CARCINOMA THYROID: DIAGNOSIS AND MANAGEMENT Professor Ravi Kant

Carcinoma of the thyroid gland is an uncommon cancer, but 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

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 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 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 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 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.

Thanks