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Medullary Thyroid Carcinoma MTC

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King Faisal Specialist Hospital and Research Centre ... Prophylactic parathyroidectomy ? controversial. Adrenalectomy if pheochromocytoma is diagnosed. ... – PowerPoint PPT presentation

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Title: Medullary Thyroid Carcinoma MTC


1
Medullary Thyroid Carcinoma (MTC)
  • Dr. Ali Al-Zahrani
  • Consultant Endocrinologist
  • King Faisal Specialist Hospital and Research
    Centre

2
  • Introduction
  • Classification
  • Clinical Presentation
  • Diagnosis
  • Screening
  • Management
  • Surgery
  • Follow up
  • Management of persistent hypercalcitoninemia

3
Medullary Thyroid Carcinoma (MTC)
  • A malignant tumor of C-cells (parafollicular) of
    the thyroid gland.

4
Thyroid Cancer Classification
  • Papillary 80
  • Follicular 10
  • Anaplastic 3
  • Medullary 5
  • Lymphoma 1
  • Others 1

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

7
Clinical Features MEN 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)

8
Clinical Features MEN 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

9
Diagnosis
  • S. Calcitonin (basal)
  • Stimulated calcitonin level
  • Pentagastrin stimulation test
  • Calcium stimulation test
  • FNA
  • RET proto-oncogene

10
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

11
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)
12
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
13
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.

14
Value of Biochemical Screening
  • Disease-specific mortality rate
  • In patients diagnosed to have MTC
  • After clinical presentation was 24
  • On biochemical screening 1.5

15
RET Proto-oncogene
5
Cysteine-rich domain
Cell membrane
Transmembrane domain
Tyrosine kinase 1
Tyrosine kinase 2
3
16
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17
RET Proto-oncogene Historical 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

18
  • 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)

19
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
20
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21
(No Transcript)
22
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23
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
24
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25
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

26
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!

27
Comparison of Pentagastrin and Ret Oncogene
Testing
28
Comparison of DNA Testing with 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
29
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.

30
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 ?

31
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).

32
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

33
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.

34
Management of MTC Other Modalities
  • External radiation effectiveness is
    questionable
  • I131 - MIBG
  • 111In - pentetreotide
  • Chemotherapy
  • Octreotide
  • Recombinant interferon alpha-2a

35
MTC Prognosis
  • The prognosis is worst in MEN 2B followed by
    sporadic MTC, MEN 2A FMTC.

36
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
37
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
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