sporadic/hereditary medullary thyroid cancer 2006/thyroid/niederle.pdfsporadic / hereditary...

Sporadic/HereditaryMedullary Thyroid Cancer

B. Niederle

Chirurgische EndokrinologieUniversitätsklinik für Chirurgie

Thyroid Cancer

Follicular cell-derivedPapillary thyroid cancerFollicular thyroid cancerAnaplastic thyroid cancer

C-CellMedullary thyroid cancer

sporadichereditary

Medullary Thyroid Cancer

• Parafollicular cells, neural chrest


• Parafollicular cells, neural chrest• 3 – 10 % of all thyroid cancers

Thyroid Neoplasms

1991-2001n = 556

FTC81 (15%)

PTC330 (59%)

ITC7 (1%)

MTC110 (20%)

others14 (3%)

Department of Surgery, Medical University, Vienna

ATC14 (3%)

Thyroid Neoplasms

Germany [1996]n = 2537

PTC1685 (66%)

FTC691 (27%)

ATC91 (4%)

MTC70 (3%)

Hölzer S. et al.: Cancer 89 (2000); 192-201

Thyroid Neoplasms

USA [1996]n = 5583

PTC4522 (81%)

FTC788 (14%)

ATC96 (2%)

MTC177 (3%)

Hundahl, S.A. et al.: Cancer 89 (2000); 202-217


• Parafollicular cells, neural chrest• 3 – 10 % of all thyroid cancers• Incidence 1 – 2 / million inhabitants / year• f / m = 1.5 / 1• Age at diagnosis (4. – 7. decade)


Clinical Presentation

12124245--331993Kallinowski

302845751:1,441± 14331989Rosenberg

201944831;1,3-1861989Bergholm

291252941:1046±161251984Saad

DiarrheaM1LNNTH

SexAgenYearAuthorSymptoms in %

SporadicMedullary Thyroid Cancer

Disease Free Survivaln = 33

Department of Surgery, Medical University, Vienna - 1990


Survival

85%94%7091994Winter (Ger MEN)

73%81%881994Längle (SMENA)

61%81%4801991Kohlwagen

68%80%2491990Bergholm

47%67%601988Schröder

61%78%1611984Saad

54%72%751983Rougier

10 Years5 YearsnYearAuthor


Treatment

There are no conservative treatment regimes –Surgery is the treatment of choice!


Treatment

There are no conservative treatment regimes –Surgery is the treatment of choice!

Extent of surgery still under discussion


pT1-3 vs pT4n = 33



pT1-3: M0 vs Mposn = 29



pT1-3 M0: N0 vs Npos vs NXn = 27



pT1-3 M0: radical vs less radical surgeryn = 27



Prognostic Factors

Univariate/ (multivariate) Analysen (EBM III)

• Distant metastasis• Lymph node metastasis• Extent of surgery • Tumor size • Age


Survival

Stage I: MTC Ø

T1-4, N0-1, M1Stage 4

T1-4, N1, M0Stage 3

T2-4, N0, M0Stage 2

T1, N0, M0Stage 1

UICC 1997


Survival

Poor prognosis -> Late diagnosis


Tumour Marker

Calcitonin

32 aminoacid polypeptide


Calcitonin Assay (I)

CIS (France) – IRMA manual, 2- stepNichols (USA) – ICMA automated, 1-step

Medgenix (Belgium) – IRMA manual, 1-step

Bieglmayer C. et al: Wien klin Wschr 2002; 114, 267-273


Calcitonin StimulationTests

Pentagastrin:0.5 µg / kg / BW (diluted in 5-10 ml NaCl; i.v. Bolus; 5-10 sec) Blood samples: 0, 2, (3), 5, (10) min

Calcium:3 mg / kg / KG (10 min)


Calcitonin „Screening“

Early diagnosis may improve the clinical and biochemicaloutcome of MTC!


„Screening“

A „preoperative“ diagnosis of MTC allows adequate initial surgery!


Calcitonin Screening

… not recommended in work-up of thyroid diseases!

Calcitonin

Routine biochemical test

32%4%43%5%Calcitonin

ETAATAETAATA

Multinodular goiterSolitary nodule

Hegedüs et al Endocrine Rev 24 (2003); 102-132

SporadicHypercalcitoninemia

Indication for Stimulation Test

Basal Calcitonin level: > 10 pg/ml

Calcitonin Assay: Nichols or CIS


Indication for Surgery

Stimulated Calcitonin level: > 100 pg/ml

Calcitonin Assay: Nichols or CIS

Sporadic Hypercalcitoninemia


The interpretation of basal and stimulated Calcitonin levelsallows a prediction of C – cell morphology


Pathological Workup

The entire surgical specimens (thyroid, lymph nodes) must be blocked and C-cell disorders may be documented by

conventional histology and immunhistochemistry

Kaserer K. et al; Wien klin Wschr 2002: 114; 274 - 278


bCT >10 pg/ml and Pentagastrin-stimulation >100 pg/mln = 260

Male n = 167 (67%)Female n = 93 (36%)

f : m = 1 : 1.857 + 13.44 years


Morphology

260 (100%)Σ

134 (51.5%)MTC

126 (48.5%)CCH

1994 - 2004

C - Cell Hyperplasia

C - Cell Hyperplasia

Definition

(Aside from tumor tissue) - at least one area with morethan 50 C-cells per low power field (magnification x100)

in both thyroid lobes(only visible in immunohistochemistry!)

C - Cell Hyperplasia / Cancer

Pathogenesis

C - Cell HyperplasieMorphology

focal diffuse

nodular neoplastic


C – Zell Hyperplasie (CCH)

126 (100%)∑

59 (47%)neoplastisch(Ca in situ?)

39 (31%)nodulär28 (22%)diffus

nMorphologie

1994 - 2004

39

2859

diffusnodulärneoplastisch (Ca in situ?)


Morphology

260 (100%)Σ

134 (51.5%)MTC

126 (48.5%)CCH

1994 - 2004


Definition

Areas of C-cell proliferation suspected of earlyinfiltration are regarded as carcinoma if a focal loss or

reduplication of basement membrane is observedthrough immunohistochemistry (or in electrone

microscopy) using antibodies against collagen IV


bCT >10 pg/ml and Pentagastrin-stimulation >100 pg/mln = 260

Male n = 167 (67%)Female n = 93 (36%)

f : m = 1 : 1.857 + 13.44 years


bCT >10 pg/ml and Pentagastrin Stimulation >100 pg/mlMedullary Thyroid Cancer (MTC)

1994 - 20040.01n.s.n.s.n.s.0.010.01

p <

78 (84)56 (34)167 / 93Σ58 (100)28 (100)28 / 58801-1 (100)5 (100)5 / 1601 - 8005 (71)5 (63)8 / 7401 - 6007 (78)5 (14)36 / 9 201 - 4007 (39)13 (14)90 / 18100 - 200

female(%)

malen (%)

MTCn

m / w

StimulatedCalcitonin

pg/ml


CT >10 pg/ml and Pentagastrin Stimulation >100 pg/mlMTC – Lymph node involvement - Persistence

28 (21)39 (29)95 (71)134Σ25 (39)32 (37)54 (63)86801-

01 (17)5 (83)6601-8001 (10)1 (10)9 (90)10401-6001 (8)2 (17)10 (83) 12201-4001 (5)3 (15)17 (85)20100-200

Persistencen (%)

N1n (%)

N0n (%)

follow-upMTCn

StimulartedCalcitonin

pg/ml

1994 - 2004


• Parafollicular cells, neural chrest• 4 – 10 % of all thyroid cancers• Incidence 1 – 2 / million inhabitants / year• f / m = 1.5 / 1• Age at diagnosis (4. – 7. decade)• Sporadic and hereditary

Thyroid Neoplasms

USA [1996]n = 5583

HMTC27 (0,5%)

SMTC150 (2,5%)

ATC96 (2%)

FTC788 (14%)

PTC4522 (81%)


Medullary Thyroid Carcinoma

Sporadic vs Hereditaryn = 177

SMTC150 (85%)

HMTC27 (15%)


Sporadic / HereditaryMedullary Thyroid Cancer

Surgical Strategy

Diagnosis before/during

surgery

Total thyroidectomy

Hereditary: Completionthyreoidectomie

Diagnosis aftersurgery Sporadic: Completion

thyroidectomy,If PG-stimulation is positive

Incl. adequate lymph node surgery


Treatment

• Thyreoidectomy

• Central neck dissection (bilateral)• functional - or modified radical (systematic) laterale

neck dissection

• transcervical or transsternale mediastinal dissection(on demand)

• Thyroid hormone (substitution)


Tumor Diameter

12.9 + 4.45 (0.6 – 90)134

Tumor diameter[mean value + SD (mm)]MTC

1994 - 2004


Lymph node surgery

71 (2 -188)134

Examined lymph nodes[n - mean number]

MTC

1994 - 2004


pT1pT2-3pT4

pT - Classification n = 116

73 (63%)31 (27%)

12 (11%)

Calcitonin screening 1994 – 2004UICC 1997


pT1-4 n = 116

bilateral22 (19%)

unilateral1 (1%)

93 (80%)

pTb

multifocalpTa

unifocal

Calcitonin screening 1994-2004


Lymph-node Metastases

all pTn (%)

116(100)12 (10)31 (26)73 (63)All

30 (26)11 (92)11 (35)8 (11)1

86 (74)1 (8)20 (65)65 (89)0

4n (%)

2, 3n (%)

1n (%)

pTpN

Calcitonin screening 1994 - 2004

Hereditary Medullary Thyroid Cancer

pT1pT2-3pT4

pT – Classification UICC 1997n = 18

8 (44%)7 (39%)

3 (17%)

Calcitonin screening 1994 – 2004UICC 1997

HereditaryMedullary Thyroid Cancer

(Bilateral) C – cell hyerplasia – Precursor lesion of thehereditary medullary thyroid cancer

Wolfe, H.J. et al; N Eng J Med 289 (1973) 437-441


pT1-4 n = 18 (Index)

bilateral16 (89%)

unilateral1 (5.5 %)

1 (5.5 %)

pTb

multifocalpTa

unifocal

Calcitonin screening 1994-2004


Lymph-node MetastasesIndex Patients

all pTn (%)

18 (100)3 (17)7 (39)8 (44)All

9 (50)3 (100)4 (57)2 (25)1

9 (50)0 3 (43)6 (75)0

4n (%)

2, 3n (%)

1n (%)

pTpN

Calcitonin screening 1994 - 2004


Molecular Genetics

22 (8 %)

18 (13%)

4 (3%)

hereditaryn

238∑ (260)

116MTC (134)

122CCH (126)

sporadic nMorphology (n)

1994 - 2004


MTC

sporadic hereditary

MTC „only“(FMTC)

Multiple Endocrine Neoplasia(MEN)

MEN 2A MEN 2B

Multiple Endocrine Neoplasia (MEN)

Definition

Hyper- and/or neoplastic proliferation of more than oneendocrine organ


+

+

+

MEN 2A

+Markedly enlarged periperalnerves

+Musculoskeletal abnormalities(Marfanoid habitus)

+Mucosal ganglioneuromas

Parathyroid hyperplasia

+Pheochromocytoma

++MTC

MEN 2BFMTC

Multiple Endocrine Neoplasia 2A

Frequency - Literature

1010--4040PHPTPHPT

40-60Phäochromozytom

100MTC

%


Chromosome 10 (10q 11.2) - RET Proto - Oncogen


RET Proto – Oncogen (Chromosome 10)

7 exons (8,10,11,13,14,15,16)

22 codons(533, 600, 609, 611, 618, 620, 630, 634, 635, 637, 768, 781, 790, 791, 804, 806, 826, 883,

891, 907, 912, 918)


Exon 81 (5%) Exon 10

3 (14%)Exon 116 (27%)

Exon 136 (27%)

Exon 144 (18%)

Exon 152 (9%)

RET Proto- Oncogen - MutationsIndex patients: n = 22

1994 - 2004


Molecular Genetics

22 (8 %)

18 (13%)

4 (3%)

hereditaryn

238∑ (260)

116MTC (134)

122CCH (126)

sporadic nMorphology (n)

1994 - 2004


C – Cell Hyperplasie (CCH)

122 (+4)*∑

56 (+3)*neoplastic(Ca in situ?)

38 (+1)*nodulär

28diffuse

nMorphology

* hereditary

1994 - 2004


Index Patients - Phenotype

3531822∑1--11MEN 2A – 3-3366MEN 2A – 222022MEN 2A - 1---99 (+4)FMTC „only“

biuniPHPT

PheoMTCn

1994 - 2004


Index Patients – Genetic Screening

10

CCH

22

Index patients

15

MTC

3038

SurgeryGene- carrier

1994 - 2004


Index Patients – Genetic Screening - MTC

10

CCH

18

Index patients

16

MTC

2631


1994 - 2004


Index Patients – Genetic Screening - CCH

n.d.

CCH

4*

Index patients

n.d.

MTC

03


* Exon 13, Codon 791; TAT>TAC; tyr>phen

1994 - 2004


Genetic Screening

Preclinical diagnosis of hereditary MTC improves survival!!


Genetic Screening

Genetic screening is the „golden standard“ for confirmationof hereditary medullary thyroid cancer (and MEN II) and

can suggest therapeutic approach and outcome.


Prophylactic Thyreoidectomy:Thyreoidectomy before tumour development

Early thyreoidectomy:Thyreoidectomy in a preclinical stage


--Transsternale mediasinal dissetion

(+)-Lateral neck dissection (functional bilateral)

++Centrale neck dissection (bilateral)

++Thyreoidectomy

earlyproph.Surgical strategy

Hereditary Medullary Thyroid Cancer

Patients (prophylactic/early surgery)

5 – 60 (15)

6, 6, 21, 22, 22, 25, 33, 36, 37, 45,

60,

7

5, 24, 52

Age (p)

4 – 71 (23)38∑

8, 15, 27, 35, 38, 42, 50, 52, 54, 5621MEN 2A – 2

4, 5, 104MEN 2A – 1

19, 20, 24, 25, 28, 30, 43, 56, 69, 7113FMTC „only“

Age (e)nDiagnosis

Department of Surgery, Medical University of Vienna; (12/2005)


Complications

0/230/230/230/2323Early

0/381/380/380/3838∑

0/151/150/150/1515Prophylactic

permanenttransientpermanenttransient

HypoparathyreoidismParese (N.L.R)nThyreoidectomy

Depatment of Surgery, Medical University of Vienna; (12/2005)


Central neck dissection bilateral

Functional neck dissection bilateral

0possible(1/12)

always(12/12)

bCT [e], sCT [e]

Central neck dissection - bilateral0

? (0/12)

probable(9/12)

bCT [n], sCT [e]

000rare (2/14)[12 CCH]

bCT [n],sCT [n]

Thyreoidectomyand

MLymph nodemetastasis

MTCCalcitonin (preop)

Department of Surgery, Medical University Vienna, (12/2005)

Hereditary Medullary Thyroid CancerCodon / Calcitonin Specific Surgical Strategy

Basal and/or stimulated Calcitonin

increased normal

5-10 y5 y1-2 y6-12 mo

[2b]high

620,618,611,609

[1]low768,

790, 791,804, 891

[2a]very high

634,630

[3]highest

918,922, 883

SynchronouslyTumour>10mm or node pos

Risk category:(Codon)

Any

Thyroidectomyat age:

Immediately

Lymph nodedissection:• central comp.• lateral comp.

Dralle H, Machens A: Surgery 139 (2006); 279-282


Follow-up

29 (22%)4

25

7 (39%)16

22 (19%)3

19

PersistingDisease (M?)

N0N1

105 (78%)9015

11 (61%)83

94 (81%)8212

CuredN0N1

ΣHereditary

MTCSporadic

MTCBiochemistry

Calcitonin screening: 1994 - 2004


Is it possible to improve the prognosis?

YES!EARLY DIAGNOSIS


Conclusion

Total thyreoidectomy and lymph node dissection(bilateral central neck dissection, bilateral later neck

dissection [transsternale mediastinal dissection])lead to the the best long-term results in clinically apparent

sporadic/hereditary MTC –nevertheless the chance to “cure“ is low!


Conclusion

Screening for MTC and early treatmenthas a nearly 100% cure rate (pT1 73/116 [63%]) .


Conclusion

• Basal Calcitonin measurements „must“ be performed in all patients idependent the „thyroid morphology“

• bCT >10pg/ml Pentagastrin stimulation• sCT > 100 pg/ml Surgery• Genetic Screening!

Multiple Endocrine Neoplasia (MEN)MEN IIA

Conclusion

Genetic screening (blood) has to be done in all patientswith medullary thyroid cancer or pheochromocytoma to

exclude MEN II.


Genetic Screening

Preclinical diagnosis of hereditary MTC improves survival


Conclusion

Hereditary medullary thyroid disease (HMTC) is a “model“ disease

prophylactic thyreoidectomyavoids malignancy!


Conclusion

Hereditary medullary thyroid disease (HMTC) is a “model“ disease

early (preclinical) thyreoidectomy“cures“ (up to 98%)!


Genetic Screening

Genetic screening for HMTC can suggest time for surgery and the extent of surgery!

New members!

WELCOME!

CONTACT

Sectretary-Treasurer

[email protected]

FAX ++43-1-40400 6827

ESESWorkshop Vienna

MAY 17-19, 2007

Topic

Endoscopic Surgery in Neuroendocrine Pancreatic

Tumors

http://www.meduniwien.ac.at/chir-endokrin

Chirurgische Endokrinologie

sporadic/hereditary medullary thyroid cancer 2006/thyroid/niederle.pdfsporadic / hereditary...

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