1. MANAGEMENT OF THYROID
CANCER
Local seminar
Medical Oncology department
By
Salah Mabruok Khalaf
South Egypt Cancer Institute
2012

2. Epidemiology
• 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
carcinoma
• Age: most common after age 30

3. Risk Factors for Thyroid Cancer
1. Neck irradiation
The only well-established risk factor for differentiated thyroid cancer .
2. Genetic factors
1. Papillary thyroid carcinoma may occur in several rare inherited
syndromes, including
i.Familial adenomatous polyposis
ii.Gardner's syndrome
iii.Cowden's disease
2. Medullary carcinoma in MEN syndrome
3. Other risk factors
i. History of goiter
ii. family history of thyroid disease
iii. Female gender
iv. Asian race.

4. 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

5. Investigations
• 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

6. • FNAC indications
I. Sonar-based criteria
 Solid nodule
1. More than 1 cm if associated with sonographic suspious features
2. More than 1.5 cm in absence of sonographic suspicion
Mixed solid and cystic
1. More than 1.5 cm if associated with sonographic suspicious features
2. More than 2 cm in absence of sonographic suspicion
Spongiform nodule (microcystic component > 50% of nodules
I. 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)

7. Fine Needle Aspiration
•Procedure of Choice – Fast, minimally invasive and few
risk
•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)

8. 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

10. Classification and Incidence of
Thyroid Cancer
Tumors of Follicular Cell Origin
􀂄 Differentiated
Papillary 75% Follicular 10% Hurthle Cell 5%
􀂄 Undifferentiated
Anaplastic 5%:
1-Small cell carcinoma.
2-Giant cell carcinoma.
Tumors of Parafollicular cells
Medullary 5%
 Other 1%
1-sarcomas 2-lymphomas 3-epidermoid carcinomas
4-Teratomas 5-metastasis from other cancers

11. Papillary Cancer
 The most common malignant
thyroid tumor (70-80% of all
cancers)
 Women predominance
 Age: 38-45
 Accounts for 90% of radiation
induced thyroid cancer
 Prognosis directly related to
tumor size

12. • Papillary Cancer
1.Histologic:
1. Psammoma bodies
2. Orphan Ann nucleus
2.Multicentric: 30-50%
3.Spread via Lymphatics-
propensity for cervical node
involvement
4.Invasion of adjacent
structures and distant mets
uncommon

13. FOLLICULAR THYROID CANCER
1.Usually Encapsulated
2.More Common Among Older Patients
3.Woman > Man
4.More Aggressive & Less Curable Than Papillary
5.Vascular Invasion (veins and arteries) within the thyroid
gland is common
6.Blood Spread (lung and bone)
7.Types:
1. Follicular carcinoma
2. Follicular carcinoma variant: Minimally Invasive Hurthle Cell
8.Rarely associated with radiation exposure

14. Hürthle Cell Neoplasms
1.More aggressive than other differentiated
thyroid carcinomas (higher mets/lower survival
rates)
2.Less affinity for I131
3.Need to differentiate from benign/malignant
4.Metastasis may be more sensitive to I131 than
primary

15. 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

16. Medullary Thyroid Cancer Occurs in Four Clinical
Settings
I- Sporadic
1.80% of all cases of medullary thyroid cancer.
2.Typically unilateral
3.No associated endocrinopathies
4.Peak onset 40 - 60.
5.Females predominance: 3:2 ratio.
6.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).

17. II-MEN II-A (Sipple Syndrome)
(Multiple Endocrine Neoplasia II A).
1.Sipple syndrome has
[1] bilateral medullary carcinoma
[2] pheochromocytoma
[3] hyperparathyroidism.
2.This syndrome is inherited in an autosomal dominant fashion.
Because of this, males and females are equally affected.
3.Peak incidence of medullary carcinoma in these patients is in the
30's.

18. III-MEN II B
1.This syndrome has
[1] medullary carcinoma
[2] Pheochromocytoma
[3] mucosal ganglioneuromas and Marfanoid habitus.
2.Inheritance is autosomal dominant as in MEN IIA (m=f)
3.Pheochromocytomas must be detected prior to any operation.
4.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.

19. IV-Inherited medullary carcinoma without associated
endocrinopathies.
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.

20. Anaplastic cancer
1)Peak onset age 65 and older
Very rare in young patients
1)Males more common than females by 2 to 1 ratio
2)Undifferentiated
3)May arise many years (>20) following radiation
exposure.
4)Neck mass usually large, diffuse, and very hard
5)Rapidly growing, often inoperable, highly recurrent

21. 7) Invade locally, metastasize both locally and distantly
(to lungs or bones)
8) Cervical metastasis are present in the vast majority
(over 90%) of cases at the time of diagnosis.
9) Mean survival 6 months
10) Often requires the patient to get a tracheostomy to
maintain their airway.

22. STAGING OF THYROID CANCER
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
(NTCTCS)

23. 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)

24. • 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
unresectable

25. • 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

26. • Distant metastases (M)
• MX: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis

27. 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

28. Papillary or follicular thyroid cancer
Age 45 years and older
Stage I Stage IVA
T4a, N0, M0
T1, N0, M0
T4a, N1a, M0
Stage II T1, N1b, M0
T2, N0, M0 T3, N1b, M0
Stage III T2, N1b, M0
T4a, N1b, M0
T3, N0, M0
Stage IVB
T1, N1a, M0 T4b, any N, M0
T2, N1a, M0 Stage IVC
T3, N1a, M0 Any T, any N, M1

29. Medullary thyroid cancer
•Stage I Stage IVA
• T1, N0, M0 T4a, N0, M0
•Stage II T4a, N1a, M0
• T2, N0, M0
T1, N1b, M0
T2, N1b, M0
•Stage III
T3, N1b, M0
• T3, N0, M0 T4a, N1b, M0
• T1, N1a, M0 Stage IVB
• T2, N1a, M0 T4b, any N, M0
• T3, N1a, M0 Stage IVC
Any T, any N, M1

30. • 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

31. • 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.

32. PROGNOSIS

33. PROGNOSIS
Prognostic schemes: GAMES scoring (PAPILLARY &
FOLLICULAR CANCER)
•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
category

34. Prognostic Risk Classification for Patients with Well-
Differentiated Thyroid Cancer (GAMES )
Low Risk High Risk
• Grade Well Differentiated Poorly Differentiated
• Age <40 >40
• Mets None Regional or Distant
• Extent No local extension, Capsular invasion,
intrathyroidal, extrathyroidal
• Sex Female Male

35. 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%

36. Treatment

37. 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.

38. II-Lobectomy:
• 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

39. Indications for total Thyroidectomy OR lobectomy: (all
present)
• 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

40. 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
features

41. • 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.

42. 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
up: node
• Clinically suspicious lymph node,
contralateral lesion, or perithyroidal node
• Aggressive variant
• Macroscopic multifocal disease
• ≥1 cm in diameter

43. POSTSURGICAL EVALUATION AFTER THYROIDECTOMY
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)

44. 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

45. Pretherapy whole body iodine scan:
•If performed, a pretherapy scan should use a low dose of 131
I
(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 I therapy
131
dose induced by a pretreatment diagnostic dose

46. Dose of RAI
•The dosing of 131I 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

47. 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

48. 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.

49. Stage IV Papillary and Follicular
1) Adequate uptake of I131
• I131
1) Inadequate uptake or not sensitive to I131
i. Localized lesions
1) Radiation therapy
2) Resection of limited metastases don't uptake of I131.
ii. 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.

50. Medullary Thyroid Cancer
treatment
• Thyroidectomy:
• total thyroidectomy + routine central and bilateral modified neck dissections
..Why?
• External radiation therapy:
• palliation of locally recurrent tumors, without evidence that it provides any survival
advantage.
• 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.

51. 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.

52. Anaplastic Thyroid Cancer
• Chemotherapy:
• Produce partial remissions in some patients.
• Approximately 30% of patients achieve a partial remission with
doxorubicin.
• 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.

53. 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.

54. 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

55. 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
duration.

56. 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

57. Systemic chemotherapy
• Doxorubicin alone
• Cisplatin and doxorubicin (better)
• BAP: Cisplatin, doxorubicin and bleomycin
• CVD: cyclophosphamide, vincristine, and dacarbazine
• Dacarbazine and 5-fluorouracil

58. • 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.
• 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.

59. 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 giant-
cell carcinomas.
• Effectiveness
• BAP regime can achieve reasonable palliation, and probably
increases survival, in poor-prognosis thyroid cancers.

60. 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
weeks.
• Cell type
• Medullary thyroid carcinoma.
• Effecetiveness
• CVD chemotherapy has moderate activity and is well tolerated in
patients with advanced MTC.

61. 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
• MTC
• Effectiveness
• Treatment of advanced thyroid carcinoma with DTIC and 5-FU
appeared to have significant activity and was well tolerated.

62. Target therapy

63. Take home messages
• FNAC is not adequate for definite diagnosis of follicular
carcinoma
• 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
cancer.
• Once medullary carcinoma is diagnosed, familial
predisposition should be checked up
• If I131 is indicated, stunning effect should be avoided

64. 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
anaplastic
•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
medullary