molecular progression of thyroid lesionsapoptotic-pathway - adhesive and migration affect line the...
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Molecular progressionof thyroidlesions
Molecular progressionof thyroidlesions
Dr. Peter Lakatos1st Department of Medicine
Semmelweis University, Budapest
Dr. Peter Lakatos1st Department of Medicine
Semmelweis University, Budapest
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Thyroid nodules
• Population: 4-7% with thyroid nodules
• More frequent in women
• Incidence increasing with age
• Malignancy: 5-10% of cold nodules
Basic question: Which nodule will become malignant?
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Thyroid cancer
• Thyroid cancer: 1.5% of all malignancies
• Incidence increasing during the last 25 years:
4.8→ 8.0 /100,000
11.7 women, 4.2 men /100,000
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History
1. Characteritics of the nodule
2. Other symptomsA.) hyperthyroidism/hypothyroidism
B) compression
3. Familiy history� MEN
4. Neck irradiation
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Physical examination
• Size
• Nodule consistency, multiple, solitary
• Fixed or mobile
• Cervical lymph nodes
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• Quickly enlarging nodule• Stiff, fixed nodule• Swelling cervical lypmh node• Hoarse voice, swallowing difficulty• Previous neck irradiation• Age: <20 yrs or >70 yrs• Male sex• Familiy history of medullary cancer• Familiy history of MEN-2
Signs indicating increasedrisk for malignancy inpatients with thyroid nodules
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• Identifying further nodules
• Determining the size of the nodules
• Looking for malignancy signs
• Guidance of FNAB
US indication in case of thyroidnodule
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• hypodensity• microcalcification• hypervascularization• solitary nodule• irregular borderline• lack of halo
The more signs are noted, the higher the risk.
Risk of thyroid cancer in a solitary nodule withmicrocalcification is 70%.
US and thyroid cancer
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Thyroid Imaging Reporting and Data System (TIRADS)
Horvath E et al, JCEM 2009. 94:1748-1751.
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FNAB• FNAB is the most reliable test• Results in classes:
- non-diagnostic- benign- follicular lesion- suspicious for malignancy- malignant
• Limitations of FNAB:– No differentiation between benign follicular or Hürthle-
cell adenoma and malignant forms (capsular and/orvascular invasion)
– No result in 15%• False negative: < 5%
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Classificationof thyroid cancers
Follicular cells• Differentiated
– Papillary 80%– Follicular 10%– Hürthle-cell 3-5%
• Non-differentiated– Anaplastic 1-2%
Parafollicular cells– Medullary 5%
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Papillary cancer
• Responsible for 90% of radiation-induced cancers
• Subclassification:: microcarcinoma, intrathyroidal, extrathyroidal– Histology variants: high-cell, clear-cell, columnar,
diffuse sclerotizing
• Multiple nodules in 30-50%
• Lymphatic spreading
• Lymph mets in 20-50%
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Follicular cancer• More frequent in iodine-deficient areas• Diagnosis: vascular and/or capsular invasion• Subclassification:: minimally or extremely invasive
– Vascular invasion→ more aggressive compared to capsular invasion
• Rarely multiple nodules• Hematogenous spreading• Frequent lung and bone mets.
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Hürthle -cell cancer
• Frequent mets.
• Iodine uptake in less than 10%
• Frequent recurrence
• High mortality – 30% / 10 yrs
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Anaplastic cancer
• Decreasing frequency
• Rapid progression >60 yrs
• Frequent mets. at the time of dg.
• Limited surgical solutions
• Irradition or chemo not effective
• Average survival: ~ 4 - 6 months
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Medullar y cancer
• Origin: parafollicular C-cells
• Calcitonin and CEA elevation in the circulation(50%)
• Sporadic: 80%
• At the time of dg.: 75%met. and 20% distantmet.
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Medullar y cancer• MEN IIA �
– MC (100%), pheo (40%), hyperparathyroidim (35%)– AD trait– Missense mutation in the RET protoonkogene (extracell. cytein)– Surgery recommended before 6 yrs of age
• MEN IIB �– MC (100%), pheo (50%), mucosal ganglioneuromas (100%),
Marfan sy– AD trait– Missense mutation in the RET tirozine-kinase domain– Recommended surgery in infant age
• Familial MC
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Differentiated thyroid cancers
● PTC and FTC comprise 90% of all thyroid malignancies.● PTC is the most common histological type of all thyroid malignancies (60-
80%). Somatic mutations are found in more than 40-70% of papillary carcinoma cases.
● FTC is the second most common histological type with a frequency is 10-15%. Mutation is present in 30-50%.
Benvenga, S., Horm Metab Res, 2008. 40(5): p. 323-8.Woodruff, S.L., et al., Am J Surg, 2010. 200(4): p. 462-6.Schlumberger, M., Ann Endocrinol (Paris), 2007. 68(2-3): p. 120-8.Cheng, S.P., et al., Langenbecks Arch Surg, 2008. 393(5): p. 729-32.
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Albarel F, Conte-Devolx B, Oliver C.,Ann Endocrinol (Paris). 2012. Apr. 13. [Epub aheadof print]
Genetic alterations and PTC
PTC frequently carries- BRAF (v-raf murine sarcoma viral oncogene homolog B1) - RET/PTC (RET tyrosine-kinase protooncogene / papillary thyroid
carcinoma) - RAS (rat sarcoma viral oncogene homolog) mutations
BRAF mutation has been associated with more aggressive tumor behavior:- extrathyroidal extension- lymph node involvement- resistance to radioactive iodine- tumor recurrence
BRAF gene mutation is an oncogenic mutation influencing the mitogen-activated protein kinase (MAPK) signaling pathway.
THERAPEUTIC INTERVENTION!
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Targeted therapy in the BRAF pathway
Cantwell-Dorris ER et al, Mol Cancer Ther; 2011. 10(3) DOI:10.1158/1535-7163.MCT-10-0799
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Albarel F, Conte-Devolx B, Oliver C.,Ann Endocrinol (Paris). 2012. Apr. 13. [Epub aheadof print]
Genetic alterations and FTCFTC is prone to have
- RAS- RET/PTC - PAX8/PPAR-gamma mutations
These alterations have been identified in approximately 30-80 % of the tumors.
RAS family activates three cascades: - MAP-kinase-pathway- phosphatidilinozitol-3-kinase/protein-kinase-b (PI3K/AKT)
apoptotic-pathway- adhesive and migration affect line
The altered RAS proteins bind with major affinity to a GTP and activate GTPase effect, thus these proteins maintain constitutive activation of proliferation in follicular cells. Therefore genomic instability and increased proliferative potential will be the consequence in these cells.
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Albarel F, Conte-Devolx B, Oliver C.,Ann Endocrinol (Paris). 2012. Apr. 13. [Epub aheadof print]
More genetic alterations recognizedRET proto-oncogene is a tyrosine-kinase transmembrane receptor and encoded on chromosome X. Occurence of frequent alterations in sporadic papillary cancer has been established.
- RET/PTC1 fusion protein is associated with less malignancy- RET/PTC2 is infrequent- RET/PTC3 marks more aggressive tumors and exhibits bad prognosis.
PAX8 (paired box 8) gene is encoding a transcription factor that has a role in tissue differentiation in embryonic age. The PAX8/PPAR-gamma-1 rearrangement may appear in follicular thyroid cancer.
Thyroid receptors as well as micro-RNAs might also contribute to the pathological processes resulting in malignant transformation of the thyroid.
THERAPEUTIC INTERVENTION!
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Kim WG, Cheng S, Biochim. Biophys. Acta (2012), doi:10.1016/j.bbagen.2012.04.002
Thyroid carcinogenesis
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de la Chapelle A, Jazdzewski K., JCEM 2011. 96:3326-36.)
Regulation of PTEN/PI3K/AKT pathway by microRNAs
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Gene Cancer type Prevalence (%)
BRAF PTC 45
not well-differentiated cancer 20
anaplastic carcinoma 20
RAS anaplastic carcinoma 50
FTC 45
not well-differentiated cancer 35
PTC 10
RET medullary carcinoma 50-95
RET/PTC PTC 20
PAX8-PPARγ FTC 35
TP53 anaplastic carcinoma 70
not well-differentiated cancer 20
Genetic alterations inthyroid cancers
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Age
men (n=40) 52.2 ± 13.2
women (n=85) 51.5 ± 14.2
number of DNA samples BRAF HRAS KRAS NRAS
papillary cc. 106 40 (37.7%) 1 (0.9%) 1 (0.9%) 1 (0.9%)
follicular cc. 12 2 (16.7%) 1 (8.3%) 0 3 (25.0%)
other cc.* 7 0 0 0 1 (14.3%)
normal tissue 121 0 0 0 0
summ 246
number of RNA samples
RET/PTC1 RET/PTC3
papillary cc. 59 5 (8.5%) 1 (1.7%)
follicular cc. 12 0 0
other cc.* 7 0 0
normal tissue 78 0 0
summ 156
*: anaplastic thyroid carcinomas, follicular adenomas and follicular neoplasia
Genetic alterations in thyroid cancers in Hungary
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Balla B et al, Thyroid 2011. 21(4):459-460.
CYP24A1 has beenidentified in PTC
• CYP24A1 is the calcitriol-neutralizing enzyme• Increased expression has been shown in colon cc and liver cc
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Changes of relative CYP24A1 gene expression in 51 human papillary tumors vs.
control thyroid tissues.
Patients’ number
CYP24A1 mRNA expression was markedly increased in 31 cases (61%) of the examined papillary cancer compared with that
of normal thyroid tissue, sometimes reaching over 106-fold elevation. We measured lower CYP24A1 transcription level in
12 tumor tissues (23.5%). There was no variation in CYP24A1 gene expression between 2 tumor and healthy control tissue,
and CYP24A1 specific mRNA was not detected in the thyroid samples of 6 patients.
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Component143210-1-2-3-4
Com
pone
nt2
4
3
2
1
0
-1
-2
-3
-4
20
30
38
39
26
1
31
11
6
8
40
19 18
21
17
10
13
12
32
34
149
37
41
25
22
29
5
42
35
4
23
333
272
7
28
24
36
16 44
15 43
Tumorlocalization 1
Winter
Lymph node metastasis
PTC oncocyter variant
CCDC6/RET
Hashimoto
Hyperthyreosis
CYP24A1 RATIOKRAS
Vascularization
Spring
Hypothyreosis
No other thyroid disease
DIRECTION
BRAFTumor size Hyperplasia
Age
ELE1/RET Tumor localization 2
Lymphocytas thyreoiditisSex
No PTC subtype/variation
Fall
HRAS
Tumor localization 3
Struma
Summer
PTC follicular variant
PTC hyalinized variant
Principal component analysis
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Component143210-1-2-3-4
Com
pone
nt2
4
3
2
1
0
-1
-2
-3
-4
Tumorlocalization 1
Winter
Lymph node metastasis
PTC oncocyter variant
CCDC6/RET
Hashimoto
Hyperthyreosis
CYP24A1 RATIOKRAS
Vascularization
Spring
Hypothyreosis
No other thyroid disease
DIRECTION
BRAFTumor size Hyperplasia
Age
ELE1/RETTumor localization 2
Lymphocytas thyreoiditisSex
No PTC subtype/variant
Fall
HRAS
Tumor localization 3
Struma
Summer
PTC follicular variant
PTC hyalinized variant
Principal component analysis
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HMGA2 (high mobility group AT-hook 2): RAS-regulatedcell proliferationpancreatic ductal adenocarcinoma, papillary serous carcinoma
MRC2 (mannose receptor, C type 2, also known as Endo 180)tumor cell migration
SFN/14-3-3r (stratifin)tumor suppressor genelung cancer, squamous cell carcinoma, pancreatic cancer,endometrial carcinoma, cervical cancer, colorectal carcinoma
Prasad NB et al, Thyroid, 2012. 22(3):275-284.
Three-Gene Molecular Diagnostic Modelfor Thyroid Cancer
Specificity: 100%Sensitivity: 80%
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Follow-up study
● FNAB samples collected● Planned: 800, accomplished to date: 710● At least 3 yrs of follow-up planned● Frequency of genetic alterations, incidence of malignancies recorded● Can genetic alterations predict malignancy?
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Genetic alteration Frequency
BRAF 4
NRAS 1
HRAS 7
KRAS 0
RET/PTC3 1
One year follow-up of 231 subjects
13
Malignant samples (cytology)
Follicular adenoma (4)
PTC 14
Medullary 1
15 (19)
malignant non-malignant
+ -
Geneticalteration
+ 5 8
- 10 223
231
4 BRAF and 1 RET/PTC3
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Melck AL, Yip L, HEAD & NECK—2011, DOI 10.1002/hed.21818.
University of Pittsburgh’s current algorithm for the evaluation of thyroid nodules
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Contribution of molecular information to thyroiddiagnostics and therapy
● Additional information to FNAB or histology
● Individual treatment options (e.g. thyrosine kinase inhibition)
● Prediction of malignancy in thyroid nodules
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Thank you foryour attention!