Medullary Thyroid Carcinoma MTC

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Medullary ThyroidCarcinoma (MTC)

• Dr. Ali Al-Zahrani
• Consultant Endocrinologist
• King Faisal Specialist Hospital and Research
  Centre

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• Introduction
• Classification
• Clinical Presentation
• Diagnosis
• Screening
• Management
• Surgery
• Follow up
• Management of persistent hypercalcitoninemia

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Medullary ThyroidCarcinoma (MTC)

• A malignant tumor of C-cells (parafollicular) of
  the thyroid gland.

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Thyroid CancerClassification

• Papillary 80
• Follicular 10
• Anaplastic 3
• Medullary 5
• Lymphoma 1
• Others 1

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Medullary Thyroid Carcinoma Classification

• Phenotypes Frequency Clinical
  Presentation
• Sporadic MTC 80 MTC
• FMTC 8 MTC
• Men 2A 9 MTC,
• pheochromocytoma 1 hyperparathyroidism
  
• MEN 2B 3 MTC,
• pheochromocytoma
• ganglioneuromatosis, marfanoid habitus

Modified from Heshmati et al. Am J Med 1997
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Clinical FeaturesSporadic MTC

• Usually unifocal
• Age of diagnosis 5th-6th decade
• Thyroid nodule
• Lymphadenopathy
• Local compression
• Paraneoplastic symptoms
• Metastases (CLN, mediastinum, lungs, liver, bone)

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Clinical FeaturesMEN 2 Syndromes

• MTC is bilateral and multifocal
• Young age of presentation
• MTC is usually the presenting feature of MEN2
  (Almost 100 penetrance)
• Pheochromocytoma occurs in up to 50 of patients
• Pheochromocytoma is usually bilateral and has
  mild or no symptoms (early diagnosis)

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Clinical FeaturesMEN 2 Syndromes (Cont.)

• Parathyroid disease occurs in only 5-20 of MEN
  2A syndromes but rarely if ever in MEN 2B
• Polyglandular parathyroid hyperplasia
• Usually asymptomatic

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Diagnosis

• S. Calcitonin (basal)
• Stimulated calcitonin level
• Pentagastrin stimulation test
• Calcium stimulation test
• FNA
• RET proto-oncogene

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Screening of MEN Family Members

• Biochemical Methods Annually until age 35-40
  yrs
• MTC
• Pentagastrin stimulation test
• Calcium stimulation test
• Pheochromocytoma
• 24-hr urine catecholamines
• epinephrine/norepinephrine ratio
• Hyperparathyroidism
• S. Ca
• PTH

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Effectiveness of Biochemical Screening of MEN
Family Members

• 117 family members with MEN 2A prospectively
  screened by pentagastrin and/or calcium
  provocative testing, Ca PTH 24-hr urine
  catecholamines
• MTC
• 12 patients underwent total thyroidectomy at
  initial screening because of abnormal provocative
  test
• Follow-up 14.5 yrs
• 3/12 patients died due to other causes (2 had
  mets)
• 3/12 patients have metastatic disease (high
  calcitonin)
• 6/12 cured

(Gagel et al, NEJM 1988)
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Effectiveness of Biochemical Screening of MEN
Family Members (Cont.)

• 22 patients underwent total thyroidectomy when
  they had abnormal provocative test
• 13 had C-cell hyperplasia, 9 microscopic MTC.
  All had normal calcitonin even after provocative
  testing (cured).Mean follow-up 11 years
• Hyperparathyroidism
• at initial screening 10/12 patients had
  parathyroid hyperplasia
• 6/12 had elevated PTH level
• on prospective screening none of 22 patients
  had evidence of hyperparathyroidism

Gagel et al, NEJM 1988
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Effectiveness of Biochemical Screening of MEN
Family Members (Cont.)

• Pheochromocytoma
• 19 patients had unilateral or bilateral
  adrenalectomy when found by screening to have
  elevated epinephrine or epinephrine/
  nonepinephrine ratio.
• 4/8 pts who underwent unilateral adrenalectomy
  needed second adrenalectomy.

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Value of Biochemical Screening

• Disease-specific mortality rate
• In patients diagnosed to have MTC
• After clinical presentation was 24
• On biochemical screening 1.5

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RET Proto-oncogene
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Cysteine-rich domain
Cell membrane
Transmembrane domain
Tyrosine kinase 1
Tyrosine kinase 2
3
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RET Proto-oncogeneHistorical Perspective

• RET gene was discovered as a novel transforming
  gene in 1985 (Takahashi et al. Cell, 1985)
• MEN Type 2 Syndromes are known to be autosomal
  dominant disorders.
• MEN gene was linked to a 480-kilobase region on
  Chromosome 10q 11.2 (Gardner et al, Hum Molec
  Genetics 1993 Mulligan et al, Hum Molec Genetics
  1993)
• This DNA segment contains RET proto-oncogene

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• This suggested that RET proto-oncogene might be
  involved in MEN 2 pathogenesis
• Mutations in RET gene were found in 20/23
  families but not in 23 normal control (Mulligan
  et al, Nature 1993)
• Functional studies confirmed that RET mutations
  in MEN 2 Syndromes lead to increased transforming
  activity of RET (Santoro et al, Science 1995)

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5
Exon Codon Syndrome
10 609,611 MEN-2A 618,620
FMTC 11 634 MEN-2A, FMTC 630
FMTC 13 768 FMTC 790 MEN 2A,
FMTC 791 FMTC 14 804
FMTC 804,806 MEN-2B 15 883
MEN-2B 891 FMTC 16 918
MEN-2B
Cysteine-rich domain
Transmembrane domain
Tyrosine kinase 1
Tyrosine kinase 2
3
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Hereditary Medullary Carcinoma of the Thyroid
Cases With Known RET Mutations
Codons
Exon
Syndrome

• 609, 611, 618, 620
• 630, 634
• 768, 790
• 883
• 918, 922
• 609, 611, 618, 620
• 630, 634
• 768, 790, 791
• 804
• 891

10 11 13 15 16 10 11 13 14 15
97 95 86
MEN 2a MEN 2b FMTC
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Interpretation of Genetic Testing

• In an individual from any MEN 2 or FMTC family
  with known mutation
• Negative testing ? no predisposition to MEN and
  no need for further testing
• Positive testing ? high likelihood of MTC (100)
  and need for prophylactic thyroidectomy
• Hereditary disease but no mutation (5)
• Linkage analysis if possible
• If negative ? annual biochemical testing

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Ret Mutations in an Apparently Sporadic MTC

• About 6 (1.5-24) of apparently sporadic MTC
  have germline Ret mutations.
• These patients have undiagnosed hereditary MTC.
• 20-70 of sporadic MTC have somatic mutations
  (codons 918, 768)
• Recommendations all cases of MTC should be
  tested for the presence of Ret mutations!

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Comparison of Pentagastrin and Ret Oncogene
Testing
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Comparison of DNA Testingwith Calcitonin
Measurements for Screening for MEN2

• 58 MEN Type 2 kindred members were tested for RET
  mutations
• 21 patients were positive for RET mutations
• Plasma calcitonin (after pentagastrin) was high
  in 9/21 patients and normal in 12
• 13 patients underwent total thyroidectomy (6 with
  normal and 7 with elevated plasma calcitonin
  levels)
• All the 13 patients had C-cell hyperplasia with
  or without MTC.

Wells et al. Annals of Surgery 1994
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Management of MTC MEN 2

• General Principles
• MTC is the main cause of death in patients with
  MEN 2, early diagnosis and treatment are
  mandatory.
• The prognosis depends on the extent of the
  disease so the aim should be to diagnose patients
  as early as possible.
• Based on the results of genetic testing, subjects
  who have inherited the predisposing RET mutation
  should undergo prophylactic total thyroidectomy
  at an early age (6 yrs for MEN 2A and earlier for
  MEN 2B).
• Pheochromocytoma should be excluded before any
  surgery.

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Management of MTC MEN2

• Total thyroidectomy central compartment
  clearance.
• Bilat. L.N. Sampling if Positive L.N. in the
  central compartment.
• Modified BND for patients with positive L.N. in
  the lateral compartments
• Prophylactic parathyroidectomy ? controversial.
• Adrenalectomy if pheochromocytoma is diagnosed.
• Unilateral or bilateral ?

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Management of Persistent/Recurrent MTC

• High basal or stimulated calcitonin level is
  considered as evidence of persistent/recurrent
  disease.
• Localizing techniques include U/S of the neck, CT
  scan, MRI, radionucleotide scans (I131 MIBG,
  octreotide scan, I131 anti-CEA and venous
  sampling).

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Management of Persistent/Recurrent MTC

• In patients with well localized and isolated
  disease, surgery is the primary treatment.
• Occult metastatic disease (high CT and no
  clinically or radiologically evident disease).
• Extensive L.N. microdissection (Tissell et al,
  Surgery 1996)
• 40 patients with persistent disease
• L.N. microdissection
• 63 had undetectable CT after re operation
• 30 had undetectable CT after mean follow up of
  64 months

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Management of Persistent/Recurrent MTC (cont.)

• Conservative (Van Heerden et al, Annals of
  Surgery 1990)
• 31 patients with persistent hypercalcitonemia
  after primary surgery
• 11 patients underwent re-exploration but continue
  to have elevated calcitonin levels
• Only 2 patients died of their disease
• 5 and 10-year survival 90 86, respectively.

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Management of MTCOther Modalities

• External radiation effectiveness is
  questionable
• I131 - MIBG
• 111In - pentetreotide
• Chemotherapy
• Octreotide
• Recombinant interferon alpha-2a

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MTCPrognosis

• The prognosis is worst in MEN 2B followed by
  sporadic MTC, MEN 2A FMTC.

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Prognostic Factors in MTC Syndromes
Good Poor Factors
Prognosis Prognosis

• RET mutations Codons 609, 611, 618,
  Codon 620, 634, 768, 804 918
• Sex Female Male
• Plasma CT Low High
• Plasma CT/CGRP High Low
• Plasma CEA Low High
• Age at surgery Young Old
• Surgical resection Complete
  Incomplete
• Tumor size Small Large
• DNA ploidy Diploid
  Nondiploid
• CT immunoreactivity High Low
• Amyloid staining Positive Negative
• Extrathyroidal invasion Absent Present
• Nodal metastasis Absent Present
• Distant metastasis Absent Present

Heshmati et al, Am J Med 1997
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100 75 50 25 0
FSC
FSY
Relative Survival
SPOR
y
0 5 10 15 20
Relative survival (RS) in patients with sporadic
medullary carcinoma of the thyroid (MCT) (Spor),
familial MCT diagnosed by symptoms (Fsy), and
familial MCT detected by screening (Fsc).
Bergholm et al, Cancer 1997