thyroid management with emphasis on radioactive iodine

1. By Dr. SAADVIK R Y
JR-1

2. INTRODUCTION
The thyroid gland is located in the central anterior neck at
the cervical–thoracic junction.
The bulk of the gland is located immediately anterior and
inferior to the thyroid cartilage.
It has two lateral lobes connected by a central isthmus.
The average adult thyroid gland measures approximately 5
× 5 cm and weighs 10 to 20 g.

4. The first-echelon nodes for thyroid cancer metastases are level 6
(the central or “visceral” compartment) between the hyoid bone
and the thoracic inlet,these include
paralaryngeal,
paratracheal, and
prelaryngeal (Delphian) nodes.
Second-echelon nodal spread is to the
mid- and lower cervical nodes (levels 3 and 4),
supraclavicular nodes, upper mediastinal nodes
(level 7), and
to a lesser extent the upper cervical nodes (level
2).
Retropharyngeal node involvement is unusual but can be
encountered in the setting of advanced nodal disease.
Level 1 (submental and submandibular) lymph nodes are rarely
involved.

5. PHYSIOLOGY-
The primary physiologic role is the production of thyroid hormone, which plays an important role in metabolic homeostasis.
A secondary role is the production of calcitonin, a hormone involved in calcium homeostasis.
The follicular cells of the thyroid gland synthesize and secrete thyroglobulin(Tg) and thyroid hormone in two biologically active forms,
thyroxine (3,5,3′,5′ iodothyronine or T4) and
triiodothyronine (3,5,3′ iodothyronine or T3).
T4 is considered the storage and transport form of the hormone and T3 is considered the metabolically active form.

6. NaIS is also present in the
• parotid glands,
• breast tissues,
• gastric mucosa, and
• nasolacrimal ducts,
placing them at risk for injury from RAI therapy.

7. PATHOLOGICAL CLASSIFICATION
BASED ON DIFFERENTIATION
WELL DIFFERENTIATED(LOW GRADE MALIGNANCY) POORLY DIFFERENTIATED( HIGH GRADE MALIGNANCY)
• Usual papillary thyroid carcinoma(PTC) Anaplastic (undifferentiated)
• Microcarcinoma(lesions <1cm)
• Cystic
• Follicular variant of PTC
• Usual follicular thyroid carcinoma (FTC)
• Hurthle cell carcinoma (HCC)
INTERMEDIATE DIFFERENTIATION
• Medullary thyroid carcinoma(MTC)
• Diffuse sclerosing variant of papillary carcinoma
• Columnar cell variant of papillary carcinoma
• Insular carcinoma
• Tall cell variant of papillary carcinoma

8. EPIDEMIOLOGY
INDIAN STATISTICS- 2012
THYROID
CANCER
INCIDENCE
MORTALIT
Y
PREVELAN
CE
NUMBE
R
%
NUMBE
R
%
NUMBE
R
%
MALE 3960 0.8 953 0.3 15562 2.3
FEMAL
E
9944 1.9 2337 0.7 39977 3.6

9. Thyroid cancer is the most commonly diagnosed endocrine cancer.
There will be an estimated 48,000 new thyroid cancer diagnoses and
1,740 thyroid cancer deaths in the United States by the end of 2011.
There is a strong female prevalence.
DTC comprises the overwhelming majority (94%) of new thyroid cancer
diagnoses.
Approximately 5% are medullary thyroid carcinoma and 1% are
anaplastic thyroid carcinoma.
• Siegel R, Ward E, Brawley O, et al. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial
disparities on premature cancer deaths. CA Cancer J Clin 2011;61:212–236.
• Aschebrook-Kilfoy B, Ward MH, Sabra MM, et al. Thyroid cancer incidence patterns in the United States by
histologic type, 1992–2006. Thyroid 2011;21:125–134.
• Sherman SI. Thyroid carcinoma. Lancet 2003;361:501–511.

10. The incidence of thyroid cancer increases with age with a
peak incidence at
• 40 to 44 years for women and
• 65 to 69 years for men.
The peak incidence for ATC is at 60 years for both sexes.

11. CLINICAL MANIFESTATIONS OF THYROID
CANCER
The most common presentation
• asymptomatic thyroid nodule found incidentally by the patient,
clinicians, or on an imaging study performed for other reasons.
Palpable thyroid nodules occur in 3% to 4% of the normal population,
and their incidence at autopsy has been reported as high as 50%
• Mortensen JD, Woolner LB, Bennett WA. Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol Metab
1955;15:1270–1280.
• Vander JB, Gaston EA, Dawber TR. The significance of nontoxic thyroid nodules. Final report of a 15-year study of the incidence of
thyroid malignancy. Ann Intern Med 1968;69:537–540.
• Nixon IJ, Ganly I, Hann LE, et al. Nomogram for predicting malignancy in thyroid nodules using clinical, biochemical,
ultrasonographic, and cytologic features. Surgery 2010;148:1120–1127.

12. Positive findings on history and physical examination that raise
suspicion that a thyroid nodule is malignant include
• rapid growth,
• firmness,
• fixation,
• vocal cord paralysis,
• cervical adenopathy,
• stridor,
• dysphagia.

13. DIAGNOSTIC EVALUATION OF
THYROID CANCER
LABORATORY STUDIES-
serum TSH,
Routine measurement of serum Tg for initial evaluation of
thyroid nodules is not recommended.
Serum calcitonin can be measured during the initial
evaluation of patients with MTC and is essential during
follow-up for these patients.

14. ULTRASOUND AND ULTRASOUND-GUIDED FINE-
NEEDLE ASPIRATE-
characteristics of a thyroid nodule associated with a higher
likelihood of malignancy include
• nodule hypoechogenicity compared to the normal thyroid
parenchyma,
• increased intranodular vascularity,
• irregular infiltrative margins,
• the presence of microcalcifications,
• an absent halo.

15. Routine FNA is not recommended for subcentimeter nodules.
Indications for FNA in subcentimeter nodules are
1) family history of PTC
2) history of external beam radiation exposure as a child
3) exposure to ionizing radiation in childhood or adolescence
4) history of prior hemithyroidectomy with discovery of thyroid
cancer; and
5)FDG-PET–positive thyroid nodules.
Subcentimeter nodule with a suspicious appearance and
when detection of abnormal lymph nodes should lead to FNA
of the lymph node.

16. COMPUTED TOMOGRAPHY AND MAGNETIC RESONANCE
IMAGING-
CT and MRI commonly detect otherwise clinically occult thyroid nodules.
MRI is superior to CT for establishing the local extent of a known cancer,
because it will more clearly show esophageal or tracheal invasion.
MRI is indicated in the presence of
hoarseness,
stridor,
dysphagia.
The ATA doesn’t recommend the routine preoperative use of imaging
studies (CT, MRI, PET).

17. NUCLEAR MEDICINE STUDIES-

18. FDG-PET is another nuclear medicine study that is
commonly used to detect metastatic disease, but the
predictive value of PET in thyroid cancer is not well defined.
TSH stimulation increases the accuracy of FDG-PET in
most types of DTC.

19. PROGNOSTIC FACTORS
The most important prognostic factor for disease recurrence and cancer mortality is the
histologic classification.
DTC, when diagnosed in an early stage, has a favorable prognosis.
Tall-cell variant can have a 10-year mortality of up to 25%.
Hürthle cell carcinoma carries a relatively poor prognosis, with a 25% rate of metastatic
disease and decreased survival at 10 years of 76%, compared with 93% and 85% for PTC
and FC, respectively.
Columnar cell variant and diffuse-sclerosing variants carry a poor prognosis relative to other
forms of DTC.
Follicular-variant PTC and most FC share the same favorable prognosis as classic PTC
relative to age and stage at diagnosis.
ATC has an abysmal prognosis. All ATCs are considered stage IV under the current AJCC
system and the overall 5-year survival is approximately 5%.

20. • NCCN guidelines for thyroid carcinoma: National Comprehensive Cancer Network 2011.
• Ruegemer JJ, Hay ID, Bergstralh EJ, et al. Distant metastases in differentiated thyroid
carcinoma: a multivariate analysis of prognostic variables. J Clin Endocrinol Metab
1988;67:501–508.
• Samaan NA, Schultz PN, Haynie TP, et al. Pulmonary metastasis of differentiated
thyroid carcinoma: treatment results in 101 patients. J Clin Endocrinol Metab
1985;60:376–380.

21. Within the classification of DTC there are several important prognostic factors, as
shown in the table-

22. STAGING-

24. SURGICAL MANAGEMENT OF
THYROID CANCER
Surgery is the primary treatment of localized thyroid cancer
of all histologies.
A total thyroidectomy is the preferred surgery.
Subtotal thyroidectomy, leaving >1 g of tissue with the
posterior capsule on the uninvolved side, is an
inappropriate operation for thyroid cancer.
It is critical to understand that even a total thyroidectomy
leaves residual thyroid tissue that will have major
implications for subsequent therapy and disease
monitoring.

25. Total thyroidectomy recommendations-
• If the primary thyroid carcinoma is >1 cm
• There are contralateral thyroid nodules present or
• Regional or distant metastases are present,
• The patient has a personal history of radiation therapy
to the head and neck, or
• The patient has first-degree family history of DTC.
Bilimoria KY, Bentrem DJ, Ko CY, Stewart AK, Winchester DP, Talamonti MS, Sturgeon C 2007 Extent of surgery affects survival for papillary thyroid cancer. Ann Surg
246:375–381.
Older age (>45 years) may also be a criterion for
recommending near-total or total thyroidectomy even with
tumors <1–1.5 cm, because of higher recurrence rates in
this age group.
Rubino C, de Vathaire F, Dottorini ME, Hall P, Schvartz C, Couette JE, Dondon MG, Abbas MT, Langlois C, Schlumberger M 2003 Second primary malignancies in thyroid
cancer patients. Br J Cancer 89:1638–1644.Thyroid lobectomy alone may be sufficient treatment for

26. Thyroid lobectomy is sufficient when-
• small (<1 cm),
• low-risk,
• unifocal,
• intrathyroidal papillary carcinomas in the absence of
• prior head and neck irradiation or
• radiologically or clinically involved cervical
nodal metastases.

27. LYMPH NODE DISSECTION
Therapeutic central-compartment (level VI) neck dissection for patients
with clinically involved central or lateral neck lymph nodes should
accompany total thyroidectomy to provide clearance of disease from the
central neck.
Prophylactic central-compartment neck dissection (ipsilateral or bilateral)
may be performed in patients with papillary thyroid carcinoma with
clinically uninvolved central neck lymph nodes, especially for advanced
primary tumors (T3 or T4).
Near-total or total thyroidectomy without prophylactic central neck
dissection may be appropriate for small (T1 or T2), noninvasive,
clinically node-negative PTCs and most follicular cancer.

28. Therapeutic lateral neck compartmental lymph node
dissection should be performed for patients with metastatic
lateral cervical lymphadenopathy.
White ML, Gauger PG, Doherty GM 2007 Central lymph node dissection in differentiated thyroid cancer.
World J Surg 31:895–904
The ATA Surgery Working Group 2009 Consensus Statement on the Terminology and Classification of
Central Neck Dissection for Thyroid Cancer. Thyroid 19:1153–1158
.Kupferman ME, Patterson M, Mandel SJ, LiVolsi V, Weber RS 2004 Patterns of lateral neck metastasis in
papillary thyroid carcinoma. Arch Otolaryngol Head Neck Surg 130:857–860.
Kupferman ME, Patterson DM, Mandel SJ, LiVolsi V, Weber RS 2004 Safety of modified radical neck
dissection for differentiated thyroid carcinoma. Laryngoscope 114:403–406.

29. Low-risk patients:
1) No local or distant metastases;
2) All macroscopic tumor has been resected;
3) There is no tumor invasion of locoregional tissues or
structures;
4) The tumor does not have aggressive histology (e.g., tall
cell, insular, columnar cell carcinoma) or vascular invasion;
5) And, if 131I is given, there is no 131I uptake outside the
thyroid bed on the first posttreatment whole-body RAI scan
(RxWBS)

30. Intermediate-risk patients:
1) Microscopic invasion of tumor into the perithyroidal soft
tissues at initial surgery;
2) Cervical lymph node metastases or 131I uptake outside the
thyroid bed on the RxWBS done after thyroid remnant
ablation or
3) Tumor with aggressive histology or vascular invasion.
High-risk patients :
1) macroscopic tumor invasion,
2) incomplete tumor resection,
3) distant metastases, and possibly
4) thyroglobulinemia out of proportion to what is seen on the
posttreatment scan.

31. ROLE OF POSTOPERATIVE RAI
REMNANT ABLATION
RAI ablation is recommended for all patients
• with known distant metastases,
• gross extrathyroidal extension of the tumor regardless of tumor size,
or
• primary tumor size >4 cm even in the absence of other higher risk
features
RAI ablation is recommended for selected patients with
• 1–4 cm thyroid cancers confined to the thyroid,
• who have documented lymph node metastases, or
• other higher risk features when the combination of age, tumor size,
lymph node status, and individual histology predicts an intermediate
to high risk of recurrence or death from thyroid cancer
RAI ablation is not recommended for patients with
• unifocal cancer <1 cm without other higher risk features
• multifocal cancer when all foci are <1 cm in the absence other higher
risk features

32. HOW SHOULD PATIENTS BE PREPARED FOR RAI
ABLATION?
Remnant ablation requires TSH stimulation.
TSH of >30 mU/L is associated with increased RAI uptake in
tumors ,
Endogenous TSH elevation can be achieved by two basic
approaches to thyroid hormone withdrawal,
• stopping LT4 and switching to LT3 for 2–4 weeks followed
by withdrawal of LT3 for 2 weeks, or
• discontinuation of LT4 for 3 weeks without use of LT3.
Both methods of preparation can achieve serum TSH levels
>30 mU/L in >90% of patients
A low-iodine diet for 1–2 weeks is recommended for patients
undergoing RAI remnant ablation, particularly for those patients
with high iodine intake.

33. For most patients, including those unable to tolerate hypothyroidism or
unable to generate an elevated TSH, remnant ablation can be achieved with
rhTSH.
A recent study has shown that ablation rates were similar with either
withdrawal or preparation with rhTSH.
Recombinant human TSH is approved for remnant ablation in the United
States, Europe, and many other countries around the world.
Chianelli M, Todino V, Graziano F, Panunzi C, Pace D, Guglielmi R, Signore A, Papini E 2009 Low dose (2.0 GBq; 54 mCi) radioiodine postsurgical remnant ablation in thyroid cancer: comparison between hormone withdrawal
and use of rhTSH in low risk patients. Eur J Endocrinol 160:431–436
Tuttle RM, Brokhin M, Omry G, Martorella AJ, Larson SM, Grewal RK, Fleisher M, Robbins RJ 2008. Recombinant human TSH-assisted radioactive iodine remnant ablation achieves short-term clinical recurrence rates similar
to those of traditional thyroid hormone withdrawal. J Nucl Med 49:764–770

34. ACTIVITY OF 131I SHOULD BE USED FOR REMNANT
ABLATION
The minimum activity (30–100 mCi) necessary to achieve
successful remnant ablation and should be utilized,
particularly for low-risk patients.
If residual microscopic disease is suspected or
documented, or if there is a more aggressive tumor
histology (e.g., tall cell, insular, columnar cell carcinoma),
then higher activities (100–200 mCi) may be appropriate
Rosario PW, Reis JS, Barroso AL, Rezende LL, Padrao EL, Fagundes TA 2004 Efficacy of low and high 131I doses for thyroid remnant ablation in patients with differentiated
thyroid carcinoma based on post-operative cervical uptake. Nucl Med Commun 25:1077–1081
Maenpaa HO, Heikkonen J, Vaalavirta L, Tenhunen M, Joensuu H 2008 Low vs. high radioiodine activity to ablate the thyroid after thyroidectomy for cancer: a randomized
study. PLoS ONE 3:e1885.

35. POSTSURGERY AND ‘RAI’ THERAPY EARLY
MANAGEMENT OF DTC
Initial TSH suppression to below 0.1 mU/L is recommended
for high-risk and intermediate-risk thyroid cancer patients.
Maintenance of the TSH at or slightly below the lower limit
of normal (0.1–0.5 mU/L) is appropriate for low-risk patients.
McGriff NJ, Csako G, Gourgiotis L, Lori CG, Pucino F, Sarlis NJ 2002 Effects of thyroid hormone suppression therapy on adverse clinical outcomes in thyroid cancer. Ann Med
34:554–564.
Brabant G 2008 Thyrotropin suppressive therapy in thyroid carcinoma: what are the targets? J Clin Endocrinol Metab 93:1167–1169

36. RADIATION SAFETY AFTER TREATMENT WITH 131I OF
PATIENTS
To release a patient treated with 131I from physician’s control
• The radiation exposure to any other individual (generally, a family
member) encountering the patient will likely not exceed 5 mSv
(500 mrem) per annum,
• The radiation dose to a child, a pregnant woman, or an individual not
involved in the care of the patient will not exceed 1 mSv (100 mrem) per
annum
• Patients should avoid public transportation.
• The patient must be capable of self-care, cannot live in a nursing home
or communal living facility.
• Patients must be given radiation safety instructions.

37. Women receiving RAI therapy should avoid pregnancy for 6–12
months.
Patients receiving therapeutic doses of RAI should have baseline CBC
and assessment of renal function.
Patients should sleep alone and at least 6 feet away from any other
individual throughout the nighttime restricted period. Use of a separate
bedroom or sleeping area would be best.
Urine is the primary excretion route for RAI and is maximal during the
first 48 hours after treatment. Sufficient fluid (3–4 L/day) should be
consumed to enable frequent urination.
Emptying of the bowel moderately reduces radiation to the patient and
also to individuals nearby.
Since RAI concentrations are present in the saliva for as long as 7
days, patients should avoid kissing, especially of children, for the period

38. ADVERSE EFFECTS OF IODINE-
131

39. EXTERNAL BEAM RADIOTHERAPY
FOR THYROID CANCER
There are no randomized control trials defining the indications for external
beam radiotherapy (EBRT) in thyroid cancer.
In general, only patients with unresectable tumor are treated with primary
EBRT.
ATA recommends EBRT
• age</=18 yr- metastasis(symptomatic), critical locations that are
otherwise untreatable.
• age 19 to 45 yr-metastasis(symptomatic), critical locations that are
otherwise untreatable.
• age> 45yr- gross ETE, gross residual tumour not amenable to furhter
surgery.

40. EXTERNAL BEAM
RADIOTHERAPY TECHNIQUE
CT simulation is used for treatment planning with patients positioned supine
with arms at their side and the neck extended such that the mandible is at
90 degrees with respect to the treatment couch.
Axial CT images are acquired from above the skull base to the middle of
the chest.
conventional anterior posterior/posterior anterior or lateral fields have been
described to treat thyroid cancer, often requiring custom bolus materials to
ensure homogenous dose distributions.
Because the target volume straddles the level of the shoulder and, in nearly
all cases, contains concavities with envaginated critical normal tissues,
therefore it useful to treat patients with intensity-modulated radiotherapy
(IMRT).

41. AP-PA photon fields
▪superior border at level of
mastoid processes, shield
mandible
▪ lateral borders covering medial
2/3 of clavicles
▪ inferior border usually just below
carina

42. TARGET VOLUMES AND DOSE-
The gross tumor volume (GTV) will be any residual gross disease.
Two CTVs:
• the high-risk CTV corresponds to the region at highest risk for
residual disease (positive margin, ETE, lymph node with
extracapsular disease, or gross residual disease) and
• the standard-risk CTV, which is the region at moderate risk for
residual disease (electively irradiated nodal stations).(upper
mediastinal nodes should also be included)
The dose prescribed is 66 to 70 Gy to the high-risk PTV and 54 to
56 Gy to the standard-risk PTV in 33 to 35 fractions using a single
IMRT plan with a simultaneous integrated boost.

43. Intensity-
modulated
radiation therapy
clinical target
volume
contouring atlas
for a patient with
T2N0M0 insular
thyroid carcinoma
status post total
thyroidectomy
and radioactive
iodine.

44. EXTERNAL BEAM RADIOTHERAPY TOXICITY-
The acute toxicities reported include
mucositis,
pharyngitis,
dysphagia,
hoarseness,
radiation dermatitis,
weight loss, and malnutrition.
Late complications include fibrosis and atrophy of the skin, lung apices, and neck
musculature and tracheal and esophageal stenosis.
The most commonly reported severe late complication is esophageal stenosis.

45. FOLLOW UP OF DTC-

46. CHEMOTHERAPY AND TARGETED AGENTS FOR
DIFFERENTIATED THYROID CARCINOMA-
As per the present ATA guidelines there is no role for the routine
adjunctive use of chemotherapy in patients with DTC.
Agents currently under investigation target specific pathways involving
inhibition of tyrosine kinase (TKI) receptors ,inhibition of vascular
endothelial growth factor receptors (VEGFR).
• Axitinib
• Motesanib
• Sorafenib and sunitinib
Motesanib, an oral TKI, was studied in a phase II trial and demonstrated
an 81% rate of disease control with a median progression-free survival
of 9.3 months.

47. A recent phase III, randomized, double blind trial for
patients with RAI refractory DTC published in Lancet.
Patients received either sorafenib or placebo.
There was an improvement in the PFS of 10.8 months vs
5.8 months in the placebo arm.
• Brose MS, Nutting CM, Jazrab B et al., Lancet 2014 Jul. PMID 24768112.

48. MANAGEMENT OF MEDULLARY
THYROID CARCINOMA
All patients with MTC should be tested for RET mutations,
including sporadic cases. Genetic screening and testing is
also indicated.
Initial primary management of localized MTC is total
thyroidectomy, which is the only completely effective therapy.
Central neck dissection should be performed in all cases and
compartment-oriented lateral neck dissection is indicated
when clinically involved.
There is no role for adjuvant RAI therapy.

49. All patients should be followed with serum calcitonin levels as this presents a sensitive
and specific marker for extent of residual disease.
The indications for EBRT in a patient with MTC depend on the patient’s age.
In children (<18 years old), EBRT is reserved for
• palliation of symptoms from tumors not amenable to other treatment or
• when tumor progression is likely to cause normal tissue damage.
For adults, EBRT is indicated
• unresectable gross disease or
• when there is a high risk of residual microscopic disease after total
thyroidectomy based on pathologic evaluation revealing positive margins,
• T4 primary tumors, or
• nodal metastases with extensive extracapsular extension.

50. Traditional cytotoxic systemic therapies have largely been
ineffective in the management of metastatic or recurrent
MTC;
Results of a recent phase III clinical trial comparing
cabozantinib(tyrosine kinase inhibitor of MET, VGEF2 and
RET) vs placebo in medullary thyroid cancer were recent
published. The study found a 28% response rate in those
receiving the study drug vs 0% in the placebo arm. There
was an associated improvement in PFS at 1 yr from 7.2%
to 47.3% in the cabozantinib arm.
Elisei R, Schlumberger MJ, Muller SP, et al.,J clin Oncol.2013oct. PMID
24002501.

51. MANAGEMENT OF ANAPLASTIC
THYROID CARCINOMA
Most ATC presents with extraglandular disease and it is not clear that
any form of therapy improves outcomes.
Complete surgical excision should be the goal of initial therapy, when
feasible.
However, surgery should be avoided when complete excision is not
possible as debulking does not improve outcomes.
There is no therapeutic role for RAI.
EBRT is the standard of care for palliation of local symptoms from
unresectable disease or as adjuvant therapy in the rare case of a
completely resected tumor.