THOUGHTS ON THYROID CANCER
From Current Concepts in Head and Neck Surgery presented by Memorial Sloan-Kettering Cancer Center and
University of Texas MD Anderson Cancer Center
| MANAGEMENT OF MEDULLARY THYROID CANCER —Gary L. Clayman, DMD, MD, Professor and Director of
Head and Neck Cancer Program; Alando J. Ballantyne Distinguished Chair of Head and Neck Surgery, University of Texas
M.D. Anderson Cancer Center, Houston
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| Medullary thyroid carcinoma (MTC): sporadic nongenetically transmitted disease—constitutes 70% to 75% of
lesions; unilateral with single disease focus; usually isolated thyroid mass or cervical metastasis; familial MTC—
constitutes 25% to 30% of lesions; bilateral and multicentric; involves germline mutations of RET proto-oncogenes; associated
with multifocal C-cell hyperplasia (premalignant lesion)
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 | Additional aspects: hereditary MTC—phenotypes (multiple endocrine neoplasia 2A [MEN 2A]; MEN 2B; disease occurs
more often in superior component of gland; multifocal; 80% to 90% incidence of lymph node metastases; 10% to
20% incidence of distant metastases; histologic progression occurs; C-cell hyperplasia (microscopic MTC)—
earliest disease manifestation; detected on screening thyroidectomy
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| Observations from prospective screening for MEN: calcitonin testing—identifies MTC in 100% of affected
individuals; sensitive screening test; high false-positive rate; provided groundwork for rapid assimilation of genetic testing;
thyroidectomy—cured 80% to 85% of patients with MTC
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| RET proto-oncogene: components—extracellular (contains cadherin-like repeats; cysteine-rich domain); transmembranous
(2 tyrosine kinase [TK] domains)
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| Mutations of MEN: found in “hot spots” involving exons 10, 11, 13, 14, 15, and 16 (represent cysteine and TK components of
domains); MEN 2B—phenotype includes marfanoid appearance, mucosal and conjunctival abnormalities, and thyroid
mass; 883 and 918 mutations phenotypically aggressive
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| Managing familial MTC: age of detection varies, some detected at birth; whether to base decision to perform thyroidectomy
on average age or earliest age of presentation remains controversial; points—physican must understand mutation phenotype
to determine level of aggressiveness required; data suggest, in addition to specific mutations of RET proto-oncogenes,
other genetic regulators or random factors contribute to disease transformation
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| Consensus guidelines: no low-risk category; points—all MTC codons (except 912 and 791 mutations) cause death;
correlation between efficiency of transformation and biologic tumor behavior
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| Highest-risk mutations: perform total thyroidectomy—during first month of life (with or without central compartment
lymph node dissection) for patients with mutations at 918 and 883; before 5 yr of age for patients in MEN 2A group
who have high-risk mutations at 634, 611, 618, 620, and 891; points—regardless of whether central compartment dissection
performed, surgeon should identify recurrent laryngeal nerve and strive to prevent lifelong hypoparathyroidism;
somatic mutations exert important effect, eg, 918 mutations have worse prognosis than wild-type mutations in
that particular RET location
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| Intermediate-risk group: includes mutations at 609, 768, 790, 791, and 804; biologic behavior varies; total thyroidectomy suggested
when calcium-stimulation or calcitonin test positive
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| Caveats: other factors that remain unclear may accelerate progression; periodic screening for pheochromocytoma—
necessary for kindreds with rare mutations; before surgery, all patients should at least undergo plasma metanephrine analysis
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| Status check: problems confronting MTC management—current rates of metastatic disease and mortality; late diagnosis
of MEN 2 or familial MTC; aggressiveness of 918 germline mutations in MEN 2B and somatic mutations; sporadic
MTC without RET mutation; current opportunities for improving management—exploitation of knowledge of molecular
defects as they relate to RET proto-oncogene; exploration of signal transduction pathways expressed by normal or
transformed C cell, eg, epidermal growth factor (EGF) receptor, TK factors; reenergize investigation of molecular abnormalities
in MTC that are negative for mutations; develop pharmacologic agents that affect apoptosis and angiogenesis and
inhibit RET phosphorylation, eg, AMG706, protein kinase inhibitor (PKI)166, and ZD6474 (Zactima)
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| MEDICAL MANAGEMENT OF THYROID CANCER —Richard J. Robbins, MD, Professor of Medicine, Memorial
Sloan-Kettering Cancer Center, New York, NY
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| Thyroid cancer: incidence increasing faster than any other solid cancer in United States; reason for rate of increase undetermined;
must be identified early on; prognosis depends on age at diagnosis, ie, patients >50 yr of age at diagnosis face increased
risk for recurrence; caveat—recurrence portends poor prognosis
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| Management after total thyroidectomy: components of postoperative protocol—remnant ablation; thyroid hormone
(TH) therapy (replaces missing hormone); deactivation of thyroid-stimulating hormone (TSH) production to prevent
progression of residual disease; surveillance; termination of TH therapy—periodically required by management
approach; stimulates production of TSH by pituitary gland; allows physician to perform ablation, check surveillance, or
treat metastatic disease with 131 I; TSH—promotes development of 2 major end points used to detect residual thyroid
cancer, ie, stimulation of iodine uptake and formation of thyroglobulin (Tg; bonds with iodine to form TH)
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| Remnant ablation: data suggest 131 I ablation—benefits patients at higher risk for recurrence; offers no benefit to patients
with lower-risk disease or tumors ≤1.5 cm; streamlined approach requires individual receive—2 injections of recombinant
human TSH 6 wk after administration of TH; 75- or 100-mCi dose of 131 I; bottom line—≈92% ablation rate
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| Pearls on TSH suppression: survivors with lowest serum TSH levels—have fewest recurrences; generally require
lowest dose of thyroxine (T4 ) necessary to reduce TSH to below lower limits of normal, ie, 0.3 mU/L; liothyronine sodium
(T3 ; [Cytomel])—provides no advantage when combined with T4 to suppress TSH; duration of suppression—if
patient shows no evidence of disease by 5 yr, stop suppression, let TSH normalize, and monitor serum Tg annually; if Tg
undetectable, patient has >98% chance of being cured; T4 absorption—blocked by certain vitamins and iron-containing
pills; if therapy fails to suppress TSH, obtain information on when patient takes medication and other pills taken with
medication
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| Surveillance: serum Tg analysis superior to whole-body scan for identifying occult residual disease in low-risk patients
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| New paradigm for patients at low risk for recurrence and clinically disease free 1 yr after thyroidectomy: when patient
receiving TH presents to office—assess serum Tg; if Tg level >1 ng/mL, look for disease (perform ultrasonography
[US] of neck in patients with papillary disease, or chest x-ray; if imaging negative and Tg high, administer 100- to 150-
mCi dose of 131 I followed by scan); if Tg >2 ng/mL look for residual disease; if disease located and managed—
bring patient back at 1 yr and repeat evaluation protocol
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| Based on pooled data: two thirds of low-risk patients who appear to be cured—have no change in serum Tg before or
after receiving recombinant human TSH; can be placed into low-surveillance mode, ie, check neck once yearly, monitor
TSH and Tg levels; patients with—0.5 to 2 ng/mL increase in Tg (perform recombinant human TSH challenge every
1.5 to 2 yr; decline in Tg level considered favorable; increasing Tg level suggestive of residual disease); Tg level >2 ng/
mL at initial evaluation, have residual disease (evaluate)
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| Neck US: cervical lymph nodes most likely location of disease recurrence after total thyroidectomy for papillary carcinoma;
indications for neck dissection debatable—US may detect small lymph nodes that harbor small amount of papillary
thyroid carcinoma (effect of disease on health and survival unknown); repeat neck dissection, based on imaging
alone, may be unnecessary (ie, disease may not pose threat); recommendations—perform TSH stimulation on patients
with low-risk disease and undetectable Tg; if Tg increases to >2 ng/mL, perform further evaluation; if Tg level remains
<2 ng/mL, imaging studies unnecessary
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| Positron emission tomography (PET): helpful when disease cannot be found in patients with high Tg levels; fluorodeoxyglucose
(FDG) good imaging agent for locating poorly-differentiated disease that takes up glucose, not iodine;
well-differentiated thyroid cancer—relatively metabolically inactive; takes up radioactive iodine, but not glucose;
undifferentiated or poorly differentiated cancers—need glucose to maintain rapid growth rate; iodine scans usually
negative; patients with positive FDG scans—cannot be treated with high-dose 131 I; require new treatment strategy;
patients with high Tg and—positive PET have median survival of 53 mo; negative PET have better outcome
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| Bottom line: patients with MTC that takes up iodine and minimal glucose—have long survival curve; require treatment
based upon PET data; patients who will die soon—require more aggressive approach; high-dose 131 I does not alter survival;
patients with FDG-positive metastatic disease—require new treatment approach; surgery and external beam radiotherapy
control some lesions causing symptoms or potential morbidity; eventually, targeted therapy required to knock
out genes and molecular events underlying disease
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| MANAGEMENT OF REGIONAL LYMPH NODES IN DIFFERENTIATED THYROID CANCER —Randal S. Weber,
MD, Hubert I and Oliver Stringer Distinguished Professor and Chairman, Department of Head and Neck Surgery, University
of Texas MD Anderson Cancer Center, Houston
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| Lymphatics of thyroid gland: diffuse throughout gland; involvement portends more advanced disease; can drain
from 1 lobe to other, ie, cross communication may lead to tumor developing in 1 lobe and metastatic disease in contralateral
paratracheal lymphatic chain; retropharyngeal lymph nodes—site of communication and drainage from tumors involving
posterior surface of thyroid; should be investigated as potential site of metastases in patients with papillary
thyroid cancer; drainage—extensive; bilateral; associated with high incidence of regional metastases; multiple lymph
node basins at risk; lymphatic channels generally parallel venous channels; data suggest—physician should maintain
comprehensive view of differentiated disease; incidence of metastases high, even in patients with clinically N0 disease;
posterior triangle involvement rare; rare to find positive lateral compartment with negative central compartment, ie, skip
metastases rare; no strong correlation between location of primary tumor and location of regional metastasis
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| Detection of nodal involvement: palpation—picks up lesions >1.5 cm; detects nodal involvement in ≈60% of cases;
associated with false-positive findings; US of thyroid and neck—gold standard for evaluating regional lymphatics; used
when increasing Tg levels cause concern about regional nodal disease; combination of neck US and fine-needle aspiration
(FNA)—accurate means of diagnosing regional disease; FNA essential when evaluating enlarging nodules;
imaging—characteristics of concern (solid nodes; calcifications; cystic or hemorrhagic nodes); size criteria do not apply
when evaluating patient with computed tomography (CT) and magnetic resonance imaging (MRI)
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| Additional aspects of evaluation: cystic lymph nodes—common; Tg test necessary when aspirate of neck mass hemorrhagic
or chocolate-appearing fluid; elevated Tg indicative of cystic metastases; anatomic imaging indicated for—
recurrent disease; suspected metastasis; points—metastatic papillary cancer characterized by large calcifications on CT of
lymph node; know location of all disease sites before surgery; lateral neck dissection not necessary in all patients with positive
central compartment; metastatic disease appears long after thyroid gland removed (once Tg elevated, look for regional
metastases)
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| Papillary cancer: high incidence of lymph node metastases found on elective neck dissection; positive nodes on every
neck level
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| Selective or function-sparing operation: feasible because—metastases push, rather than invade; extracapsular spread rare;
nodal fixation and invasion rare, unless patient underwent prior surgery or irradiation; fascial planes respected; points—
nodes generally do not traverse fascial compartments (neck can be cleared of disease by knowing levels at risk and removing
appropriate compartments); patients have indolent disease and will live with morbidity for life; goals—eradicate
disease in context of preserving parathyroid glands and voice and swallowing function; observations—most patients require
comprehensive dissection of levels II through VI and upper mediastinum; elective lymph node dissection detects
disease in 50% of patients but does not affect survival; because comprehensive dissection includes level IIB, use any incision
necessary to reach anatomic location
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| Comprehensive dissections: warn patient about potential complications—27% of patients studied experienced
marked postoperative shoulder weakness (other complications included chyle leak and temporary hypoparathyroidism);
patients can also develop nerve palsy or neuropathic pain syndrome; sympathetic trunk may be sacrificed when
managing disease in scalene node
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| Central compartment reoperation: common in patients with increasing Tg levels; US detects involved nodes; confirm
disease cytologically before surgery; preserve superior parathyroid gland along with blood supply during initial thyroidectomy;
when possible, preserve main trunk of inferior thyroid artery; nerve monitoring helpful; complications—
nerve injury; hypocalcemia; residual disease; pointers—locate nerve inferiorly in patients with no prior surgery; preserve
inferior thyroid artery; avoid superior parathyroid gland; dissect upper mediastinum
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| To avoid recurrence: perform—complete thyroidectomy; FNA to confirm presence of nodal disease preoperatively;
patients at high risk for paratracheal disease—include older patients and those with tall-cell variant disease, extrathyroidal
extension, and larger tumors; require elective ipsilateral mediastinal dissection with examination of contralateral
side
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Educational Objectives
| The goal of this program is to educate the listener about current concepts in the management of thyroid cancer. After hearing
and assimilating this program, the clinician will be better able to:
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| 1. Assess genetic components of medullary thyroid carcinoma (MTC).
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| 2. Describe consensus guidelines for managing MTC.
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| 3. Discuss the role of the postthyroidectomy remnant.
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| 4. Determine the merits of postthyroidectomy surveillance using serum thyroglobulin, ultrasonography, and positron
emission tomography (PET).
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| 5. Manage regional lymph node disease in patients with differentiated thyroid cancer.
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Discussed on This Program
AMG706
Gabapentin [Neurontin]
Levothyroxine sodium (T4 ; L -thyroxine) [several trade names and preparations]
Liothyronine sodium (T3 ) [Cytomel, Triostat]
Pentagastrin [Peptavlon](discontinued)
PKI166
ZD6474 (Zactima)
Suggested Reading
Alzahrani AS et al: Diagnostic accuracy of high-resolution neck ultrasonography in the follow up of differentiated thyroid
cancer: a prospective study. Endocr Pract 11:165, 2005; Clayman GL, el-Baradie TS: Medullary thyroid cancer. Otolaryngol
Clin North Am 36:91, 2003; Hughes CJ et al: Impact of lymph node metastasis in differentiated carcinoma of
the thyroid: a matched pair analysis. Head Neck 18:127, 1996; Robbins RJ et al: Factors influencing the basal and recombinant
human thyrotropin-stimulated serum thyroglobulin in patients with metastatic thyroid carcinoma. J Clin Endocrinol
Metab 89:6010, 2004; Robbins RJ, Pentlow KS: Coming of age: recombinant human thyroid-stimulating hormone as a
preparation for (131)I therapy in thyroid cancer. J Nuci Med 44:1069, 2003.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship
with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reported
nothing to disclose.
Drs. Clayman, Robbins, and Weber gave their scientific presentations at Current Concepts in Head and Neck Surgery,
presented November 12-13, 2005, in New York City, NY, by Memorial Sloan-Kettering Cancer Center and the
University of Texas MD Anderson Cancer Center. The Audio-Digest Foundation thanks the speakers and the sponsors
for their cooperation in the production of this program.
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