Thyroid disorders are common. This presentation reviews the causes of benign thyroid disease as well as therapy, including new therapies for advanced thyroid cancer.

1. Recent advances in the diagnosis
and treatment for benign and
malignant thyroid disease
Professor Steven Boyages
The University of Sydney
Westmead Hospital
May 2015

3. Nutrition Related DisordersNutrition Related Disorders
MicronutritionMicronutrition
Undernutrition PCMUndernutrition PCM
Minerals and VitaminsMinerals and Vitamins
Folic AcidFolic Acid
Vitamin D deficiencyVitamin D deficiency
Vitamin A deficiencyVitamin A deficiency
Fe deficiencyFe deficiency
Selenium deficiencySelenium deficiency
Iodine deficiencyIodine deficiency
MicronutritionMicronutrition
Undernutrition PCMUndernutrition PCM
Minerals and VitaminsMinerals and Vitamins
Folic AcidFolic Acid
Vitamin D deficiencyVitamin D deficiency
Vitamin A deficiencyVitamin A deficiency
Fe deficiencyFe deficiency
Selenium deficiencySelenium deficiency
Iodine deficiencyIodine deficiency
MacronutritionMacronutrition
ObesityObesity
HyperlipidemiaHyperlipidemia
Insulin ResistanceInsulin Resistance
DiabetesDiabetes
AlcoholAlcohol
MacronutritionMacronutrition
ObesityObesity
HyperlipidemiaHyperlipidemia
Insulin ResistanceInsulin Resistance
DiabetesDiabetes
AlcoholAlcohol

4. Iodine Deficiency DisordersIodine Deficiency Disorders
SIGNIFICANCESIGNIFICANCE
 One of the commonest nutritional disordersOne of the commonest nutritional disorders
 Over 1 billion people live in deficientOver 1 billion people live in deficient
environmentsenvironments
 Affects primarily the thyroid but secondarilyAffects primarily the thyroid but secondarily
may impact on brain developmentmay impact on brain development
 Most preventable cause of mentalMost preventable cause of mental disabilitydisability
 Not limited to developing countriesNot limited to developing countries
 Principles of food fortification to populationsPrinciples of food fortification to populations
 Structural basis of scientific thinking (Kuhn)Structural basis of scientific thinking (Kuhn)

5. Early recognition of goitre withEarly recognition of goitre with
impaired mental abilityimpaired mental ability
"Hence while travelling in a"Hence while travelling in a
certain region in the Countycertain region in the County
Tyrol, under the jurisdictionTyrol, under the jurisdiction
of the Bishop of Gurk, I wasof the Bishop of Gurk, I was
astonished at the very largeastonished at the very large
number ofnumber of madmen, fools andmadmen, fools and
doltsdolts; but when I considered; but when I considered
the frigidity and the humiditythe frigidity and the humidity
of the air, and also perceivedof the air, and also perceived
the crudity of the watersthe crudity of the waters
from the very frequentfrom the very frequent
occurrence ofoccurrence of goitregoitre... all... all
astonishment ceasedastonishment ceased
entirely."entirely."
 EUSTACHIUS RUDIUS, AEUSTACHIUS RUDIUS, A
PHYSICIAN FROMPHYSICIAN FROM
UTRECHTUTRECHT
 (1551-1611)(1551-1611)

6. Thyroid PhysiololgyThyroid Physiololgy

7. Thyroid Function TestsThyroid Function Tests
 TSH, direct measure of thyroidTSH, direct measure of thyroid
hormone actionhormone action
– Different types of thyroid hormoneDifferent types of thyroid hormone
receptorsreceptors
 Free T4, estimatesFree T4, estimates
 Free T3, estimatesFree T3, estimates

8. Iodine is essential for normalIodine is essential for normal
thyroid hormone synthesisthyroid hormone synthesis

9. Na Iodide TransporterNa Iodide Transporter

10. What is normal intake?What is normal intake?
Too little and Too much can be aToo little and Too much can be a
problemproblem

11. Recommended intakesRecommended intakes
The American Thyroid Association has recently recommended that all
women receive 150 µg iodine supplements above their dietary intake
during pregnancy and lactation, and that the iodine content in all prenatal
vitamins should be standardized at 150 µg

12. Sources of iodineSources of iodine
 SaltSalt
 MilkMilk
 BreadBread
 Other foods, eg kelp, seaweed, laverOther foods, eg kelp, seaweed, laver
 MedicationsMedications

13. Sources of iodineSources of iodine
 Dietary iodine Daily intake (µg)Dietary iodine Daily intake (µg)
 Dairy productsDairy products 5252
 GrainsGrains 7878
 MeatMeat 3131
 Mixed dishesMixed dishes 2626
 VegetablesVegetables 2020
 DessertsDesserts 2020
 EggsEggs 1010
 Iodized saltIodized salt 380380
 Other iodine sourcesOther iodine sources(µg)(µg)
 Vitamin/mineral prep (per tablet)Vitamin/mineral prep (per tablet) 150150
 Amiodarone (per tablet)Amiodarone (per tablet) 75,00075,000
 Povidone iodine (per mL)Povidone iodine (per mL) 10,00010,000
 Ipodate (per capsule)Ipodate (per capsule) 308,000308,000

14. Endemic GoitreEndemic Goitre

16. Change in incidence rates of
cancer 1991-2009

17. Top 10 cancers and Top 10 cancer
deaths

18. Trends in incidence (1982-2009)
and death rates (1968-2007)

19. Mortality and incidence ratio

20. Thyroid-Cancer Incidence and Related Mortality in South Korea, 1993–2011.
Ahn HS et al. N Engl J Med 2014;371:1765-1767.

21. Penetration of Thyroid-Cancer Screening (2008–2009) and Incidence of Thyroid Cancer (2009)
in the 16 Administrative Regions of South Korea.
Ahn HS et al. N Engl J Med 2014;371:1765-1767.

22. Rising incidence of thyroid cancer
Over the past few decades an increase in the
incidence of thyroid cancer has been recorded
in many countries around the world, and has
been particularly marked in the Australian state
of New South Wales (NSW).
The reasons for this increase remain unclear, but
heightened medical surveillance and increased
technological sensitivity could be contributing
to greater detection of asymptomatic disease.

23. Objective
To describe the pathways to diagnosis of thyroid
cancer for a cohort of newly diagnosed
patients in NSW and compare these pathways
in groups of people defined by age, gender,
place of residence, ethnic background and
medical insurance status.
Pathways to the diagnosis of thyroid cancer in New South Wales: a population-based
cross-sectional study.Kahn C, Simonella L, Sywak M, Boyages S, Ung O, O'Connell
D.Cancer Causes Control. 2012 Jan; 23(1):35-44. Epub 2011 Oct 15

24. Methods
Newly diagnosed cases of thyroid cancer
(n=452) were identified and recruited through
the population-based NSW Central Cancer
Registry.
Participants completed a questionnaire and diary
of doctor visits and investigations that led to
their diagnosis.
Tumour characteristics were obtained from
pathology reports.

25. Pathways to cancer paper
recruitment

26. Results
60% of patients had their cancer discovered
serendipitously, while 40% initially presented to
their doctor with a lump or symptom specific to
thyroid cancer.
The pathways to diagnosis varied significantly
with tumour size (p=0.001) and also by age in
men and place of residence in women
(p=0.008 and p=0.05 respectively).

27. Pathways of detection for thyroid
cancer NSW
Men n=108 Women n=344 Total n=452 Weighted
Pathway n % n % n % %*
Patient
detected 39 36.1 140 40.7 179 39.6 38.8
Doctor
detected 23 21.3 49 14.2 72 15.9 16.4
Imaging 22 20.4 28 8.1 50 11.1 10.9
After benign
disease 14 13 104 30.2 118 26.1 26.2
Other 10 9.3 23 6.7 33 7.3 7.6
Table 3: Pathways to the diagnosis of thyroid cancer in men and women in NSW, Australia
* Weighted to population distribution by place of residence

28. Factors associated with
pathways to diagnosis
The pathways to diagnosis varied significantly by
age group (p=0.009), sex (p<0.001), tumour size
(p<0.001), spread of cancer at diagnosis
(p=0.006), treatment for another disease at time of
diagnosis (p=0.02), and current work status
(p=0.001).
Variables that were not statistically significantly
associated with the pathways to diagnosis
included health insurance status, education level,
smoking, alcohol consumption, number of other
illnesses, previous cancer, family history of thyroid
cancer, time from last pregnancy for women, and
cancer type.

29. Multi-regression model
After adjusting for all factors in the model the only factor
that differed significantly across the pathway groups
was tumour size (p=0.001).
The odds of a patient with a large tumour (>3cm) being
initially detected by a doctor (vs patient detected) were
66% (OR=0.34, 95% CI 0.1, 0.9) lower than a patient
with a small tumour (<1cm).
Patients with large tumours also had 60% (OR=0.4, 95%
CI 0.2, 0.9) lower odds of being detected after treatment
for benign thyroid disease (vs patient detected) than
patients with a tumour less than 1cm.
Patients with tumours between 2 and 3 cm had 6.85
greater odds (95% CI 2.3, 20.7) of being diagnosed as
an incidental finding of imaging (vs patient detected)
than patients with a tumour less than 1cm.

30. Conclusion
As the majority of participants had serendipitous
diagnoses, the reported incidence of thyroid
cancer is likely to be influenced by diagnostic
technology and medical surveillance practices.

31. Thyroid-Cancer Incidence and Related Mortality in South Korea, 1993–2011.
Ahn HS et al. N Engl J Med 2014;371:1765-1767.

32. Penetration of Thyroid-Cancer Screening (2008–2009) and Incidence of Thyroid Cancer (2009)
in the 16 Administrative Regions of South Korea.
Ahn HS et al. N Engl J Med 2014;371:1765-1767.

33. Dilemma
Nodular thyroid disease is common and the
incidence of thyroid cancer is rising
Increasing cost of over-investigation leading to
the potential for unnecessary surgery and
unnecessary aggressive treatment for thyroid
cancer
Implications for Diagnosis; Surgery; and
radioactive iodine therapy

34. Thyroid cancer models

36. Original Article
Preoperative Diagnosis of Benign Thyroid Nodules
with Indeterminate Cytology
Erik K. Alexander, M.D., Giulia C. Kennedy, Ph.D., Zubair W. Baloch, M.D., Ph.D.,
Edmund S. Cibas, M.D., Darya Chudova, Ph.D., James Diggans, Ph.D., Lyssa
Friedman, R.N., M.P.A., Richard T. Kloos, M.D., Virginia A. LiVolsi, M.D., Susan J.
Mandel, M.D., M.P.H., Stephen S. Raab, M.D., Juan Rosai, M.D., David L.
Steward, M.D., P. Sean Walsh, M.P.H., Jonathan I. Wilde, Ph.D., Martha A.
Zeiger, M.D., Richard B. Lanman, M.D., and Bryan R. Haugen, M.D.
N Engl J Med
Volume 367(8):705-715
August 23, 2012

37. Study Overview
• A significant fraction of fine-needle aspirates obtained from thyroid
nodules are read as indeterminate.
• A new molecular test accurately predicts whether a cytologically
indeterminate nodule is benign 93% of the time, permitting a
conservative approach to management.

38. The Afirma Thyroid FNA Analysis
Process

39. Results
Of the 265 indeterminate nodules, 85 were malignant. The
gene-expression classifier correctly identified 78 of the
85 nodules as suspicious (92% sensitivity; 95%
confidence interval [CI], 84 to 97), with a specificity of
52% (95% CI, 44 to 59).
The negative predictive values for “atypia (or follicular
lesion) of undetermined clinical significance,” “follicular
neoplasm or lesion suspicious for follicular neoplasm,”
or “suspicious cytologic findings” were 95%, 94%, and
85%, respectively.
Analysis of 7 aspirates with false negative results
revealed that 6 had a paucity of thyroid follicular cells,
suggesting insufficient sampling of the nodule.

40. Algorithm for Evaluating Thyroid Nodules.
Jameson JL. N Engl J Med 2012;367:765-767.

41. Conclusions
• These data suggest consideration of a more conservative approach for
most patients with thyroid nodules that are cytologically indeterminate
on fine-needle aspiration and benign according to gene-expression
classifier results.

42. Types of thyroid surgery

43. Type of surgery

45. Should Prophylactic Central (Level 6)
Lymph Node Dissections be Performed?
There is agreement that therapeutic central and lateral lymph node dissections should be
performed at the time of total thyroidectomy when lymph nodes are suspicious or proved to
harbor cancer by sonographic appearance or by FNA analyses preoperatively or when
suspicious lymph nodes are found at operation. Prophylactic lateral lymph node dissections
were common in the past, but have been abandoned for several decades or longer.
Recently, Delbridge and his group and others have proposed that unilateral or bilateral
prophylactic central lymph node dissections (level 6 dissections) with parathyroid
autotransplantation be performed in all cases of papillary thyroid cancer at the time of total
thyroidectomy. This, they state, might decrease mortality from thyroid cancer, would greatly
decrease recurrence of cancer, and would further clarify who needs radioiodine therapy
postoperatively. Some studies by very experienced surgeons demonstrate no increase in
hypoparathyroidism or recurrent laryngeal nerve injuries after this procedure, while other
equally competent surgeons have found an increase in permanent hypoparathyroidism.
We and others do not routinely perform this procedure because of the increased risk of
hypoparathyroidism, but reserve it for cases in which ipsilateral central lymph nodes are clearly
involved with tumor. 27d

46. Minimally invasive thyroidectomy
• No visible neck scar
Axillae, Chest
• Smaller scar
Video assisted endoscopic approach
• Robotic transaxillary thyroidectomy

47. Original Article
Strategies of Radioiodine Ablation in Patients with
Low-Risk Thyroid Cancer
Martin Schlumberger, M.D., Bogdan Catargi, M.D., Ph.D., Isabelle Borget, Pharm.D.,
Ph.D., Désirée Deandreis, M.D., Slimane Zerdoud, M.D., Boumédiène Bridji, M.D.,
Ph.D., Stéphane Bardet, M.D., Laurence Leenhardt, M.D., Ph.D., Delphine
Bastie, M.D., Claire Schvartz, M.D., Pierre Vera, M.D., Ph.D., Olivier Morel, M.D.,
Danielle Benisvy, M.D., Claire Bournaud, M.D., Françoise Bonichon, M.D., Catherine
Dejax, M.D., Marie-Elisabeth Toubert, M.D., Sophie Leboulleux, M.D., Marcel
Ricard, Ph.D., Ellen Benhamou, M.D., for the Tumeurs de la Thyroïde Refractaires
Network for the Essai Stimulation Ablation Equivalence Trial
N Engl J Med
Volume 366(18):1663-1673
May 3, 2012

48. Study Overview
• This trial compared two thyrotropin-stimulation methods and two 131
I
doses for postoperative ablation in patients with low-risk thyroid
cancer.
• Rates of ablation were similar in all treatment groups.
• Doses lower than those currently recommended may be adequate for
this condition.

49. Randomization and Follow-up of the Study Patients.
Schlumberger M et al. N Engl J Med 2012;366:1663-1673

50. Initial Characteristics of the 752 Randomized Patients, According to Thyrotropin-Stimulation
Method and 131
I Dose.
Schlumberger M et al. N Engl J Med 2012;366:1663-1673

51. Follow-up Testing of Thyroid Ablation 6–10 Months after 131
I Administration in the 684 Patients
Who Could Be Evaluated, According to Thyrotropin-Stimulation Method and 131
I Dose.
Schlumberger M et al. N Engl J Med 2012;366:1663-1673

52. Adverse Events, According to Thyrotropin-Stimulation Method and 131
I Dose.
Schlumberger M et al. N Engl J Med 2012;366:1663-1673

53. Conclusions
• The use of recombinant human thyrotropin and low-dose (1.1 GBq)
postoperative radioiodine ablation may be sufficient for the
management of low-risk thyroid cancer.

54. Original Article
Ablation with Low-Dose Radioiodine and
Thyrotropin Alfa in Thyroid Cancer
Ujjal Mallick, F.R.C.R., Clive Harmer, F.R.C.P., Beng Yap, F.R.C.P., Jonathan
Wadsley, F.R.C.R., Susan Clarke, F.R.C.P., Laura Moss, F.R.C.P., Alice
Nicol, Ph.D., Penelope M. Clark, F.R.C.Path., Kate Farnell, R.C.N., Ralph
McCready, D.Sc., James Smellie, M.D., Jayne A. Franklyn, F.Med.Sci., Rhys
John, F.R.C.Path., Christopher M. Nutting, M.D., Kate Newbold, F.R.C.R., Catherine
Lemon, F.R.C.R., Georgina Gerrard, F.R.C.R., Abdel Abdel-Hamid, F.R.C.R., John
Hardman, F.R.C.R., Elena Macias, M.D., Tom Roques, F.R.C.R., Stephen
Whitaker, M.D., Rengarajan Vijayan, F.R.C.R., Pablo Alvarez, M.Sc., Sandy
Beare, Ph.D., Sharon Forsyth, B.Sc., Latha Kadalayil, Ph.D., and Allan
Hackshaw, M.Sc.
N Engl J Med
Volume 366(18):1674-1685
May 3, 2012

55. Study Overview
• In this trial, low-dose radioiodine was as effective as high-dose
radioiodine in patients with differentiated thyroid tumors, and
recombinant human thyrotropin (thyrotropin alfa) was as effective as
thyroid hormone withdrawal.

56. Days of Hospital Isolation, According to Radioiodine Dose.
Mallick U et al. N Engl J Med 2012;366:1674-1685

57. Baseline Characteristics of the Patients.
Mallick U et al. N Engl J Med 2012;366:1674-
1685

58. Symptoms Reported by Patients during the 4 Weeks before Ablation.
Mallick U et al. N Engl J Med 2012;366:1674-1685

59. Conclusions
• Low-dose radioiodine plus thyrotropin alfa was as effective as high-
dose radioiodine, with a lower rate of adverse events.

60. RAI resistance
The cure rates for DTC are generally high when
patients are treated with surgery or RAI. However,
between 5% and 15% of patients develop RAI
resistance, and these patients typically have an
expected survival of 2.5 to 3.5 years.
No standard therapy exists for patients who
experience disease progression.
New agents that either induce sodium iodide
symporter activity or that inhibit tyrosine kinase
inhibitor
o Sorafenib
o Selumetinib

61. Inhibitors of kinase signalling pathways
in tumour cells and vascular
endothelial cells

63. Sorefenib
Sorafenib, a tyrosine kinase inhibitor, inhibits multiple kinases,
including the Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3,
PDGFR-B, KIT, FLT-3 and RET, which are associated with
tumor cell proliferation and angiogenesis.
The drug is currently approved by the FDA to treat unresectable
hepatocellular carcinoma and advanced renal cell carcinoma.

64. Original Article
Selumetinib-Enhanced Radioiodine Uptake in
Advanced Thyroid Cancer
Alan L. Ho, M.D., Ph.D., Ravinder K. Grewal, M.D., Rebecca Leboeuf, M.D., Eric J.
Sherman, M.D., David G. Pfister, M.D., Desiree Deandreis, M.D., Keith S. Pentlow,
M.Sc., Pat B. Zanzonico, Ph.D., Sofia Haque, M.D., Somali Gavane, M.D., Ronald A.
Ghossein, M.D., Julio C. Ricarte-Filho, Ph.D., José M. Domínguez, M.D., Ronglai
Shen, Ph.D., R. Michael Tuttle, M.D., Steve M. Larson, M.D., and James A. Fagin,
M.D.
N Engl J Med
Volume 368(7):623-632
February 14, 2013

65. Inhibitors of kinase signalling pathways
in tumour cells and vascular
endothelial cells

66. Study Overview
• Inhibition of mitogen-activated protein kinase resulted in an increase in
expression of the sodium–iodide symporter in 12 of 20 patients, 8 of
whom had sufficient uptake to warrant treatment with radioiodine.
• Five patients had a response, and 3 had stable disease.

67. Protocol Design and Changes in Iodine Uptake.
Ho AL et al. N Engl J Med 2013;368:623-632

68. Iodine-124 PET-CT Scans Obtained before and after Selumetinib Treatment in Selected Patients
with Positive Responses.
Ho AL et al. N Engl J Med 2013;368:623-632

69. Quantification of Iodine-124 PET Uptake in a Lesion in a Patient with an NRAS Mutation Who
Later Received Radioiodine.
Ho AL et al. N Engl J Med 2013;368:623-632

70. Conclusions
• Selumetinib produces clinically meaningful increases in iodine uptake
and retention in a subgroup of patients with thyroid cancer that is
refractory to radioiodine; the effectiveness may be greater in patients
with RAS-mutant disease.

71. Original Article
Lenvatinib versus Placebo in Radioiodine-
Refractory Thyroid Cancer
Martin Schlumberger, M.D., Makoto Tahara, M.D., Ph.D., Lori J. Wirth, M.D., Bruce
Robinson, M.D., Marcia S. Brose, M.D., Ph.D., Rossella Elisei, M.D., Mouhammed
Amir Habra, M.D., Kate Newbold, M.D., Manisha H. Shah, M.D., Ana O. Hoff, M.D.,
Andrew G. Gianoukakis, M.D., Naomi Kiyota, M.D., Ph.D., Matthew H. Taylor, M.D.,
Sung-Bae Kim, M.D., Ph.D., Monika K. Krzyzanowska, M.D., M.P.H., Corina E.
Dutcus, M.D., Begoña de las Heras, M.D., Junming Zhu, Ph.D., and Steven I.
Sherman, M.D.
N Engl J Med
Volume 372(7):621-630
February 12, 2015

72. Study Overview
• In a phase 3, placebo-controlled study, lenvatinib was associated with a
significant increase in progression-free survival (18.3 months vs. 3.6
months).
• Toxic effects with lenvatinib were substantial and included hypertension,
diarrhea, and unexplained death.

73. Enrollment, Randomization, and Treatment.
Schlumberger M et al. N Engl J Med
2015;372:621-630

74. Kaplan–Meier Estimate of Progression-free Survival in the Intention-to-Treat Population.
Schlumberger M et al. N Engl J Med 2015;372:621-630

75. Baseline Characteristics in the Intention-to-Treat Population.
Schlumberger M et al. N Engl J Med
2015;372:621-630

76. Efficacy Measures.
Schlumberger M et al. N Engl J Med 2015;372:621-630

77. Adverse Effects.
Schlumberger M et al. N Engl J Med 2015;372:621-630

78. Conclusions
• Lenvatinib, as compared with placebo, was associated with significant
improvements in progression-free survival and the response rate among
patients with iodine-131–refractory thyroid cancer.
• Patients who received lenvatinib had more adverse effects.

79. Inhibitors of kinase signalling pathways
in tumour cells and vascular
endothelial cells