Description of anatomy, physiology, diagnosis and management of thyroid carcinoma

1. By Dr DEEPAK KUMAR DAS
MOD- PROF. R. KAPOOR
PGIMER, CHANDIGARH

2. ANATOMY
 Located anterior and inferior to thyroid
cartilage
 Consists of two lateral lobes connected by
central isthmus
 Lateral lobes extend superiorly to the level
of midthyroid cartilage and inferiorly to
the sixth tracheal ring
 Lateral extent is just medial to common
carotid artery
 Recurrent laryngeal nerve, sympathetic
trunk and phrenic nerve are immediately
posterior to the gland

3. BLOOD SUPPLY
AND LYMPHATIC
DRAINAGE
 Blood supply is by paired superior thyroid
artery ( branch of external carotid artery)
and inferior thyroid artery
 First-echelon nodes for thyroid metastasis
are located in level 6( paralaryngeal,
paratracheal and prelaryngeal nodes)
 Second-echelon nodal spread is to level 3
and 4, supraclavicular nodes and upper
mediastinal nodes ( level 7)
 Retropharyngeal node involvement is
unusual and can be encountered in case of
advanced disease

4. PHYSIOLOGY

5. ETIOLOGY
 Most important risk factor for differentiated thyroid cancer is previous
irradiation, especially before the age of 16 years
 Other predisposing factors are:
- Genetic predisposition
- Hashimoto’ s disease
- Iodine content of the diet

6. PATHOLOGICAL CLASSIFICATION
 Follicular epithelial cell
-Differentiated thyroid cancer
 papillary and mixed cell variant
 Classic
 Papillary microcarcinoma
 Encapsulated variant
 Follicular variant
 Aggressive variants
a. Diffuse sclerosing
b. Tall cell variant
c. Columnar cell variant
 Follicular cancer
a. Classic morphology- Follicular carcinoma
b. Hurthle cell variant

7. - Poorly differentiated thyroid cancer
- Insular carcinoma
-Undifferentiated thyroid cancer( anaplastic carcinoma)
Parafollicular cell ( C cell)
Medullary carcinoma
 Non epithelial tumors
- Lymphoma
- sarcoma
- hemangioendothelioma

8. PAPILLARY THYROID CANCER

9. PATHOLOGIC FINDINGS
- Nuclear enlargement, hypochromasia, nuclear pseudoinclusions,
nuclear grooves and distinct nucleoli
- After formalin fixation nucleus resemble “ Orphan Annie’s eyes”
Tall cell variant
- At least 70% of the carcinoma is composed of cells that are at least
twice as tall as they are wide
( papillary thyroid cancer) ( tall cell variant)

10. FOLLICULAR CARCINOMA

11. Diagnosis of FC is dependent on the presence of one of two histologic features
 Tumor invasion through the entire tumour capsule or
 Tumor invasion into a blood vessel located in the tumour capsule or immediately
outside the tumour capsule

12. HURTHLE CELL CARCINOMA
-Also called as oncocytic carcinoma
-Characterised by large cells with abundant granular eosinophilic cytoplasm
- At least 75% of the tumour must be comprised of Hurthle cells to designate it
Hurthle cell carcinoma
ANAPLASTIC THYROID CARCINOMA
-Comprise <5% of all malignant thyroid neoplasms
- Most aggressive form of thyroid carcinoma
- Most patients are diagnosed at the age of 65 years or older
- Usually accompanied by bulky mediastinal lymphadenopathy and distant
metastatic spread
-Mean overall survival from the time of diagnosis is 3-6 month
MEDULLARY THYROID CARCINOMA
-Comprise 5-10% of all thyroid cancer
- Seen sporadically( 80%) or in association with familial multiple endocrine
neoplasia( MEN IIA, MEN IIB, pure familial MTC)

13. -50-70% of MEN associated tumour is multifocal, but sporadic tumors are more often
unifocal
-Prognosis depends on the tumour subtype
Non MEN familial> MEN associated> sporadic > MEN
- Overall mean 10 year survival is 75-80%

14. CLINICAL PRESENTATION
Thyroid nodule ( 10-50% of solitary
nodule)
 Cervical lymphadenopathy
 Hoarseness
 Haemoptysis
 Stridor
 Dysphagea
 Hyperthyroidism
 Diarrhoea

16. INVESTIGATIVE WORK UP
 Complete hemogram, biochemistry
 CXR
 FNAC
- safe, easy, cheap and reliable test to distinguish between benign and
malignant thyroid nodule
RESULTS OF FNAC
 Degenerative condition( 75%)
 Thyroid cyst
-Fluid should be sent for malignant cytology
 Degenerative or colloid nodule
- < 1% risk of malignancy
 Neoplastic condition( 4% positive, 11% suspicious)
 Papillary neoplasm
- 90% accuracy in positive cases
- 60% accuracy in suspicious reports

17. Follicular neoplasm
- Unable to distinguish between adenoma and well differentiated follicular
carcinoma: biopsy required
 Medullary carcinoma
- Reliable test when combined with calcitonin staining
 Anaplastic carcinoma
- Usually diagnostic but may not distinguish from lymphoma or metastatic
carcinoma
 Lymphoma
- Open biopsy required for immunohistochemistry
 Inconclusive(10% cases)
-FNAC should be repeated under USG guidance

18. ULTRASONOGRAPHY
-Most sensitive method for evaluating thyroid nodule
- Ideally used in combination with FNAC for preliminary assessment
- Distinguishes solitary thyroid nodule from dominant thyroid nodule in a multi-
nodular goitre
- Assessing size and position of cervical lymphadenopathy

19. RADIONUCLIDE SCANNING
TECHNETIUM 99m
 Uptake by thyroid gland is low.
 Scans are neither sensitive nor
specific
 Information is provided in terms
of hot or cold nodules

20. I123
Ideal
 No longer used as a first line investigation of thyroid nodule
 Involuble for total body imaging post total thyroidectomy in case of
well differentiated thyroid cancer

21. DMSA AND MIBG scan
 May locate recurrent or metastatic disease in case of medullary carcinoma
 Not taken by cells as readily as I123 in differentiated cancer and positive
scans occur only in 30% cases

22. CT/MR IMAGING
INDICATION
NECK
 Possible bilateral involvement
 Extrathyroid invasion of trachea, larynx, esophagus, carotid vessels
 LN involvement
THORAX
 Retrosternal spread
 Superior mediastinal nodes involvement
 Pulmonary metastasis in MTC/ anaplastic carcinoma
ABDOMEN
 Exclusion of pheochromocytoma in MTC
 Liver metastasis in MTC/ anaplastic carcinoma
 Lymphoma staging

23. Main disadvantage with CT scan is the necessary administration of
iodine contrast which can block both diagnostic and therapeutic use
of radioiodine for 6 months.
 MR involves neither radiation or iodine and with better diagnostic ability
is the investigation of choice in differentiated thyroid cancer

24. TFT- Free serum T3, T4 and TSH
- Indicated in all patients of thyroid cancer
 Thyroid autoantibodies- Anti-microsomal, antithyroglobulin
- Indicated if Hashimoto’s disease or
thyroid lymphoma suspected
 Tumor markers- Thyroglobulin, calcitonin, CEA
- Preoperatively in all cases
- Proven role in monitoring and follow up
- Calcitonin also helps in initial diagnosis

25. Peak calcium infusion
- less than or equal to 130 pg/ml in males
- less than or equal to 90 pg/ml in females
 Basal calcitonin levels are high in most patients with sporadic MTC but
are normal in those with familial MTC or MEN type 2
 So in these patients a calcium infusion provocative test or pentagastrin
infusion test is used todetect the abnormality
CALCITONIN

26. OTHER INVESTIGATION
 Indirect or fibreoptic laryngoscopy to assess vocal cord
and/or intratracheal disease is indicated in all patients with
suspected thyroid malignancy.
 Mandatory for both preoperative and post operative
assessment

27. STAGING SYSTEMS OF THYROID CANCER

28. AGES, Mayo clinic, 1987
Age>40, grade>1, extrathyroid extension, size>3 cm

29. AMES( Lahey clinic, 1988)
40 year survival for low risk group was 95% and 45% for high risk group

30. GAMES( MSKCC 1992)
Grade>2, age>45 years, distant metastasis, extension beyond thyroid capsule,
Size> 4 cm

31. MACIS( Mayo Clinic, 1993)
Metastasis, Age>40, Completeness of resection, Extrathyroid invasion, Size

32. DAMES( Karolinska Institute, 1992)
DNA ploidy, Age> 40 year in female and 50 year in male, Metastasis, Extension beyond
Thyroid capsule, Size> 5 cm

33. AJCC 2010 TNM STAGING SYSTEM
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour 2 cm or less in greatest dimension and limited to the thyroid gland
T1a Tumour 1 cm or less in greatest dimension and limited to the thyroid gland
T1b Tumour > 1cm but not > 2 cm in greatest dimension and limited to thyroid gland
T2 Tumour > 2 cm but not > 4 cm in greatest dimension and limited to the thyroid
gland
T3 Tunour > 4cm in greatest dimension limited to the thyroid or any tumour with
minimal extrathyroidal extension to the sternothyroid muscle or perithyroid soft
tissue
T4 Advanced disease defined as more than minimal extrathyroid extension
T4a Tumor of any size extending beyond the thyroid capsule to invade subcutaneous
soft tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve
T4b Tumor invades prevertebral fascia, encases carotid artery or mediastinal vessels

34. STAGING CONT......
 All anaplastic carcinomas are considered T4 tumors
T4a Intrathyroidal anaplastic carcinoma
T4b Anaplastic carcinoma with gross extrathyroidal extension
Regional lymph node(N)
Nx Regional LN cannot be assessed
N0 No evidence of regional LN metastasis
N1 Regional LN metastasis
N1a Metastasis to level VI
N1b Metastasis to unilateral, bilateral, contralateral cervical or retropharyngeal
or superior mediastinal LN
Distant metastasis
M0 No distant metastasis
M1 Distant metastasis

35. COMPOSITE STAGING

37. MANAGEMENT
 Surgery
-Lobectomy or total thyroidectomy
- Extent of neck dissection
 Hormonal therapy
 Radioactive iodine therapy
 EBRT
 Chemotherapy

38. SURGERY
 Surgery is the primary treatment of localised thyroid cancer of all
histologies
 Total thyroidectomy is the preferred oncologic procedure, because
- The gland is surgically accessible
- Its primary endocrine function can be replaced by exogenous
hormones
 Even a total thyroidectomy leaves residual thyroid tissue that will have
major implication for subsequent therapy and disease monitoring
-The ligament connecting the posterior surface of thyroid capsule
to the trachea harbors microscopic nests of thyroid tissue and is
rarely completely resected in order to reduce the risk of tracheal
injury
- Recurrent laryngeal nerve is embedded in thyroid tissue at the
point where nerve enters the larynx and it is not possible to
remove all of the thyroid tissue without injuring the nerve and
compromising voice quality and laryngeal function

39. There are three critical issues regarding the surgical management of thyroid
Cancer
 When is surgery indicated for the evaluation of a thyroid nodule with non-
diagnostic cytology
 When is it safe to consider hemithyroidectomy for thyroid carcinoma
 What is the appropriate extent of neck dissection

40. SURGICAL EVALUATION OF THYROID NODULE
 Cytology is suspicious for PTC
 Cytology contains follicular cells with no concordant
functioning nodule on an RAI scan, especially with low to
normal range serum TSH
 Cytology contains Hurthle cell neoplasm, which does not
warrant an RAI study and should be managed with
lobectomy or total thyroidectomy, depending on the lesion’
s size and other risk factors
 Growing nodules, even in the face of benign cytology

41. LOBECTOMY IN THE MANAGEMENT OF THYROID CANCER
 Age between the age of 15 and 45 years with PTC tumor <4 cm
 No prior radiotherapy
 No distant metastasis
 No cervical LN metastasis
 No extrathyroidal extension
 Absence of aggressive histologic variant
Completion thyroidectomy is indicated in
 Tumor > 4 cm in diametre
 Positive margin
 Gross extrathyroid extension
 Macroscopic multifocal disease
 Macroscopic nodal metastasis
 Confirmed contralateral disease
 Vascular invasion

42. ADVANTAGE OF TOTAL THYROIDECTOMY

43. NECK DISSECTION IN THYROID CANCER
 Elective neck dissection is not performed for DTC of follicular cell
origin
 Modified radical neck dissection is done for thyroid cancer when there
is visible or palpable positive node
RECOMMENDATION
 Central compartmental ( level VI) is recommended for all patients with
clinically involved nodes
 Prophylactic central neck dissection in clinically N0 patients with T3 or
T4 tumors
 Lateral level II to level IV should only be reserved for biopsy proven
metastatic lateral cervical LAP
 Level I, V, VII should only be dissected when clinically suspicious
 Central and lateral neck dissection are part of standard primary
therapy for all patients with sporadic and hereditary forms of
medullary thyroid cancer

44. RADIOACTIVE IODINE THERAPY
BIOCONCENTRATION
Radioactive iodine is taken up by thyroid tissue, including DTC of follicuar epithelial
Origin at a rate 6.6 times more than most tissues of the body.

46. RADIOACTIVE DECAY OF IODINE-131
 I-131 is produced from the fission of uranium atoms durin the operation
of nuclear reactors
 I-131 decays by beta decay to Xe- 131
 This first transition results in a beta particle with a range of energies
from 250 to 800 KeV
 Because energies of this energy range will deposit their energy within a
milimeter, only the cells taking up the I-131 are affected.
 In the second decay step, unstable Xe-131 decays to stable xenon,
releasing photon of energy 364 KeV
 This product is therapeutically undesirable, because the photon will
travel far from the source where iodine is concentrated.
 It contributes very little cytotoxicity to thyroid cancer cells and
increases the total body dose, however it is this property that makes
RAI useful for diagnostic imaging, forming the foundation for DxWBS
and RxWBS.

47. GOALS OF RADIOACTIVE IODINE THERAPY
Two basic purposes are
a) Thyroid remnant ablation
b) Adjuvant therapy for residual microscopic disease
I. RAI provides potent cytotoxicity by targeting thyroid cancer cells
remaining in the operative bed, occult LN metastasis, and distant
metastasis
II. Rx WBS provides critical informatiopn including staging, prognosis,
and determining which patients are likely to require additional
treattments
III. Ablation of the remaining thyroid tissue facilitates the use of serum
Tg as a very sensitive and specific marker for disease persistence after
primary therapy

48. PATIENT SELECTION FOR RAI
 All patients with distant metastasis
 Gross extrathyroidal extension of the tumour regardless of tumour size
 Primary tumor size> 4 cm, even in the absence of other higher risk
features
 Patients with 1-4 cm thyroid tumor with high risk features
 LN metastasis
 Age> 45 years
 Intra thyroid vascular invasion
 Aggressive histologic variants ( tall cell, columnar cell, or insular carcinoma
 All patients with follicular and Hurthle cell variants except those with
smallest unifocal FCs manifesting as only capsular invasion and
without vascular invasion
 Patients with persistent disease

49. RAI is not recommended in
 Unifocal PTCs< 1 cm
 Without high risk features
 When all the foci in multifocal disease are < 1 cm
 Patients without residual disease or high risk histology, when post op
Tg < 1 ng/ml and anti-Tg antibodies and RAI imaging are negative

50. SELECTION OF I-131 ACTIVITY

51. FORMS AVAILABLE
I131 is available in the form of
 Capsule
 Liquid preparation
 Intravenous
Capsule is the most common used because of safety and easy
of administration

52. PATIENT PREPARATION FOR I-131
Low iodine diet -A diet that is low in iodine( <
50mcg/day) for 2 weeks before,
and 2 days after I-131
- Salty product to be avoided
Intravenous iodine exposure -Should be avoided
- Who recieved iodine contrast within 6
months of RAI should have therapy
delayed for 3-6 months and require 24
hr urinary iodine measurement
Urinary iodine measurement -Only done in patient with history
of iodinated contrast exposure
within 6 months
- 24 hr urinary iodine on day 7 of a
low iodine diet < 150 mcg/ml
rhTSH 0.9 mg im injection 2 day and 1 day
before I-131 administration

53. Stop thyroid
hormone
replacement
Levothyroxine and other thyroid replacement should
be withheld 6 weeks before I-131 unless rhTSH is
administered in which case stop T4 and T3 3 days
before and the day of I-131 administration
Lithium carbonate
to increase the
potency of I-131
Lithium carbonate is administered at 20mg/kg/day for 7
days beginning 5 days before I-131 administration

54. PRECAUTION AFTER RAI

56. CONTRAINDICATION

57. ADVERSE EFFECT OF RADIOACTIVE IODINE THERAPY

59. PGI PROTOCOL
Criteria Low Intermediate High
Histology & Tg Non aggressive
histology
Aggressive histology(
tall cell, columnar &
vascular invasion)
Possibly Tg out of
proportion to post
therapy scan
Tumour status Macroscopic
tumour resected
completely& no
microscopic
invasion
Microscopic invasion Incomplete
tumour resection/
macroscopic
tumour invasion
Metastasis No local or distant
metastasis
Cervical LN
metastasis
Distant metastasis
Post therapy
I131
No uptake outside
thyroid bed
Uptake outside
thyroid bed
Distant metastasis

60. Low risk: 30-50 mCi
Inermediate risk: 100-150 mCi
High risk: 200 mCi

61. TSH SUPPRESSION FOR DIFFERENTIATED THYROID
CANCER
Rationale- Administartion of subtherapeutic doses of T4 in an effort to
drive the TSH below detectable limits( < 0.1 Miu/L), thereby decreasing
stimulation of residual benign and malignant follicular derived
thyroid cells
RECOMMENDATION
 TSH suppression to just below 0.1 Mu/L for high risk patients
 Maintainance of TSH at or slightly below the lower limit of normal(
0.1-0.5 Mu/l) in low risk patients
LIMITATION
 Subclinical and even overt thyrotoxicosis
 Tachyarrhythmia
 Conduction abnormalities
 Ventricular hypertrophy
 Systolic and diastolic dysfunction

62. EBRT

63. CONVENTIONAL FIELD MARGINS
Position- supine with neck extended and
arm lying by the side
 Superior- angle of mandible
 Inferior- angle of loui
 Lateral- to cover the neck

64. CONFORMAL RADIOTHERAPY
 High risk CTV: region at highest risk for residual disease
: Positive margin, ETE, LN with extracapsular extension,
gross residual disease
 Standard risk CTV: Moderate risk for residual disease
 Dose to high risk PTV: 66-70 Gy, 2 Gy per #
 Dose to standard risk PTV: 54-56 Gy, 2 Gy per #

65. Contouring of high risk and standard risk PTV

68. TOXICITY OF EBRT
ACUTE TOXICITY LATE TOXICITY
Mucositis Fibrosis and atrophy of skin, lung
apices, musculature
Taste changes Tracheal stenosis
Xerostomia Esophageal stenosis
Pharyngitis
Dysphagea
Hoarseness
Radiation dermatitis
Weight loss
Malnutrition

69. RESULTS OF EBRT

71. CHEMOTHERAPY IN DTC
 Systemic chemotherapy has no significant role in the management of
DTC
 Poor response rate on the order of 25- 40%
 The most commonly used agent is doxorubicin, either alone or in
combination with cisplatin.

72. MANAGEMENT OF MTC
 All patients with MTC should be tested for RET mutation, Including
sporadic cases
 Primary management of localised is total thyroidectomy, which is the
only completely effective therapy
 Central neck dissection should be performed in all cases
 Compartment-oriented lateral neck dissection is indicated when
clinically involved
 No role of adjuvant RAI
INDICATION OF EBRT
CHILDREN(<18 YEARS)
 Palliation of symptoms from tumors not amenable to other treatment
 When tumour progression is likely to cause normal tissue damage

73. ADULTS
Treatment of unresectable gross disease
Positive margin
T4 primary tumors
Nodal metastasis with extensive extracapsular extension

74. CHEMOTHERAPY IN MTC

77. MOLECULAR TARGETED AGENTS IN MTC

78. ROLE OF OCTREOTIDE IN MTC
Octreotide is recommended to manage symptoms due to elevated
calcitonin level in medullary thyroid cancer like diarrhoea
Dose is
 100-250 mcg tid sc
 Octrotide LAR 20-30 mg im every 4 week

79. ROLE OF I131 MIBG THERAPY IN MTC
 MIBG( meta-iodo benzyl guanidine) is a radiopharmaceutical specific
for tumors originating from neural crest, including MTC. It is
structurally similar to norepinephrine.
 It is taken up actively and transported to the catecholamine storing
granules of sympathomedullary tissues
INDICATION
 Patients with tumour progrssion
 Quality of life compromising symptoms including diarrhoea
 Should be indicated when conventional therapies and chemotherapy
fails
 Surgical options should be excluded
 Diagnostic MIBG scan should be prominent to allow successful
treatment
 Medications interfering with MIBG like sympathomimetics, calcium
channel blockers, reserpine should be withdrawn according to
biological half life.

80. Dose: 200-300 mCi
Infusion should last 45-60 minutes to prevent acute side effects
Management of rise of BP should be managed by alpha blockers

81. MANAGEMENT OF ATC
 Complete surgical excision should be the goal of initial therapy, when
feasible
 Surgery should be avoided when complete excision is not possible as
debulking does not improve outcomes
 No therapeutic role for RAI
 EBRT is the standard of care for palliation of local symptoms from
unresectable disease or as adjuvant therapy in rare case a completely
resected tumor

82. TREATMENT ALGORITHM

83. CONCLUSION
 Surgery is the primary treatment modality in localised thyroid cancer
of all histologies.
 Total thyroidectomy is preferred surgical procedure in most cases.
 LN dissection is indicated when clinically involved except MTC where
level VI is indicated in all cases.
 In DTC, RAI is indicated in patients with distant metastasis or high risk
histopathological features
 EBRT is indicated in DTC when there is gross residual tumor or gross
ETE which is not amenable for surgery or RAI.
 EBRT is the standard of care for palliation of symptoms in ATC.