Thyroid Cancer And Thymoma Flashcards
What is one main risk factor for thyroid cance?
Ionizing radiation
- risk greater with younger age at exposure
Frequency difference in gender for thyroid cancer?
Male: Female = 1:3
What are the different types of thyroid cancer? And their frequency
1) Differentiated thyroid cancer
- Papillary Thyroid Cancer 80%
- Follicular Thyroid Cancer 10%
» Hurthle cell carcinoma is classified as a subset of FTC
- Poorly differentiated thyroid cancer
2) Medullary Thyroid Cancer 2%
3) Anaplastic Thyroid Cancer
How often do you find thyroid cancer in all the thyroid nodules investigated ?
5%
In the evaluation of thyroid nodules, what would you order?
1) Thyroid function testing
2) Thyroid US
3) FNAC
What are the ultrasound features of a thyroid cancer?
Peripheral halo absent Irregular Border Extra-thyroidal extension Spongiform nodules Size Solid aspect Shape (Taller than wide in transverse plane)
Hypechogenicity
Intranodular Blood Flow
MicrocalcaIcifications
What are the limitations of FNAC?
Inadequate samples
Yielding of follicular neoplasia
What are the high-risk clinical features for thyroid nodules?
Radiation exposure (as child, adolescent)
First degree relative with thyroid cancer/MEN2
FDG Pet-scan avid
Thyroid-ca associated conditions (FAP, Carney Complex, Cowden)
Hx of thyroid cancer in lobectomy
What constitutes a spongiform thyroid nodules?
Aggregation of multiple micro cystic components in >50% of the volume of the nodule
What are some of the follicular lesions that you know about
Follicular neoplasm
Hurthle cell neoplasm
Atypical of unknown significance (AUS)
Follicular lesions of undetermined significance (FLUS)
How does Levothyroxine work in the management of thyroid cancer?
TSH is a trophies hormone that can stimulate the growth of cells from thyroid follicular epithelium.
When Levothyroxine is taken, this suppresses the level of TSH, and hence the cancer.
What are the potential toxicities a/w Levothyroxine ?
Cardiac arrhythmias (ESP in elderly) Bone demineralization (ESP in post-menopausal women) Frank symptoms of thyrotoxicosis
What needs to be given concurrent with Levothyroxine?
Calcium (1200 mg/day) Vitamin D (1000 units/day)
What are the principles of kinase inhibitor therapy in Advanced thyroid cancer?
Oral kinase inhibitors demonstrate clinically significant activity in RCTs for locally recurrent Unresectable and metastatic medullary thyroid cancer (MTC) and in radio-iodine-refractory differentiated thyroid cancer (DTC)
Oral kinase inhibitors can be a/w PFS, but not curative.
Expected to cause s/e RT may affect QoL
Natural history of MTC/DTC is variable, with rates of disease progression ranging from a few months to many years.
What sort of US imaging of the thyroid/neck you need?
Thyroid and neck ultrasound
Including central and lateral compartments
What are the indications for total thyroidectomy intraooperatively?
Any present would suffice:
Bilateral nodularity Tumor >4cm in diameter Poorly differentiated Extrathyroidal extension Cervical LN mets Known distant mets Consider for radiation history
If a prior lobectomy + Isthmusectomy was done before, what are the indications for completion thyroidectomy to be done?
Any of the following would suffice: Tumor >4cm Positive resection margins Gross extrathyroidal extension Macroscopic Multifocal disease Macroscopic nodal mets Vascular invasion
When is completion thyroidectomy not required ?
Small volume pathologic N1 micro mets
I.e. 5 or less involved LN with no micro mets >0.5cm in largest dimension
If a papillary CA was found post-lobectomy, what are the indications for completion thyroidectomy?
Tumor >4cm Positive resection margins Gross extra-thyroidal extension Macroscopic Multifocal disease Confirmed nodal mets (but no need if small volume pathologic N1 micro mets) Confirmed Contralateral disease Vascular invasion Poorly differentiated
When is RAI typically recommended?
If any present:
Gross extrathyroidal extension
Primary tumor > 4cm
Postoperative unstimulated Tg > 5-10 Ng/mL
- Tg values obtained 6-12 weeks after total thyroidectomy
When is RAI typically NOT recommended?
If ALL present:
Classic papillary thyroid carcinomas (PTC)
Primary tumor
In the work up of thyroid malignancy, what are the molecular testing you will send off for and why.
BRAF, RAS, RET/PTC and PAX8/PPAR mutations
- presence of which strongly a/w cancer
- 97% of mutation positive nodules had malignancy
- can help in evaluating pt with indeterminate FNA, but indeterminate results ESP in suspicious nodule would necessitate surgery
What are the advantages of Thyroidectomy?
1) Better disease control
- foci of papillary CA in both lobes in 35-85% of patients
- 5-10% chance of recurrences in Contralateral lobe
- RAI ablation and treatment of met disease is better if as much thyroid tissue is resected
2) Better follow up
- US of Contralateral lobe may pick up non-spec abnormalities
- monitoring of Tg, RAI scan can only be done in thyroidectomy patient
3) RAI therapy
What are the advantages of lobectomy?
1) ?similar OS in “low risk” disease
2) lesser complications of hypoPTH and recurrent laryngeal nerve injury
3) US of thyroid is reasonably accurate
What are the main complications to total thyroidectomy?
1) Injury to recurrent laryngeal nerve (3% risk)
2) Hypoparathyroidism (long term risk 3 %)
What is the general prognosis for papillary thyroid cancer?
5y OS 100% for stage I and II
5y OS >90% for stage III
5y OS 50% for stage IV
Tell me about the N staging?
N1 regional lymph node mets
N1a: Level VI (pretracheal, paratracheal, pre laryngeal (=Delphian LN)
N1b: unilateral/bilateral/Contralateral Cervical or retro pharyngeal or superior mediastinal LN
Tell me about the T staging
T1:
Tumor 2 cm or less, limited to thyroid
T2:
Tumors >2cm - 4cm, limited to thyroid
T3:
- > 4 cm in size, limited to the thyroid
- Any tumor with minimal extrathyroid extension
T4a:
- Moderately advanced disease
- any size that extends beyond the thyroid capsule to invade subcutaneous soft tissue, larynx, trachea, esophagus or recurrent laryngeal nerve
- Intrathyroid anaplastic carcinoma
T4b:
- Very advanced disease
- invades pre vertebral fascia or encases carotid artery or mediastinal vessels
- anaplastic carcinoma with gross extrathyroid extension
Tell me some generalizations of the staging in TNM?
A) Under 45yo
- Stage 1: Tx Nx M0
- Stage 2: Tx Nx M1
B) 45 yo and above:
Stage I: T1 N0 M0
Stage II: T2 N0 M0
Stage III: T3N0M0
- once N1a, at least stage III
- once T4a, at least stage IVA
Stage IV:
- Once T4b, at least stage Ivb
- once N1b, at least stage IVA
Stage IVC:
TxNxM1
What is the Initial American Thyroid Association risk of recurrence classification?
Like the ETA guidelines, this estimates recurrence risk
3 risk groups:
(1) Low Risk (all must be present)
- No local/distant mets
- All macroscopic tumor has been resected
- No invasion of locoregional tissues
- No aggressive histology
- No vascular invasion
- No 131-I uptake outside thyroid bed on post-treatment scan
(2) Intermediate Risk (any present):
- Microscopic invasion into perithyroidal soft tissues
- Cervical LN mets or 131-I uptake outside thyroid bed on post-treatment scan done after thyroid remnant ablation
- Tumor with aggressive histology/vascular invasion
(3) High Risk (Any present):
- Macroscopic tumor invasion
- Incomplete Tumor resection with gross residual disease
- Distant mets
What constitutes aggressive histology?
Tall cell Insular carcinoma - well-defined nidi of small uniform cells with frequent areas of tumor necrosis and micro follicles with thyroglobulin . Poorer prognosis Columnar cel carcinoma Hurthle cell carcinoma Follicular thyroid cancer
Name me some scoring systems for prognosis/survival
1) AMES (Age, mets, extent, size)
2) MACIS
3) AJCC/TNM
What is the MACIS score?
It is a scoring system for prognosis and survival
M.A.C.I.S Mets outside neck (distant mets) - Yes = 3 points, No =0 Age at time of diagnosis - 40yo, score = 0.08xage Invasion into surrounding areas of neck as seen by naked eye - Yes =1 ; No =1 Completeness of surgical resection of tumor - Incomplete = 1; Complete =0 Size of tumor - Score = 0.3x size in cm
Sum of MACIS Score correlate with 20yr survival
- 8 = 20%
What is the required TSH suppression levels?
Normal range 0.65 - 3.7 mU/L
Low risk disease = 0.1 - 0.5
Intermediate to high risk disease =
What is the utility of Radio-iodine therapy in DTC?
1) Ablate normal thyroid remnant
- facilitates long-term surveillance based on serum Tg and diagnostic WBS
2) Adjuvant ablation of residual tumor
- decreases locoregional recurrence risk
3) Treatment of known residual or met thyroid cancer
4) Imaging for possible met/recurrent disease with diagnostic whole body 131-I scan
What are the 2 methods to stimulate TSH?
1) Thyroxine hormone withholding
2) Recombinant human TSH (rhTSH), while LT4 is continued
- less functional impairment
- needs 2 doses
What preparation is needed for RAI imaging and treatment?
Admit 3 days prior
Avoid all iodine-containing medications
Limit dietary intake of iodine for 1 week
Avoid CT scan with IV contrast 6-8 weeks prior (high iodine load)
Preferred cumulative iodine dose in a patient is
What are some iodine-containing medications:
Aminodarone
Phenytoin
Carbamazepine
Lithium
What food contains iodine?
Seaweed COD Iodized salt Baked potato with peel Milk Shrimp Fish sticks Turkey breast Beans Tuna canned in oil Egg Cured food Chocolates Pizza
What does serum TG detect?
Thyroid tissue
What if a patient has high Tg but negative RAI scan?
False negative scan:
- Inadequate TSH stimulation
- Iodine contamination
- Tumor deposits too small
- loss of iodine uptake via tumor de differentiation
Consider for neck USS/Chest CT (without iodinated contrast)
If Stimulated Tg >10 Ng/ml, consider PET scan
NO Evidence that treating in Tg+/Scan NED patients benefit survival
What constitutes RAI -refractory disease?
Lack of uptake on WBS after Diagnostic/Therapeutic RAI
Progression of lesions documented by conventional imaging after therapeutic RAI
Cumulative dose >600 mCi of 131-I
FDG avid lesions on FDG PET
What is the most common genetic alteration in thyroid cancer?
BRAF V600E point mutation
- most common in 50-80% of PTC, less common in FTC
BRAF oncogene activates MAPK pathway
Is RAS mutation more common in PTC or FTC?
FTC. Up to 40%
Which TKI can cause QTC prolongation ?
Vandetanib
Tell me about the DECISION trial
Marcia Brose et al Lancet 2014
N=400
RAI-refractory locally advanced or metastatic DTC
2 arms:
1) Sorafenib 400 mg BD
2) Placebo
Cross-over allowed.
Results:
Median PFS 11m vs 6m (placebo) HR 0.6 and p significant.
* Median PFS longer in those with BRAF Mutations 20m vs 9m
* wt BRAF med PFS also doubled 9m vs 4m
OS ~
70% crossover to Sorafenib
ORR 10% vs 0.5% (Placebo)
How often does DTC developed metastatic disease?
5-20%
What does Sorafenib inhibit?
VEGFR-1, VEGFR-2, VEGFR-3
RET
RAF
PDGFR-Beta
Tell me about the SELECT trial
Schlumberger NEJM 2015
N=260
RAI Refractory progressive thyroid cancer
2 arms:
1) Lenvatinib 24mg OD Q28days
2) Placebo
Crossover allowed
RESULTS:
Median PFS 18m vs 3.6m (placebo), HR 0.2 and p significant
RR 65% vs 1.5%
What does Lenvatinib inhibit?
VEGFR 1,2,3 FGFR 1-4 PDGFRA RET KIT
Which codon in RET mutation is considered the highest risk for MTC, such that prophylactic thyroidectomy should be offered earlier rather than later?
Codon 634
What are some of the bad prognosticators in medullary Thyroid cancer ?
Calcitonin doubling time
What are the 2 blood tests done to surveil MTC?
Basal Calcitonin
CEA
Tell me about Vandetanib
Used for advanced Medullary Thyroid Cancer.
Samuel Wells JCO 2011
N=300
2 arms: Vandetanib (300mg/day) vs placebo, cross over allowed
Incl criteria:
- measurable, Unresectable, locally advanced/met, hereditary or sporadic MTC
- PS 0-2
- Serum calcitonin 500 pg/mL or more
RESULTS:
PFS 19m (placebo) not reached but estimated to be 30m for Vandetanib.
PFS at 6m 80% vs 60%
How frequent are sporadic RET mutations in MTC?
50%
- of these, 85% will have M918T mutation
What is Hepaocyte growth factor receptor also known as?
MET
Tell me about Cabozaninib in MTC
Rossella JCO 2013
N=300
Radiological PD of met MTC
2arms:
A) Cabozantinib (140 mgOD)
B) Placebo
RESULTS:
Median PFS 11m vs 4m (placebo) HR 0.3 p sig
PFS 1y 50% vs 10%
RR 30% vs 0% (Placebo)
What does Cabozantinib inhibit?
Hepatocyte growth factor receptor (MET)
VEGFR2
Rearranged during Transfection (RET)
What are the side effects o Cabozantinib?
Nausea, LOW LOA PPE Diarrhea Fatigue
What is the usual presentation of anaplastic thyroid cancer?
Large hard mass, with invasion to neck
Compressive symptoms
50% with distal mets at presentation
What is the WHO classification of thymic tumors based on?
And what does it correlate to?
1) Morphology of epithelial tumor cells
- increasing atypical from A to C
2) proportion of lymphocytic involvement
3) Resemblance to normal thymic tissue
Correlates with 5-y OS A/AB/B1: 90-95% B2: 75% B3: 70% C: 50%
What is the WHO Classification of Thymic Malignancies?
A (Medullary) = neoplastic oval/spindle cells; no atypia; no lymphocytes
AB (Mixed) = Type A with foci of lymphocytes
B1 (Predominantly Cortical) = Plump epithelioid cells resembling normal thymic medulla
B2 (Cortical) = scattered foci of atypical epithelial cells with lymphocytes
B3 (well-diff Thymic carcinoma) = round/polygonal epithelial cells with mild atypia with minor component of lymphocytes
C (High-grade Thymic Carcinoma) = Thymic carcinoma (histological subs ping needed)
What are the histological subtypes of Thymic carcinoma that you know of?
1) Squamous cell
2) Lymphoepithelioma-like
3) Clear-cell
4) Basaloid
4) Mucoepidermoid
5) Papillary
6) Undifferentiated carcinoma
What is the staging that we used for Thymic malignancies?
Masoka staging.
- focuses on integrity of Thymic capsule.
- micro vs macroscopic invasion into adjacent structures
What is the Masoka staging?
I:
- Macroscopically completely encapsulated tumor
- No microscopic capsular invasion
II: some degree of invasion
IIA: microscopic invasion into capsule
IIB: Macroscopic invasion into surrounding fatty tissue/mediastinal pleural
III: Macroscopic invasion into neighboring organs
- pericardium, great vessels, lung
IV: Systemic disease
IVA: pleural/pericardial dissemination
IVB: lymphatogenous or hematogenous mets
What are the differences between Thymoma and Thymic cancers?
Stage at Dx:
Early for Thymoma with no mets, but Thymic cancers are locally adv/met
5y OS:
>80% for Thymoma
40% for Thymic cancer
Response to chemo:
Good for Thymoma
Poor for Thymic cancers
Spread:
Thymoma: rarely beyond pleura/lung
Thymic CA: often with pleural pericardial effusions
Treatment:
Thymoma: post-op RT dependent on extent of resection
Thymic ca: post-op RT required regardless of margins, extent of resection
Chemo choices:
Thymoma: CAP, ADOC
Thymic Ca: Pac/Carbo, ADOC
Molecular abnormalities:
Thymic C: C-Kit over expressed, IGF-1R expression
What are the associated autoimmune syndromes?
1) Myasthenia Gravis
- 30-50% of thymomas
2) Pure red cell aplasia
- 5-15% of thymomas
3) Hypogamaglobulinemia
-
What is the role of adjuvant therapy post-op for Thymic malignancies?
R0 = Not required for stage I Thymomas/Thymic Ca unless;
- capsular invasion
- close margins
- WHO Grade B tumor
- tumor adherent to pericardium
- If any of above, then to consider adjuvant RT*
R1 = PORT
- 45-50Gy
R2 = PORT
- up to 60Gy
Stage III - recommend PORT
No adjuvant chemo unless Thymic carcinoma in R1 and R2
What are the common chemo agents?
Cisplatin
- RR 10%
- OS 76 weeks
Ifosfamide
- RR 40-50%, 5y OS 60%
- Retrospective study
Pemetrexed
- RR 10-20%
- Thymoma RR 25%
What are the combination chemo agents that you know for Thymic malignancies ?
1) ADOC (Doxo, CDDP, Vincristine, Cyclophosphamide)
- RR 80-90%, OS 15-45m
2) CAP
- ORR 50%
- OS > 30 m
3) EP
- OR 56%
4) VIP
- OR 30%
5) Pac/Cabo
- RR 40% in Thymoma; 20% in Thymic Carcinoma
No standard 2nd line treatment
What is Carney Complex?
Multiple neoplasia and Lentiginosis syndrome, which affects endocrine glands
When is a lobectomy sufficient?
Papillary Microcarcinomas (<1cm) No extrathyroidal extension No Vascular invasion No LN mets Unifocal disease No previous exposure to radiation, no other risk factors No distant mets Minimally invasive follicular Thyroid cancer
When is completion thyroidectomy indicated?
Tumor >4cm Positive margins Gross extrathyroidal extension Macroscopic multifocal disease Macroscopic nodal mets Contralateral disease Vascular invasion When remnant ablation is anticipated If long-term f/u is planned with serum Tg determinations +/- Whole body 131I imaging
What is the function of the thymus gland?
The thymus gland is involved in the processing and maturation of lymphocytes
The lymphocytes become T-lymphocytes upon release into the circulation
What is the thymus composed of?
1) Epithelial cells
2) Hassall’s corpuscles
- degenerated keratinised epithelial cells
3) Myoid cells
4) Thymic lymphocytes = Thymocytes
5) B-lymphocytes
