- 1. Dr. Varun Goel MEDICAL ONCOLOGISTRAJIV GANDHI CANCER
INSTITUTE, DELHI
2. Introduction The most common endocrine malignancy 95% of all
endocrine cancers accounts for ~3% of all cancers Female to Male
Ratio 3:1 sixth most frequently diagnosed cancer in women continued
increased incidence with an estimated48,020 new cancer cases in
2011. six deaths per 1 million people occur annually. 3. based on
pathology can be divided into three generalsubtypes differentiated
(papillary, follicular, and Hrthle cell), more than 90% of thyroid
cancers medullary, and anaplastic thyroid cancers The prognosis is
excellent for most patients withthyroid cancer overall survival
rate of 85% at 10 years. Most effectively treated by thyroidectomy
and use ofradioactive iodine. Despite low mortality rates, local
recurrence occurs in up to 20% of patients, and distant metastases
in approximately 10% at 10 years. 4. HistorySymptoms The most
common presentation painless mass inthe region of the thyroid gland
(Goldman, 1996). Symptoms consistent with malignancy Pain dysphagia
Stridor hemoptysis rapid enlargement hoarseness 5. Important
History Radiation to neck / chest MEN syndrome Family history
Diarrhoea Adrenal tumour 6. History (continued...)Risk factors
Thyroid exposure to irradiation low or high dose external
irradiation (40-50 Gy [4000-5000 rad]) especially in childhood for:
large thymus, enlarged tonsils, cervical adenitis, sinusitis,
andmalignancies 30%-50% chance of a thyroid nodule to be
malignant(Goldman, 1996) 7. History (continued...)Risk factors
(continued) Age and Sex Benign nodules occur most frequently in
women 20-40years (Campbell, 1989) 5%-10% of these are malignant
(Campbell, 1989) Men have a higher risk of a nodule being malignant
Belfiore and co-workers found that: the odds of cancer in men
quadrupled by the age of 64 a thyroid nodule in a man older than 70
years had a 50% chanceof being malignant 8. History (continued)
Family History family member with medullary thyroid carcinoma
family member with other endocrine abnormalities(parathyroid,
adrenals) familial polyposis (Gardners syndrome) 9. Familial
SyndromesFamilial Non-Medullary Thyroid Cancer GardnerPTCIntestinal
polyps, osteomas, APCSyndromefibromas, lipomas Cowden PTCBreast
cancer, hamartomasPTENSyndromeFTC Carney FTCMyxoma, Schwannoma,
?Syndrome pigmented adrenal nodules,pituitary adenomas, testicular
tumors Familial PTC 5-10% of sporadic PTC?PTC 10. Evaluation of the
thyroid Nodule Physical Exam Blood Tests Ultrasonography CT Scan
PET Scan Radioisotope Scanning FNAC 11. Physical ExamExamination of
the thyroid nodule: consistency - hard vs. soft size Multinodular
vs. solitary nodule multi nodular - 3% chance of malignancy
(Goldman, 1996) solitary nodule - 5%-12% chance of
malignancy(Goldman, 1996) Mobility with swallowing Mobility with
respect to surrounding tissues Well circumscribed vs. ill defined
borders 12. Blood Tests Thyroid function tests thyroxine (T4)
triiodothyronin (T3) thyroid stimulating hormone (TSH) Serum
Calcium Thyroglobulin (TG) Calcitonin 13. UltrasonographyAdvantages
Sensitive for identifying lesions in the thyroid (2-3mm) 90%
accuracy in categorizing nodules assolid, cystic, or mixed
(Rojeski, 1985) Best method of determining the volume of a
nodule(Rojeski, 1985) Can detect the presence of lymph node
enlargementand calcifications Noninvasive and inexpensive 14.
Ultrasonography (Continued)Disadvantages Unable to reliably
diagnose true cystic lesions Cannot accurately distinguish benign
from malignantnodules 15. CT Scan Not commonly needed Better when
suspecting mediastinal disease PET Scan FNAC Accurate for PTC and
MTC Cannot diagnose FTC 16. Radioisotope Scanning Prior to FNA, was
the initial diagnostic procedure ofchoice Performed with:
technetium 99m pertechnetate orradioactive iodine Technetium 99m
pertechnetate cost-effective readily available short half-life
trapped but not organified by the thyroid - cannot
determinefunctionality of a nodule 17. Radioisotope Scanning
(Continued) Radioactive iodine radioactive iodine (I-131, I-125,
I-123) is trapped and organified can determine functionality of
athyroid nodule 18. Radionuclide Scan PossibilitiesColdHot 19.
Limitations of Radionuclide Scan Cold nodules usually benign...but
could be cancer Hot nodules never cancerand revealed by low TSH 20.
Radioisotope Scanning (continued...)Limitations Not as sensitive or
specific as FNA indistinguishing benign from malignant nodule
90%-95% of thyroid nodules are hypofunctioning, with 10%-20%being
malignant (Geopfert, 1994, Sessions, 1993) Campbell and Pillsbury
(1989) performed a meta-analysis of 10studies 17% of cold nodules,
13% of warm or cool nodules, and 4% of hotnodules to be malignant
21. Fine-Needle Aspiration Currently considered to be the best
first-line diagnosticprocedure in the evaluation of the thyroid
nodule: Advantages: Safe Cost-effective Minimally invasive Leads to
better selection of patients for surgery than any othertest
(Rojeski, 1985) 22. Fine-NeedleAspiration (continued) FNA halved
the number of patients requiring thyroidectomy (Mazzaferri, 1993)
FNA has double the yield of cancer in those who do undergo
thyroidectomy (Mazzaferri, 1993) 23. Fine-Needle Aspiration
(continued)Limitations skill of the aspirator Sampling error in
lesions 4cm, multinodular lesions, andhemorrhagic lesions Error can
be diminished using ultrasound guidance expertise of the cytologist
difficulty in distinguishing some benign cellularadenomas from
their malignant counterparts (follicularand Hurthle cell) False
negative results = 1%-6% (Mazzeferri, 1993) False positive results
= 3%-6% (Rojeski, 1985, Mazzeferri, 1993, Hall, 1989) 24. Molecular
Pathogenesis of Thyroid Cancer 25. Thyroid Cancer
TypeMutationPrevalence, %Papillary BRAF[V600E]45 BRAF copy gain
3RET/PTC 20RAS 10 PI3KCA 3PI3KCA copy gain12PTEN2FollicularBRAF
copy gain35 RAS45PAX8-PPAR35 PTEN< 10PI3KCA < 10PI3KCA copy
gain12Medullary RET (familial)> 95 RET (sporadic) 50 26. In last
30 years, it has become clear that thyroidcancers are associated
with genetic mutations thatlead to aberrant intracellular signaling
inhibition of intracellular signaling cascades includingMAPK and
PI3K pathways may be effective in thetreatment . Ahmed 2011; Hong
2011; Carr 2010; Robinson 2010; Lam 2010; Sherman
2008;Gupta-Abramson 2008 27. Classification of Malignant
ThyroidNeoplasms Papillary carcinoma Medullary Carcinoma Follicular
variant Miscellaneous Tall cell Sarcoma Diffuse sclerosing Lymphoma
Encapsulated Squamous cell carcinoma Follicular carcinoma
Mucoepidermoid carcinoma Overtly invasive Clear cell tumors
Minimally invasive Pasma cell tumors Hurthle cell carcinoma
Metastatic Direct extention Anaplastic carcinoma Kidney Giant cell
Colon Small cell Melanoma 28. WDTC - Papillary Carcinoma Pathology
Gross - vary considerably in size- often multi-focal-
unencapsulated but often have a pseudocapsule Histology - closely
packed papillae withlittle colloid- psammoma bodies- nuclei are
oval or elongated,pale staining withground glass appearanc -Orphan
Annie cells 29. WDTC - Follicular Carcinoma Pathology Gross -
encapsulated, solitary Histology - very
well-differentiated(distinction between follicularadenoma and
carcinomaiddifficult) - Definitive diagnosis -evidence of vascular
andcapsular invasionFNA and frozen section cannotaccurately
distinquish between benignand malignant lesions 30.
CEASynaptophysin ChromograninCalcitonin ThyroglobulinS03-12297 31.
72 yr old female, 2 week history enlarging thyroid mass2-3 day
history of hoarseness and stridor FNA: poorly differentiated
thyroid cancerThyroglobulin negSpindle cells Giant
cellsPTCAnaplastic 32. WDTC - PROGNOSIS Prognostic schemes:AMES
(Lahey Clinic, Burlington, MA)GAMES (Memorial Sloan-Kettering
Cancer Center, NY)AGES (Mayo Clinic, Rochester, MN) GAMES scoring
(PAPILLARY & FOLLICULAR CANCER)G - GradeA - Age of patient when
tumor discoveredM - Metastases of the tumor (other than Neck LN)E -
Extent of primary tumorS - Size of tumor (>5 cm) The patient is
then placed into a high or low risk category 33. WDTC - Prognosis
(Continued)1) Low risk group - men younger than 40 years andwomen
younger than 50 years regardlessof histologic type - recurrence
rate -11% - death rate - 4%(Cady and Rossi, 1988) 34. WDTC -
Prognosis (Continued) 1) Intermediate risk group - Men older than
40 years and women older than 50 years who have papillary carcinoma
- recurrence rate - 29% - death rate - 21% 2) High risk group - Men
older than 40 years and women older than 50 years who have
follicular carcinoma - recurrence rate - 40% - death rate - 36% 35.
AJCC :Classification of Thyroid CancerPrimarytumorTXPrimary tumor
cannot be assessedT0No evidence of primary tumorT1Tumor < 2 cm
confined to the thyroidT2Tumor >2 cm and 4 cm confined to the
thyroidor Tumor of any size with minimal extrathyroid extensionT4a
Tumor of any size with extrathyroid extension to subcutaneoussoft
tissues, larynx, trachea, esophagus, or recurrent laryngealnerveor
Intrathyroidal anaplastic carcinoma- resectableT4b Tumor invading
prevertebral fascia/encasing carotid artery ormediastinal vessels
or Extrathyroidal anaplastic carcinoma -unresectable 36. Regional
LN(N) (central compartment, lateralcervical, and upper
mediastinal)NXRegional lymph nodes cannot beassessedN0No regional
lymph node metastasisN1Regional lymph node metastasisN1a Metastasis
to level VI (pretracheal orparatracheal, and prelaryngeal)N1b
Metastasis to unilateral, bilateral, orcontralateral
cervical(Levels I, II, III, IV orV) or superior mediastinal lymph
nodes(Level VII ) 37. Distantmetastasis(M)MX Distant metastasis
cannot be assessedM0 No distant metastasisM1 Distant metastasis 38.
Papillary/Follicular Thyroid Cancer 39. AJCC/UICC StagingThyroid
CancerPapillary/Follicular StageAge < 45 yrs Age > 45 yrs
IAny T, any N, M0 4cm, N0, M0or T1-3, N1a, M0 IV Any T, Any N,
Gross ETE, or M1 Hrthle cell carcinoma is considered a follicular
carcinoma. All anaplastic carcinomas are stage IV. 40. staging of
thyroid cancer is the only one inoncology that takes patient age at
diagnosis intoaccount. age is the most important prognostic
variable formortality a large proportion of thyroid cancers
(primarilyPTC) occur in women under the age of 45. As a group these
are highly sensitive to RAI; thus, even with metastatic disease can
be cured withRAI following surgery. As the age of diagnosis
increases, the mortality rateincreases as well, most sharply after
the age of 60 years. 41. Overall, the differentiated thyroid
cancers areassociated with a good prognosis and 10-yearsurvival
rates are 93% for papillary 85% for follicular and 76% for Hrthle
cell carcinomas, respectively. 42. Initial ManagementSurgery is the
definitive management of thyroid cancer, excluding most cases of
ATC and lymphomaTypes of operations: lobectomy with isthmusectomy
minimal operation required for a potentially malignant thyroid
nodule total thyroidectomy - removal of all thyroid tissue
preservation of the contralateral parathyroid glands subtotal
thyroidectomy anything less than a total thyroidectomy 43.
Management (WDTC) - Papillary and FollicularSubtotal vs. total
thyroidectomy 44. (continued) Rationale for total thyroidectomy1)
30%-87.5% of papillary carcinomas involve opposite
lobe(Hirabayashi, 1961, Russell, 1983)2) 7%-10% develop recurrence
in the contralateral lobe(Soh, 1996)3) Residual WDTC has the
potential to dedifferentiate to ATC 45. (Continued) Rationale for
subtotal thyroidectomy 1) Lower incidence of complications
Hypoparathyroidism (1%-29%) (Schroder, 1993) Recurrent laryngeal
nerve injury (1%-2%) (Schroder, 1993) Superior laryngeal nerve
injury 2) Long term prognosis is not improved by total
thyroidectomy (Grant, 1988) 46. (continued)Indications for total
thyroidectomy1) Patients older than 40 years with papillary or
follicular carcinoma2) Anyone with a thyroid nodule with a history
of irradiation3) Patients with bilateral disease 47.
(continued)Managing lymphatic involvement pericapsular and
tracheoesophageal nodes should bedissected and removed in all
patients undergoingthyroidectomy Overt nodal involvement requires
exploration ofmediastinal and lateral neck If any cervical nodes
are clinically palpable or identifiedby MR or CT imaging as being
suspicious a neckdissection should be done (Goldman, 1996)
Prophylactic neck dissections are not done (Gluckman) 48.
Management (WDTC) - Papillary and Follicular (continued)
Postoperative therapy/follow-up Radioactive iodine (administration)
Scan at 4-6 weeks postop repeat scan at 6-12 months after ablation
repeat scan at 1 year then... every 2 years thereafter 49.
Management (WDTC) - Papillary and
Follicular(continued)Postoperative therapy/follow-up Thyroglobulin
(TG) (Gluckman) measure serum levels every 6 months Level >30
ng/ml are abnormal Thyroid hormone suppression (control TSH
dependent cancer) (Goldman, 1996) should be done in 1) all total
thyroidectomy patients 2) all patients who have had radioactive
ablation of any remaining thyroid tissue 50. neck ultrasound should
be performed 6 and 12 months after surgery, and then annually for 3
to 5 years, depending on the patients risk for recurrence and
Tgstatus. CT and PET scans has been increasingly used in the
surveillance of patients with iodine-negative, differentiated
thyroid carcinoma. 51. (WDTC) - Hurthle Cell Carcinoma Variant of
follicular carcinoma Lymphatic spread seen in 30% of patients
(Goldman, 1996) Distant metastases to bone and lung is seen in 15%
atthe time of presentation Total thyroidectomy is recommended
because:1) Lesions are often Multifocal2) They are more aggressive
than WDTCs3) Most do not concentrate iodine 52. Treatment of
Differentiated Thyroid Cancer[NCCN 2011;Cooper 2009] 53. Medullary
Thyroid Carcinoma 10% Arises from the parafollicular cell or
C-cells of the thyroidgland derivatives of neural crest cells of
the branchial arches secrete calcitonin which plays a role in
calcium metabolism Developes in 4 clinical settings: Sporadic MTC
(SMTC) Familial MTC (FMTC) Multiple endocrine neoplasia IIa (MEN
IIa) Multiple endocrine neoplasia IIb (MEN IIb) 54. Medullary
Thyroid Carcinoma(continued)Sporadic MTC:70%-80% of all MTCsMean
age of50 yearsUnilateral and Unifocal (70%)Slightly more aggressive
than FMTC and MEN IIa Familial MTC: Autosomal dominant transmission
Not associated with any other endocrinopathies Mean age of 43
Multifocal and bilateral Has the best prognosis of all types of MTC
100% 15 year survival 55. Medullary Thyroid Carcinoma(continued)
MEN IIa (Sipples Syndrome): MTC, Pheochromocytoma, parathyroid
hyperplasia Autosomal dominant transmission Mean age of 27 100%
develop MTC 85%-90% survival at 15 years MEN IIb (Wermers
Syndrome): Pheochromocytoma, multiple mucosal neuromas, marfanoid
body habitus 90% develop MTC by the age of 20 Most aggressive type
of MTC 15 year survival is 300 pg/ml)2) serum calcium3) 24 hour
urinary catecholamines (metanephrines, VMA, nor- metanephrines)4)
carcinoembryonic antigen (CEA) Fine-needle aspiration Genetic
testing of all first degree relatives RET proto-oncogene 57.
Medullary Thyroid Carcinoma(Management) Recommended surgical
management total thyroidectomy central lymph node dissection
lateral jugular sampling if suspicious nodes - modified radical
neck dissection If patient has MEN syndrome remove pheochromocytoma
before thyroid surgery 58. Medullary Thyroid
Carcinoma(Management)Postoperative management disease surveillance
serialcalcitonin and CEA 2 weeks postop 3/month for one year, then
biannually If calcitonin rises metastatic work-up surgical excision
if metastases - external beam radiation 59. Anaplastic Carcinoma of
the Thyroid Highly lethal form of thyroid cancer Median survival 70
years) Mean age of 60 years 53% have previous benign thyroid
disease 47% have previous history of WDTC 60. Anaplastic Carcinoma
of the Thyroid Pathology Classified as large cell or small cell
Large cell is more common and has a worse prognosis Histology -
sheets of very poorly differentiated cellslittle cytoplasmnumerous
mitosesnecrosisextrathyroidal invasion 61. Anaplastic
Carcinoma(Management) Most have extensive extrathyroidal
involvement at the time of diagnosis surgery is limited to biopsy
and tracheostomy Current standard of care is: maximum surgical
debulking, possible adjuvant radiotherapy and chemotherapy 62.
Recurrent DTC 85% of patients with DTC :disease-free after
initialtreatment 1015% : recurrent disease Most recurrences occur
within the first five years afterinitial treatment 5%: distant
metastaseslungs (50%), bones (25%), lungs and bones (20%) ,
10-year-survival rates ranging from 25% to 42% 63. Treatment
methods Surgery (when feasible) Radioiodine treatment in presence
of radioiodine uptake in tumor foci Other local treatments
(dependent on location and extent of disease): external radiation
beam treatment, embolisation, radiofrequency New treatment methods,
eg, molecularly targeted treatments, 64. Selection of patients
withmetastases for treatment Candidates for radioiodine treatment
Younger age Well differentiated tumour High radioiodine uptake
Small metastases Location in lungs Low uptake of fluorodeoxyglucose
Loss of RAI uptake is often associated with the increased uptakeof
PET scanning. Repeated radioiodine treatment (response rate: 85%,
with 96% of complete responses seen with a cumulative activity
