1. Dr. Varun Goel
MEDICAL ONCOLOGIST
RAJIV GANDHI CANCER INSTITUTE, DELHI

2. Introduction
 The most common endocrine malignancy
 95% of all endocrine cancers
 accounts for ~3% of all cancers
 Female to Male Ratio 3:1
 sixth most frequently diagnosed cancer in women
 continued increased incidence with an estimated
48,020 new cancer cases in 2011.
 six deaths per 1 million people occur annually.

3.  based on pathology can be divided into three general
subtypes
 differentiated (papillary, follicular, and Hürthle cell),
 more than 90% of thyroid cancers
 medullary, and
 anaplastic thyroid cancers
 The prognosis is excellent for most patients with
thyroid cancer
 overall survival rate of 85% at 10 years.
 Most effectively treated by thyroidectomy and use of
radioactive iodine.
 Despite low mortality rates,
 local recurrence occurs in up to 20% of patients, and
 distant metastases in approximately 10% at 10 years.

4. History
Symptoms
 The most common presentation painless mass in
the region of the thyroid gland (Goldman, 1996).
 Symptoms consistent with malignancy
 Pain
 dysphagia
 Stridor
 hemoptysis
 rapid enlargement
 hoarseness

5. Important History
 Radiation to neck / chest
 MEN syndrome
 Family history
 Diarrhoea
 Adrenal tumour

6. History (continued...)
Risk factors
 Thyroid exposure to irradiation
 low or high dose external irradiation
 (40-50 Gy [4000-5000 rad])
 especially in childhood for:
 large thymus, enlarged tonsils, cervical adenitis, sinusitis, and
malignancies
 30%-50% chance of a thyroid nodule to be malignant
(Goldman, 1996)

7. History (continued...)
Risk factors (continued…)
 Age and Sex
 Benign nodules occur most frequently in women 20-40
years (Campbell, 1989)
 5%-10% of these are malignant (Campbell, 1989)
 Men have a higher risk of a nodule being malignant
 Belfiore and co-workers found that:
 the odds of cancer in men quadrupled by the age of 64
 a thyroid nodule in a man older than 70 years had a 50% chance
of being malignant

8. History (continued…)
 Family History
 family member with medullary thyroid carcinoma
 family member with other endocrine abnormalities
(parathyroid, adrenals)
 familial polyposis (Gardner’s syndrome)

9. Familial Syndromes
Familial Non-Medullary Thyroid Cancer
Gardner PTC Intestinal polyps, osteomas, APC
Syndrome fibromas, lipomas
Cowden PTC Breast cancer, hamartomas PTEN
Syndrome FTC
Carney FTC Myxoma, Schwannoma, ?
Syndrome pigmented adrenal nodules,
pituitary adenomas,
testicular tumors
Familial PTC 5-10% of “sporadic” PTC ?
PTC

10. Evaluation of the thyroid Nodule
 Physical Exam
 Blood Tests
 Ultrasonography
 CT Scan
 PET Scan
 Radioisotope Scanning
 FNAC

11. Physical Exam
Examination of the thyroid nodule:
 consistency - hard vs. soft
 size
 Multinodular vs. solitary nodule
 multi nodular - 3% chance of malignancy (Goldman, 1996)
 solitary nodule - 5%-12% chance of malignancy
(Goldman, 1996)
 Mobility with swallowing
 Mobility with respect to surrounding tissues
 Well circumscribed vs. ill defined borders

12. Blood Tests
 Thyroid function tests
 thyroxine (T4)
 triiodothyronin (T3)
 thyroid stimulating hormone (TSH)
 Serum Calcium
 Thyroglobulin (TG)
 Calcitonin

13. Ultrasonography
Advantages
 Sensitive for identifying lesions in the thyroid (2-3mm)
 90% accuracy in categorizing nodules as
solid, cystic, or mixed (Rojeski, 1985)
 Best method of determining the volume of a nodule
(Rojeski, 1985)
 Can detect the presence of lymph node enlargement
and calcifications
 Noninvasive and inexpensive

14. Ultrasonography (Continued…)
Disadvantages
 Unable to reliably diagnose true cystic lesions
 Cannot accurately distinguish benign from malignant
nodules

15.  CT Scan
 Not commonly needed
 Better when suspecting mediastinal disease
 PET Scan
 FNAC
 Accurate for PTC and MTC
 Cannot diagnose FTC

16. Radioisotope Scanning
 Prior to FNA, was the initial diagnostic procedure of
choice
 Performed with: technetium 99m pertechnetate or
radioactive iodine
 Technetium 99m pertechnetate
 cost-effective
 readily available
 short half-life
 trapped but not organified by the thyroid - cannot determine
functionality of a nodule

17. Radioisotope Scanning (Continued…)
 Radioactive iodine
 radioactive iodine (I-131, I-125, I-123)
 is trapped and organified
 can determine functionality of a
thyroid nodule

18. Radionuclide Scan Possibilities
Cold Hot

19. Limitations of Radionuclide Scan
 Cold nodules usually benign...
but could be cancer
 Hot nodules never cancer…
and revealed by low TSH

20. Radioisotope Scanning (continued...)
Limitations
 Not as sensitive or specific as FNA in
distinguishing benign from malignant nodule
 90%-95% of thyroid nodules are hypofunctioning, with 10%-20%
being malignant (Geopfert, 1994, Sessions, 1993)
 Campbell and Pillsbury (1989) performed a meta-analysis of 10
studies
 17% of cold nodules, 13% of warm or cool nodules, and 4% of hot
nodules to be malignant

21. Fine-Needle Aspiration
 Currently considered to be the best first-line diagnostic
procedure in the evaluation of the thyroid nodule:
 Advantages:
 Safe
 Cost-effective
 Minimally invasive
 Leads to better selection of patients for surgery than any other
test (Rojeski, 1985)

22. Fine-Needle
Aspiration (continued…)
 FNA halved the number of patients requiring
thyroidectomy (Mazzaferri, 1993)
 FNA has double the yield of cancer in those who do
undergo thyroidectomy (Mazzaferri, 1993)

23. Fine-Needle Aspiration (continued…)
Limitations
 skill of the aspirator
 Sampling error in lesions <1cm, >4cm, multinodular lesions, and
hemorrhagic lesions
 Error can be diminished using ultrasound guidance
 expertise of the cytologist
 difficulty in distinguishing some benign cellular
adenomas from their malignant counterparts (follicular
and Hurthle cell)
 False negative results = 1%-6% (Mazzeferri, 1993)
 False positive results = 3%-6%
(Rojeski, 1985, Mazzeferri, 1993, Hall, 1989)

24. Molecular Pathogenesis of Thyroid Cancer

25. Thyroid Cancer Type Mutation Prevalence, %
Papillary
BRAF[V600E] 45
BRAF copy gain 3
RET/PTC 20
RAS 10
PI3KCA 3
PI3KCA copy gain 12
PTEN 2
Follicular
BRAF copy gain 35
RAS 45
PAX8-PPARγ 35
PTEN < 10
PI3KCA < 10
PI3KCA copy gain 12
Medullary
RET (familial) > 95
RET (sporadic) 50

28.  In last 30 years, it has become clear that thyroid
cancers are associated with genetic mutations that
lead to aberrant intracellular signaling
 inhibition of intracellular signaling cascades including
MAPK and PI3K pathways may be effective in the
treatment .
 Ahmed 2011; Hong 2011; Carr 2010; Robinson 2010; Lam
2010; Sherman 2008;Gupta-Abramson 2008

29. Classification of Malignant Thyroid
Neoplasms
 Papillary carcinoma  Medullary Carcinoma
 Follicular variant  Miscellaneous
 Tall cell  Sarcoma
 Diffuse sclerosing  Lymphoma
 Encapsulated  Squamous cell carcinoma
 Follicular carcinoma  Mucoepidermoid carcinoma
 Overtly invasive  Clear cell tumors
 Minimally invasive  Pasma cell tumors
 Hurthle cell carcinoma  Metastatic
Direct extention
 Anaplastic carcinoma 
 Kidney
 Giant cell
 Colon
 Small cell  Melanoma

30. WDTC - Papillary
Carcinoma
 Pathology
 Gross - vary considerably in size
- often multi-focal
- unencapsulated but often have a
pseudocapsule
 Histology - closely packed papillae with
little colloid
- psammoma bodies
- nuclei are oval or elongated,
pale staining with
ground glass appearanc -
Orphan Annie cells

31. WDTC - Follicular Carcinoma
 Pathology
 Gross - encapsulated, solitary
 Histology - very well-differentiated
(distinction between follicular
adenoma and carcinomaid
difficult)
- Definitive diagnosis -
evidence of vascular and
capsular invasion
 FNA and frozen section cannot
accurately distinquish between benign
and malignant lesions

32. CEA Synaptophysin Chromogranin
Calcitonin Thyroglobulin
S03-12297

33. 72 yr old female, 2 week history enlarging thyroid mass
2-3 day history of hoarseness and stridor
FNA: poorly differentiated thyroid cancer
Thyroglobulin neg
Spindle cells Giant cells
PTC
Anaplastic

34. WDTC - PROGNOSIS
 Prognostic schemes:
AMES (Lahey Clinic, Burlington, MA)
GAMES (Memorial Sloan-Kettering Cancer Center, NY)
AGES (Mayo Clinic, Rochester, MN)
 GAMES scoring (PAPILLARY & FOLLICULAR CANCER)
G - Grade
A - Age of patient when tumor discovered
M - Metastases of the tumor (other than Neck LN)
E - Extent of primary tumor
S - Size of tumor (>5 cm)
 The patient is then placed into a high or low risk category

35. WDTC - Prognosis (Continued…)
1) Low risk group - men younger than 40 years and
women younger than 50 years regardless
of histologic type
- recurrence rate -11%
- death rate - 4%
(Cady and Rossi, 1988)

36. WDTC - Prognosis (Continued…)
 1) Intermediate risk group - Men older than 40 years and
women older than 50 years
who have papillary carcinoma
- recurrence rate - 29%
- death rate - 21%
 2) High risk group - Men older than 40 years and women
older than 50 years who have follicular
carcinoma
- recurrence rate - 40%
- death rate - 36%

37. AJCC :Classification of Thyroid Cancer
Primary
tumor
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor < 2 cm confined to the thyroid
T2 Tumor >2 cm and <4 cm confined to the thyroid
T3 Tumor >4 cm confined to the thyroid
or Tumor of any size with minimal extrathyroid extension
T4a Tumor of any size with extrathyroid extension to subcutaneous
soft tissues, larynx, trachea, esophagus, or recurrent laryngeal
nerve
or Intrathyroidal anaplastic carcinoma- resectable
T4b Tumor invading prevertebral fascia/encasing carotid artery or
mediastinal vessels or Extrathyroidal anaplastic carcinoma -
unresectable

38. Regional LN(N) (central compartment, lateral
cervical, and upper mediastinal)
NX Regional lymph nodes cannot be
assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
N1a Metastasis to level VI (pretracheal or
paratracheal, and prelaryngeal)
N1b Metastasis to unilateral, bilateral, or
contralateral cervical(Levels I, II, III, IV or
V) or superior mediastinal lymph nodes
(Level VII )

39. Distant
metastasis
(M)
MX Distant metastasis
cannot be assessed
M0 No distant metastasis
M1 Distant metastasis

40. Papillary/Follicular Thyroid Cancer

41. AJCC/UICC StagingThyroid Cancer
Papillary/Follicular
Stage Age < 45 yrs Age > 45 yrs
I Any T, any N, M0 <2 cm, intrathyroidal, N0, M0
II Any T, Any N, M1 2- 4cm, intrathyroidal, N0, M0
III Minimal ETE, or > 4cm, N0, M0
or T1-3, N1a, M0
IV Any T, Any N, Gross ETE, or M1
Hürthle cell carcinoma is considered a follicular carcinoma. All anaplastic
carcinomas are stage IV.

42.  staging of thyroid cancer is the only one in
oncology that takes patient age at diagnosis into
account.
 age is the most important prognostic variable for
mortality
 a large proportion of thyroid cancers (primarily
PTC) occur in women under the age of 45.
 As a group these are highly sensitive to RAI;
 thus, even with metastatic disease can be cured with
RAI following surgery.
 As the age of diagnosis increases, the mortality rate
increases as well, most sharply after the age of 60 years.

44.  Overall, the differentiated thyroid cancers are
associated with a good prognosis and 10-year
survival rates are
 93% for papillary
 85% for follicular and
 76% for Hürthle cell carcinomas, respectively.

45. Initial Management
Surgery is the definitive management of
thyroid cancer, excluding most cases of ATC
and lymphoma
Types of operations:
 lobectomy with isthmusectomy –
 minimal operation required for a potentially malignant
thyroid nodule
 total thyroidectomy - removal of all thyroid tissue
 preservation of the contralateral parathyroid glands
 subtotal thyroidectomy
 anything less than a total thyroidectomy

46. Management (WDTC) - Papillary and
Follicular
Subtotal vs. total thyroidectomy

47. (continued…)
 Rationale for total thyroidectomy
1) 30%-87.5% of papillary carcinomas involve opposite
lobe (Hirabayashi, 1961, Russell, 1983)
2) 7%-10% develop recurrence in the contralateral lobe
(Soh, 1996)
3) Residual WDTC has the potential to dedifferentiate to
ATC

48. (Continued…)
 Rationale for subtotal thyroidectomy
1) Lower incidence of complications
Hypoparathyroidism (1%-29%) (Schroder, 1993)
Recurrent laryngeal nerve injury (1%-2%) (Schroder, 1993)
Superior laryngeal nerve injury
2) Long term prognosis is not improved by total
thyroidectomy (Grant, 1988)

49. (continued)
Indications for total thyroidectomy
1) Patients older than 40 years with papillary or
follicular carcinoma
2) Anyone with a thyroid nodule with a history of
irradiation
3) Patients with bilateral disease

50. (continued)
Managing lymphatic involvement
 pericapsular and tracheoesophageal nodes should be
dissected and removed in all patients undergoing
thyroidectomy
 Overt nodal involvement requires exploration of
mediastinal and lateral neck
 If any cervical nodes are clinically palpable or identified
by MR or CT imaging as being suspicious a neck
dissection should be done (Goldman, 1996)
 Prophylactic neck dissections are not done (Gluckman)

51. Management (WDTC) - Papillary and Follicular
(continued)
 Postoperative therapy/follow-up
 Radioactive iodine (administration)
 Scan at 4-6 weeks postop
 repeat scan at 6-12 months after ablation
 repeat scan at 1 year then...
 every 2 years thereafter

52. Management (WDTC) - Papillary and Follicular
(continued)
Postoperative therapy/follow-up
 Thyroglobulin (TG) (Gluckman)
 measure serum levels every 6 months
 Level >30 ng/ml are abnormal
 Thyroid hormone suppression
 (control TSH dependent cancer) (Goldman, 1996)
 should be done in –
1) all total thyroidectomy patients
2) all patients who have had
radioactive ablation of any remaining thyroid tissue

53.  neck ultrasound should be performed 6 and 12 months
after surgery, and then annually for 3 to 5 years,
 depending on the patients risk for recurrence and Tg
status.
 CT and PET scans has been increasingly used in the
surveillance of patients with iodine-negative,
differentiated thyroid carcinoma.

54. (WDTC) - Hurthle Cell Carcinoma
 Variant of follicular carcinoma
 Lymphatic spread seen in 30% of patients (Goldman,
1996)
 Distant metastases to bone and lung is seen in 15% at
the time of presentation
 Total thyroidectomy is recommended because:
1) Lesions are often Multifocal
2) They are more aggressive than WDTCs
3) Most do not concentrate iodine

55. Treatment of Differentiated Thyroid Cancer[NCCN 2011;
Cooper 2009]

56. Medullary Thyroid Carcinoma
 10%
 Arises from the parafollicular cell or C-cells of the thyroid
gland
 derivatives of neural crest cells of the branchial arches
 secrete calcitonin which plays a role in calcium metabolism
 Developes in 4 clinical settings:
 Sporadic MTC (SMTC)
 Familial MTC (FMTC)
 Multiple endocrine neoplasia IIa (MEN IIa)
 Multiple endocrine neoplasia IIb (MEN IIb)

57. Medullary Thyroid Carcinoma
(continued…)
Sporadic MTC:
70%-80% of all MTCs
Mean age of 50 years
Unilateral and Unifocal (70%)
Slightly more aggressive than FMTC and MEN IIa
 Familial MTC:
 Autosomal dominant transmission
 Not associated with any other endocrinopathies
 Mean age of 43
 Multifocal and bilateral
 Has the best prognosis of all types of MTC
 100% 15 year survival

58. Medullary Thyroid Carcinoma
(continued…)
 MEN IIa (Sipple’s Syndrome):
 MTC, Pheochromocytoma, parathyroid hyperplasia
 Autosomal dominant transmission
 Mean age of 27
 100% develop MTC
 85%-90% survival at 15 years
 MEN IIb (Wermer’s Syndrome):
 Pheochromocytoma, multiple mucosal neuromas, marfanoid
body habitus
 90% develop MTC by the age of 20
 Most aggressive type of MTC
 15 year survival is <40%-50%

59. Medullary Thyroid Carcinoma
(continued…)
 Diagnosis
 Labs: 1) basal and pentagastrin stimulated serum
calcitonin levels (>300 pg/ml)
2) serum calcium
3) 24 hour urinary catecholamines
(metanephrines, VMA, nor-
metanephrines)
4) carcinoembryonic antigen (CEA)
 Fine-needle aspiration
 Genetic testing of all first degree relatives
 RET proto-oncogene

60. Medullary Thyroid Carcinoma
(Management)
 Recommended surgical management
 total thyroidectomy
 central lymph node dissection
 lateral jugular sampling
 if suspicious nodes - modified radical neck dissection
 If patient has MEN syndrome
 remove pheochromocytoma before thyroid surgery

61. Medullary Thyroid Carcinoma
(Management)
Postoperative management
disease surveillance
 serial calcitonin and CEA
 2 weeks postop
 3/month for one year, then…
 biannually
If calcitonin rises
 metastatic work-up
 surgical excision
 if metastases - external beam radiation

62. Anaplastic Carcinoma of the Thyroid
 Highly lethal form of thyroid cancer
 Median survival <8 months
 1%-10% of all thyroid cancers
 Affects the elderly (30% of thyroid cancers in
patients >70 years)
 Mean age of 60 years
 53% have previous benign thyroid disease
 47% have previous history of WDTC

63. Anaplastic Carcinoma of the Thyroid
 Pathology
 Classified as large cell or small cell
 Large cell is more common and has a worse prognosis
 Histology - sheets of very poorly differentiated cells
little cytoplasm
numerous mitoses
necrosis
extrathyroidal invasion

64. Anaplastic Carcinoma
(Management)
 Most have extensive extrathyroidal
involvement at the time of diagnosis
 surgery is limited to biopsy and tracheostomy
 Current standard of care is:
 maximum surgical debulking, possible
 adjuvant radiotherapy and chemotherapy

65. Recurrent DTC
 85% of patients with DTC :disease-free after initial
treatment
 10–15% : recurrent disease
 Most recurrences occur within the first five years after
initial treatment
 5%: distant metastases
lungs (50%), bones (25%), lungs and bones (20%) ,
 10-year-survival rates ranging from 25% to 42%

66.  Treatment methods
 Surgery (when feasible)
 Radioiodine treatment in presence of radioiodine
uptake in tumor foci
 Other local treatments (dependent on location and
extent of disease): external radiation beam
treatment, embolisation, radiofrequency
 New treatment methods, eg, molecularly targeted
treatments,

67. Selection of patients with
metastases for treatment
 Candidates for radioiodine treatment
 Younger age
 Well differentiated tumour
 High radioiodine uptake
 Small metastases
 Location in lungs
 Low uptake of fluorodeoxyglucose
 Loss of RAI uptake is often associated with the increased uptake
of PET scanning.
 Repeated radioiodine treatment (response rate:
85%, with 96% of complete responses seen with a
cumulative activity <600 mCi)

68. Advanced Disease
 when recurrent or metastatic lesions either
 no longer take up radioactive iodine (RAI) or
 have grown in the setting of recent treatment
with RAI (RAI-refractory), or
 if the recommended lifetime dose of RAI
(600 mCi) has been exceeded.
 survival drops to an average of 2.5-3.5
years.[Robbins 2006

69.  Very few treatment options.
 Cytotoxic chemotherapy
 The experience with chemotherapy is limited
 benefits have been marginal.

70.  Among 49 patients with metastatic differentiated thyroid
carcinoma treated with five chemotherapy protocols,
 a combination of doxorubicin, etoposide, 5-fluorouracil and
cyclophosphamide;
 elliptinium acetate;
 doxorubicin;
 cisplatin;
 and the combination of doxorubicin and cisplatin.
 only two (3%) patients had objective responses.
(Droz et al, 1990)
 In a review of published series, 38% of patients had a
response defined as a reduction in tumor mass to
doxorubicin.
 three most widely applied cytostatics are adriamycin,
bleomycin and cis-platinum, and it seems that adriamycin
monotherapy, is superior to all other therapies, even
combinations
(Ahuja and Ernst, 1987)

71.  Doxorubicin, approved by the U.S FDA for use in
advanced thyroid cancer in the 1970s
 Tumor response rates with doxorubicin, range
between 0% and 22% and are short-lived and
without survival benefit .

72.  Administration of doxorubicin with cisplatin
has been equally disappointing.
 Randomized phase II study - ECOG
 Cisplatin/Doxorubicin vs. Doxorubicin
 Cisplatin/Doxorubicin Arm (43 patients)
 CR 5; PR 5; SD 13
 Doxorubicin (41 patients)
 CR 0; PR 7; SD 9
Shimaoka K, et al: Cancer 56:2155-2160, 1985
 Combination chemotherapy is not clearly superior to
doxorubicin therapy alone.
(Mazzaferri, 1993)

73.  The role of external beam radiation therapy
(EBRT) to control cervical disease in patients with
progressive DTC is not well-defined.
 Progress in the knowledge of genetic alterations in
thyroid cancer cells is rapidly offering several
opportunities to develop new drugs directed to
specific targets

74. Targets in cell signalling and angiogenesis
 Papillary carcinomas :
 80% :mutations of genes of mitogen-
activated protein kinase (MAPK)
pathway.
 5–30%: RET/PTC rearrangements
 10%: RAS mutations
 40%: BRAF mutations
 Follicular carcinomas:
 20–35% : RAS mutations
 30% :PAX8/PPARɣ rearrangements
 Medullary Thyroid Cancer
 RET
 Anaplastic Thyroid Cancer
 p53, Vascular Structures

75.  Drugs currently proposed for
molecular therapy include:
(a) monoclonal antibodies;
(b) kinase inhibitors;
(c) anti-angiogenetic drugs;
(d) proteasome inhibitors;
(e) retinoic acid and PPAR-c ligands;
(f) radionuclide therapy;
(g) epigenetic drugs (deacetylase inhibitors and demethylating
agents).
 The results of several phase II trials using molecular
drugs look promising.
 None of the treated patients, however, had CR, and only
a minority of them had a PR.

76.  Several tyrosine kinase inhibitors have shown
activity
 majority (motesanib, sunitinib, sorafenib,
and pazopanib) target the mitogen-activated
protein kinase and antiangiogenic pathways.
 [Ahmed 2011; Hong 2011; Carr 2010; Robinson 2010;Lam 2010]

78. Phase II studies in advanced thyroid cancer

79. VANDETANIB
 Vandetanib is a tyrosine kinase inhibitor
 activity against RET, VEGFR and endothelial growth
factor receptor pathways.
 Vandetanib was approved by FDA in 2011 for use in
patients with unresectable metastatic medullary
thyroid cancer on the basis of a phase III clinical trial
(N = 331).
• [Wells 2011]

80.  Once-Daily Vandetanib 300mg or Placebo.
 significantly prolonged PFS
 (median 30.5 months vs 19.3 months;
 ORR 45% Versus 13%
 No difference in OS
Wells SA Jr, J Clin Oncol. 2010
 associated with a higher incidence of QT
prolongation
 Elevated rates of hypertension and diarrhea
also observed.