THYROID DISEASE: MANAGEMENT CONCEPTS
| THYROID NODULE: EVALUATION AND MANAGEMENT —Jonas Johnson, MD, Department of Otolaryngology,
University of Pittsburgh Medical Center, Pittsburgh
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| Benign indications for thyroid lobectomy: unclear diagnosis; compression—can cause neuropathy, dysphagia,
and dyspnea on exertion; neuropathy—usually caused by cancer; rarely resolves after thyroidectomy; benign goiter
can compress, stretch—and paralyze vocal cord; cervical sympathetic chain to produce unilateral Horner’s syndrome;
large goiters that adversely affect cosmesis—early treatment reduces incidence of problem; occasional goiter has cancer
focus; if lesion present for short time (eg, 3 wk), consider anaplastic cancer
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| Risk factors for thyroid cancer: cystic nodules generally benign (does not rule out possibility of cancer); exposure to
radiation during childhood can increase cancer risk later in life (less common problem today); age—women 20 to 40 yr
of age have 3% to 5% chance of having single malignant nodule; individuals <20 or >40 yr of age at increased risk; sex—
men face higher (20% to 30%) risk of developing malignant nodule
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| Fine needle aspiration (FNA): key evaluation tool (sensitivity 95% to 98%); Pittsburgh approach—limit FNA to
nodules ≥10 mm; use ultrasonography to follow patients with <10-mm nodules; if nodule grows, perform FNA; points—
benign thyroid nodules can develop from cystic problem or glandular degeneration; follow patients who had benign FNA
(FNA associated with 3%-4% false-negative rate); to achieve accurate pathologic assessment, FNA specimen must contain
tissue cells (blood or cystic fluid useless)
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| Follicular neoplasia: 80% benign; assessment requires histology, not just morphology, ie, capsular or microvascular invasion
must be present to distinguish between adenoma and carcinoma; follicular neoplasm indication for thyroid lobectomy;
caveats—frozen section analysis less accurate than FNA for distinguishing carcinoma from adenoma; capsular invasion
detected on serial sectioning provides evidence of cancer (ie, lesion size does not define diagnosis); total thyroidectomy—
mandated for carcinoma; contraindicated for adenoma
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| Multinodular goiters: FNA lacks sensitivity in evaluating multinodular disease because each nodule has discrete and finite
risk for malignancy (FNA indicated for each nodule); usually benign; problem goiters usually identified by patient
history (eg, rapid growth) or symptoms (eg, vocal cord paralysis)
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| Total thyroidectomy: therapy of choice for well-differentiated thyroid cancer; must remove as much thyroid tissue as
possible; most patients retain 3% to 5% of thyroid tissue
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| Disease behaves differently depending on patient age: people <45 yr of age—stage II or lower; rarely die of
differentiated disease; children with pulmonary metastases curable; cervical metastases make no difference for survival;
people >45 yr of age—can die from differentiated thyroid cancer; cervical metastases associated with ≈25% mortality
rate; in patients <45 yr of age, further surgery unnecessary if—primary lesion <10 mm; cancer focus 3 mm in large
goiter; multifocal malignancy—some data suggest patient may require total thyroidectomy and that foci can behave differently
(ie, genetically different cancers); unknown whether some small cancers remain dormant
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| Postoperative care: 131 I therapy—routinely used to ablate residual thyroid tissue after thyroidectomy; efficacy for curing
metastatic disease debatable; thyroglobulin levels—used to monitor patients after total thyroidectomy and 131 I therapy;
thyroglobulin level >2 ng/mL indicates recurrence; thyroglobulin evaluation and 131 I scans—both used to monitor
patients, ie, some people who are thyroglobulin-negative can be 131I positive and vice versa; more sensitive when patient
profoundly hypothyroid, ie, thyroid-stimulating hormone (TSH) >25 mU/L; to produce hypothyroid state—stop thyroid
hormone replacement therapy or administer thyrotropin α (recombinant human thyrotropin; Thyrogen); 2 injections of
Thyrogen artificially raise TSH, allowing monitoring of thyroglobulin without making patient profoundly hypothyroid;
presence of thyroglobulin antibody believed—by some to prevent accurate monitoring of thyroglobulin; by others to indicate
recurrence; points—after administering Thyrogen, perform whole-body scan; if abnormality detected, use ultrasonography
(US) and FNA to localize recurrence; clinical significance of recurrence and need for reoperation uncertain;
positron emission tomography (PET)—used when patient thyroglobulin positive, 131 I negative, and tumor capable of
taking up fluorine 18-fluoro-2-deoxyglucose (FDG); rarely used for well-differentiated disease
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| Options for neck disease: cervical metastasis mandates comprehensive neck dissection; patients with papillary thyroid
cancer and N0 neck—do not derive survival benefit from elective neck dissection; most surgeons perform zone
6 dissection instead; caveat—absence of metastases in central neck does not preclude skip metastases elsewhere
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 | Nodal metastases in papillary thyroid carcinoma: present in 30% to 80% of cases (usually occult); occur most often in
central compartment between carotid arteries; data show—patients rarely develop one positive node (presence of multiple
nodes renders “berry picking” ineffective); patients can develop lateral cervical nodal metastases without central
metastases (skip metastases may not follow anatomic pathway); functional comprehensive neck dissection avoids need
to reoperate on patients who present with metastatic well-differentiated cancer
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| Women 70 yr of age with well-differentiated thyroid cancer: have ≈30% disease-related mortality rate; can develop
untreatable pulmonary metastases and inoperable neck disease; require same treatment approach used for younger patients,
ie, total thyroidectomy with 131 I therapy; follicular disease—higher treatment failure rate; patients with Hürthle cell
disease develop pulmonary metastases and live with untreatable disease for long time
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| MEDULLARY THYROID CANCER: MANAGEMENT —David W. Eisele, MD, Professor and Chairman, Department of
Otolaryngology—Head and Neck Surgery, University of California, San Francisco, School of Medicine
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| Medullary thyroid cancer (MTC): unusual (<5% of thyroid cancers); secretes calcitonin; parafollicular cells—C
cells; originate in neural crest; give rise to MTC; can produce, store, and secrete calcitonin; understanding of genetic
basis improves clinician’s ability to—predict disease risk; understand disease progression and outcomes; guide surgical
management (eg, prophylactic surgery) in patients predisposed to develop disease; forms of MTC—sporadic in
≈80% of patients; ≈20% hereditary; no exogenous predisposing etiologic factor for development of MTC
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| Hereditary MTC: autosomal dominant inheritance; related to germline mutation of rearranged-during-transfection
(RET) proto-oncogene; bilateral and multicentric with or without C-cell hyperplasia; RET proto-oncogene—prevalent
in neuroectodermal tissues; has extracellular, intracellular, and transmembrane domains
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| Types: multiple endocrine neoplasia type 2A (MEN-2A) associated with—pheochromocytoma in ≈50% of patients,
hyperparathyroidism in ≈20%; MEN type 2B (MEN-2B) associated with—pheochromocytoma; marfanoid phenotype
with mucosal and intestinal neuromas; familial MTC—not associated with endocrinopathies seen with MEN-2A or
MEN-2B
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| Codon point mutations: identified for each type of hereditary MTC; DNA analysis of blood samples—identifies patients
carrying point mutations; recommended for all patients with MTC and at-risk relatives, ie, most sensitive and
specific method for guiding management in family members; identification of individual carrying gene enables clinician
to—provide genetic counseling; perform prophylactic thyroidectomy on younger patients
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| Consensus guidelines for prophylactic surgery: codon point mutation determines tumor aggressiveness; tailor
timing of thyroidectomy to type of codon mutation—for aggressive MEN-2B tumors, perform thyroidectomy and central
neck dissection at ≤6 mo of age; for less aggressive MEN-2A tumors, thyroidectomy can be delayed for ≤5 yr; for
less virulent hereditary MTC, thyroidectomy can be delayed longer
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| Initial evaluation: sex distribution equal for MTC; most patients present with palpable thyroid nodule (≈50% have clinical
cervical nodal involvement); some patients have more aggressive tumors with airway compression or invasion;
most patients present in fourth decade of life; most aggressive tumors—present clinically during first and second decades
of life; detected earlier with RET testing
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| Tools: calcitonin screening—not considered cost-effective in United States; lacks specificity, eg, false-positive elevations
occur in patients with renal or liver failure, or women who are nursing or using birth control pills; point—10% to
15% incidence of distant metastases at presentation; options—needle biopsy (characteristic cytopathology accompanies
MTC); calcitonin staining (specific); family history; head and neck examination; associated signs and
symptoms—pheochromocytoma (eg, fluctuating blood pressure and palpitations); distant metastases (eg, diarrhea;
flushing from elevated calcitonin; bone pain from metastases)
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| Preoperative evaluation: serum calcitonin—may be elevated; ≤10 pg/mL considered normal; carcinoembryonic
antigen (CEA)—potentially helpful marker for dedifferentiated MTC; as tumor dedifferentiates, serum calcitonin declines
and CEA increases; pheochromocytoma screen—mandatory to avoid intraoperative catastrophe, ie, pheochromocytoma
must be treated before managing MTC; patients at risk can be identified with urine catecholamine screen or
genetic screen; hyperparathyroidism screening—elevated serum calcium levels mandate assessment of parathyroid
hormone (PTH) levels; imaging—computed tomography (CT) or magnetic resonance imaging (MRI) of neck and mediastinum;
US to assess extent of disease; routine chest radiographs to rule out chest metastases; CT of chest and
abdomen—helps detect distant metastases by providing baseline for comparison of subsequent images; distant
metastases—miliary and fine; go to liver; may be poorly visualized on chest and abdominal CT
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| Principles of treatment: surgery—only curative method; should be individualized; calcitonin marker for—
completeness of resection; persistent or recurrent disease
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| Total thyroidectomy: MTC usually multicentric; sporadic form—intraglandular lymphatic spread can involve contralateral
lobe; may be familial; some believe lobectomy sufficient for managing incidentally found, sporadic MTC; if local
invasion detected—lack of effective adjuvant therapy mandates total tumor removal
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| Central neck dissection: recommended for eliminating central neck involvement, since 80% of patients with palpable tumor
harbor metastases to central neck nodes; dissection extends from carotid to carotid and from innominate vessels inferiorly
to hyoid and upper mediastinum; point—recent data suggest thorough “cleanout” of central neck improves survival
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| Parathyroid glands: 4-gland parathyroidectomy—permits thorough dissection of central neck; facilitates management
of patients with MEN-2A disease who may develop subsequent hyperparathyroidism; point—if concomitant hyperparathyroidism
present, excise single adenoma; same rules apply for multiglandular hyperplasia
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| Lateral neck node involvement: common—palpable nodes present in 20% to 40% of cases; 50% to 75% of patients with palpable
primary tumor or positive central neck node have ipsilateral nodes; incidence of lateral neck metastases varies directly
with tumor size; patients with high calcitonin levels may have higher risk of harboring lateral neck metastases; patient
evaluation—imaging probably best approach; frozen section analysis poor intraoperative guide; nodal distribution—
similar to well-differentiated thyroid carcinoma; tends to occur along jugular chain and involve levels 2 through 5
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| Conclusions from assessment of disease incidence and distribution: patients with MTC require ipsilateral
neck dissection, ie, selective neck dissection (involves levels 2 through 5, with preservation of important structures); dissection
of contralateral neck—controversial if central and ipsilateral neck N0; risk for contralateral nodal involvement
supports more aggressive surgery when any compartment harbors signs of disease; alternative approach uses staged neck
dissections based on postoperative calcitonin levels
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| Postoperative management: administer L-thyroxine replacement therapy (suppression therapy contraindicated); obtain
serum calcitonin and CEA levels at 2 to 3 mo postoperatively (if calcitonin elevated, suspect residual neck disease or
distant metastases); point—continued risk for pheochromocytoma or hyperparathyroidism mandates annual screening of
all patients initially negative for these conditions
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| Adjuvant radiation therapy: data suggest approach provides slight improvement in local and regional disease-free
survival; consider for—extraglandular invasion; microscopic residual disease; extracapsular nodal spread; inoperable
tumors; symptomatic bone metastases; additional surgery may require operating on irradiated tissue
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| Cervical reoperation: individualized according to extent and adequacy of initial surgery; patients with advanced disease
de novo probably—have distant metastases; not candidates for reoperation; candidates for cervical reoperation
include patients who—had inadequate initial surgery in neck; have localized neck disease; are carefully selected to undergo
palliation of local regional recurrence, despite presence of distant metastases; reassess patients for extended
disease—look for obvious local regional disease or distant metastases; noninvasive localizing studies include US, MRI,
radionuclide studies, dimercaptosuccinic acid (DMSA), and PET; invasive techniques detect metastases, eg, laparoscopic
evaluation of liver most sensitive approach for detecting miliary metastases; selective venous catheterization rarely used
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| Poor prognostic indicators: high stage; extracapsular spread; bilateral nodes; older age; male sex; elevated CEA and
serum calcitonin; point—no survival difference between familial and sporadic disease
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| Clinical course: variable; patients usually have long lifespan; children detected early on do well after prophylactic thyroidectomy;
patients with—palpable tumor at presentation have 50% rate of persistent postoperative hypercalcitonemia;
extrathyroidal extension of primary tumor rarely achieve biochemical cure; disease in multiple nodes and nodal compartments
have abnormal calcitonin levels; patients with distant metastases—experience disease spread to liver, lung, bone,
and brain; can have indolent disease requiring palliative therapy
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Educational Objectives
| The goal of this program is to educate the listener about current concepts in the management of thyroid nodules and medullary
thyroid cancer. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Assess the role of fine needle aspiration biopsy in the evaluation of thyroid nodules.
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| 2. Select appropriate primary and follow-up care for patients with well-differentiated thyroid cancer.
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| 3. Diagnose patients presenting with medullary thyroid carcinoma.
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| 4. Review principles governing the management of medullary thyroid carcinoma.
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| 5. Describe the role of adjuvant radiation therapy and cervical reoperation in the management of medullary thyroid carcinoma.
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Discussed on This Program
Levothyroxine sodium (T4 ; L-thyroxine) [Levothroid, Levoxyl, Synthroid, Unithroid]
Thyrotropin Alfa [Thyrogen]
Suggested Reading
Bugalho MJ et al: Preoperative diagnosis of medullary thyroid carcinoma: fine needle aspiration cytology as compared
with serum calcitonin measurement. J Surg Oncol 91:56, 2005; Chang TC et al: Medullary thyroid carcinoma: pitfalls
in diagnosis by fine needle aspiration cytology and relationship of cytomorphology to RET proto-oncogene mutations. Acta
Cytol 49:477, 2005; Frates MC et al: Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound
consensus conference statement. Radiology 237:794, 2005; Frilling A et al: Prophylactic thyroidectomy in multiple
endocrine neoplasia: the impact of molecular mechanisms of RET proto-oncogene. Langenbecks Arch Surg 338:17,
2003; Lin JD et al: Thyroid cancer in the thyroid nodules evaluated by ultrasonography and fine-needle aspiration cytology.
Thyroid 15:708, 2005; Machens A et al: Contralateral cervical and mediastinal lymph node metastasis in medullary
thyroid cancer: systemic disease? Surgery 139:28, 2006; Ogilvie JB, Kebebew E: Indication and timing of thyroid
surgery for patients with hereditary medullary thyroid cancer syndromes. J Natl Compr Canc Netw 4:139, 2006;
Vierhapper H et al: Early diagnosis and curative therapy of medullary thyroid carcinoma by routine measurement of
serum calcitonin in patients with thyroid disorders. Thyroid 15:1267, 2005.
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.
Dr. Eisele gave his scientific presentation at Contemporary Management of Thyroid and Parathyroid Disorders, presented
April 28 to 30, 2005, in Augusta, Georgia, by the Medical College of Georgia; Dr. Johnson gave his scientific presentation
at the Annual Clinical Conference of the Kansas Society of Ophthalmology and Otolaryngology, held January 6
to 7, 2006, in Kansas City, Missouri. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation
in the production of this program.
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