyroidal nodes

Laterally out
to surface of
the internal
jugular veins
+ delphic
nodes
2 & 4 compartment dissection
What to do in pre-clinical disease?
Disease detected on genetic screening
No detectable primary tumour:
 total thyroidectomy

 bilateral central neck dissection

Clinical node-negative disease

Detectable tumour of any size:

 total thyroidectomy
 bilateral central neck dissection

 ipsilateral lateral neck dissection?

measurement of calcitonin post-operatively

 contralateral lateral neck dissection if persistent
detectable calcitonin?
 lymph node metastases
tumour central ipsilateral contra-
size mets lateral lateral
incidence of lymph (cm) mets mets
node metastases by
0-0.9 3/4 3/4 3/4
compartment
compared to 1-1.9 8/9 8/9 3/9
tumour size 2-2.9 4/5 3/5 3/5
3-3.9 2/5 3/5 3/5
4+ 9/9 4/9 4/9
J Moley J Int Med 2003;253:616
total 81% 81% 44%
 biochemical
cure
Progression and cure 100%

0%
distant mets palpable lymph nodes biochemical &
diarrhea palpable thyroid mass molecular screening
 Management of Parathyroid disease

• 20-30% develop hyperparathyroidism

• Dealt with at time of thyroid surgery

• Leave one fully viable parathyroid in situ & remove rest?

Not a well defined therapeutic

strategy for treating this condition.
Tends to be a mild form of
disease, easily cured
 Parathyroid pathology

pathologic findings:
single adenoma 54%
multiple adenomas 1%
hyperplasia 39%
• 94% cure rate
• 12% recurrence (1/2 post total parathyroidectomy)
94 % recurrence rate, Raue. J Int Med 1995;238:369
independent of operation
performed.
 Management of adrenal disease
• phaeochromocytoma affects 50%
• 274 MEN-2A patients with
phaeochromocytoma
• mean age at presentation 39 yrs
• malignant 4%
• bilateral 67 %
Modigliani. J Int Med 1995;238:363
Collaborative European study
 Total vs unilateral adrenalectomy
• Bilateral adrenalectomy
• risk of Addisonian crisis (25%)
Lairmore. Ann Surg 1993;217(6):595
• Unilateral adrenalectomy
• risk of contralateral disease (35%)
Modigliani. J Int Med 1995;238:363
• Cortical sparing adrenalectomy
• risk of local recurrence
Based on the high incidence of bilateral phaeos, bilateral
adrenalectomy would appear to be the logical treatment choice.
However, complications, quality of life important considerations.
Surgical approaches

Midline

Rooftop
Lumbar
Right lap adrenalectomy
Phaeochromocytoma
Retroperitoneoscopic adrenalectomy
Hammersmith protocol
unilateral adrenalectomy with long term screening

?contralateral cortical-sparing adrenalectomy if

contralateral recurrence does develop in the future
Samantha
codon 804 gene positive
total thyroidectomy + central node dissection
at surgery 4 normal parathyroids
uncomplicated recovery
normal calcitonin, calcium, catecholamines
final pathology:
 Pathology
•nodular C-cell hyperplasia (= medullary carcinoma-in-situ)
•negative central nodes
Summary

Genetics increasingly allow the surgeon to

intervene before disease presents thus
allowing the true cure of patients with MTC
and other life threatening disease.
Thank You

Questions?

Mr Fausto Palazzo MS FRCS

Department Endocrine Surgery
Hammersmith Hospital