Last update of thyroid cancer management from diagnosis till follow up You can request other lectures by emailing me at salahmab76@yahoo.com or calling me 0020 100 408 1234 Dr Salah Mabrouk Khallaf

1. MANAGEMENT OF THYROID CANCER
By
Salah Mabruok Khalaf
South Egypt Cancer Institute
2017
Course of Medical Oncology
Medical Oncology department

2. Epidemiology

3. Epidemiology
• Thyroid Cancer accounts for 3% of all cancers
• The most common endocrine malignancy (93% of all endocrine cancers)
• The incidence of thyroid cancer has increased nearly 3-fold from 1975 to
2009
• Sex: Female to Male Ratio 3:1 except anaplastic carcinoma
• Age: most common after age 3rd
decade
• 3 types of thyroid cancer: differentiated, medullary, anaplastic
• Anaplastc 3% and Hürthle Cell Carcinoma 3%
• OS of metastatic or advanced differentiated cancer of about 3 years
• OS of anaplasticcancer of about 3-6 months
Rule of 3

4. Risk Factors

5. Risk Factors
1. Neck irradiation
The only well-established risk factor for differentiated thyroid cancer .
1. 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
2. Other risk factors
i. History of goiter
ii. Family history of thyroid disease
iii. Female gender
iv. Asian race.

6. Pathology and Natural history

7. Classification of Thyroid Cancer
Tumors of Follicular Cell Origin
􀂄 Differentiated
Papillary 80% Follicular 8% Hurthle Cell 3%
􀂄 Undifferentiated
Anaplastic 3%:
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

8. FOLLICULAR THYROID CANCER
Functioning or “Well Differentiated”
Females more than female
Older Patients are more affected
Lung and Osseous mets are common than nodal mets
Less Curable than Papillary
Invasive subtype or Minimally Invasive Hurthle Cell
Encapsulated
Aggressive and Angioinvasion into blood vessels (veins
and arteries) within the thyroid gland is common
Rarely associated with radiation exposure

9. 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

10. • 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

11. 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

12. 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).

13. 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.

14. 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.

15. 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.

16. 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
Anaplastic cancer

17. 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.

18. Diagnosis

19. Clinical Manifestation
• Thyroid enlargement
• Most patients are euthyroid and
present with a thyroid nodule
• Symptoms such as dysphagia,
dyspnea and hoarseness of voice
usually indicate advanced disease
• Cervical lymph node enlargement

20. Investigations
• Initial investigations
• Serum TSH
• High Resolution Thyroid and neck US
• The result of TSH and neck sonar will detect the subsequent
investigations:
• FNAC
• Thyroid Isotope Scanning

23. Hypoechoic nodule.
Bożena Popowicz et al. Eur J Endocrinol 2009;161:103-111
© 2009 European Society of Endocrinology

24. Microcalcifications in thyroid nodule.
Bożena Popowicz et al. Eur J Endocrinol 2009;161:103-111
© 2009 European Society of Endocrinology

25. Nodule with anterior–posterior to the transverse dimension ≥1.
Bożena Popowicz et al. Eur J Endocrinol 2009;161:103-111
© 2009 European Society of Endocrinology
Oval shaped thyroid nodule: a sonographic appearance concerning for thyroid
cancer, particularly when the anterior-posterior dimension: transverse dimension
ratio is > 1

26. Nodule with intranodular vascular pattern.
Bożena Popowicz et al. Eur J Endocrinol 2009;161:103-111
© 2009 European Society of Endocrinology

27. Diagnosis
• Indication MSCT OR MRI NECK
1. Bulky disease
2. Retrosternal extension
3. Fixed disease
4. Nodal involvement

28. 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)

29. 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)

30. • 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

31. • 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

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

33. 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
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

34. 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

35. • 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

36. • 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.

37. PROGNOSIS

38. 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

39. 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

40. 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%

41. Treatment

42. 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.

43. Stage I and II Papillary and Follicular
I-Total thyroidectomy:
• Indications
• Tumor > 4 cm in diameter
• Prior radiation
• Positive resection margin
• Distant metastases
• Cervical lymph node metastases
• Extrathyroidal extension
• Macroscopic multifocal disease
• Vascular invasion
• Confirmed Contralateral disease

44. 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

45. • Indications lobectomy: (all present)
• T1
• N0
• R0
• No contrateral lesion
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

46. When complete total thyroidectomy after lobectomy:
• Aggressive variants
• Tall cell, columnar cell, insular, oxyphilic, or poorly differentiated
features
• Macroscopic multifocal disease
• Positive isthmus margins
• Cervical lymph node metastases
• Extrathyroidal extension

47. • 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.

48. Thyroid carcinoma after lobectomy for benign
lesions
I-Completion of thyroidectomy:
• > 4 cm
• Positive margins
• Extra-thyroidal invasion (T3 or T4(
II- Completion of Thyroidectomy or follow
up:
• Clinically suspicious lymph node,
contralateral lesion, or perithyroidal node
• Aggressive variant
• Macroscopic multifocal disease
• ≥1 cm in diameter
III- follow up:
• Negative margins
• No contralateral lesion
• < 1 cm in diameter
• No suspicious lymph
node

49. POSTSURGICAL EVALUATION AFTER THYROIDECTOMY
I-No gross Residual Disease in neck:
• Follow up (TSH + Tg+ antithyroglobulin antibodies)
II- Gross Residual Disease in neck:
• Resectable >>>>>>>> Surgery
• Unresectable
• TSH + Tg+ antithyroglobulin antibodies after surgery by 6-12 wks
• Total body radioiodine scan (not preferred)
 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)

50. Postoperative 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)
1.RAI uptake
2.Aggressive variant
3.Distant metastases
4.Lymphatic Invasion
5.More than One cm (> 1 cm)
6.Detectable Anti-Tg antibodies
7.Cervical lymph node metastases
8.Tg level > 5-10 ng/ml
9.Vascular invasion
10.Extrathyroidal extension
Aggressive variants
1.Poorly differentiated
2.Tall cell
3.Columnar cell
4.Hobnail variant

51. Postoperative I131
Not Indicated: (All present)
1.Classic papillary thyroid carcinoma
2.No Distant metastases
3.Tumor < 1 cm
4.No Cervical lymph node metastases
5.Tg level < 1 ng/ml
6.No detectable anti-Tg antibodies
7.Intrathyroidal disease

52. Pretherapy whole body iodine scan: not recommended
but individulized used
•If performed, a pretherapy scan should use a low dose of 131
I
(1 to 5 mCi) or 123
I.
• 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 131
I therapy.
•Stunning is defined as a reduction in uptake of the 131
I therapy
dose induced by a pretreatment diagnostic dose

53. Dose of RAI
•The dosing of 131
I 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
•100-200 mCi
• For all patients with metastatic disease that treated with repeated
therapeutic doses of 131
I

54. 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

55. 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.

56. 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.

57. Medullary Thyroid Cancer
treatment
• Diagnostic procedures like differentiated tumor with addition
of the followings:
1. Serum calcitonin
2. CEA
3. Screening for pheochromocytoma
4. Calcium level
5. Genetic couselling
6. MSCT chest and liver may be required
7. RET proto-oncogene mutations

58. Medullary Thyroid Cancer
treatment
• Thyroidectomy:
• Total thyroidectomy + routine central and bilateral modified neck
dissections
• Postoperative levothyroxine to normalize TSH
• External radiation therapy:
• Palliation of locally recurrent tumors or grossly residual unresectable
tumor, without evidence that it provides any survival advantage.
• Radioactive iodine has no place in the treatment of patients with
MTC.

59. Medullary Thyroid Cancer
treatment
• Palliative chemotherapy:
• Dacarbazine-based 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.
• Target therapy
• Candetanib (FDA approval)
• Cabozatinib (FDA approval)

60. Anaplastic Thyroid Cancer
• Stage IVa and IVb (locorgional disease)
• Radical surgery to achieve R0 or R1 followed by RT ±
chemotherapy
• In case of R2 resection or unresectable, RT ± chemotherapy is
indicated then assess for surgery if amenable
• Stage IVc
• Palliative Radical surgery if resectable (R0/1 can be obtained)
• Palliative RT
• Palliative Chemotherapy

61. Anaplastic Thyroid Cancer
• Chemotherapy:
• Produce partial remissions in some patients.
• Approximately 30% of patients achieve a partial remission with
doxorubicin.
• Protocols can be used in anaplastic carcinoma
• Paclitaxel/carboplatin either weekly or every 3 wks
• Docetaxel/doxorubicin either weekly or every 3 wks
• Paclitaxel either weekly or every 3 wks
• Doxorubicin either weekly or every 3 wks

62. 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.

63. 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

64. • 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.
Treatment of recurrent thyroid cancer

65. • 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
Treatment of recurrent thyroid cancer

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

67. 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.

68. 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.

69. 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.

70. Target therapy

71. 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

72. 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

73. Dr. Salah Mabrouk Khalaf
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