The Interaction of Mutant B-RAF Protein and Expression of VEGF-C as Risk Factor

for Regional Lymph Node Metastasisin Papillary Thyroid Carcinoma

Dimyati Achmad, Johan S. Masjhur, Muchlis Ramli, Bethy S. Hernowo

INDONESIA

Papillary Thyroid Carcinoma (PTC)

• Is one of the least morbid solid carcinoma

• Slow growing tumor

• Favorable long-term survival

But Approximately 33% to 61% of PTC will have

involvement of cervical lymph nodes at the

time of diagnosis

The regional lymph node metastasis in PTC

appear no correlation with overall survival but

consistenly correlate with local or regional

reccurence.

Until now, molecular pathogenesis of lymph

node metastasis in PTC is still controversial.

Under this circumstances, we would like to

emphasis on the risk factor that plays an

important role in the migration and invasion of

PTC cells to extra thyroidal structure, which is

related to mutant B-RAF protein and also VEGF-C

expression in lymphangiogenesis process.

The aim of this study is to prove the existence

of interaction between mutant B-RAF protein

and VEGF-C expression, as the risk factor of

lymph node metastasis in PTC.

This study is:• Case – control study

• Comparative observation between:–38 subjects PTC with LN. metastases–38 subjects PTC without LN. metastasesas a control group, selected by matching process.

• The Independent Variable–Mutant B-RAF protein–VEGF-C expression

• The Dependent Variable–Regional lymph node metastasis

• The mutant B-RAF protein and VEGF-C expression were identified by immunohistochemistry examination.

• And the result define by histoscore: based on McCarty Criteria (1995).

Highest intensity 50 – 80% distribution

The Analysis:

We analyzed data by :• The McNemar bivariant analysis test

For compare each independent variable with dependent variable

• The double logistic regression multivariant analysis test and the stratification analysis testFor compare two independent variable with dependent variable

The Associaton Between Mutant B-RAF Protein and LN. Metastasis in PTC

The result showed an evidence significant association(p < 0.05)

Mutant B-RAF Protein

Casen = 38

Controln = 38

p. Value

Positive 32 (84.2%) 18 (47.4%)0.023

Negative 6 (15.8%) 20 (52.6%)

Mc Nemar testOR: 5.92 (95% CI: 2.01 – 17.45)

Results:

The Associaton Between VEGF-C Expression and LN. Metastasis in PTC

The result showed unrelated association(p > 0.05)

VEGF-C Expression

Casen = 38

Controln = 38 p. Value

Positive 33 (86.8%) 30 (78.9%)0.272

Negative 5 (13.2%) 8 (21.1%)

Mc Nemar testOR: 1.76 (95% CI: 0.51 – 5.97)

An Interaction Between Mutant B-RAF Protein and VEGF-C Expression as Risk Factor of LN Metastasis in PTC

The multivariant analysis testShowed: a significant resultp = 0.001, OR 5.92 (95% CI: 2.01 – 17.44)

The stratification analysis testShowed: a significant resultp = 0.004, OR 6.44 (95% CI: 1.23 – 33.80)

Summary

MAPK

MutantB-RAF Protein

PTC Cell

Conclusions :

Molecular Pathogenesis Lymph node metastesis in PTC occurs due to interaction between two processes: Invasion of PTC cell to Extrathyroidal Structure and Lymphangiogenesis process.

The interaction between mutant B-RAF protein and VEGF-C expression, has a role as a dominant risk factor of lymph node metastasis in PTC.

Thank You

Summary of Significant Differences

• Mutant B-raf• Initiation of MAPK

pathway occur through Central Protein

• Activation HIF1α occur through two mechanisms

• Hypoxia Condition and Crosstalk between ERK and HIF1α

• Shorter Process

• Non-Mutant B-raf• Initiation of MAPK

pathway occur through Thyrocinekinase receptor

• Activation HIF1α occur through hypoxia condition

• Longer Process• No crosstalk

Summary