SETS December 2009

Update on Thyroid Cancer

Prof. Ranil Fernando Dept of Surgery Faculty of Medicine University of Kelaniya

Update on Thyroid Cancer

Introduction
Thyroid cancer is an uncommon cancer with a good prognosis Rising incidence in the West ( smaller tumors)- Sri Lanka? Management of differentiated thyroid cancer based on risk stratification is important Total thyroidectomy is gaining wider acceptance There is some debate about the treatment of low grade cancers Genetics of thyroid cancer is being studied in detail therapeutic and preventive measures will emerge from these studies Management of Medullary Carcinoma needs further evaluation

Update on Thyroid Cancer

Risk stratification
Many groups have developed a systems of assigning patients with Differentiated Thyroid Carcinoma (DTC)into well- defined risk groups

This has enabled clinicians to develop a rationale treatment policy with predictable outcome
AGES AMES age age grade mets extent extent size size - Lahey Clinic - Mayo Clinic

DAMES Diploid age MACIS mets age

mets

extent

size

- Memorial Sloan-Kettering

completeness invasion size - Mayo Clinic

Prognostic scoring systems do not include lymph node metastases

Update on Thyroid Cancer

M + 3 if metastasis is found

A C
I S

<= 39 years of age = 3.1. = 40 = age (y) x 0.08 + 1 if resection is in Complete

+ 1 if invasive growth (pathologists report) 0.3 x largest diameter in centimeters

MACIS Score of > 6 High risk

Prognostic score
<6

20 year survival
99 %

6-6
7-8 >8

89 %
56 % 24 %

Update on Thyroid Cancer

Low-risk group age younger than 45 years

tumors <4 cm in size

low-grade histology

absence of distant metastasis

absence of extrathyroidal extension High Risk age over 45 years follicular histology ( some types)

extrathyroidal extension
tumor size exceeding 4 cm presence of distant metastases The Memorial Sloan Kettering hospital in New York Introduced the concept of an intermediate group - Shaha et al

Update on Thyroid Cancer

Papillary thyroid cancer risk groups Low Intermediate Intermediate risk risk risk
<45 TI/T2 MO <45 T3/T4 and/or Ml an >~45 TI/T2 d/or M0 High risk >45 T3/ T4 and/or M 1 and/or

Low grade

High grade

Low grade

High grade
Annals of Surgical Oncology, 1996 3(6):534--53

Ashok R. Shaha, Jatin P. Shah, and Thom R. Loree

20-year survival low-risk - 99% intermediate-risk - 83% high-risk group - 43%

Treatment of low grade cancers is controversial

Update on Thyroid Cancer

Selective management of differentiated thyroid carcinoma
Low-risk Criteria Age: <45 years >45 years <45 years >45 years Intermediate-risk High-risk

Tumour size
Histology:

<4c
favourable

<4cm
favourable

>4cm
unfavourable*

>4cm
unfavourable*

Extrathyroidal extension:
Distant metastases: Nodal metastases:

No
No +/-

No
No -

Yes
Yes +/-

Yes
Yes +

Treatment Therapy options Thyroid surgery: Thyroxine: Radioiodine Limited? Yes No Individualized Yes +/Total Yes Yes

*Hrthle cell or Tall cell variant histology

Update on Thyroid Cancer

Genetics
Thyroid cell growth requires the combined effects of TSH, working via cAMP, and growth factor signaling (e.g. IGF-I)

These factors work through MAP kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)
Mutations along these same signaling pathways play prominent roles in the pathogenesis of thyroid neoplasia

MicroRNA (miRNAs) are non-coding single stranded RNAs that control cell growth, differentiation and apoptosis
MiRNAs negatively regulate their target genes and recently have been implicated in tumourigenesis

Update on Thyroid Cancer

Oncogene (defective)

+ microRNA

Target Cell

Altered Differentiation, Growth, Apoptosis Tumour

RET/PTC (an oncogene) -induced tyrosine phosphorylation of PDK1 may be one of the mechanisms by which it acts as an oncogenic tyrosine kinase in thyroid carcinogenesis.

70% of papillary thyroid cancers have mutations of either RET/PTC, RAS or B-RAF Mutations

Update on Thyroid Cancer

Medullary Carcinoma
This cancer is derived from the parafollicular C cells Accounts for about 5 to 10 % of all cancers of the thyroid gland Hereditary autosomal dominant type genetic defect has been located in chromosome 10 - RET proto oncogene Screening for RET proto-oncogene is very effective Siblings can be offered Pre- emptive surgery (codon Based) MEN2b has the worst prognosis in Medullary carcinoma Unaffected siblings must be offered surgery before the age of 2

Prophylactic Node dissection ( even Bilateral) is indicated in Medullary Cancer

Update on Thyroid Cancer

Hurtle Cell Tumours
Hurthle cell tumours are diagnosed when more than 75% of a lesion is composed of Hrthle cells
They are thought to be variants of follicular (& papillary) adenoma & carcinoma -5% - Follicular? /Papillary ?
Hurthle cell (Askanazy cell)

Differentiation between adenoma and carcinoma is difficult

Hurtle cell cancer is often bilateral and less sensitive for treatment with radioactive isotopes

Higher rate of metastasis and lower survival than differentiated thyroid cancers
The prognosis is not as good as for papillary or follicular thyroid cancer

Update on Thyroid Cancer

Surgery
Surgery remains the main form of therapy for thyroid cancer

In Medullary , Follicular and Intermediate and High grade papillary cancers - Total Thyroidectomy is the treatment of choice
Low grade Papillary ,Micro papillary & Minimally invasive follicular lesions may be dealt with by a lesser procedure

Lymph nodes - Selective Dissection Level VI is a must in all other levels Dissect Palpable nodes
In Medullary there is a place for Prophylactic dissection

Update on Thyroid Cancer

Post Operative Treatment of DTC
If a diagnostic whole body I-131 scan is positive, further imaging to evaluate the possibility of surgical resection If no surgically resectable disease is identified, thyroid hormone ( Suppressive Dose)withdrawal and I-131 treatment is recommended

I-131 treatment is recommended prior to external beam radiation therapy unless the Whole Body iodine scan is negative
Iodine negative & thyroglobulin positive patients may be considered for FDG-PET before treatment to assess surgical options FDG PET is effective for detecting recurrent or metastatic DTC with high sensitivity and specificity, particularly in patients with negative radioiodine scans and elevated Tg levels

Update on Thyroid Cancer

Post Operative Radioiodine Diagnostic - small dose Therapeutic
Dose of I-131 sodium iodide
Remnant ablation (post-op) Low Risk 50 mCi High Risk 100 mCi Regional Lymph Node metastasis 150 mCi

Distant Metastasis

200 mCi

The above doses can be administered on an outpatient basis. Written radiation safety guidelines will be given to the patient. RAI doses > 200 mCi require hospital admission.
University of California, Los Angeles Guidelines for I-131 Therapy in Differentiated Thyroid Cancer

Update on Thyroid Cancer

Newer treatments
Stimulation Protocol with Thyrogen - Recombinant TSH Consider if contraindications to thyroid hormone withdrawal Thyrogen 0.9 mg IM for 2 days and treat on 3rd day - Costly Targeted treatment / Genetic Modulators ( Still being studied) Sorafenib - Tyrosine Kinase inhibitor ( Only in trials) EGFR inhibitors ( Only in trials)