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A. Introduction navigator

  1. Epidemiology
    1. Overall ~1% of all new malignant disease
    2. ~30,000 new cases in USA in 2006 (40% increase over 2000)
    3. From 1973 to 2002, 2.3X increase in cases (mainly papillary) [3]
    4. ~1500 deaths annually from thyroid cancer in 2000 and 2006 in USA
  2. Thyroid Nodules and Malignancy [1,4]
    1. Cancer is found in ~12% of patients with palpable thyroid nodule
    2. For suspicious follicular lesions, cancer rate is ~20%
    3. ~4% of thyroid fine needle aspirates contain cancer
    4. Risk factors for carcinoma: Larger nodules, increased age, male sex are
  3. Risk Factors for Thyroid Carcinoma
    1. Age <20, >60
    2. Male > Female
    3. Radiation exposure, usually in childhood, including childhood cancers [5]
    4. Inadequate iodine intake (associated with goiter as well)
    5. Genetic Syndromes: MEN II, Cowden Disease, Familial Adenomatous Polyposis (FAP) [14]
    6. Note: iodine-131 exposure is not associated with increased incidence of cancers

B. Typesnavigator

  1. Papillary (PTC; ~75%)
    1. Most common thyroid tumor type; Female > Male
    2. Increasing incidence (detection) of small PTC (<1cm) with no increase in mortality rate [3]
    3. Bilateral disease commonly, multifocal, independent clones in ~20% [6]
    4. Spreads most commonly via lymph nodes (LN)
    5. Histologically, long strings of cells in "papillae", cells have ground-glass appearance
    6. Miliary calcifications, Psammoma bodies occur
    7. Size associated strongly with outcome
    8. Hepatitis C Virus infection may be a risk factor [7]
    9. FAP, with mutation in APC (adenomatous polyposis coli) gene, have 1-2% risk of PTC [14]
    10. Thyrotropin (TSH) is a growth factor for these cells
  2. Follicular (~20%)
    1. Functional tumors may present with hyperthyroidism
    2. Unilateral most often with cells related to thyroid follicular lining
    3. Hematogenous spread is most common
    4. Small increased risk of follicular thyroid cancer with APC mutations [14]
    5. Treated with radioactive iodine after resection
    6. Thyrotropin (TSH) is also a growth factor for these cells
  3. Medullary (MTC; ~5%) [8,9]
    1. Hereditary (~20%) or non-hereditary (sporadic, ~80%) forms
    2. Hereditary types may be familial (~8%) or as part of MEN Type II Syndrome (12%)
    3. Tumor of thyroid C cells, with increased calcitonin levels
    4. May present with hypocalcemia and increased CEA levels
    5. Must rule out other multiple endocrine neoplasias (Type II MEN)
  4. Anaplastic (~1%)
    1. Male > Female; patients usually older
    2. Large Goiter
    3. Very poor prognosis due to rapid spread and highly aggressive nature
  5. Thyroid Lymphoma - unusual

C. Pathophysiology [5]navigator

  1. Rearrangements of various oncogenes have been linked to thyroid cancers
    1. RET and TRK genes are tyrosine (Tyr) kinases
    2. Rearrangements of the Tyr kinase domains with unknown protein found in some cancers
    3. RET rearrangements found in ~20% of non-radiation associated papillary carcinomas
    4. RET rearrangements found in ~70% of papillary carcinomas associated with radiation
  2. MTC [8,9]
    1. Ret mutations without rearrangements associated with MTC [9]
    2. Progression of age related thyroid C-cell hyperplasia to local MTC
    3. Local MTC then progresses with lymph node (LN) metastases
    4. LN metastases not observed in patients <14 years old with germline RET mutations
    5. However, risk of progression depends on specific RET codon mutations
    6. Prophylactic thyroidectomy is recommended in patients with germline RET mutations
  3. PTC is frequently multifocal, arising as independent tumors [6]
  4. Activating point mutations of ras found in thyroid adenomas and carcinomas
  5. Inactivating point mutations found in p53 in many cases of anaplastic thyroid carcinoma
  6. Likely that stepwise accumulation of genetic abnormalities occurs in carcinoma development
  7. Radiation doses 20-30 Gy associated with increased thyroid ca risk [5]
  8. Radiation >30 Gy associated with less thyroid ca likely due to cell killing effect [5]

D. Diagnosis [2,10] navigator

  1. Lump in thyroid on physical examination
  2. Endocrine Abnormalities
    1. Symptoms of hyperthyroidism, hypothyroidism, or calcitonin secretion are uncommon
    2. Thyroid function tests not usually helpful
  3. Ultrasound
    1. Performed in all patients with suspected thyroid nodules
    2. Suspicious ultrasound findings: blurred margins, mixed echogenicity, intranodular calcification, Doppler flow
    3. Suspicious ultrasound findings should prompt biopsy
  4. Fine Needle Aspiration Biopsy (FNA) [1,2,10]
    1. Absolutely essential for evaluation of thyroid nodules
    2. 10-20% indeterminent
    3. 80-90% diagnostic
    4. This test is now standard initial evaluation of thyroid nodule
    5. Ultrasound guidance may be used to assist aspiration or detect cycsts
  5. Nuclear Medicine Scans
    1. 99mTc - uptake scan for definite nodule
    2. 131-I scan to assess functionality - most cold nodules are neoplastic
  6. CT or MRI scans should be used to evaluation tumor spread, extension
  7. Genetic testing may be appropriate for MTC
  8. Stagining
    1. Differs for age <45 years and age >45 years
    2. Stage I: Any T, Any N, M0 (<45) OR T1, N0, M0 (>45)
    3. Stage II: Any T, Any N, M1 (<45) OR T2 or T3, N0, M0 (>45)
    4. Stage III: T4 OR N1, M0 (age >45)
    5. Stage IV: Any T, Any N, M1 (age >45)

E. Treatment [2,5]navigator

  1. Overview
    1. Surgical resection
    2. Radiotherapy: radioactive iodine or external beam radiation
    3. Chemotherapy: cytotoxics or tyrosine kinase inhibitors (TKI)
  2. Surgical Resection
    1. May be bilateral, spare at least one parathyroid however
    2. In general, total or near-total thyroidectomy (<3gm tissue remaining) recommended
    3. Removal of essentially all thyroid gland facillitates total ablation with Iodine-131
    4. Total thyroidectomy with radio-iodine ablation can reduce recurrences to near zero
    5. LN dissection, especially for PTC is recommended
    6. Prophylactic thyroidectomy is recommended in patients with germline RET mutations [8]
  3. Complications of Thyroid Surgery
    1. Hypoparathyroidism - low Calcium; treat with Vitamin D + Calcium
    2. Hemorrhage and Infection
    3. Laryngeal nerve injury - hoarseness
    4. Tracheal and Esophageal damage
    5. Thyroid Storm
  4. Radioactive Iodine (Sodium Iodide) [9]
    1. Iodine-131 (I-131) radioisotope is used for several reasons
    2. Highly concentrated in thyroid, kills any remaining normal or abnormal cells
    3. This increases sensitivity of subsequent I-131 scanning for recurrence
    4. Also improves sensitivity of thyroglobulin levels for recurrence
    5. Likely destroys any metastatic occult carcinoma cells
    6. I-131 scanning is performed 4-6 weeks after surgery to assess residual disease
    7. Initial dose is usually 30-100 mCi (1110-3700 GBq), effective in >80% of patients
    8. Metastatic and/or recurrent disease should be treated with 100-200 mCi q4-6 months
    9. Complete remissions of metastatic disease occur in ~50% of patients
  5. External Beam Radiation Therapy
    1. Mainly for localized disease control
    2. Exposure to >30Gy radiation in childhood associated with less thyroid ca than 20-25 Gy [5]
  6. Chemotherapy
    1. No clear data that chemotherapy improves morbidity or mortality
    2. Doxorubicin 60-70mg/m2 q3 weeks is often used for palliative therapy
    3. Paclitaxel has also shown some reduction in tumors
  7. Tyrosine Kinase Inhibitors [15,16]
    1. Sorafenib (Nexavar®) is a multikinase inhibitor approved for renal cancer [17]
    2. Has shown ~25% partial response in metastatic differentiated thyroid carcinoma
    3. Motesanib is an inhibitor of VEGF receptors, PGDF receptor, and KIT
    4. Motesanib 125mg po qd: 14% partial response in metastatic differentiated thyroid carcinoma
    5. Stable disease achieved in 67% of motesanib-treated patients; about half for >24 weeks
  8. Other Medical Therapy
    1. Inhibitors of iodination are used for for symptomatic hyperthyroidism
    2. Long term L-thyroxine suppressive therapy (keeps TSH very low) slows cancer growth
    3. The L-thyroxine (T4) dose may be decreased over time
    4. Monitor for osteoporosis and hypertension during L-thyroxine therapy
    5. However, there have been no studies on effects of reducing T4 dose on cancer growth

F. Followup and Prognosis [5]navigator

  1. Thyroid Carcinomas
    1. Monitoring for tumor recurrence is essential
    2. Recurrence can take decades; occurs in 5-20% of differentiated thyroid cancers
    3. Follow calcitonin levels in MTC to detect residual/recurrent disease [4]
    4. Thyroglobulin levels can be used to monitor recurrence of follicular cancers
    5. Serum thyroglobulin >2µg/L indicates recurrence
    6. However, antibodies to thyroglobulin may mask increases in this glycoprotein
    7. Total body 131-iodine scanning can also be performed at 6-12 month intervals
  2. Monitoring Recurrence in Thyroid Hormone Sensitive Tumors [11]
    1. Previously by T4 discontinuation and radio-iodine scan
    2. Required several weeks T4 discontinuation leading to symptomatic hypothyroidism
    3. T4 discontinuation is no longer recommended for monitoring recurrence
    4. Thyrotropin (TSH, Thyrogen®) can be used instead of T4 withdrawal for imaging [12]
    5. Thyrogen prevents clinical hypothyroidism during withdrawal
    6. Day 1: measure serum thyrotropin (TSH) and thyroglobulin
    7. Give 0.9mg thyrotropin IM on day 1 after laboratory tests and on day 2
    8. Day 3: measure TSH (should be >30 mU/L) and give 150 MBq iodine-131
    9. Day 5: measure serum thyroglobulin and perform whole body scanning
  3. In vitro phosphorus-31 magnetic resonance spectroscopy is being developed to distinguish between normal residual tissue and tumor following radio-iodine therapy [13]
  4. Low Risk of Recurrence [12]
    1. Age at time of diagnosis <40 years
    2. Tumor smaller than 1.0-1.5 cm (increased risk with tumor size >4.0 cm)
    3. Unilateral disease
    4. Absence of local invasion
    5. Absence of lymph node and distant metastasis
    6. Minimal capsular invasion (for follicular cancers)
  5. Prognosis [2]
    1. Overall survival rate for PTC and follicular Ca 76% over median of 15.7 years
    2. Recurrence rate was <20% with cancer death rate ~4%
    3. Follicular had slightly higher mortality and recurrence rates over PTC
    4. In patients with distant metastases + local resection, 131-I ablation improved survival
    5. All patients received suppressive hormone therapy (synthetic T4 to suppress TSH)
    6. The 131-I ablation following surgery increased survival by ~65% over T4 hormone alone
    7. Ten year survival rate after discovery of metastatic disease in differentiated thyroid cancers is 40%
    8. Despite increasing incidence of PTC, no increase in overall mortality due to PTC [3]

References navigator

  1. Sherman SI. 2003. Lancet. 361(9356):501 abstract
  2. Mazzaferri EL. 2006. JAMA. 295(18):2179 abstract
  3. Davies L and Welch HG. 2006. JAMA. 295(18):2164 abstract
  4. Alexander EK, Hurwitz S, Heering JP, et al. 2003. Ann Intern Med. 138(4):315 abstract
  5. Sigurdson AJ, Ronckers CM, Mertens AC, et al. 2005. Lancet. 365(9476):2014 abstract
  6. Shattuck TM, Westra WH, Ladenson PW, Arnold A. 2005. NEJM. 352(23):2406 abstract
  7. Antonelli A, Ferri C, Fallahi P. 1999. JAMA. 281(17):1588 abstract
  8. Machens A, Niccoli-Sire P, Hoegel J, et al. 2003. NEJM. 349(16):1517 abstract
  9. Chatal JF and Hoefnagel CA. 1999. Lancet. 354(9182):931 abstract
  10. Castro MR and Gharib H. 2005. Ann Intern Med. 142(11):926 abstract
  11. Toft A and Beckett G. 2002. Lancet. 359(9321):1874 abstract
  12. Basaria M, Graf H, Cooper DS. 2002. Am J Med. 112(9):721 abstract
  13. Moka D, Dietlein M, Raffelt K, et al. 2002. Am J Med. 112(8):634 abstract
  14. Chung DC, Maher MM, Faquin WC. et al. 2006. NEM. 355(22):2349 (Case Record) abstract
  15. Sherman SI, Wirth LJ, Droz JP, et al. 2008. NEJM. 359(1):31 abstract
  16. Gupta-Abramson V, Troxel AB, nellore A, et al. 2008. J Clin Oncol. in press
  17. Sorafenib. 2007. Med Let. 49(1255):19