MANAGEMENT OF THYROID CANCER

Local seminar
Medical Oncology department

By

Salah Mabruok Khalaf

South Egypt Cancer Institute 2012

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

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. ii. iii. Familial adenomatous polyposis Gardner's syndrome Cowden's disease

2.

Medullary carcinoma in MEN syndrome

3. Other risk factors

History of goiter ii. family history of thyroid disease iii. Female gender iv. Asian race.
i.

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

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

 FNAC indications I. Sonar-based criteria

Solid nodule

1. 2.

More than 1 cm if associated with sonographic suspious features More than 1.5 cm in absence of sonographic suspicion
1. 2. More than 1.5 cm if associated with sonographic suspicious features More than 2 cm in absence of sonographic suspicion

Mixed solid and cystic

Spongiform nodule (microcystic component > 50% of I.

nodules 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 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)

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%

1-sarcomas 4-Teratomas

2-lymphomas 3-epidermoid carcinomas 5-metastasis from other cancers

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

 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

1.

2.
3. 4. 5. 6. 7.
1. 2.

FOLLICULAR THYROID CANCER 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) Types:
Follicular carcinoma Follicular carcinoma variant: Minimally Invasive Hurthle Cell

8. Rarely associated with radiation exposure

1.

2. 3.

4.

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

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 Settings

I- Sporadic
1. 2.

80% of all cases of medullary thyroid cancer. Typically unilateral

3.
4. 5. 6.

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).
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.

III-MEN II B
1.

This syndrome has

[1] medullary carcinoma

[2] Pheochromocytoma [3] mucosal ganglioneuromas and Marfanoid habitus.
2. 3. 4.

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 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.

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

exposure.
5) Neck mass usually large, diffuse, and very hard 6) Rapidly growing, often inoperable, highly recurrent

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.

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)

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 carcinomasurgically resectable T4b: Extrathyroidal anaplastic carcinomasurgically unresectable

 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 Idisease limited to the thyroid gland

Class IIlymph node involvement Class IIIextrathyroidal invasion Class IVdistant metastases.

PROGNOSIS

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

Prognostic Risk Classification for Patients with Well-Differentiated Thyroid Cancer (GAMES )
Grade Age Mets Extent

Low Risk Well Differentiated <40 None No local extension, intrathyroidal, Female

High Risk Poorly Differentiated >40 Regional or Distant Capsular invasion, extrathyroidal Male

Sex

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%

Treatment

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.

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

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

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

 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:
> 4 cm Positive margins

III- follow up:

Negative margins No contralateral lesion < 1 cm in diameter

Extra-thyroidal invasion (T3 or T4(

II- Completion of Thyroidectomy or follow up:

Clinically suspicious lymph node,

No suspicious lymph

node

contralateral lesion, or perithyroidal node

Aggressive variant Macroscopic multifocal disease 1 cm in diameter

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)

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
131I

(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

131I

therapy dose induced by a pretreatment diagnostic dose

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

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

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.

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.

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

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.

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 duration.

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. 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 weeks. 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
MTC

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

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

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