CARCINOMA THYROID: DIAGNOSIS AND MANAGEMENT

Professor Ravi Kant

• Carcinoma of the thyroid gland is an uncommon cancer, but

none the less, is the most common malignancy of the

endocrine system (90% of all endocrine cancers).

• Constitute less than 1% of all human malignant tumors

Pathological classification of malignant thyroid neoplasms.

A. Carcinoma:

1. Papillary adenocarcinma

a. Pure papillary adenocarcinoma

b. Mixed papillary and follicular carcinoma

c. Papillary micro carcinoma

d. Diffuse sclerosing carcinoma

2. Follicular carcinoma

a. Pure follicular carcinoma

b. Clear cell carcinoma

c. Hurthle (Oxyphil) cell carcinoma

3. Medullary carcinoma

4. Undifferentiated carcinoma

B. Other Malignant tumors

1. Lymphoma

2. Sarcoma

3. Fibrosarcoma

4. Epidermoid carcinoma

5. Mucoepidermoid carcinoma

6. Metastatic tumor

Clinical and investigative work up of a patient with

suspected thyroid cancer

Goal: To identify those patients who have a particularly high risk

for malignancy and to effectively manage those patients who

harbor malignant lesions.

• MC presentation solitary nodule (90%) with or without

adenopathy.

• Fixation of mass to trachea, unusual firmness, recent growth,

symptoms of dysphagia, hoarseness and presence of enlarged

lymph nodes clearly suggest the possibility of the lesion

being malignant.

• Cancer is more likely in a nodule if:

a) Male sex or children

b) History of previous radiation exposure

c) Age > 60 yrs

d) Cold nodule

e) In a patient with grave’s disease

f) family history of MEN

1. Fine needle aspiration cytology

• Gold standard for diagnosis of thyroid carcinoma and nodal

metastasis.

• Fairly accurate except in follicular carcinoma

• Sensitivity ranges from 65-98% and specificity 52-100%.

2. Ultrasonography

• Solid vs cystic

• Can help in USG guided FNAC

• Evaluation of recurrent thyroid cancer in the thyroid bed and

in regional lymph nodes

features s/o malignancy.

- Hypoechogenicity

- Micro calcification

- Thick, irregular or absent halo

- Irregular margins

- Invasive growth

- regional lymphadenopathy, and

- higher intranodular flow

3. Serum calcitonin

• This polypeptide is produced only by C cells and its

measurement is sensitive, accurate and consistent to a degree

that makes it possible to diagnose MTC as small as 1 mm.

• An elevated serum calcitonin in the presence of thyroid mass

is highly s/o malignancy; while a negative test makes the

diagnosis of MTC highly unlikely.

4. Serum thyroglobulin

• Reliable marker of persistent, recurrent or metastatic diseases

• Low preoperative thyroglobulin levels have been suggested

to be associated with less differentiated tumors and having a

poor prognosis.

• After near total or total thyroidectomy, thyroglobulin levels

fall down below 5-10 ng/ml by postop day 25 (Half Life 65

hrs).

5. Isotope imaging

- I131, I133, Tc99m pertechnetate

- Thallium 201 chloride (201TL) 99mTc methoxy

isobutyl isonitrite (99mTc sestamibi)

- 99mTc 1,2-bis ethane (99mTc Tetrofosmin)

- Indium 111 octreotide

- Fluoro - 18 -deoxyglucose

Isotope imaging (cont.)

• 80-85% of all thyroid nodules are hypofunctional but only

10-15% of hypofunctional nodules are malignant so scanning

has a low specificity.

• Important modality to detect cancer recurrence and

metastases in the post operative period.

• Ablation of any remnant by radioiodine and withdrawal of

supplementary thyroid hormone will increase the levels of

TSH and hence the ability of the metastasis to pickup

radioiodine and consequently their chances of being picked

up in the scan.

6. X-ray neck

• Airway displacement and compression

• Fine stippled calcification in papillary carcinoma

• Dense calcification and calcified nodes in medullary

carcinoma

7. CT and MRI

• Extrathyroid tumor extension and/or invasion

• Destruction, infiltration or displacement of larynx, trachea,

esophagus, carotids

• Retrosternal extension

• Can assess cervical adenopathy

• Can locate local and distant metastatic deposits.

• CT has a advantage because of its wide availability,

familiarity and lower cost.

8. Genetic markers in thyroid cancer

• RET/PTC

• RAS mutations

• Inactivated mutations of p53

• Thyroglobulin mRNA

PRIMARY TREATMENT

Papillary thyroid carcinoma (PTC)

• Minimal PTCs are defined as cancers smaller than 1 cm,

which do not extend beyond the thyroid capsule and are not

metastatic or angioinvasive.

• Death rate 0.1% and recurrence rate 5%.

• Unilateral total lobectomy may be an appropriate

definitive procedure.

Papillary thyroid carcinoma (PTC) (cont.)

• Total or near total thyroidectomy is the preferred operation

for high risk patients with PTC.

• Opinions differ in low risk PTC (Hemi vs total) Most of

these patients have an excellent prognosis as long as gross

tumor is completely resected. Some surgeons advocate less

than a complete thyroidectomy to avoid hypoparathyroidism

and recurrent laryngeal nerve injury.

Papillary thyroid carcinoma (PTC) (cont.)

• Arguments in favour of total thyroidectomy

- Multifocal disease

- facilitates postoperative use of 131I to ablate residual

thyroid tissue and to identify and treat residual or

distant tumor.

- Increases thyroglobulin sensitivity as a indicator of

residual disease.

Papillary thyroid carcinoma (PTC) (cont.)

• Should remove all enlarged lymph nodes in central and

lateral neck areas.In the central neck, removal is essential

because reoperations in this area difficult. Prophylactic

lateral neck dissection not recommended; when lymph nodes

found, modified RND should be done.

Follicular and Hurthle cell neoplasms

• Typically, FNA cytologic findings are reported as

“indeterminate or suspicious for follicular or

Hurthle cell neoplasm”. About 80% of follicular

and Hurthle cell neoplasm are benign.

• Most surgeons recommend a total thyroid

lobectomy with isthmusectomy for follicular or

Hurthle cell neoplasm. When the lesion is benign,

no further therapy is needed; when the tumor is

malignant, completion (total) thyroidectomy may

be indicated to facilitate subsequent radioactive

iodine (RAI) scanning and therapy.

Follicular (cont.)

• Some clinicians use RAI to ablate the residual lobe, in

as much as follicular carcinomas are rarely bilateral.

• When follicular carcinoma is minimally invasive and

characterized only by limited capsular invasion, lobectomy

is likely to provide definitive therapy.

Follicular (cont.)

• Ipsilateral lymph node metastatic lesions occur in only

about 10% of patients with follicular thyroid cancer (FTC)

and in about 25% of patients with Hurthle cell cancer.

Enlarged lymph nodes in the central neck area should be

removed. A functional lateral neck dissection is indicated

for patients with clinically palpable nodes

Stage Papillary or follicular Medullary, any age

Anaplastic, any age

Age < 45 yr Age > 45 yr

I M0 T1 T1 -

II M1 T2-3 T2-4 -

III - T4 or N1 N1 -

IV - M1 M1 Any

Staging System for Thyroid Carcinoma

Established by the American Joint Committee on Cancer

Risk group assignment

EORTC:

Age in years: + 12 if male, + 10 if medullary, + 10 if poorly

differentiated follicular, + 45 if anaplastic, + 10 if extending

beyond thyroid, + 15 if one distant metastasis, + 30 if multiple

distant metastasis.

AMES:

High risk if female older than 50 y, male older than 40 y, male

older than 40 yrs, tumor > 5 cm (if older age), distant metastases,

substantial extension beyond tumor capsule (follicular) or gland

capsule (papillary).

Risk group assignment (cont.)

AGES:

0.5 x Age in yrs. (if > 40), + 1 (if grade 2), + 3 (if grade 3 or 4), + 1

(if extrathyroidal), + 3 (if distant spread), + 0.2 x max. tumor

diameter.

MACIS:

3.1 (if age < 39 yr) or 0.08 x age (if age > 40 yr), + 0.3 x tumor size

(in cm), + 1 (if incompletely resected), + 1 (if locally invasive), + 3

(if distant metastases present).

• Lymph node metastatic lesions at the time of initial

examination do not increase the risk of death from PTC but

do increase the risk of local and regional recurrence.

Initial nodal metastatic disease in MTC predicts a higher

risk of recurrence and death.

• Several rare thyroid cancer histologic subtypes may

indicate a worse prognosis. These include the

Hurthle cell (oxyphilic) tall cell and columner variants of

PTC and possible, the diffuse sclerosing variant.

• DNA aneuploidy does not have prognostic value in PTC or

typical FTC but may predict significantly increased

mortality in oxyphilic FTC.

• Adjuvant treatment and close follow-up can then be

targeted to high risk patients, whereas a less

intensive interventional approach can be used in low

risk patients.

Adjuvant therapy

1. Thyroid hormone:

• Growth of FCDC cells is TSH dependent so administration

of supraphysiologic doses of thyroid hormone to suppress

serum TSH.

• Long term levothyroxine suppressive therapy may have

adverse effect on bone and the heart, including accelerated

bone turnover, osteoporosis and AF.

Adjuvant therapy (cont.)

• Consequently, many experts maintain that long term

complete TSH suppression (< 0.01 to < 0.1 Iu/ml) should

be reserved for high risk patients; Less degree of TSH

suppression will suffice for most patients with PTC

classified as low risk (0.1 - 0.4 Iu/ml)

Adjuvant therapy (cont.)

2. Radioiodine Remnant ablation (RRA)

• Defined as “the destruction of residual

macroscopically normal thyroid tissue after surgical

thyroidectomy”.

• Used as an adjunct to surgical treatment when the

primary FCDC has been completely resected.

Adjuvant therapy (cont.)

• Three Potential advantages (RRA):

a) 131I may destroy microscopic cancer cells

b) Subsequent detection of persistent or recurrent disease by

radioiodine scanning is facilitated.

C) After RRA, the sensitivity of serum Tg measurements

is improved during follow up

• Issue of RRA in low risk patients remains unsettled.

Long term follow up

(I). Thyroglobulin

• Highly specific tumor marker for differentiated thyroid

cancer.

• Level should be <2 ng/ml after surgery and ablation.

• Most useful in patients with high risk FCDC when TSH

level is high after either levothyroxine withdrawal or rh

TSH administration.

Long term follow up

(II) Diagnostic scanning

• Levothyroxine discontinued for 6 weeks before scan; T3

given during first 4 weeks (TSH should be > 25 Iu/ml)

• 131I WBS generally performed 48-72 hrs. after giving

2-5 mCi of 131I

Diagnostic scanning (cont.)

• Ablative doses of RAI (30-150 mCi) are given when

functioning remnants in the thyroid bed; higher doses

when metastatic disease.

• Post treatment scan 4-10 days after therapeutic dose.

• Problems

- Unpleasant symptoms of hypothyroidism

- Poor patient compliance

- Severe pulmonary or cardiovascular disease

- Intracranial mets

Recombinant thyrotropin

• Highly purified recombinant form of human TSH

synthesized in a chinese hamster ovary cell line, longer half

life.

• 131I WBS results were concordant between rh TSH

stimulated and levothyroxine withdrawal phases in most of

the patients in various clinical trials.

• rh TSH is safe and effective means of stimulating 131I

uptake and serum Tg levels in patients undergoing

assessment for cancer recurrence. No symptoms of

hypothyroidism in this group.

III. Additional imaging studies

• High serum Tg levels but negative WBS

• Pulmonary metastatic lesions - chest X-ray or CT

Bone metastasis - conventional radiographic bone survey or

bone scan.

Intracranial, intra abdominal mets - CT/MRI

Alternative scans like thallium, sestamibi, Tetrofosmin or

fluorodeoxy glucose PET scan.

In patients with an increased serum Tg level and negative 131I WBS

some authorities have administered a large therapeutic does of 131I

without any additional imaging procedures

Persistent or recurrent disease

(I) Secondary surgical intervention

- Local recurrence

- Bulky mediastinal lesions (when 131I is ineffective)

- Focal pulmonary or rib metastatic lesion

(II) Radioactive iodine

- Nodal metastatic lesions not large enough to excise

- Locally recurrent invasive FCDC after surgical

resection.

- Diffuse lung metastatic growths

S/E: Nausea, Vomiting

Salivary gland damage

Bone marrow depression (anaemia, leukopenia, thrombo

cytopenia)

Small increase in bladder and breast cancer

Transient reduction in sperm count

(III) External irradiation

- Anaplastic thyroid cancers

- Lymphoma of the thyroid

- Postoperative patients with FCDC who have gross

evidence of local invasion

Medullary Thyroid carcinoma

• Represents malignant transformation of neuroectodermally

derived parafollicular C cells.

• 75% are sporadic and 25% are hereditary.

Sporadic

Surgical treatment should include total thyroidectomy, central

compartment lymph node dissection and ipsilateral modified

radical neck dissection.

Risk factors for recurrence and death include tumor size,

preoperative calcitonin level, advanced age, extrathyroid tumor

extension, progression of cervical nodal disease to the

mediastinum, extra nodal tumor extension and incomplete tumor

excision.

Sporadic (cont.)

• Serum calctonin levels should be measured 8-12 wks.

Postoperatively to assess the presence of residual disease.

For residual local disease - USG of neck

For metastatic lesions -

CT and MRI

Scanning with sestamibi, radioiodinated MIBG, Octreotide

and 131I anti CEA antibody

Laparoscopic liver biopsy

Hereditary medullary carcinoma:

• MEN type II A, MEN II B and isolated familial MTC;

MEN II A is most common.

• MEN II A includes MTC (in 100% of patients),

pheochromocytoma or adrenal medullary hyperplasia (in

50%) and hyperparathyroidism (in 35%).

Hereditary medullary carcinoma:

• MEN II B includes MTC (more virulent and at early age),

pheochromocytoma, Marfanoid habitus, mucosal neuromas,

ganglioneuromatosis of GIT.

• Family MTC is defined by presence of 4 or more cases in a

family without other associated endocrinopathy.

Hereditary (cont.)

• Specific germline mutations of RET proto-oncogene which

codes for tyrosine kinase receptor.

• Genetic testing should begin by no later than age 6 yrs in

MEN II A and shortly after birth in MEN II B families.

Hereditary (cont.)

• Current standard of care is to recommend surgical

treatment for MTC family members diagnosed with

appropriate RET mutations.

• This treatment may be accomplished as early as age 2

years; all should be screened preoperatively for

pheochromocytoma.

• Prophylactic total thyroidectomy and central

compartment lymph node dissection.

Anaplastic thyroid carcinoma

• Highly aggressive tumor

• 5th-6th decades of life

• Rapidly expanding thyroid mass with hoarseness,

dyspnea, dysphagia, cervical pain, tracheal

obstruction and metastasis.

• May be multiple and bilateral; short duration of

symptoms.

• Histologically 3 predominant features: spindle cell,

giant cell and squamoid cell.

• Treatment controversial. Surgical biopsy may be

necessary for confirmation of the diagnosis and

protection of airway although some surgeons attempt

primary resection. Value of prophylactic tracheostomy

is uncertain, may lead to local wound healing

complications that could prevent or delay use of

postoperative external beam radiotherapy.

• The use of combination therapies to include

preoperative irradiation and chemotherapy

(doxorubicin, cisplatin, bleomycin, vincristin and 5-

FU in various combinations) followed by

aggressive local tumor resection may yield an

increased duration of survival.