Differential thyroid Carcinoma

1. DIFFERENTIATED THYROID
CARCINOMA
DR LAVANYA BONNY
SR, DEPT OF ENDOCRINOLOGY
ST JOHNS MEDICAL COLLEGE
BANGALORE

2. EPIDEMIOLOGY
■ 5% to 10% of all thyroid nodules
■ 1% to 2% of all solid human malignancies
■ median age at diagnosis - 45 to 50 years
■ rare in patients younger than 16 years old
■ F:M = 3:1
■ Favourable prognosis – lower cancer deaths

3. EPIDEMIOLOGY
■ Most curable cancer
■ The rate of death from thyroid cancer is stable, confirming that the increase is the
result of the discovery of subclinical, indolent tumors.

4. EPIDEMIOLOGY
■ prevalent histotype is PTC both in iodine sufficient or iodine-deficient areas
■ In iodine deficient areas, ratio of FTC/PTC is nearly the same
■ iodine-sufficient areas - PTC is predominant

5. ETIOLOGY
■ RADIATION EXPOSURE
■ strong positive association between radiation dose and thyroid carcinoma
■ strong inverse relationship between age at exposure and radiation-related
thyroid carcinoma risk
■ Women more sensitive to the effects of radiation

6. ETIOLOGY
■ RADIATION EXPOSURE
■ latency period between exposure and diagnosis is usually 5 years
■ maximal at about 20 years
■ remains high for about 20 years, and then decreases gradually

7. ETIOLOGY
■ RADIATION EXPOSURE
■ linear dose response relationship between external irradiation and thyroid
cancer
■ From doses as low as 10 cGy and up to 1500 cGy.
■ Beyond this, risk decreases - thyroid cell killing
■ Diagnostic or therapeutic administration of 131I to adults – no increased risk
for thyroid cancer

8. ETIOLOGY

9. ETIOLOGY
■ PREEXISTING THYROID DISEASE
■ Thyroid carcinoma is often preceded by other thyroid abnormalities - endemic
and sporadic goiter, benign thyroid nodules, lymphocytic thyroiditis, and GD
■ history of goiter or benign thyroid nodules is a strong thyroid carcinoma risk
factor
■ Coexistence of Hashimoto's disease and GD with thyroid carcinoma is higher
than expected

10. ETIOLOGY
■ HORMONAL AND REPRODUCTIVE FACTORS
■ more frequent in women than men - hormonal factors are involved in its
pathogenesis
■ Difference between females and males in thyroid cancer incidence rates
declines consistently with age
■ significant trend for increasing risk with increasing parity was demonstrated in
a Norwegian study

11. ETIOLOGY
■ HORMONAL AND REPRODUCTIVE FACTORS
Suggested risk factors for thyroid carcinoma in women are
■ exogenous estrogens, including OCPs
■ lactation suppressant drugs
■ postmenopausal estrogen therapy
■ fertility drugs, particularly clomiphene and progesterone
■ generally weak and are not consistent across studies

12. ETIOLOGY
■ DIETARY FACTORS
■ Iodine
■ Effects of iodine intake on cancer incidence is not consistent among studies
■ effects of iodine intake on specific histologic types of thyroid carcinomas are
clearer.
■ In endemic goiter areas, FTCs are more common
■ In Hawaii (high iodine intake) – more PTC

13. ETIOLOGY
■ DIETARY FACTORS
■ Iodine
■ When iodine supplementation is introduced into an iodine-insufficient area,
the ratio of papillary to follicular carcinomas increases
■ Iodine supplementation may also lower the incidence of anaplastic thyroid
carcinoma, as found in some studies

14. ETIOLOGY
■ ANTHROPOMORPHIC AND METABOLIC FACTORS
■ recent studies find a positive relationship between weight and thyroid
carcinoma.
■ Changes in hormonal metabolism and levels of inflammation have been
proposed as mechanisms

15. ETIOLOGY
■ ANTHROPOMORPHIC AND METABOLIC FACTORS
■ TSH levels are a possible factor in the interrelationship of obesity, the
metabolic syndrome, and thyroid carcinoma.
■ They are positively associated with increasing BMI

16. ETIOLOGY
■ SMOKING AND OTHER ENVIRONMENTAL AGENTS
■ Case-control studies - uniformly found that cigarette smoking is associated
with a decreased risk for thyroid carcinoma
■ Protective effect was present in both men and women and was proportional to
measures of the extent of smoking
■ Reason not clear

17. ETIOLOGY
■ SMOKING AND OTHER ENVIRONMENTAL AGENTS
■ Occupational studies - strongest association for workers in the wood, leather,
and pulp and papermaking industries
■ Jobs resulting in prolonged (10 years or more) exposure to benzene and
formaldehyde were associated with thyroid carcinoma

18. ETIOLOGY
■ ONCOGENES
■ most frequent mutational event in DTC - point mutations of the BRAF gene.
■ Frequency of 40% in PTC
■ 10 % in FTC
■ can be seen also in anaplastic and poorly differentiated thyroid neoplasms
■ correlates with aggressive tumor characteristics such as tall cell variant,
extrathyroidal extension, advanced tumor stage at presentation, and lymph node
or distant metastases

19. ETIOLOGY
■ ONCOGENES
■ Rearrangements involving the RET and TRK protooncogenes - causative events
specific for a subset of PTC
■ In the case of RET rearrangements, the resulting chimeric oncogenes have
been called PTC
■ most common RET/PTC 1, 2, and 3
■ Found in only 20% to 30% of cases of PTC.

20. ETIOLOGY
■ ONCOGENES
■ In PTC post irradiation - 60% and 70%
■ RET/PTC 3 in solid variant
■ in classic papillary variants of radiation-induced cancers - RET/PTC 1 is
predominant

21. ETIOLOGY
■ ONCOGENES
■ Mutated forms of the H-ras, K-ras, and N-ras protooncogenes are found in DTC
■ Also in 30% of follicular thyroid adenoma, so not specific
■ OTHERS – C-myc, C-fos, RB tumor suppressor gene, PAX8/PPARgamma, p53 (in
undifferentiated)

22. ETIOLOGY
■ GENETIC PREDISPOSITION
■ 12% patients with FAP and Gardner’s syndrome (FAP+ osteomas + epidermoid cyst ,
desmoid tumors)
■ Mutations in APC gene – Autosomal dominant
■ Most common non colonic malignancy – thyroid cancer
■ Early age
■ Pap Ca with cribriform pattern and solid spindle cell containing areas

23. ETIOLOGY
■ GENETIC PREDISPOSITION
■ Cowdens syndrome – PTEN inactivating mutations
■ Autosomal dominant
■ Papillary and follicular carcinomas , found in almost half of abnormal thyroids

26. PATHOLOGY
■ Papillary and follicular carcinomas are the two most common entities
■ usually referred to as differentiated thyroid cancer
■ diagnosis of papillary carcinoma is based on the presence of typical features.
■ diagnosis of follicular carcinoma is based on the presence of follicular
differentiation without the typical features of papillary cancer

27. PTC
■ DEFINITION – A malignant epithelial tumor showing evidence of follicular cell
differentiation, and characterized by the formation of papillae and/or a set of
distinctive nuclear changes
■ 85% of thyroid cancers
■ Indolent clinically
■ often multicentric in one lobe and bilateral

28. PTC
■ Papillary carcinomas occur at any age.
■ rare in children and increase in frequency in the fourth and fifth decades of life.
■ Lymph node metastases - 12% to 64%
■ 10% have extrathyroidal invasion
■ 3% to 6% have distant metastases
■ In older patients - invasive and behaves in some instances like undifferentiated
carcinoma.

29. PTC
■ Positive cervical nodes - no adverse risk in young individuals
■ but imply a worse prognosis in patients > 40 years
■ Pulmonary metastasis - large “snowballs” or diffuse mottling appearance on
CXR
■ Almost all papillary cancer metastases have some ability to take up 131I when
first diagnosed

30. PTC
■ Mortality - 8% to 20%
■ mainly among older patients who have fixed or invasive cervical lesions or
distant metastases at the time of diagnosis
■ Children experience lymph node or pulmonary metastases more often than
adults
■ but extremely low mortality

31. PTC
■ Classic Type
■ may be classified as microcarcinomas, carcinomas limited to the thyroid
gland, and carcinomas extending outside the thyroid.
■ Microcarcinomas are tumors smaller than 1 cm in diameter
■ they may appear as unencapsulated sclerotic nodules of a few millimeters,
infiltrating the surrounding thyroid

32. PTC
■ Classic type - MICROSCOPY
■ papillary areas with a focal distribution or with a diffuse pattern.
■ papillae consist of a stromal-vascular axis lined by characteristic cells
■ The presence of true papillae is a peculiar feature of PTC
■ D/D of true papillae - pseudopapillae and the macropapillae seen in GD, in
benign nodules, or in goiter with hypothyroidism

34. PTC
■ Classic type - MICROSCOPY
■ Follicles filled with colloid or a trabecular or lobular aspect,
■ squamous metaplasia, and
■ psammoma bodies are other distinguishing features present in 40% to 50% of
tumors

36. PTC
■ Nuclear features
■ They are larger than those in normal follicular cells
■ with overlapping
■ pale and transparent at the center
■ contain hypodense chromatin and prominent nuclear membranes
■ shape is irregular and they may be “fissured” like “coffee grains.”
■ Large, circular, well-delimited intranuclear inclusions, an expression of
cytoplasmic invagination
■ In the absence of other features of the tumor, the diagnosis of papillary cancer
is based on typical features of the nuclei

40. PTC
■ Classic type - MICROSCOPY
■ Scattered lymphocytes are often found at the periphery of the tumor.
■ More rarely, a true lymphocyte infiltrate resembling chronic lymphocytic
thyroiditis is seen within the tumor

41. PTC
■ Regional lymph node metastases are extremely common (>50%) at initial
presentation
■ Invasion progresses from the perithyroid chains to more distant chain
■ does not apparently adversely affect long-term prognosis especially in patients
<45 years
■ Distant metastases to lungs and bones - 5–7% of cases

42. PTC VARIANTS
■ FOLLICULAR VARIANT
■ The most frequent variant
■ grossly encapsulated
■ diffuse pattern of follicular growth with small colloid-containing follicles
■ typical nuclear features of PTC helps to recognize the papillary nature of this
tumor

43. PTC VARIANTS
■ FOLLICULAR VARIANT
■ RAS-mutated PTC are associated with the follicular variant
■ Follicular variant PTCs with vascular invasion spread infrequently to regional
lymph nodes
■ retain the expression of iodine-metabolism genes
■ usually radioiodine-avid

44. PTC VARIANTS
■ FOLLICULAR VARIANT
■ Encapsulated noninvasive follicular variants of PTC have recently been
reclassified as a benign entity
■ renamed as “noninvasive follicular thyroid neoplasms with papillary-like
nuclear features

45. PTC VARIANTS
■ DIFFUSE SCLEROSING VARIANT
■ characterized by diffuse involvement of one or both thyroid lobes, widespread
lymphatic permeation, prominent fibrosis, and lymphoid infiltration.
■ diffuse thyroid enlargement as seen in goiter, but with both lobes replaced by a
very firm and calcified tumor.
■ At microscopy - often multicentric.
■ Tumor papillae are associated with squamous metaplasia without keratinization
and abundant psammoma bodies.

46. PTC VARIANTS
■ DIFFUSE SCLEROSING VARIANT
■ Extensive lymphocytic infiltration of the gland
■ lymph node metastases in 100% of cases
■ found most often in children and young adults
■ distant metastases are common.
■ The prognosis is less favorable than for classic papillary cancer, although the
response to treatment may be excellent

47. PTC VARIANTS
■ TALL CELL VARIANT
■ characterized by well-formed papillae that are covered by cells twice as tall
as they are wide.

48. PTC VARIANTS
■ COLUMNAR CELL VARIANT
■ prominent nuclear stratification of
elongated cells
■ tumor is usually large and extends outside
the thyroid gland
■ Vascular invasion is commonly seen
■ typical of older patients.
■ poor prognosis

49. PTC VARIANTS
■ ENCAPSULATED VARIANT
■ characterized by a capsule similar to an adenoma but focally invaded.
■ The typical cytologic and nuclear features of papillary tumor and psammoma
bodies are found microscopically.
■ This variant represents 8% to 13% of cases
■ hobnail variant with micropapillary pattern is a recently recognized poor
prognostic finding

52. FTC
■ Represent 2 to 5% of thyroid cancers.
■ FTC and follicular variants of PTC are a/w mutually exclusive mutations of RAS
or of the PAX8–PPARG fusion oncogene
■ Usually is seen as a solitary, more-or-less encapsulated nodule in the thyroid.
■ tumor is classified as minimally invasive (encapsulated) or widely invasive

53. FTC
■ older age group - peak incidence in the fifth decade of life.
■ slowly growing thyroid mass
■ extrathyroidal invasion in 25%
■ local nodes in 5% to 10%
■ distant metastases in 10% to 20%
■ Direct invasion of strap muscles and the trachea is characteristic

54. FTC
■ Minimally invasive carcinomas represent more than 50% of cases.
■ The diagnosis of malignancy is based totally on the demonstration of
unequivocal vascular invasion
■ and/or invasion of the full thickness of the capsule and the lack of typical
nuclear features of papillary PTC

55. FTC
■ Cytologically cannot be distinguished from benign adenomas.
■ FNAC is of no help in the differential diagnosis between benign and malignant
lesions
■ Morphology is variable
■ ranges from well differentiated with well-formed follicles full of colloid to
poorly differentiated with a solid, cellular growth pattern

56. FTC
■ Follicular cancer invades blood vessels but rarely invades lymphatics
■ Metastases are spread hematogenously to the lungs, bones, and, less
commonly, the brain and liver.
■ Metastases are common with the widely invasive variant
■ less common with the minimally invasive variant

57. FTC
■ Commonly, lesions retain the ability to accumulate radioactive iodide
■ theoretically susceptible to 131I treatment.
■ slightly more lethal than papillary tumors
■ mortality beyond 10 to 15 years after diagnosis is 10% to 20%

59. FTC VARIANTS
■ CLEAR CELL TUMOR
■ rare variant
■ architectural and clinical features similar to those of the usual follicular
carcinomas.
■ The cells are clear because of the formation of intracytoplasmic vesicles,
glycogen or fat accumulation, or intracellular Tg deposition.
■ D/D - clear cell adenoma, from parathyroid adenoma or carcinoma, and from
metastatic clear cell renal carcinoma

60. FTC VARIANTS
■ INSULAR CARCINOMA
■ rare variant.
■ Poorly differentiated, invasive follicular cancer with a solid aspect and
follicular differentiation
■ cells are very homogeneous in shape and are smaller and denser than in
typical follicular cancer.

61. FTC VARIANTS
■ INSULAR CARCINOMA
■ Metastases, which are common, are found in lymph nodes and in distant
organs.
■ poor prognosis

62. FTC VARIANTS
■ HURTHLE CELL (OXYPHILIC CELL) CARCINOMA
■ composed of cells derived from the follicular epithelium
■ characterized by large size with abundant granular, eosinophilic cytoplasm,
large nuclei, and prominent nucleoli.
■ Large number of mitochondria inside the cell confers the granular appearance
of the cytoplasm

63. FTC VARIANTS
■ HURTHLE CELL (OXYPHILIC CELL) CARCINOMA
■ When more than 75% of cells in an FTC exhibit Hurthle cell (or oncocytic) features,
the tumor is classified as a Hurthle cell or an oncocytic carcinoma or an oxyphilic
variant FTC
■ Hürthle cells can be found in
■ papillary carcinomas
■ nodular goiter
■ Hyperthyroidism
■ Hashimoto’s thyroiditis
■ benign nodules

64. FTC VARIANTS
■ HURTHLE CELL (OXYPHILIC CELL) CARCINOMA
■ macroscopically the oxyphilic variant is seen as a solitary thyroid nodule with
complete or partial encapsulation.
■ Criteria for malignancy is invasion
■ prognosis less favorable than for the follicular cell type

65. FTC VARIANTS
■ HURTHLE CELL (OXYPHILIC CELL) CARCINOMA
■ tendency to recur in the neck many years after the original resection
■ May cause death by local invasion
■ Widely invasive Hurthle-cell carcinomas - extensive capsular and vascular
invasion
■ often metastasize to lung and bone and are particularly refractory to
radioiodine

67. DIFFERENTIATED
THYROID CARCINOMA -
2
INITIAL MANAGEMENT

68. SPECIFIC GOALS OF INITIAL THERAPY
■ Remove the primary tumor, disease that has extended beyond the thyroid
capsule, and clinically significant lymph node metastases
■ Minimize the risk of disease recurrence and metastatic spread most
importantly by adequate surgery, also RAI treatment and TSH suppression
■ Facilitate post-operative treatment with RAI

69. SPECIFIC GOALS OF INITIAL THERAPY
■ Permit accurate staging and risk stratification of the disease
■ Minimize treatment-related morbidity
■ presence of metastatic disease does not obviate the need for surgical excision of
the primary tumor in DTC
■ Because metastatic disease may respond to RAI therapy, removal of the thyroid as
well as the primary tumor and accessible loco-regional disease remains an
important component of initial treatment

70. ROLE OF PREOPERATIVE STAGING
WITH DIAGNOSTIC IMAGING AND LAB
TESTS
■ Preoperative neck US for cervical (central and especially lateral neck
compartments) lymph nodes is recommended for all patients undergoing
thyroidectomy for malignant or suspicious for malignancy cytologic or
molecular findings
– (Strong recommendation, Moderate-quality evidence)
■ US-guided FNA of sonographically suspicious lymph nodes > 8-10 mm in the
smallest diameter should be performed to confirm malignancy if this would
change management
– (Strong recommendation, Moderate-quality evidence)

71. ROLE OF PREOPERATIVE STAGING
WITH DIAGNOSTIC IMAGING AND LAB
TESTS
■ The addition of FNA-Tg washout in the evaluation of suspicious cervical lymph
nodes is appropriate in select patients - interpretation difficult in patients with an
intact thyroid gland.
– (Weak recommendation, Low-quality evidence)
■ Confirmation of malignancy in lymph nodes with a suspicious sonographic
appearance is achieved by US-guided FNAC and/or measurement of Tg in the
needle washout
■ Tg <1 ng/mL is reassuring, and the probability of N1 disease increases with higher
Tg levels

72. ROLE OF PREOPERATIVE STAGING
WITH DIAGNOSTIC IMAGING AND LAB
TESTS
■ FNA measurement of Tg is valid even in patients with circulating Tg
autoantibodies
■ Tg washout may be helpful- esp when lymph nodes are cystic, cytologic
evaluation of the lymph node is inadequate, or the cytologic and sonographic
evaluations are divergent
■ false positive Tg washout may occur, esp in LN in the central compartment
when the thyroid gland is still present
■ Pak et al - FNA-Tg cutoff of 32 ng/mL - best sensitivity and specificity in
patients with intact thyroid gland.

73. ■ highest sensitivity - absence of a hilum (100%), but this has a low specificity of
29%
■ Malignant lymph nodes are more likely to occur in levels III, IV, and VI than in level
II

74. Neck imaging
■ Preoperative use of CT, MRI with i.v contrast is recommended for patients with
clinical suspicion for advanced disease including invasive primary tumor, or
clinically apparent multiple or bulky lymph node involvement.
■ Routine preoperative 18 FDG-PET scanning is not recommended.
■ The sensitivities of MRI and PET for the detection of cervical lymph node
metastases are relatively low (30%–40%)

75. Neck imaging
■ Iodine is generally cleared within 4–8 weeks in most patients
■ So, no significant delay in subsequent whole-body scans or RAI treatment after
contrast imaging
■ When there is concern, a urinary iodine to creatinine ratio can be measured.
■ Routine preoperative measurement of serum Tg or anti-Tg antibodies is not
recommended

78. OPERATIVE APPROACH FOR A BIOPSY DIAGNOSTIC
FOR FOLLICULAR CELL–DERIVED MALIGNANCY
■ The initial surgical procedure should include a near-total ( leaving no more
than 1 g of thyroid tissue ) or total thyroidectomy and gross removal of all
primary tumor
– For patients with thyroid cancer >4 cm,
– or with gross extrathyroidal extension (clinical T4),
– or clinically apparent metastatic disease to nodes (clinical N1) or distant
sites (clinical M1)

79. OPERATIVE APPROACH FOR A BIOPSY DIAGNOSTIC
FOR FOLLICULAR CELL–DERIVED MALIGNANCY
■ The initial surgical procedure can be either a bilateral procedure (near-total
or total thyroidectomy) or a unilateral procedure (lobectomy)
– For patients with thyroid cancer >1 cm and < 4 cm
– without extrathyroidal extension,
– and without clinical evidence of any lymph node metastases (cN0)

80. OPERATIVE APPROACH FOR A BIOPSY DIAGNOSTIC
FOR FOLLICULAR CELL–DERIVED MALIGNANCY
■ For patients with thyroid cancer <1 cm without extrathyroidal extension and
cN0, the initial surgical procedure should be a thyroid lobectomy unless there
are clear indications to remove the contralateral lobe
■ in the absence of prior head and neck irradiation, familial thyroid carcinoma,
or clinically detectable cervical nodal metastases

81. OPERATIVE APPROACH FOR A BIOPSY DIAGNOSTIC
FOR FOLLICULAR CELL–DERIVED MALIGNANCY
■ Near-total or total thyroidectomy is necessary if the overall strategy is to
include RAI therapy post-operatively
■ Older age (>45 years), contralateral thyroid nodules, a personal history of
radiation therapy to the head and neck, or familial DTC - recommend bilateral
procedure

82. LYMPH NODE METASTASES
■ The most common site of nodal metastases is in the central neck which is
cervical level VI
■ Lymph nodes in compartment VI are located in
1. The tracheoesophageal groove (paratracheal nodes),
2. In front of the trachea (pretracheal nodes),
3. Around the thyroid gland (parathyroidal nodes), and
4. On the cricothyroid membrane (precricoid or Delphian node)

83. LYMPH NODE METASTASES
■ The boundaries of selective level VI dissection are the hyoid bone superiorly,
the suprasternal notch inferiorly, and the carotid sheaths on both sides

84. LYMPH NODE METASTASES
■ Therapeutic central-compartment (level VI) neck dissection for patients with
clinically involved central nodes should accompany total thyroidectomy to
provide clearance of disease from the central neck
■ Prophylactic central-compartment neck dissection (ipsilateral or bilateral)
should be considered :
– in patients with PTC with clinically uninvolved central neck lymph nodes
(cN0) who have advanced primary tumors (T3 or T4),
– clinically involved lateral neck nodes (cN1b)

85. LYMPH NODE METASTASES
■ Prophylactic dissection often converts patients from clinical N0 to pathologic
N1a, upstaging many patients over age 45 from AJCC stage I to stage III
■ However, microscopic nodal positivity does not carry the recurrence risk of
macroscopic clinically detectable disease

86. LYMPH NODE METASTASES
■ prophylactic dissection is considered for patients with some prognostic
features associated with an increased risk of metastasis and recurrence
– older or very young age
– larger tumor size
– multifocal disease
– extrathyroidal extension
– known lateral node metastases to contribute to decision-making and
disease control

87. LYMPH NODE METASTASES
■ Therapeutic lateral neck compartmental lymph node dissection should be
performed for patients with biopsy-proven metastatic lateral cervical
lymphadenopathy
■ Thyroidectomy without prophylactic central neck dissection is appropriate for
small (T1 or T2), noninvasive, clinically node-negative PTC (cN0) and for most
follicular cancers.

88. COMPLETION THYROIDECTOMY
■ should be offered to those patients for whom a bilateral thyroidectomy would
have been recommended had the diagnosis been available before the initial
surgery
■ Therapeutic central neck lymph node dissection should be included if the
lymph nodes are clinically involved
■ Thyroid lobectomy alone may be sufficient treatment for low risk papillary and
follicular carcinomas

89. COMPLETION THYROIDECTOMY
■ RAI ablation in lieu of completion thyroidectomy is not recommended
routinely
■ Ablation of the remaining lobe with RAI has been used as an alternative to
completion thyroidectomy
■ similar clinical outcomes with a slightly higher proportion of patients with
persistent detectable Tg.
■ Used when completion thyroidectomy carries some increased risk and for
whom a delay in the length of time required to achieve destruction of the
normal thyroid is acceptable.

90. NERVES
■ RLN and external branch of the SLN are of major surgical significance
■ Damage to these nerves leads to disability in phonation and/or to difficulty
breathing
■ Injury to one RLN - hoarseness of the voice, aspiration, and difficulty
breathing.
■ Bilateral RLN injury - need for tracheostomy
■ SLN - inability to sing high notes

91. NERVES
■ Factors making the RLN vulnerable to injury
■ Nonrecurrent laryngeal nerve- always associated with a vascular anomaly.
■ More on the right side (0.6%) than on the left (0.04%)
■ Right non-recurrent nerve is associated with an aberrant takeoff of the right
subclavian artery from the descending aorta
 Left non-recurrent nerve is present with a right-sided aortic arch

92. NERVES
■ Factors making the recurrent laryngeal nerve vulnerable to injury
■ Proximity of the recurrent nerve to the thyroid gland
■ Relationship of the recurrent nerve to the inferior thyroid artery.
– Nerve often passes anterior, posterior, or through the branches of the
inferior thyroid artery
■ Deformities from large thyroid nodules.
– In the presence of large nodules and substernal goiters, the laryngeal nerves
may be found even anterior to the thyroid

93. PREOPERATIVE VOICE ASSESSMENT
Should be performed in all patients with:
■ A) Preoperative voice abnormalities
■ B) History of cervical or upper chest surgery, which places the RLN or vagus
nerve at risk
■ C) Known thyroid cancer with posterior extrathyroidal extension or extensive
central nodal metastases

94. PREOPERATIVE VOICE ASSESSMENT
■ Patients should have a laryngeal exam even if the voice is normal
■ if he or she has a history of neck surgery that placed at risk either the RLN
– (such as past thyroid or parathyroid surgery)
■ or the vagus nerve
– (such as carotid endarterectomy, cervical esophagectomy, and anterior
approach to the cervical spine)
■ or a history of prior external beam radiation to the neck.

95. PREOPERATIVE VOICE ASSESSMENT

96. INTRAOPERATIVE NERVE
PRESERVATION
■ Visual identification of the RLN during dissection is required in all cases
■ Steps should also be taken to preserve the external branch of the superior
laryngeal nerve (EBSLN) during dissection of the superior pole of the thyroid
gland
■ Intraoperative neural stimulation (with or without monitoring) may be
considered to facilitate nerve identification and confirm neural function

97. PARATHYROID GLANDS
■ The parathyroid glands and their blood supply should be preserved during
thyroid surgery.
■ If the parathyroids cannot be located - dissect on the thyroid capsule and
ligate the inferior thyroid artery very close to the thyroid, since the majority
of parathyroid glands receive their blood supply from this vessel

98. PARATHYROID GLANDS
■ If the parathyroid glands are inadvertently or unavoidably removed (e.g. they
are intrathyroidal, or require removal during a central lymph node dissection)
or devascularized,
■ confirmation of cancer-free parathyroid tissue should be performed,
■ and then the glands can be autotransplanted into the strap or
sternocleidomastoid muscles

99. POST OPERATIVE CARE
■ Patients should have their voice assessed in the postoperative period.
■ Formal laryngeal exam should be performed if the voice is abnormal
■ Voice assessment can be performed at 2 weeks to 2 months after surgery

100. POST OPERATIVE CARE
■ Early detection of vocal cord motion abnormalities after thyroidectomy is
important for facilitating prompt intervention
■ Management of RLN paralysis- includes voice therapy, vocal cord injection
techniques, and open vocal cord medialization
■ choice is insertion of a piece of Silastic to move the paralyzed cord to the
midline; this procedure is called a laryngoplasty

101. BASIC PRINCIPLES OF HPE OF
THYROIDECTOMY SAMPLES
■ A) In addition to the basic tumor features required for AJCC/UICC thyroid
cancer staging including status of resection margins,
■ pathology reports should include additional information helpful for risk
assessment including :
■ The presence of vascular invasion and the number of invaded vessels
■ Number of lymph nodes examined and involved with tumor
■ Size of the largest metastatic focus to the lymph node
■ Presence or absence of extranodal extension of the metastatic tumor

102. BASIC PRINCIPLES OF HPE OF
THYROIDECTOMY SAMPLES
■ Histopathologic variants of thyroid carcinoma
■ unfavorable - e.g. tall cell, columnar cell, and hobnail variants of PTC; widely
invasive FTC; poorly differentiated carcinoma or
■ more favorable - e.g. encapsulated follicular variant of PTC without invasion,
minimally-invasive FTC

103. BASIC PRINCIPLES OF HPE OF
THYROIDECTOMY SAMPLES
■ Histopathologic variants associated with familial syndromes
– cribriform-morular variant of papillary carcinoma often associated with
FAP
– follicular or papillary carcinoma associated with PTEN-hamartoma tumor
syndrome
■ should be identified

104. BASIC PRINCIPLES OF HPE OF
THYROIDECTOMY SAMPLES
■ Traditionally, follicular carcinomas have been subdivided into minimally
invasive (encapsulated) and widely invasive
■ minimally invasive carcinomas - fully encapsulated tumors with
microscopically identifiable foci of capsular or vascular invasion
■ widely invasive carcinomas - tumors with extensive, frequently vascular
and/or extrathyroidal, invasion

105. BASIC PRINCIPLES OF HPE OF
THYROIDECTOMY SAMPLES
■ More recent approaches consider encapsulated tumors with only microscopic
capsular invasion as minimally-invasive, whereas angioinvasive tumors are
placed into a separate category
■ It is preferable, as it distinguishes encapsulated tumors with capsular invasion
and no vascular invasion - highly indolent with mortality <5%,
■ from angioinvasive follicular carcinomas, which, depending on the number of
invaded blood vessels, have a mortality ranging from 5 to 30%

106. BASIC PRINCIPLES OF HPE OF
THYROIDECTOMY SAMPLES
■ Extrathyroidal extension is defined as tumor extension into the adjacent
tissues.
■ subdivided into
– Minimal - invasion into immediate perithyroidal soft tissues or
sternothyroid muscle typically detected only microscopically (T3 tumors)
– Extensive - tumor invasion into subcutaneous soft tissues, larynx,
trachea, esophagus, or RLN (T4a tumors).

107. BASIC PRINCIPLES OF HPE OF
THYROIDECTOMY SAMPLES
■ The size of the metastatic focus in a lymph node and tumor extension beyond
the capsule of a lymph node affects cancer risk
■ Therefore, the pathology report should indicate
– the size of the largest metastatic focus to the lymph node
– presence or absence of extranodal tumor extension
– number of examined and involved lymph node

108. BASIC PRINCIPLES OF HPE OF
THYROIDECTOMY SAMPLES
■ Invasion of multiple (4 or more) blood vessels - poorer outcomes, particularly
in follicular carcinomas
■ Therefore, the number of invaded blood vessels (less than 4 or more) should
be stated in the pathology report

109. BASIC PRINCIPLES OF HPE OF
THYROIDECTOMY SAMPLES
■ Vascular invasion is diagnosed as direct tumor extension into the blood vessel
lumen
■ or a tumor aggregate present within the vessel lumen, typically attached to
the wall and covered by a layer of endothelial cells.
■ More rigid criteria for vascular invasion - require the presence of a fibrin
thrombus attached to the intravascular tumor cells
■ invaded blood vessels should not be located within the tumor nodule
parenchyma, but rather in the tumor capsule or outside of it

110. BASIC PRINCIPLES OF HPE OF
THYROIDECTOMY SAMPLES
■ solid variant of papillary carcinoma should be distinguished from poorly
differentiated thyroid carcinoma - shares the insular, solid, and trabecular
growth patterns
■ The distinction is based primarily on the preservation of nuclear features and
lack of necrosis and high mitotic activity in the solid variant
■ poorly differentiated thyroid carcinoma has a much poorer prognosis - 5-year
survival of 72% and 10-year survival of 46%

111. BASIC PRINCIPLES OF HPE OF
THYROIDECTOMY SAMPLES
■ Diagnostic criteria for poorly differentiated carcinoma
■ based on the consensus Turin proposal
■ include the following three features:
– (i) solid/trabecular/insular microscopic growth pattern,
– (ii) lack of well-developed nuclear features of papillary carcinoma, and
– (iii) convoluted nuclei (evidence for partial loss of differentiation in
papillary cancer), tumor necrosis, or three or more mitoses per 10 high-
power fields

112. BASIC PRINCIPLES OF HPE OF
THYROIDECTOMY SAMPLES
■ Tumors with insular, solid, or trabecular architecture, but lacking other
diagnostic features of poorly differentiated carcinoma, do not demonstrate
such an aggressive behavior - not be considered as poorly differentiated.
■ high mitotic rate (>5 mitoses/10 high-power fields or Ki-67 labeling index >4%)
or tumor necrosis - less favorable outcome irrespective of the presence of the
solid/trabecular/insular growth pattern

113. ROLE OF POST-OPERATIVE STAGING
SYSTEMS AND RISK STRATIFICATION
■ AJCC/UICC staging is recommended for all patients with DTC, based on its
utility in predicting disease mortality, and its requirement for cancer registries
■ However, AJCC/IUCC staging was developed to predict risk for death, not
recurrence
■ Since initial staging is based on clinico-pathologic factors that are available
shortly after diagnosis and initial therapy, the AJCC stage of the patient does
not change over time

114. ROLE OF POST-OPERATIVE STAGING
SYSTEMS AND RISK STRATIFICATION
■ However, depending on the clinical course of the disease and response to
therapy, the risk of recurrence and the risk of death may change over time
■ Appropriate management requires an ongoing reassessment of the risk of
recurrence and the risk of disease-specific mortality as new data are obtained
during follow-up
■ The 2009 ATA Initial Risk Stratification System is recommended for DTC
patients treated with thyroidectomy, based on its utility in predicting risk of
disease recurrence and/or persistence

117. ATA 2009 RISK STRATIFICATION SYSTEM
WITH MODIFICATIONS

118. ATA 2009 RISK STRATIFICATION SYSTEM
WITH MODIFICATIONS

119. ATA 2009 RISK STRATIFICATION SYSTEM
WITH MODIFICATIONS

120. ROLE OF POST-OPERATIVE STAGING
SYSTEMS AND RISK STRATIFICATION
■ Subsequent studies have retrospectively validated the 2009 ATA risk of recurrence
staging system
■ estimates of patients who subsequently had no evidence of disease (NED) in each
ATA Risk Category after total thyroidectomy and radioactive iodine remnant
ablation:
■ a) Low Risk 78-91% NED
■ b) Intermediate Risk 52-64% NED, and
■ c) High Risk 31-32% NED
■ In these datasets, NED was defined as a stimulated Tg < 1 ng/mL with no other
radiological or clinical evidence of disease

121. ROLE OF POST-OPERATIVE STAGING
SYSTEMS AND RISK STRATIFICATION
■ Additional prognostic variables (such as the extent of lymph node
involvement, mutational status, and/or the degree of vascular invasion in
follicular thyroid cancer), not included in the 2009 ATA Initial Risk
Stratification system, may be used to further refine risk stratification for DTC
in the Modified Initial Risk Stratification system
■ However, the incremental benefit of adding these specific prognostic variables
to the 2009 Initial Risk Stratification system has not been established

122. ROLE OF POST-OPERATIVE STAGING
SYSTEMS AND RISK STRATIFICATION
■ In most circumstances, the presence or absence of BRAF V600E mutation does
not affect the modified ATA risk classification (i.e. - intrathyroidal papillary
microcarcinomas are ATA low risk whether or not BRAF is mutated)
■ However, in intrathyroidal T1a/T2 PTC tumors, the risk of structural disease
recurrence increases from 1.5% in BRAF wild type tumors (n=58) to 12.1% in
BRAF V600E mutated tumors
– intrathyroidal PTC in the 1-4 cm range that are BRAF wild type - ATA low
risk
– same size tumor with a BRAF V600E mutation - intermediate risk

124. ROLE OF POST-OPERATIVE STAGING
SYSTEMS AND RISK STRATIFICATION
■ Three additional studies, in which the ATA risk classification system was
retrospectively evaluated, have also suggested that the ATA risk of recurrence
model may be applied in low and intermediate risk patients in the absence of
RAI remnant ablation
■ Over a median follow-up period that ranged from 5-10 years, structural
disease recurrence was identified in less than 1-2% of ATA low risk patients and
8% of ATA intermediate risk patients who underwent thyroid surgery without
RAI ablation as initial therapy

125. ROLE OF POST-OPERATIVE STAGING
SYSTEMS AND RISK STRATIFICATION
■ The type of persistent disease also varies according to ATA initial risk
stratification
– 70%–80% of the persistent disease in ATA low-risk patients manifested by
abnormal serum Tg levels (suppressed or stimulated Tg >1 ng/mL)
without structurally identifiable disease
– only 29%– 51% of the ATA intermediate-risk patients
– 19%–21% of ATA high-risk patients

126. ROLE OF POST-OPERATIVE STAGING
SYSTEMS AND RISK STRATIFICATION
■ FTC
■ Well-differentiated FTCs demonstrating only capsular invasion (without
vascular invasion) usually have an excellent prognosis with recurrence rates of
0%–7% - low-risk tumor
■ if extensive vascular invasion is present, risk of the development of newly
identified distant metastases is as high as 30%–55% - high risk

127. MODIFICATION OF INITIAL RISK
ESTIMATES OVER TIME
■ Initial recurrence risk estimates should be continually modified during follow-
up, because the risk of recurrence and disease-specific mortality can change
over time as a function of the clinical course of the disease and the response
to therapy

128. EVALUATION OF POSTOPERATIVE DISEASE
STATUS
■ POSTOPERATIVE SERUM TG
■ Can be done on thyroid hormone therapy or after TSH stimulation
■ can help in assessing the persistence of disease or thyroid remnant and
predicting potential future disease recurrence.
■ Tg reaches its nadir by 3–4 weeks postoperatively in most patients.
■ The optimal cutoff value for postoperative serum Tg is not known

129. EVALUATION OF POSTOPERATIVE DISEASE
STATUS
■ POSTOPERATIVE SERUM TG
■ Postoperative Tg – independent predictor of persistent or recurrent disease
■ High postoperative stimulated Tg values (>10–30 ng/mL) are associated with
poorer survival
■ Postoperative stimulated Tg values <1–2 ng/mL are strong predictors of
remission

130. EVALUATION OF POSTOPERATIVE DISEASE
STATUS
■ POSTOPERATIVE SERUM TG
■ Can also be used to predict the likelihood of successful remnant ablation.
■ Postoperative thyroid hormone withdrawal stimulated Tg values >5–6 ng/mL
were associated with higher rates of failed ablation after administered
activities of both 30 mCi and 100 mCi

131. EVALUATION OF POSTOPERATIVE DISEASE
STATUS
■ POSTOPERATIVE SERUM TG
■ Postoperative serum Tg value will be more helpful in identifying patients that
may benefit from RAI ablation rather than in identifying patients that do not
require ablation
■ Values >10 ng/mL in all patients - additional evaluations and even additional
therapies
■ In high-risk patients, a postoperative Tg value <1 ng/mL does not rule out RAI-
avid disease and therefore is unlikely to alter the decision to proceed with RAI
ablation

132. EVALUATION OF POSTOPERATIVE DISEASE
STATUS
■ POSTOPERATIVE USG
■ Negative predictive values for biochemical and structural recurrence increases
when normal postoperative neck US is combined with Tg measurements

133. DIFFERENTIATED
THRYOID CARCINOMA -
3
MANAGEMENT - CONTINUED

134. POSTOPERATIVE DISEASE STATUS IN DECISION-
MAKING FOR RAI THERAPY
■ Postoperative disease status (i.e., the presence or absence of persistent
disease) should be considered in deciding whether additional treatment may
be needed
■ Postoperative Tg can help in assessing the persistence of disease
■ nadir by 3–4 weeks postoperatively
■ optimal cutoff value for Tg or state in which it is measured (on thyroid
hormone therapy or after TSH stimulation) is not known

135. POSTOPERATIVE DISEASE STATUS IN DECISION-
MAKING FOR RAI THERAPY
■ Postoperative diagnostic RAI WBSs may be useful when the extent of residual
disease cannot be accurately ascertained from the surgical report or USG
■ Identification and localization of uptake foci may be enhanced by concomitant
SPECT/ CT
■ pretherapy diagnostic scans utilize 123I (1.5–3 mCi) or a low activity of 131I
(1–3 mCi)
■ therapeutic activity optimally administered within 72 hours of diagnostic
activity.

136. ROLE OF RAI AFTER THYROIDECTOMY
■ primary goal of postoperative administration of RAI after total thyroidectomy
include
■ (i) RAI remnant ablation (to facilitate detection of recurrent disease and
initial staging by tests such as Tg or whole-body RAI scans)
■ 2) RAI adjuvant therapy (to improve disease-free survival by theoretically
destroying suspected, but unproven residual disease)
■ 3) RAI therapy (to improve disease-free survival by treating persistent disease
in higher risk patients)

137. ATA LOW RISK
■ little evidence to suggest that RAI may improve disease-specific mortality in
low-risk DTC patients
■ lack of a significant effect on recurrence
■ unlikely to improve disease-free survival in papillary microcarcinoma

138. ATA LOW RISK

139. ATA INTERMEDIATE RISK
■ Postsurgical RAI treatment - associated with improved survival for aggressive
PTC histologies such as tall cell, diffuse sclerosing, and insular variants
■ Greatest benefit –
– adverse thyroid cancer histologies
– increasing volume of nodal disease
– lymph node disease outside the central neck
– advancing patient age

141. ATA HIGH RISK
■ improved overall survival in patients with PTC with distant metastases
■ (when distant metastases combined with age >45 years, tumor size >2 cm, and
positive lymph nodes at primary diagnosis)
■ Routine postsurgical RAI treatment is recommended

143. THYROID HORMONE WITHDRAWAL BEFORE RAI
■ If thyroid hormone withdrawal is planned prior to RAI therapy or diagnostic
testing, LT4 should be withdrawn for 3–4 weeks.
■ Liothyronine (LT3) may be substituted for LT4 in the initial weeks if LT4 is
withdrawn for 4 or more weeks
■ LT3 should be withdrawn for at least 2 weeks

144. THYROID HORMONE WITHDRAWAL BEFORE RAI
■ TSH of >30 mIU/L – before RAI therapy or diagnostic testing
■ Recent RCTs - either direct LT4 withdrawal or LT4 withdrawal with substitution
of LT3 in initial weeks is associated with similar short-term quality of life and
hypothyroidism symptom scores
■ Remnant ablation success rate comparable

145. USE OF RECOMBINANT TSH BEFORE RAI
■ acceptable alternative to thyroid hormone withdrawal for achieving remnant
ablation - In patients with ATA low-risk and ATA intermediate risk DTC without
extensive lymph node involvement
■ considered as an alternative to thyroid hormone withdrawal- In patients with
ATA intermediate-risk DTC who have extensive lymph node disease (multiple
clinically involved LN) in the absence of distant metastases

146. USE OF RECOMBINANT TSH BEFORE RAI
■ In patients with DTC of any risk level with significant comorbidity that may
preclude thyroid hormone withdrawal- rhTSH should be considered
– (a) a significant medical or psychiatric condition that could be acutely
exacerbated with hypothyroidism
– (b) inability to mount an adequate endogenous TSH response with thyroid
hormone withdrawal.
■ ATA high-risk DTC – not recommended at present

147. USE OF RECOMBINANT TSH BEFORE RAI
■ Advantages
– Superior short-term quality of life
– Noninferiority of remnant ablation efficacy
– no significant difference in long-term outcomes

148. IODINE IN DIET
■ A low iodine diet (LID) for approximately 1–2 weeks should be considered for
patients undergoing RAI treatment.
■ <50 mcg/d of iodine for 1–2 weeks
■ associated with reduction in urinary iodine excretion as well as increase in
131I uptake
■ avoid restriction of noniodized salt – may cause hyponatremia

149. ACTIVITY OF 131I FOR REMNANT ABLATION OR
ADJUVANT THERAPY
■ If RAI remnant ablation is performed after total thyroidectomy for ATA low-
risk thyroid cancer or intermediate-risk disease with lower risk features
(low-volume central neck nodal metastases with no other known gross
residual)
■ Low administered activity of approximately of 30 mCi

150. ACTIVITY OF 131I FOR REMNANT ABLATION OR
ADJUVANT THERAPY
■ for initial adjuvant therapy to treat suspected microscopic residual disease -
up to 150mCi
■ Successful remnant ablation - defined by an undetectable stimulated serum
Tg, in the absence of interfering Tg antibodies
■ Or if Tg antibodies are present - as the absence of visible RAI uptake on a
subsequent diagnostic RAI scan

151. POSTTHERAPY SCAN
■ Posttherapy WBS (with or without SPECT/CT) is recommended after RAI
remnant ablation or treatment, to inform disease staging and document the
RAI avidity of any structural disease
■ Timing of scans is between 2 and 12 days following therapeutic RAI

152. EARLY MANAGEMENT OF DTC – TSH SUPPRESSION
■ high-risk - initial TSH suppression to below 0.1 mU/L
■ intermediate-risk thyroid cancer patients - 0.1– 0.5 mU/L
■ low-risk patients who have undergone remnant ablation and have
undetectable serum Tg levels - 0.5– 2mU/L (continue surveillance for
recurrence)

153. EARLY MANAGEMENT OF DTC – TSH SUPPRESSION
■ low-risk patients who have undergone lobectomy - 0.5–2 mU/L(mid to lower
reference range)
■ Thyroid hormone therapy may not be needed if patients can maintain their
TSH in this target range

154. EARLY MANAGEMENT OF DTC – TSH SUPPRESSION
■ DTC expresses the TSH receptor on the cell membrane
■ responds to TSH stimulation by increasing the expression of several thyroid
specific proteins (Tg, NIS) and by increasing the rates of cell growth
■ Suppression of TSH, using supraphysiologic doses of LT4 - to decrease the risk
of recurrence

155. EARLY MANAGEMENT OF DTC – TSH SUPPRESSION
■ Studies have demonstrated that TSH suppression to below 0.1 mU/L may
improve outcomes in high-risk patients
■ no such evidence of benefit has been documented in low-risk patients.
■ Higher degrees of suppression to <0.03mu/L has no additional benefit

156. EARLY MANAGEMENT OF DTC – TSH SUPPRESSION
■ Adverse effects of TSH suppression
– exacerbation of angina in patients with IHD
– increased risk for AF in older patients
– increased risk of osteoporosis in postmenopausal women

157. MODIFICATION OF INITIAL RISK
ESTIMATES OVER TIME
■ FOUR RESPONSE-TO THERAPY CATEGORIES
■ described by Tuttle et al. and modified by Vaisman et al
– Excellent response
– Biochemical incomplete response
– Structural incomplete response
– Indeterminate response

158. EXCELLENT RESPONSE
■ no clinical, biochemical, or structural evidence of disease identified on
risk-appropriate follow-up studies
■ If a total thyroidectomy and RAI ablation were done - TSH stimulated Tg of <1
ng/mL in the absence of structural or functional evidence of disease (and in
the absence of TG antibodies)
■ achieved in
– 86%–91% of ATA low-risk patients
– 57%–63% of ATA intermediate-risk patients
– 14%–16% of ATA high-risk patients

159. EXCELLENT RESPONSE
■ once a patient achieves an excellent response to therapy - patient reclassified
as having a subsequent very low risk of recurrence
■ In patients who presented with high-risk disease but have an excellent
(clinically and biochemically free of disease) or indeterminate response to
therapy - TSH 0.1–0.5 mU/L for up to 5 years after which the degree of TSH
suppression can by reduced

160. EXCELLENT RESPONSE
■ In patients with an excellent or indeterminate response to therapy, especially
those at low risk for recurrence - TSH 0.5–2 mU/L
■ In patients who have not undergone remnant ablation or adjuvant therapy who
demonstrate an excellent or indeterminate response to therapy with a normal
neck US, and low or undetectable suppressed serum Tg, and Tg or anti-Tg
antibodies that are not rising- TSH - 0.5–2 mU/L

161. BIOCHEMICAL INCOMPLETE RESPONSE
■ persistently abnormal suppressed and/ or stimulated Tg values or rising
anti-Tg antibodies without structural evidence of disease that can be
detected using risk appropriate structural and functional imaging
■ Rising anti-Tg antibody titers (or new appearance of anti-Tg antibodies) are
associated with an increased risk of disease recurrence

162. BIOCHEMICAL INCOMPLETE RESPONSE
■ To define a biochemical incomplete response, previous studies have used
– non stimulated Tg values of >5 ng/mL at 6 months
– nonstimulated Tg values >1 ng/mL more than 1 year after ablation
– TSH-stimulated Tg values >10 ng/mL more than 1 year after ablation
– In patients with a biochemical incomplete response to therapy - TSH
between 0.1 and 0.5 mU/L

163. STRUCTURAL INCOMPLETE RESPONSE
■ structural or functional (RAI scan, 18FDG-PET) evidence of loco-regional or
distant metastases
– seen in 2%–6% of ATA low-risk patients
– 19%–28% of ATA intermediate-risk patients
– 67%–75% of ATA high-risk patients
In patients with a structural incomplete response to therapy - TSH below 0.1
mU/L indefinitely in the absence of specific contraindications.

164. INDETERMINATE RESPONSE
■ biochemical, structural, or functional findings that cannot be confidently
classified as either excellent response or persistent disease
■ the majority of patients with an indeterminate response to therapy remain
disease-free during prolonged follow-up.
– seen in 12%– 29% of ATA low-risk patients
– 8%–23% of ATA intermediate risk patients
– 0%–4% of ATA high-risk patients

170. LONG-TERM MANAGEMENT OF
DTC

171. GOALS
■ Accurate surveillance for possible recurrence in patients thought to be free of
disease
■ Early detection of recurrent disease offers the best opportunity for effective
treatment
■ monitor thyroxine suppression or replacement therapy, to avoid under-
replacement or overly aggressive therapy

172. CRITERIA FOR ABSENCE OF PERSISTENT TUMOR
(EXCELLENT RESPONSE)
■ In patients who have undergone total or near-total thyroidectomy and RAI
treatment (remnant ablation, adjuvant therapy or therapy)
■ 1) No clinical evidence of tumor
■ 2) No imaging evidence of tumor by radioiodine imaging (WBS) or neck
ultrasound
■ 3) Low serum Tg levels during TSH suppression (Tg <0.2 ng/mL) or after
stimulation (Tg <1 ng/mL) in the absence of interfering antibodies

173. ROLE OF TG MEASUREMENT IN LONG TERM FOLLOW
UP
■ Tg antibodies should be quantitatively assessed with every measurement of
serum Tg
■ currently use immunometric assays to measure serum Tg
■ Serum Tg and Tg antibodies should be assessed longitudinally in the same
laboratory and using the same assay for a given patient

174. ROLE OF TG MEASUREMENT IN LONG TERM FOLLOW
UP
■ Stimulated or unstimulated
■ TSH stimulation generally increases basal serum Tg by 5- to 10-fold

175. ROLE OF TG MEASUREMENT IN LONG TERM FOLLOW
UP
■ Tg assay with a functional sensitivity of 0.1–0.2 ng/ mL may reduce the need
to perform TSH-stimulated Tg measurements
■ A single rhTSH-stimulated serum Tg <0.5–1.0 ng/mL in the absence of anti-Tg
antibody - 98%–99.5% likelihood of identifying patients completely free of
tumor
■ 1 g of neoplastic thyroid tissue will increase the serum Tg by 1 ng/mL during
LT4 treatment and by approximately 2–10 ng/mL following TSH stimulation

176. ROLE OF TG MEASUREMENT IN LONG TERM FOLLOW
UP
■ Tg level on thyroid hormone around 0.2–0.3 ng/mL - best sensitivity and
specificity for detecting persistent disease
■ Tg cutoff level above 2 ng/mL following rhTSH stimulation is highly sensitive
in identifying patients with persistent tumor
■ Rising unstimulated or stimulated serum Tg indicates disease that is likely to
become clinically apparent

177. ROLE OF TG MEASUREMENT IN LONG TERM FOLLOW
UP
■ ATA high-risk patients (regardless of response to therapy) and all patients with
biochemical incomplete, structural incomplete, or indeterminate response -
Tg every 6–12 months for several years
■ low-risk and intermediate-risk patients who have had remnant ablation or
adjuvant therapy and negative cervical US - Tg every 6–18 months on
thyroxine therapy with a sensitive Tg assay (<0.2 ng/ml) or after TSH
stimulation to verify absence of disease (excellent response).
■ In ATA low and intermediate risk patients that achieve an excellent response to
therapy subsequent Tg testing may not be required

178. ROLE OF TG MEASUREMENT IN LONG TERM FOLLOW
UP
■ Serum TSH - measured at least every 12 months in all patients on thyroid
hormone
■ ATA high risk patients (regardless of response to therapy) and all patients with
biochemical incomplete, structural incomplete, or indeterminate response
– Tg every 6-12 months for several years

179. ROLE OF TG MEASUREMENT IN LONG TERM FOLLOW
UP
■ Tg may be negative in
– small amounts of residual tumor
– anti-Tg antibodies
– Because of defective or absent production and secretion of
immunoreactive Tg by tumor cells

180. ANTI-TG ANTIBODIES
■ anti-Tg autoantibodies commonly cause falsely low serum Tg
■ Variability in Tg autoantibody assays may result in falsely negative antibody
levels associated with a misleadingly undetectable serum Tg
■ Presence of Tg autoantibodies - suspected in presence of background
Hashimoto thyroiditis

181. ANTI-TG ANTIBODIES
■ 25% of thyroid cancer patients and 10% of the general population
■ Falsely lower serum Tg determinations in immunometric assays
■ May rise transiently postoperatively and following ablation

182. ANTI-TG ANTIBODIES
■ Serial serum anti-Tg antibody quantification- imprecise surrogate marker of
residual normal thyroid tissue, Hashimoto thyroiditis, or tumor
■ Following total thyroidectomy and RAI remnant ablation, anti-Tg antibodies
usually disappear over a median of about 3 years in patients without evidence
of persistent disease

183. ANTI-TG ANTIBODIES
■ Levels declining over time are considered a good prognostic sign
■ Rising antibody levels - increases risk that the patient will subsequently be
diagnosed with persistent or recurrent thyroid cancer

184. TG MEASUREMENT IN PATIENTS WHO HAVE NOT
UNDERGONE RADIOIODINE REMNANT ABLATION
■ Tg determination on LT4 treatment and neck US at 9–12 months
■ In low and intermediate risk pts – if Tg remains elevated, remnant ablation or
adjuvant therapy with 131I may be considered

185. ROLE OF US AND OTHER IMAGING TECHNIQUES
DURING FOLLOW UP
■ Following surgery, cervical US to evaluate the thyroid bed and central and
lateral cervical nodal compartments - at 6–12 months
■ Biopsy for - suspicious lymph nodes > 8-10 mm in the smallest diameter with
Tg measurement in the needle washout fluid
■ <8-10 mm - followed without biopsy with consideration for FNA or intervention
if there is growth

186. ROLE OF US AND OTHER IMAGING TECHNIQUES
DURING FOLLOW UP
■ USG may then be repeated periodically, depending on the patient’s risk for
recurrent disease and Tg status.
■ Low-risk patients who have had remnant ablation, negative cervical US, and a
low serum Tg on thyroid hormone therapy in a sensitive assay (<0.2 ng/ml) or
after TSH stimulation (Tg <1 ng/ml) - followed primarily with clinical
examination and Tg measurements on thyroid hormone replacement

187. DIAGNOSTIC WHOLE-BODY RAI SCANS
■ 6–12 months after adjuvant RAI therapy - in the follow-up of patients with high
or intermediate risk (higher risk features) of persistent disease
■ Not required – for low-risk and intermediate-risk patients (lower risk features)
with an excellent response to therapy
■ Iodine 131 or 123I whole-body scintigraphy may be performed after the
administration of either a diagnostic (usually 2–5 mCi) or a therapeutic activity
(30–150 mCi) of RAI.

188. DIAGNOSTIC WHOLE-BODY RAI SCANS
■ Diagnostic WBS indicated in
– (i) patients with abnormal uptake outside the thyroid bed on posttherapy
WBS
– (ii) patients with poorly informative postablation WBS because of large
thyroid remnants with high uptake of 131I
– (iii) patients with Tg antibodies, at risk of false-negative Tg
measurement

189. ROLE OF FDG PET
■ Should be considered in high risk DTC patients with elevated serum Tg (> 10
ng/ml) with negative radioiodine imaging

190. ROLE OF FDG PET
■ may be considered
– as part of initial staging in poorly differentiated thyroid cancers and
invasive Hürthle cell carcinomas
– prognostic tool in patients with metastatic disease to identify patients at
highest risk for rapid disease progression and mortality
– as an evaluation of posttreatment response following systemic or local
therapy of metastatic or locally invasive disease

191. ROLE OF FDG PET
■ Low sensitivity in patients with a TSH stimulated Tg <10 ng/mL - < 10% to 30%
■ consider 18 FDG-PET only in DTC patients with a stimulated Tg level equal to
or >10ng/mL
■ no evidence that TSH stimulation improves the prognostic value of 18FDG-PET
imaging

192. ROLE OF FDG PET
■ Factors influencing 18 FDG-PET/CT sensitivity - tumor de-differentiation,
larger tumor burden
■ More sensitive in patients with an aggressive histological subtype, including
poorly differentiated, tall cell, and Hürthle cell thyroid cancer

193. ROLE OF FDG PET
■ 18 FDG uptake on PET in metastatic DTC patients - negative predictive factor
for response to radioiodine treatment and an independent prognostic factor
for survival
■ Lesions with high 18FDG uptake may be more aggressive and should be
targeted for therapy or close monitoring

194. ROLE OF CT AND MRI
Should be considered
■ 1) bulky and widely distributed recurrent nodal disease where ultrasound may not
completely delineate disease
■ 2) In the assessment of possible invasive recurrent disease with potential
aerodigestive tract invasion
■ 3) When neck ultrasound is felt to be inadequately visualizing possible neck nodal
disease (high Tg, negative neck US)

195. ROLE OF CT AND MRI
■ CT imaging of the chest - considered in high risk DTC patients with elevated
serum Tg (generally > 10 ng/ml) or rising Tg antibodies
■ MRI- may better delineate any involvement of the aerodigestive tract

196. ROLE OF CT AND MRI
■ Imaging of other organs including MRI brain, MR skeletal survey, and/or CT or
MRI of the abdomen
■ should be considered in high-risk DTC patients with elevated serum Tg (>10
ng/mL) and negative neck and chest imaging
■ who have symptoms referable to those organs
■ or who are being prepared for TSH-stimulated RAI therapy and may be at risk
for complications of tumor swelling.

197. PATIENTS WITH SUSPECTED STRUCTURAL NECK
RECURRENCE
■ Therapeutic compartmental central and/or lateral neck dissection- for
patients with biopsy-proven persistent or recurrent disease for central neck
nodes >8 mm and lateral neck nodes > 10 mm
■ Surgery is considered for clinically apparent, macroscopic nodal disease US
and/or CT rather than through isolated Tg elevation

198. PATIENTS WITH SUSPECTED STRUCTURAL NECK
RECURRENCE
■ Typical revision lateral neck dissection involves levels II, III, and IV
■ revision central neck dissection includes at least one paratracheal region with
prelaryngeal and pretracheal subcompartments.
■ Bilateral central neck dissection is offered only when dictated by disease
distribution
■ Basal Tg decreases by 60%–90% after compartmental dissection for recurrent
nodal disease

199. PERCUTANEOUS ETHANOL INJECTION
■ PEI for patients with metastatic lymph node is a nonsurgical directed therapy
for patients with recurrent DTC
■ in patients who are poor surgical candidates
■ Many patients will likely need more than one treatment session
■ lymph nodes > 2 cm may be difficult to treat with PEI

200. PERCUTANEOUS ETHANOL INJECTION
■ Formal neck compartmental dissection is still the first-line therapy in DTC
patients with clinically apparent or progressive lymph node metastases
■ Similarly RFA or laser ablation - in high risk surgical patients or in patient
refusing additional surgery

201. OTHER THERAPEUTIC OPTIONS
■ Stereotactic radiotherapy (SBRT) can be successfully used to treat isolated
metastatic disease foci
■ has no role in most patients with resectable lymph node metastases.
■ EBRT using techniques such as intensity modulated radiotherapy and
sterotactic radiation - for loco-regional recurrence that is not surgically
resectable or with extranodal extension or involvement of soft tissues
■ systemic therapies (such as cytotoxic chemotherapy or kinase inhibitors) for
loco-regional disease - only after all surgical and radiation therapy options
have been exhausted.

202. 131 I FOR LOCO-REGIONAL OR METASTATIC
DISEASE
■ RAI may be employed in patients with low-volume disease or in combination
with surgery
■ Also used adjunctively following surgery for regional nodal disease or
aerodigestive invasion if residual RAI-avid disease is present or suspected

203. 131 I FOR LOCO-REGIONAL OR METASTATIC
DISEASE
■ The radiosensitivity is higher in patients who are
– younger
– with small metastases from well-differentiated papillary or follicular
carcinoma
– with uptake of RAI but no or low 18 FDG uptake

204. TREATMENT OF PULMONARY METASTASES
■ Should be treated with RAI therapy
■ repeated every 6–12 months as long as disease continues to concentrate RAI
and respond clinically
■ Dosage of 100–200 mCi, or 100-150 mCi for patients >70 yrs or estimated by
dosimetry to limit whole-body retention to 80 mCi at 48 hours and 200 cGy to
the bone marrow

205. TREATMENT OF PULMONARY METASTASES
■ Radioiodine-avid macronodular metastases may be treated with RAI
■ treatment may be repeated when objective benefit is demonstrated (decrease
in the size of the lesions, decreasing Tg),
■ complete remission is not common and survival is poor
■ a reduction in serum Tg and in RAI uptake with no concomitant decrease or
with an increase in tumor size suggests refractoriness to RAI therapy

206. TREATMENT OF PULMONARY METASTASES
■ ADVERSE EFFECTS
– Pulmonary pneumonitis and fibrosis
– bone marrow suppression
– pulmonary function testing including diffusing capacity of the lungs for
carbon monoxide can be markers of pulmonary toxicity

207. RAI TREATMENT OF BONE METASTASES
■ RAI therapy of iodine-avid bone metastases has been associated with improved
survival
■ rarely curative
■ The RAI activity administered can be given empirically (100–200 mCi) or
determined by dosimetry

208. RAI TREATMENT OF BONE METASTASES
■ When distant metastases are evident, MRI of the brain and spine is recommended
to detect mets
■ high-dose corticosteroid therapy to limit the risk of acute tumor swelling and
compromised function.
■ Dexamethasone 2–4 mg every 8 hours starting 6–12 hours prior to rhTSH and RAI
dosing or after 10–12 days of thyroid hormone withdrawal
■ steroids tapered for 1 week post therapy, for 48–72 hours after rhTSH
administration, or for 72 hours after re-institution of thyroxine therapy

209. TREATMENT OF BRAIN METASTASES
■ surgical resection and stereotactic EBRT are the mainstays of therapy for CNS
metastases
■ RAI can be considered if CNS metastases concentrate RAI.
■ stereotactic EBRT and concomitant glucocorticoid therapy are recommended
prior to RAI therapy to minimize the effects of TSH-induced increase in tumor
size and RAI-induced inflammatory response.

210. EMPIRIC RAI THERAPY
■ Considered in patients with significantly elevated serum Tg levels, rapidly
rising serum Tg levels or
■ rising Tg antibody levels,
■ in whom imaging (anatomic neck/chest imaging and/or 18 FDG-PET/CT) has
failed to reveal a tumor source that is amenable to directed therapy
■ Patients with a suppressed or stimulated serum Tg of >5 ng/mL or higher are
unlikely to demonstrate a decline without therapy

211. EMPIRIC RAI THERAPY
■ If persistent nonresectable disease is localized after an empiric dose of RAI,
and there is objective evidence of significant tumor reduction - RAI therapy
may be repeated until the tumor has been eradicated or no longer responds to
treatment
■ Empiric (100–200 mCi) or dosimetrically-determined radioactive iodine therapy
may be considered
■ If empiric RAI therapy is given and the post-therapy scan is negative - RAI-
refractory disease and no further RAI therapy should be administered.

212. EMPIRIC RAI THERAPY
■ tumors that are 18FDG-PET positive – RAI usually not effective

213. COMPLICATIONS OF RAI
■ salivary gland damage - hydration, sour candies, amifostine, and cholinergic
agents
■ dental caries
■ nasolacrimal duct obstruction
■ secondary malignancies (bone and soft tissue malignancies, including breast,
colorectal, kidney, and salivary cancers, and leukemia) – laxatives and oral
hydration

214. COMPLICATIONS OF RAI
■ RAI therapy should be deferred until lactating women have stopped
breastfeeding for at least 3 months.
■ A diagnostic 123I or low-dose 131I scan should be considered in recently
lactating women to detect breast uptake
■ Temporary amenorrhea/ oligomenorrhea lasting 4–10 months in 20%–27% of
menstruating women after 131I therapy
■ Men receiving cumulative RAI activities >400 mCi should be counseled on
potential risks of infertility - sperm banking

215. RADIO REFRACTORY DTC
■ classified in patients with appropriate TSH stimulation and iodine preparation
in four basic ways:
■ (i) malignant metastatic tissue does not ever concentrate RAI (no uptake
outside the thyroid bed at the first therapeutic WBS)
■ (ii) the tumor tissue loses the ability to concentrate RAI after previous
evidence of RAI-avid disease
■ (iii) RAI is concentrated in some lesions but not in others
■ (iv) metastatic disease progresses despite significant concentration of RAI

216. THANK YOU