thyroid malignant disorders

1. THYROID
MALIGNANCIES
+ LT COL VIPIN V NAIR
+ ASSO PROF AND PLASTIC SURGEON
+ AFMC PUNE
THYROID
MALIGNANCIES
Dr VIPIN V NAIR
ASSO PROF SURGERY AND PLASTIC SURGEON
AFMC PUNE

2. INTRODUCTION
 Most common endocrine tumor (95%)
 Female to male ratio- 3:1

4.  Differentiated
carcinomas peak in 3rd
and 4th decade.
 Medullary Ca thyroid
peaks in 5th and 6th
decade.
 Anaplastic carcinomas
peak in 7th decade.

5. Long term
survival.

6. EPIDEMIOLOGY
 Indian population - thyroid cancer forms 1.5%
of all malignant tumours
 Papillary thyroid carcinoma: Iodine sufficient
areas
 Follicular thyroid carcinoma: Iodine deficient
areas

7. DUNHILL CLASSIFICATION
DIFFERENTIATED – arise from Follicular cells
• Papillary carcinoma (60 - 70%)
• Follicular carcinoma (10%)
• Papillo-follicular variant
• Hurthle cell carcinoma
UNDIFFERENTIATED
Anaplastic carcinoma (10%) – arise from
undifferentiated follicular cells

8. CLASSIFICATION
• MEDULLARY CARCINOMA (5%) –
arise from parafollicular cells
• MALIGNANT LYMPHOMA (5%) –
arise from lymphoid cells
• SECONDARIES TO THYROID (RARE) –
kidney, breast, direct invasion from
aero-digestive tract squamous cell
carcinoma

9. WHO Classification
Adenomas
A. Follicular
1. Colloid variant
2. Embryonal
3. Fetal
4. Hurthle cell variant
B. Papillary (probably malignant)
C. Teratoma
Malignant

10. Malignant
A)Differentiated
1.Papillarycarcinoma(and variants)
2.Follicularcarcinoma(variants)
a.Minimallyinvasive b.Extensivelyinvasive
B)Medullary carcinoma
C)Undifferentiated
1.Giantcell 2.Carcinosarcoma
D)Miscellaneous
1.Lymphoma,sarcoma 4.Mucoepithelialcarcinoma
2.Squamouscellepidermoidcarcinoma 5.Metastatictumor
3.Fibrosarcoma

11. AGE RELATED PREVALENCE
Carcinoma Age group
a) Papillary Thyroid carcinoma
b) Medullary thyroid carcinoma associated with
MEN type 2
Children
a) Follicular thyroid carcinoma
b) Anaplastic carcinoma
c) Sporadic Medullary thyroid carcinoma
Elderly

12. THYROID CANCERS IN YOUNG AGE
 Papillary carcinoma: most common
 Radiation related
 More chances of multifocality
 More aggressive ??
 Extra-thyroid extension: more likely
 60%-80%: lymph node metastasis
 Lung metastasis(10%)
 Recurrence risk: 10% to 35%
 Mortality rate: 3 to 5 %

13. ETIOLOGY
Thyroid lymphomas: Intra-thyroid lymphoid tissue
Sarcomas: Connective tissue of thyroid gland
Endodermally derived
Follicular cells
• Papillary
• Follicular
• Anaplastic
Neuroendocrine derived
calcitonin producing C cells
• Medullary
Thyroid cancers arise from 2 types of cells

14. 1) Radiation Exposure
 Papillary Carcinoma
Differentiated carcinoma – Irradiation under 5 years of age
 Prior neck irradiation early in life
 Treatment for acne, tonsillitis (200-150 cGy)
 Treatment for malignancies: Hodgkin’s (4000 cGy)
 Nuclear holocausts/ accidents
 Chernobyl incident (Ukraine 1986): 100 times increase
 Long latency period: 20 to 30 yrs

15. 2) Pre-existing
Thyroid Lesions
 Pre-existing MNG: Follicular carcinoma
 SNT (esp. old age, males and in extremes of
age)
 Hashimoto’s thyroiditis: Papillary thyroid
carcinoma
 Any solitary nodule ~ 5% chances of
malignancy
 Solitary nodules with definite h/o radiation
exposure: 30 % chances of malignancy

16. FAMILIAL CANCER SYNDROMES
• Medullary carcinoma: Multiple
endocrine neoplasia (MEN) 2A or
2B syndrome, as well as familial
MTC (FMTC) syndrome
 4-10 times increased risk in 1st degree relatives
SYNDROMES
THYROID CANCERS
Cowden’s syndrome FTC and rarely PTC and
Hurthle cell tumors
FAP PTC
Werner’s syndrome PTC, FTC, Anaplastic Cancer
Carney complex type 1 PTC, FTC
McCune Albright
syndrome
PTC Clear cell

17. CLINICAL
PRESENTATION
 Commonest
presentation: painless
thyroid swelling

18. Patients with MTC may
complain of a dull
aching sensation

19. Presentation s/o malignancy –
Recent onset pain
Recent rapid enlargement in a long
standing nodule
Dysphagia
Stridor
Hemoptysis
Hoarseness

21. WORKUP
 H/o risk factors (radiation, family history)
 Examination findings
 Firmness (hard, gritty usually s/o
malignancy)
 Mobility/ adherence to surrounding
structures
 Presence of LNpathy
 Berry’s sign
 IDL for vocal cord assessment
 USG Neck followed by FNAC

22. LABORATORY
INVESTIGATIONS
Serum TSH levels
 Low TSH - autonomously functioning nodule
(usually benign)
 Does not rule out malignancy (1% risk)
Serum calcitonin levels (MTC or MEN 2)
 Highly suggestive of MTC if raised
PCR assays for germline mutations in the RET proto-
oncogene
 Diagnostic in Familial MTC
Serum CEA level
 Increased in MTC but nonspecific
 Better indicator of prognosis than Calcitonin

23. IMAGING STUDIES
ULTRASONOGRAPHY
 Highly sensitive for
thyroid nodules
 Can detect sub-
clinical/small nodules
 Differentiate solid from
cystic
 Detect sub-clinical
cervical
lymphadenopathy

24. TI-RADS

25. BETHESDA CRITERIA
 Accuracy of FNAC: 70 – 97 %
 False Negatives: 1 – 6 %
 Chances of malignancy in:
i. FLUS – 10 – 35 %
ii. AUS – 60 – 75 %
 Suspicious for malignancy : 60 %
turn out to be malignant
 Malignant : 97 % are malignant
Despite negative aspirate
thyroidectomy indicated if
large, hard nodule fixed to
surrounding structures
FROZEN SECTION
Lobectomy ???

26. RADIO IODINE STUDIES
 Recommended in patients having
Follicular neoplasm on FN and
suppressed TSH
 Determine functional status of a nodule
Based on radioisotope studies nodule
can be
 Hot - Autonomous toxic nodule
 Warm - Normally functioning
 Cold - Non functioning nodule (likely
malignant but not always)

30. Thyroid scintigraphy Indium-111 octreotide scan for MTC
X-rays : CXR and X-ray skull to rule out metastatic deposits
COLD NODULE
THYROID SCANS

32. STAGING

36. PAPILLARY THYROID
CARCINOMA

37. CHARACTERISTIC
FEATURES
 60%-80% of all thyroid malignancies
 Found in iodine-sufficient areas
 Predominant in children and radiation exposed cases
 Females : Males = 2:1 (most euthyroid)
 Mean age at presentation 30-40 yrs
 Lymphatic spread commoner (mode of presentation in
many)
 Distant mets: upto 20 % cases (lungs > bone > liver > brain)
 Lateral aberrant thyroid: metastatic spread to cervical LN
 Multifocality common (upto 85%)

38. DIAGNOSIS
AND PRE-OP
WORK UP
 ORPHAN ANNIE NUCLEI: intra-nuclear cytoplasmic
inclusions
 Papillary projections: characteristic
 Mixed pattern/ follicular pattern (follicular variant)
 Follicular variant: behave biologically like papillary
 Psammoma bodies
 BRAF mutations

39. DIAGNOSIS AND PRE-OP WORK UP
 Basis of diagnosis: FNAC of thyroid mass/ LN mass
 Complete USG Neck:
 Contralateral lobe
 LN stations
 If suspected clinically: metastatic workup
 Prognostic scores

40. PROGNOSTIC MARKERS
LN involvement does not alter the
prognosis/survival rates
Predicts local recurrence All scoring systems categorize the
patient as
High risk
Low risk

41. SURGICAL MANAGEMENT
 CURRENT GUIDELINES: Near- total or total thyroidectomy for primary cancers >1 cm
(Unless surgery is contraindicated)
 Reduced recurrence rates
 Improved survival rates
 MRND type III: in case of proven lateral lymph node involvement
 No role of prophylactic lateral neck node dissection, micro-mets can be addressed by
RAI therapy

42. ARGUMENTS IN
FAVOR OF TOTAL
THYROIDECTOMY

43. SURGICAL MANAGEMENT
 Hemithyroidectomy is considered sufficient in cases of:
 Small tumours (<1 cm)
 Incidentally discovered/ low-risk/ unifocal/ intrathyroidal papillary ca
 Absence of prior head and neck irradiation
 Absence of radiologically/clinically involved cervical LN mets
 FNAC suspicious for papillary Ca: Hemithyroidectomy + removal of adjacent nodes
 If frozen-section of lymph node or tumor confirms carcinoma:
 Completion total or near-total thyroidectomy is performed
 Completion thyroidectomy can be performed at a later setting based on HPE

44. SURGICAL MANAGEMENT
Large/ Locally aggressive/ Metastatic tumours
 Total thyroidectomy + excision of adjacent involved structures + appropriate nodal
surgery
 Followed by radio-ablation
 Along with long term TSH suppression

45. LOW RISK GROUP

46. MICROPAPILLARY OR OCCULT MICRO CA
 “Micropapillary carcinoma is a tumour, clinically not detectable or less than 1cm with no
evidence of local invasion through the thyroid capsule or angioinvasion”
 Size criterion < 1.0 cm
 Usually clinically silent, more indolent than macro type
 Most are found incidentally at HPE/ autopsy
 25 % associated with occult LN mets

47. VARIANTS
1. Follicular variant
2. Encapsulated
3. Diffuse Sclerosing
4. Diffuse Follicular
5. Tall cell
6. Columnar cell
7. Oxyphilic (Oncocytic, Hürthle Cell)
8. Warthin Tumor-like
9. Cribriform-Morular Variant
10. Trabecular
11. Adenoid Cystic Carcinoma–like
12. Macrofollicular
13. Clear cell
14. Hobnail
15. Micropapillary
16. Variant with Spindle Cell Metaplasia.
17. Variant with Exuberant Nodular
Fasciitis–like Stroma
18. Papillary Carcinoma with
Lipomatous Stroma
19. Dedifferentiated Papillary

48. FOLLICULAR VARIANT
 Lindsay tumor
 Psammoma bodies and sclerosis may be present
 Diagnosis rests on identification of the typical nuclear features of papillary carcinoma
 Further divided into two subtypes:
 Infiltrative (non-encapsulated)
 Encapsulated

49. FOLLICULAR THYROID
CARCINOMA

50. Follicular Carcinoma vs Follicular Adenoma
 Unequivocal vascular and/or capsular invasion: follicular carcinoma
 Examination of the tumor-thyroid interface
 Histologic examination features favoring follicular Ca:
 Thick fibrous capsule
 High cellularity, with solid or trabecular growth pattern
 Diffuse nuclear atypia
 Readily identified mitotic figures

51. CHARACTERISTIC FEATURES
 10% of all thyroid ca
 More common in iodine deficient areas
 Female : Male = 3:1
 Presentation at older age: 5th decade
 Cervical LN uncommon at presentation
 Haematogenous spread more common

52. CHARACTERISTIC
FEATURES
 Usual presentation:
 SNTs: recent rapid increase in size
 Long standing MNG
 Rarely present as thyrotoxicosis (hyper-functioning
nodule)
 Indicators of malignancy in cases with FNAC
showing follicular features
 Distant mets
 Large tumours >4 cm in old males
 Bony mets: typically vascular/warm/pulsatile.
Commonly in skull, long bones, ribs

53. DISTANT METS IN FOLLICULAR CA

54. PATHOLOGICAL FEATURES
 Usually solitary lesions
 Majority are encapsulated
 Minimally invasive tumours: microscopic capsular invasion, no parenchymal invasion
 Widely invasive tumours – widespread capsular invasion, e/o large vessel invasion
 Tumor thrombi a characteristic feature
 Due to limitations of FNAC: Novel genetic markers
BRAF, RAS, RET/PTC, MicroRNA 197, 346

55. SURGICAL MANAGEMENT
 Follicular lesion on FNAC:Hemithyroidectomy (80% adenomas)
 If HPE shows follicular Ca: Completion thyroidectomy
 Total thyroidectomy indications:
 Older patients
 Lesion >4cm ( cancer risk is 50%)
 Atypia on FNAC
 Family history of thyroid cancer
 History of radiation exposure
 Total thyroidectomy advocated mainly because RAI can be used to eliminate residual/
metastatic disease

56. NECK DISSECTION
 Occasional spread to cervical lymph nodes (10%)
 Prophylactic nodal dissection not indicated
 Proven nodal metastases: therapeutic neck dissection recommended
 Prophylactic central neck dissection may be considered in patients
with large tumors >4 cm

57. PROGNOSIS: FOLLICULAR CA
 The approximate cumulative mortality
 15% at 10 years
 30% at 20 years
 Poor long-term prognosis predicted by:
1. Age >50 years at presentation
2. Tumor size >4 cm
3. Higher tumor grade
4. Marked vascular invasion
5. Extra-thyroidal invasion
6. Distant metastases at time of diagnosis

58. HÜRTHLE CELL VARIANT
 Oncocytic, Oxyphilic, Ashkenazy cell neoplasms (3%)
 Subtype of follicular Ca, cannot be diagnosed on FNAC
 Differs from classical Follicular Ca:
 More often multifocal and bilateral (about 30%)
 Usually does not take up RAI (about 5%)
 More likely to metastasize to local nodes (25%) and have distant mets at
presentation
 Higher mortality rate (about 20% at 10 years)

59. HÜRTHLE CELL VARIANT
 Routine central neck node dissection recommended
 MRND if lateral neck nodes are positive (palpable/ USG)
 Radio-iodine scanning & ablation usually ineffective
 Should still be considered to ablate residual thyroid tissue and
occasionally ablate tumors as there is no other good therapy

60. POST OPERATIVE MANAGEMENT OF DTC
RADIOIODINE THERAPY
RAI ablation indications:
 All patients with stage III and IV disease
 All Patients with stage II disease <45 years
 Stage I disease with aggressive histology or size >1.5 cm
 Nodal mets
 Multifocal disease
 Extra-thyroidal or vascular invasion

61. RADIOIODINE THERAPY
 More sensitive than X-ray/ CT in detecting metastatic/ residual ca
 6 weeks after thyroidectomy, hypothyroid can be induced by discontinuing replacement to obtain
high serum TSH levels (30mU/L)
 Diagnostic dose of I131 or I123 is given initially (1-3 mCi)
 Whole-body scanning is performed to detect uptake of radioiodine
 If any normal thyroid remnant or metastatic disease detected, therapeutic dose of I131 is
administered to ablate the tissue
 Low-dose ablation (OPD Basis) - <30mCi (low risk cases)
 High doses (100 – 200 mCi) for high risk, old age, incomplete resection

62. RADIOIODINE THERAPY
FOLLOW-UP
Unstimulated - cut-off 0.5 ng

63. TSH SUPPRESSION THERAPY
 High risk patients maintained at serum TSH level <0.1 mU/L
 Low risk cases 0.1 – 0.5 mU/L (equivocal opinion based on recent trials)
 Suppressive dose is 0.3 mg OD lifelong (titration required)
 Reduces tumoral growth and recurrence rates

64. MEDULLARY CARCINOMA THYROID

65. MEDULLARY CARCINOMA
 Para-follicular C-cell derivative
 UB bodies, neuro-ectodermal origin (4th pharyngeal pouch)
 5% of all thyroid ca
 Concentrated supero-laterally on thyroid lobes
 Most MTCs: sporadic
 25 % - syndromic (MEN2A, MEN2B, familial MTC)
 Hereditary forms - germline mutation of the RET proto-oncogene
 C cell hyperplasia (pre-malignant): familial cases

66. FEATURES OF
MEDULLARY
THYROID
CANCER
SYNDROMES
Syndrome Manifestations
MEN2A MTC, pheochromocytoma, primary
hyperparathyroidism, lichen planus
amyloidosis
MEN2B (MOST
AGGRESSIVE)
MTC, pheochromocytoma, Marfanoid
habitus,
mucocutaneous ganglioneuromatosis
Familial MTC MTC
MEN2A and
Hirschsprung’s
disease
MTC, pheochromocytoma, primary
hyperparathyroidism, Hirschsprung's
disease

67. MEDULLARY
CARCINOMA
Presentation-
1. Thyroid mass with palpable cervical LN (~20%)
2. Aching type pain
3. Locally invasive symptoms - dysphagia, hoarseness,
dyspnoea
4. Diarrhea (40%)
 Hematogenous metastases (liver, bone), late feature
 Female : Male = 1.5 : 1
 Secrete Calcitonin, CEA, serotonin, PG, other peptides
 Sporadic cases – 80 % unilateral
 Familial cases – 90 % multicentric / Bilateral

68. MTC –
DIAGNOSIS
Histological feature – marked heterogeneity, amyloid
(diagnostic)
IHC – Calcitonin/ CEA / Calcitonin-gene related peptide
All fresh cases – screened for PHT, phaeochromocytoma,
RET point mutations
Provocative tests – pentagastrin-stimulated calcitonin
level
Calcitonin & CEA – markers for persistence/recurrence
Calcitonin – more sensitive marker
CEA – better predictor of prognosis
NECK USG – central/ lateral neck compartments, superior
mediastinum

69. MTC –
METASTATIC
WORK-UP
Metastatic work-up indicated in cases with:
Palpable/ USG proven positive node
Calcitonin level >400ng/mL
CECT Neck + Chest
Triple-phase CT for liver metastases

70. MTC – MANAGEMENT
 Total thyroidectomy + bilateral central neck node dissection treatment of choice because:
 Radio-Iodine ablation usually ineffective
 High incidence of multicentricity
 Palpable cervical lymph nodes: MRND
 Tumour >1.5 cm: Ipsilateral prophylactic MRND
 If node positive then contralateral node dissection
 If phaeochromocytoma present: operated first

71. MTC – MANAGEMENT
 In unresectable/ metastatic/ locally recurrent disease
tumour debulking surgery indicated to alleviate symptoms:
 Pain
 Flushing
 Diarhhoea
 Protective from death due to central neck/ mediastinal disease
 External beam radiation: role in unresectable residual or recurrent tumour mass or
symptomatic bony mets

72. PALLIATION – METASTATIC MTC
 Palliation for Liver mets (usually multiple, >1.5 cm):
 Laparoscopic RF ablation
 Chemoembolization
TARGET THERAPIES:
 Vandetanib (FDA approved) – inhibits VEGFR, multikinase & EGFR
 Anti-CEA monoclonal anti-body – Labetuzumab (CEA-Cide)
 Multikinase inhibitors – sorafenib, sunitinib

73. MANAGEMENT IN
MEN SYNDROMES
 If PTH raised and hypercalcemia present,
at thyroidectomy, only obviously enlarged
parathyroid gland is removed
 Other PTH glands should be marked and
preserved (20 % in MEN 2A develop HPT)
 If devascularized PTH gland, auto-
transplantation to be done
 Non-dominant forearm
 SCM

74. PROPHYLACTIC
THYROIDECTOMY
 Family members to be evaluated
with calcitonin level / RET
mutation screening, if positive
prophylactic total thyroidectomy
indicated
 Prophylactic central neck node
dissection:
1. Avoided in calcitonin negative
and normal USG neck
2. To be done - If calcitonin
positive + USG s/o cancer
SCREENING CHARACTERISTICS AGE AT
SURGERY
Less aggressive mutations, normal annual
serum calcitonin, less aggressive family
history, normal neck USG
>5 yrs
Mutations at codon 634 <5 yrs
MEN-2B related mutations <1 yrs

75. FOLLOW-UP
&
PROGNOSIS
 Annual monitoring:
 Clinical examination
 Calcitonin & CEA levels
 USG Neck/ higher imaging if suspicion
 FGD PET scan: Superior to other radionuclide
based studies for MTC
10 yr survival rate :
 80 % - LN negative cases
 45 % - LN involved
 35 % - MEN2B worst prognosis

76. MANAGEMENT OF
RECURRENCE - MTC
Local recurrence:
surgical excision
Non localized
– I131 radioablation
– External beam
radiotherapy

77. ANAPLASTIC CARCINOMA
(UNDIFFERENTIATED TYPE)

78. CHARACTERISTIC FEATURES
 Very aggressive, one of the most lethal malignancy
 Median survival: 4 to 5 months from diagnosis
 1-3 % of total thyroid malignancies (on a decline)
 Median age 63-74 yrs
 Female to male ratio = 1.5:1

79. CHARACTERISTIC FEATURES
Commonly related to prior/ concurrent well-differentiated thyroid ca or
benign thyroid disease which suggests:
 Risk factors are similar
 De-differentiation of well-differentiated thyroid cancer tissue, eventually
replaces all well-differentiated tissue

80. UNDIFFERENTIATED (ANAPLASTIC)
CARCINOMA
Presentation
 Recent rapid enlargement in a long-standing goiter (commonest)
 Recent growth with rapid increase in size
 Regional invasion into trachea, larynx, RLN Palsy
 Distant mets (most commonly lungs, bones & liver)
Mortality
 Aggressive loco-regional invasion e.g. upper airway invasion/ obliteration

81. ATC - MANAGEMENT
 Aggressive local therapy warranted
 I131 ablation has no role
 Doxorubicin + platinum based chemo: more effective than doxorubicin alone. No other
agent has a role
 Best management strategy:
 Early diagnosis + aggressive surgical resection + EBRT followed by doxorubicin based
chemo
 Recent trials – Paclitaxel may have a role
 Tracheostomy/ isthmusectomy: Relieve airway obstruction in unresectable cases

82. THYRIOD LYMPHOMA

83. THYRIOD LYMPHOMA
 Relatively rare disease
 <1 % of thyroid malignancies
 2 % of extra-nodal non-Hodgkin’s lymphoma
 Most common: Non-Hodgkin B cell lymphomas
 Majority are intermediate grade (70-90%)
 Many are considered MALToma
 May be associated with similar lesions in extra-nodal sites e.g. GI tract

84. THYROID
LYMPHOMA
 Commonly arises from chronic
lymphocytic thyroiditis
 Chronic antigenic lymphocyte
stimulation: lymphocyte
transformation
 Radiosensitive
 Good prognosis

85. THYRIOD
LYMPHOMA
 Strong female preponderance 3:1 to 8:1
 Age at diagnosis – 7th decade commonest
 Presentation:-
 F/s/o local invasion
 Frequently have features of hypothyroidism
 Correct diagnosis -
 FNAC – may have f/o autoimmune or Hashimoto’s
thyroiditis
 IHC crucial for correct identification (vs Anaplastic Ca)

86. MANAGEMENT
Optimal therapy possible due to:
 Combination chemo + ability to obtain correct
diagnosis without surgery (Trucut Biopsy)
 Ideal treatment – EBRT + combination
chemotherapy based on the histopathological
subtype
 Most authors support rapid initiation of EBRT +
chemotherapy over surgical excision as it has lower
morbidity
CHOP regime (Cyclophosphamide, Doxorubicin,
Vincristine, and Prednisolone)

87. METASTASES TO THYROID
 <1 % of all thyroid malignancies
 Common sources:
 Commonest: RCC (23%)
 Breast (16%)
 Lungs (15 %)
 Melanoma (5 %)
 Colon (5%)
 Larynx (5%)

88. METASTASES TO THYROID
Occasional presentation
– thyroid mass from
occult primary
FNAC helps in
identification
Thyroid mets may grow
rapidly to cause airway
obstruction
Some patients may
require thyroidectomy to
control local symptoms

89. THANK YOU