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Local seminar
Medical Oncology department
Salah Mabruok Khalaf
South Egypt Cancer Institute
• Thyroid Cancer accounts for 1.5% of all cancers
• The most common endocrine malignancy (95% of all
endocrine cancers)
• Sex: Female to Male Ratio 2.5:1 except anaplastic
• Age: most common after age 30
Risk Factors for Thyroid Cancer
Neck irradiation
The only well-established risk factor for differentiated thyroid cancer .
2. Genetic factors
Papillary thyroid carcinoma may occur in several rare inherited
syndromes, including
Familial adenomatous polyposis
Gardner's syndrome
Cowden's disease
Medullary carcinoma in MEN syndrome
3. Other risk factors
History of goiter
ii. family history of thyroid disease
iii. Female gender
iv. Asian race.
Clinical Manifestation
• Thyroid enlargement
• Most patients are euthyroid and
present with a thyroid nodule
• Symptoms such as dysphagia,
dyspnea and hoarseness usually
indicate advanced disease
• Cervical lymph node enlargement
• Serum TSH
• Fine Needle Aspiration Cytology (FNA)
• High Resolution Thyroid US- helpful in
detecting non palpable nodule and solid versus
cystic lesion
• Thyroid Isotope Scanning- to assess functional activity of
a nodule
• FNAC indications
Sonar-based criteria
 Solid nodule
More than 1 cm if associated with sonographic suspious features
More than 1.5 cm in absence of sonographic suspicion
 Mixed solid and cystic
More than 1.5 cm if associated with sonographic suspicious features
More than 2 cm in absence of sonographic suspicion
 Spongiform nodule (microcystic component > 50% of
High risk Clinical feature
RT exposure
Genetic predisposition
Sonographic suspicious features
(hypoechoic, microcalcification,
increased central vascularity,
infiltrative margin or taller than wide in
transverse plan)
Fine Needle Aspiration
• Procedure of Choice – Fast, minimally invasive and few
• Incidence of False positive: 1%
• Incidence of False negative: 5%
• FNA is not a tissue diagnosis
• Limitation of FNA:
• Cannot distinguish a benign follicular from a malignant lesion
(cancer invade capsule)
FNA Results of Thyroid Nodule
• Benign(70%) --> F/U 6-12 months
• Indeterminate(10%) --> repeat FNA, I123 scan
• Follicular neoplasm(5%) --> I123 scan or surgery
• Suspicious (10%) --> surgery
• Carcinoma (5%) --> surgery
Classification and Incidence of
Thyroid Cancer
Tumors of Follicular Cell Origin
􀂄 Differentiated
Papillary 75%
Follicular 10%
􀂄 Undifferentiated
Anaplastic 5%:
1-Small cell carcinoma.
2-Giant cell carcinoma.
Hurthle Cell 5%
Tumors of Parafollicular cells
Medullary 5%
 Other 1%
2-lymphomas 3-epidermoid carcinomas
5-metastasis from other cancers
Papillary Cancer
 The most common malignant
thyroid tumor (70-80% of all
 Women predominance
 Age: 38-45
 Accounts for 90% of radiation
induced thyroid cancer
 Prognosis directly related to
tumor size
• Papillary Cancer
1. Histologic:
1. Psammoma bodies
2. Orphan Ann nucleus
2. Multicentric: 30-50%
3. Spread via Lymphatics-
propensity for cervical node
4. Invasion of adjacent
structures and distant mets
Usually Encapsulated
More Common Among Older Patients
Woman > Man
More Aggressive & Less Curable Than Papillary
Vascular Invasion (veins and arteries) within the thyroid
gland is common
Blood Spread (lung and bone)
Follicular carcinoma
Follicular carcinoma variant: Minimally Invasive Hurthle Cell
8. Rarely associated with radiation exposure
Hürthle Cell Neoplasms
More aggressive than other differentiated
thyroid carcinomas (higher mets/lower survival
Less affinity for I131
Need to differentiate from benign/malignant
Metastasis may be more sensitive to I131 than
Medullary Thyroid Cancer
1. Usually present as a mass ± lymphadenopathy
2. It can also be diagnosed by fine-needle aspiration biopsy
microscopically typically.
3. Family members should be screened for calcitonin
elevation and/or for the RET proto-oncogene mutation
4. Not associated with radiation exposure
5. Residual disease (following surgery) or recurrence can be
detected by measuring calcitonin
Medullary Thyroid Cancer Occurs in Four Clinical
I- Sporadic
80% of all cases of medullary thyroid cancer.
Typically unilateral
No associated endocrinopathies
Peak onset 40 - 60.
Females predominance: 3:2 ratio.
One third will present with intractable diarrhea.
Diarrhea is caused by increased gastrointestinal secretion and hypermotility due to
the hormones secreted by the tumor (calcitonin, prostaglandins, serotonin, or VIP).
II-MEN II-A (Sipple Syndrome)
(Multiple Endocrine Neoplasia II A).
Sipple syndrome has
[1] bilateral medullary carcinoma
[2] pheochromocytoma
[3] hyperparathyroidism.
This syndrome is inherited in an autosomal dominant fashion.
Because of this, males and females are equally affected.
Peak incidence of medullary carcinoma in these patients is in the
This syndrome has
[1] medullary carcinoma
[2] Pheochromocytoma
[3] mucosal ganglioneuromas and Marfanoid habitus.
Inheritance is autosomal dominant as in MEN IIA (m=f)
Pheochromocytomas must be detected prior to any operation.
The idea here is to remove the pheochromocytoma first to
remove the risk of severe hypertensive episodes while the
thyroid or parathyroid is being operated on.
IV-Inherited medullary carcinoma without associated
This form of medullary carcinoma is the least aggressive.
Like other types of thyroid cancers, the peak incidence is
between the ages of 40 and 50.
Anaplastic cancer
1) Peak onset age 65 and older
Very rare in young patients
2) Males more common than females by 2 to 1 ratio
3) Undifferentiated
4) May arise many years (>20) following radiation
5) Neck mass usually large, diffuse, and very hard
6) Rapidly growing, often inoperable, highly recurrent
Invade locally, metastasize both locally and distantly
(to lungs or bones)
Cervical metastasis are present in the vast majority
(over 90%) of cases at the time of diagnosis.
Mean survival 6 months
10) Often requires the patient to get a tracheostomy to
maintain their airway.
In differentiated thyroid carcinoma, several classification and
staging systems have been introduced. However, no clear
consensus has emerged favoring any one method over another
• AMES system/AGES System/GAMES system
• TNM system
• MACIS system
• University of Chicago system
• Ohio State University system
• National Thyroid Cancer Treatment Cooperative Study
TNM Staging
• Primary tumor (T) (All categories may be subdivided into (a)
solitary tumor or (b) multifocal tumor.)
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
T1: Tumor ≤ 2 cm, limited to the thyroid
T2: Tumor > 2 cm but ≤4 cm, limited to the thyroid
T3: Tumor > 4 cm limited to the thyroid or any tumor with
minimal extrathyroid extension (e.g., extension to
sternothyroid muscle or perithyroid soft tissues)
• T4a: Tumor of any size extending beyond the thyroid capsule
to invade subcutaneous soft tissues, larynx, trachea,
esophagus, or recurrent laryngeal nerve
• T4b: Tumor invades prevertebral fascia or encases carotid
artery or mediastinal vessels
All anaplastic carcinomas are considered T4 tumors.
• T4a: Intrathyroidal anaplastic carcinoma—surgically resectable
• T4b: Extrathyroidal anaplastic carcinoma—surgically
• Regional lymph nodes (N)
(Regional lymph nodes are the central compartment, lateral cervical, and upper
mediastinal lNs)
• NX: Regional lymph nodes cannot be assessed
• N0: No regional lymph node metastasis
• N1: Regional lymph node metastasis
• N1a: Metastasis to level VI (pretracheal, paratracheal, and
prelaryngeal/Delphian on the cricothyroid membrane (precricoid)
lymph nodes)
• N1b: Metastasis to unilateral or bilateral cervical or superior
mediastinal lymph nodes
• Distant metastases (M)
• MX: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis
AJCC Stage Groupings
Papillary or follicular thyroid cancer
• Younger than 45 years
• Stage I
• Any T, any N, M0
• Stage II
• Any T, any N, M1
• Age 45 years and older
• Stage I
• T1, N0, M0
• Stage II
• T2, N0, M0
• Stage III
• T3, N0, M0
• T1, N1a, M0
• T2, N1a, M0
• T3, N1a, M0
Papillary or follicular thyroid cancer
Age 45 years and older
Stage I
T1, N0, M0
Stage II
T2, N0, M0
Stage III
T3, N0, M0
T1, N1a, M0
T2, N1a, M0
T3, N1a, M0
Stage IVA
T4a, N0, M0
T4a, N1a, M0
T1, N1b, M0
T3, N1b, M0
T2, N1b, M0
T4a, N1b, M0
Stage IVB
T4b, any N, M0
Stage IVC
Any T, any N, M1
Medullary thyroid cancer
• Stage I
• T1, N0, M0
• Stage II
• T2, N0, M0
• Stage III
• T3, N0, M0
• T1, N1a, M0
• T2, N1a, M0
• T3, N1a, M0
Stage IVA
T4a, N0, M0
T4a, N1a, M0
T1, N1b, M0
T2, N1b, M0
T3, N1b, M0
T4a, N1b, M0
Stage IVB
T4b, any N, M0
Stage IVC
Any T, any N, M1
• Anaplastic thyroid cancer
• All anaplastic carcinomas are considered
stage IV.
• Stage IVA
• T4a, any N, M0
• Stage IVB
• T4b, any N, M0
• Stage IVC
• Any T, any N, M1
• University of Chicago system:
• Class I—disease limited to the thyroid gland
• Class II—lymph node involvement
• Class III—extrathyroidal invasion
• Class IV—distant metastases.
Prognostic schemes: GAMES scoring (PAPILLARY &
• G Grade
• A Age of patient when tumor discovered
• M Metastases of the tumor (other than Neck LN)
• E Extent of primary tumor
• S Size of tumor (>5 cm)
• The patient is then placed into a high or low risk
Prognostic Risk Classification for Patients with Well-Differentiated
Thyroid Cancer (GAMES )
• Grade
Low Risk
Well Differentiated
• Age
• Mets
• Extent
• Sex
No local extension,
High Risk
Poorly Differentiated
Regional or Distant
Capsular invasion,
MACIS Scoring
• Developed by the Mayo Clinic for staging.
• It is known to be the most accurate predictor of a
patient's outcome with papillary thyroid cancer (M =
Metastasis, A = Age, I = Invasion, C = Completeness
of Resection, S = Size)
• MAICS Score 20 year Survival
 < 6 = 99%
 6-7 = 89%
 7-8 = 56%
 > 8 = 24%
Stage I and II Papillary and Follicular
I-Total thyroidectomy:
• Rationale?
􀂄 Bilateral cancers are common (30-85%)
􀂄 improved effectiveness for I131 ablation
􀂄 lowers dose needed for I131 ablation
􀂄 allows f/u with thyroglobulin levels
􀂄 decreased recurrence in all groups
􀂄 improved survival in high risk pts.
􀂄 Decreased risk of pulmonary mets
• Disadvantage?
higher incidence of hypoparathyroidism, but this
complication may be reduced when a small amount of
tissue remains on the contralateral side.
• Rationale?
􀂄 Most patients are low risk and excellent prognosis
􀂄 Role of adjuvant treatment not defined
􀂄 Complications of Total
􀂄 Occult multicentric tumor not clinically significant
􀂄 Most local recurrences treated with surgery
􀂄 Excellent outcome with lobectomy in low risk patients
• Disadvantage?
• approximately 5% to 10% of patients will have a recurrence
Indications for total Thyroidectomy OR lobectomy: (all
• Age 15 y - 45 y
• No prior radiation
• No distant metastases
• No cervical lymph node metastases
• No extrathyroidal extension
• Tumor < 4 cm in diameter
• No aggressive variant
When complete total thyroidectomy after lobectomy:
• Aggressive variant
• Macroscopic multifocal disease
• Positive isthmus margins
• Cervical lymph node metastases
• Extrathyroidal extension
Aggressive=Tall cell, columnar cell, insular, oxyphilic, or poorly differentiated
• Node removal ?
• Selective node removal can be performed, and radical
neck dissection is usually not required.
• This results in a decreased recurrence rate, but has not
been shown to improve survival.
Thyroid carcinoma after lobectomy for benign lesions
I-Completion of thyroidectomy:
III- follow up:
• > 4 cm
• Negative margins
• Positive margins
• No contralateral lesion
• Extra-thyroidal invasion (T3 or T4(
• < 1 cm in diameter
II- Completion of Thyroidectomy or follow
• No suspicious lymph
• Clinically suspicious lymph node,
contralateral lesion, or perithyroidal node
• Aggressive variant
• Macroscopic multifocal disease
• ≥1 cm in diameter
I-No gross Residual Disease in neck:
• Follow up (TSH + thyroglobulin measurement +
antithyroglobulin antibodies)
II- Gross Residual Disease in neck:
• Resectable >>>>>>>> Surgery
• Irresectable >>>>>>>> Total body radioiodine scan:
Inadequate uptake >>>>>>RT
Adequate uptake >>>>> Radioiodine treatment or RT
No scan performed >>>>>Radioiodine treatment or RT
• Total body radioiodine scan is done after adequate TSH stimulation (thyroid
withdrawal or recombinant rhTSH stimulation)
Postoberative I131?
a postoperative course of therapeutic (ablative)
doses of I131 results in a decreased recurrence
rate among high-risk patients with papillary and
follicular carcinomas.
Indications: (any present)
• Age < 15 y or > 45 y
• Radiation history
• Known distant metastases
• Bilateral nodularity
• Extrathyroidal extension
• Tumor > 4 cm in diameter
• Cervical lymph node metastases
• Aggressive variant
Pretherapy whole body iodine scan:
• If performed, a pretherapy scan should use a low dose of
(1 to 5 mCi) or 123I.
• To detect residual thyroid tissue, thyroid cancer, and metastatic foci
• To reduce the potential for sublethal radiation stunning of thyroid tissue that
prevents optimal uptake of future 131I therapy.
• Stunning is defined as a reduction in uptake of the
therapy dose induced by a pretreatment diagnostic dose
Dose of RAI
• The dosing of
for ablation is somewhat controversial.
• Low-dose ablation with less than 30 mCi administered on
an outpatient basis:
• For low-risk young patients
• High-dose ablation with100 to 200 mCi
• For high-risk patients
• 300 mCi
• For all patients with metastatic disease that treated with repeated
therapeutic doses of 131I
Replacement therapy?
• Postoperative treatment with exogenous thyroid hormone
in doses sufficient to suppress thyroid-stimulating
hormone (TSH) with development of thyrotoxic
manifestations; decreases incidence of recurrence.
• Administration of Thyroid Hormone
 To suppress TSH and growth of any residual thyroid
 To maintain patient euthyroid
o Maintain TSH level 0.1uU/ml in low risk pts
o Maintain TSH Level < 0.1uU/ml in high risk pts
Stage III Papillary and Follicular
A. Surgery
• Total thyroidectomy plus removal of involved lymph nodes or
other sites of extrathyroid disease.
B. Adjuvant therapy
• I131 ablation following total thyroidectomy if the tumor
demonstrates uptake of this isotope.
• External-beam radiation therapy if I131 uptake is minimal
• Replacement therapy for all patients.
Stage IV Papillary and Follicular
1) Adequate uptake of I131
• I131
1) Inadequate uptake or not sensitive to I131
Localized lesions
1) Radiation therapy
2) Resection of limited metastases don't uptake of I131.
Disseminated disease
1) TSH suppression with thyroxine is effective.
2) Chemotherapy has been reported to produce occasional complete
responses of long duration.
3) Clinical trials testing new approaches to this disease.
Medullary Thyroid Cancer treatment
• Thyroidectomy:
• total thyroidectomy + routine central and bilateral modified neck dissections
• External radiation therapy:
• palliation of locally recurrent tumors, without evidence that it provides any survival
• Radioactive iodine has no place in the treatment of patients with MTC.
• Palliative chemotherapy:
• Palliative chemotherapy has been reported to produce occasional responses in
patients with metastatic disease.
• No single drug regimen can be considered standard.
• Some patients with distant metastases will experience prolonged survival and can
be observed until they become symptomatic.
Anaplastic Thyroid Cancer
• Surgery:
• Tracheostomy is frequently necessary.
• If the disease is confined to the local area, which is rare, total
thyroidectomy is warranted to reduce symptoms caused by the
tumor mass.
• Radiation therapy:
• Used in patients who are not surgical candidates or whose tumor
cannot be surgically excised.
Anaplastic Thyroid Cancer
• Chemotherapy:
• Produce partial remissions in some patients.
• Approximately 30% of patients achieve a partial remission with
• The combination of doxorubicin plus cisplatin appears to be more
active than doxorubicin alone and has been reported to produce
more complete responses.
Treatment options under clinical evaluation:
• The combination of chemotherapy plus radiation therapy in patients following
complete resection may provide prolonged survival but has not been compared to
any one modality alone.
Recurrent Thyroid Cancer
• Recurrence rate for differentiated thyroidis about 10-30%
• 80% develop recurrence with disease in the neck alone, and
• 20% develop recurrence with distant metastases. The most common
site of distant metastasis is the lung.
• The prognosis for patients with clinically detectable
recurrences is generally poor, regardless of cell type.
Treatment of recurrent thyroid cancer
The selection of further treatment depends on many
factors, including
 Cell type
 Uptake of I131
 Prior treatment
 Site of recurrence
 Individual patient considerations
Treatment of recurrent thyroid cancer
• Adequate I131 uptake
• Localized
• Surgery with or without I131 ablation can be useful in controlling local
recurrences, regional node metastases, or, occasionally, metastases at other
localized sites.
• I131 ablation
• RT
• Disseminated
• I131 ablation
• Systemic chemotherapy for tumor not sensitive to I131. Chemotherapy has
been reported to produce occasional objective responses, usually of short
Treatment of recurrent thyroid cancer
• Inadequate I131 uptake or insensitive to I131
• Localized
• Surgery with or without I131 ablation can be useful in controlling local
recurrences, regional node metastases, or, occasionally, metastases at other
localized sites.
• RT
• Disseminated
• Systemic chemotherapy
Systemic chemotherapy
• Doxorubicin alone
• Cisplatin and doxorubicin (better)
• BAP: Cisplatin, doxorubicin and bleomycin
• CVD: cyclophosphamide, vincristine, and dacarbazine
• Dacarbazine and 5-fluorouracil
• Combined treatment of anaplastic thyroid carcinoma
with surgery, chemotherapy, and hyperfractionated
accelerated external radiotherapy.
• Two cycles of doxorubicin (60 mg/m(2)) and cisplatin (120
mg/m(2)) were delivered before RT and four cycles after
• RT consisted of two daily fractions of 1.25 Gy, 5 days per
week to a total dose of 40 Gy to the cervical lymph node
areas and the superior mediastinum).
• Improve OS and decrease RR.
BAP regimen
• Schedule
• BAP regimen which consisted of bleomycin (B) 30 mg a day for
three days, adriamycin (A) 60 mg/m2 iv in day 5, and cisplatinum
(P) 60 to mg/m2 iv in day 5.
• Cell type
• Several histologic types of thyroid carcinoma responded, but the
best responses were observed in medullary and anaplastic giantcell carcinomas.
• Effectiveness
• BAP regime can achieve reasonable palliation, and probably
increases survival, in poor-prognosis thyroid cancers.
CVD regimen
• Schedule
• cyclophosphamide (750 mg/m2), vincristine (1.4 mg/m2), and
dacarbazine (600 mg/m2 daily for 2 days in each cycle) every 3
• Cell type
• Medullary thyroid carcinoma.
• Effecetiveness
• CVD chemotherapy has moderate activity and is well tolerated in
patients with advanced MTC.
Dacarbazine and 5-fluorouracil
• Schedule
• 5 day intravenous courses of dacarbazine (DTIC) (250
mg/sqm) and 12 hour infusion 5-fluorouracil (450 mg/sqm),
given every 4 weeks. Six cycles
• Cell type
• Effectiveness
• Treatment of advanced thyroid carcinoma with DTIC and 5-FU
appeared to have significant activity and was well tolerated.
Target therapy
• Sunitinib Malate in Patients
more radioiodine sensitive,
With Iodine I 131-Refractory,
which will allow for detection of
Unresectable Welltumor and make further
Differentiated Thyroid Cancer ablation treatment effective(.
or Medullary Thyroid Cancer • Pazopanib Hydrochloride in
• Sorafenib Tosylate in
Patients With Advanced
Patients With Metastatic or
Thyroid Cancer
Unresectable, Iodine Non• Bortezomib in Patients With
Avid, Resistant Thyroid Cancer Metastatic Papillary or
• Valproic Acid (Depakote ER) Follicular Thyroid Cancer
in Patients With WellUnresponsive to Prior
Differentiated Advanced
Radioiodine Therapy
Thyroid Cancer (valproic acid
may make thyroid cancers
Take home messages
• FNAC is not adequate for definite diagnosis of follicular
Because the mixed papillary-follicular variant tends to
behave like a pure papillary cancer, it is treated in the
same manner and has a similar prognosis.
Thyroglobulin as a marker of follow up is useful only in
absence of any thyroid tissue in differentiated thyroid
Once medullary carcinoma is diagnosed, familial
predisposition should be checked up
If I131 is indicated, stunning effect should be avoided
Take home messages
All except rule
• All risk factors of differentiated thyroid cancers are not
established except Radiotherapy
• All types are caused by RT except medullary
• All types commonly occur before age of 50y except
• All types are commoner in females than in males except
anaplastic (M > F) and familial MTC (M=F)
• All types rarely associated with genetic syndrome except