THYROID SURGERY
From the 35th Annual Phoenix Surgical Symposium
Electron Kebebew, MD, Professor of Surgery, University of California, San Francisco, School of Medicine
Changing Management of Thyroid Nodules
| Reasons for change: increased incidence of thyroid nodules and thyroid cancer, most of which nonpalpable; Framingham
study—late 1960s and early 70s; evaluated prevalence of thyroid nodules on clinical examination and palpation; ≈5% of
population of United States has palpable thyroid nodule; when occult papillary thyroid cancer looked for on autopsy, reported
rate 30%; thyroid nodules—more frequent in older patients (fourth and fifth decades of life), in women, those
with family history of goiters or thyroid cancers, and in residents of areas with iodine deficiency or endemic goiter; currently
see nonpalpable thyroid nodules (<1-2 cm; discovered on imaging studies) and increasing incidence of thyroid
cancer (incidence doubled in last 10 yr); Cancer Registry data show increasing incidence of papillary thyroid cancer
(with extremely good prognosis); at time of diagnosis, most tumors <2 cm and clinically nonpalpable; mortality rate unchanged
(≈5%); data suggest more detection of thyroid incidentalomas
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| Work-up of subclinical thyroid nodule: risk-stratify patient; questions to consider when evaluating patients (do they have
thyroid cancer? do they have hyperthyroidism?); risk factors—therapeutic external beam irradiation in childhood (latency
period 20-30 yr; risk for thyroid cancer ≈40%); in this group of patients, false-negative rate of fine-needle aspiration
(FNA) biopsy 20% (thyroid cancer often located adjacent to dominant nodule or contralateral thyroid lobe); in
patient with significant history of external beam irradiation, irrespective of FNA biopsy, total thyroidectomy recommended;
another established risk factor family history of thyroid cancer; most patients with medullary thyroid cancer
(MTC) have had genetic testing and know this beforehand; larger group of patients those with familial non-MTC; individual
with 2 family members with thyroid cancer has high likelihood of having familial non-MTC (tends to be more aggressive);
make sure no local symptoms (eg, hoarse voice, difficulty swallowing) associated with thyroid nodule;
thyroid-stimulating hormone (TSH)—if normal, nothing further necessary; if suppressed, patient should have radioiodine
scan; perform FNA biopsy if patient has “cold” nodule; if patient has hyperthyroidism, exclude Graves’ disease (radioiodine
scan shows diffuse uptake) or solitary nodule (increased uptake, with remaining thyroid tissue showing suppressed
uptake); calcitonin—not routinely checked in United States; excellent marker for MTC; not cost-effective (<0.5% of
thyroid nodules end up being MTC); results of FNA biopsy—80% have benign cytologic features (accuracy >95%);
<10% have malignant diagnosis (often papillary thyroid cancer, which accounts for 80%-85% of thyroid cancer; rarely
anaplastic cancer); nodules that are indeterminate or suspicious for papillary thyroid cancer difficult to manage (need diagnostic
thyroidectomy); 5% to 10% risk that nondiagnostic biopsy result actually positive for thyroid cancer; having cytologist
review slides at time of FNA biopsy reduces rate of nondiagnostic biopsies; benign cytologic feature on FNA
biopsy of thyroid nodule carries risk of missing cancer (5% of patients); thyroid nodules often grow, so obtain follow-up
ultrasonography (US) of neck after 6 to 18 mo; if stable for several years, not necessary to see patient yearly; no agreed-
upon criteria for appropriate increase in thyroid nodule; most clinicians suggest if increase >20% in any of 3 dimensions
of measurement, reevaluation warranted; thyroid hormone—suppresses TSH to prevent thyroid nodule from growing;
studies in United States suggest no significant effect; however, studies in Europe (where iodine deficiency present) suggest
TSH suppression possibly helpful; consider risk for atrial fibrillation and future osteoporosis
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| Role of neck US in evaluating thyroid nodule: risk-stratification of dominant nodule and detection of presence of other
nodules; guiding FNA biopsy; assessment of lymph node involvement; features of US—hypoechogeneity of thyroid; irregular
or blurred margins; vascularity within thyroid nodule; microcalcifications; can determine whether nodule solid,
cystic, or complex; increasing number of studies demonstrate benefit of routine preoperative neck US and office-based
US; study showed routine preoperative US altered surgical management in 20% (identified cervical lymphadenopathy);
another study detected additional disease in 31% of patients with thyroid cancer; in those with multinodular goiter, US
helps identify cancer in nondominant nodule (in one-third of cases); reduces risk for persistent or recurrent disease;
should not be used as screening test but routinely used in patients with palpable and nonpalpable thyroid nodules (improves
surgical management); extension of physical examination; when should US-guided FNA biopsy be performed in
nonpalpable thyroid nodules or subclinical thyroid nodules?—debate about whether nodules <1.5 cm need to be biopsied;
outcome data show life expectancy of these patients near normal and risk for recurrence <6% (≤17-yr follow-up);
Japanese study of 162 participants with thyroid nodules <1.5 cm found that 70% of patients (median follow-up >4 yr),
had no progression of disease; 10% had increase in tumor size and subsequently underwent thyroidectomy and/or lymph
node dissection; only 1.2% developed new cervical lymph node metastases; stratification of subclinical thyroid
nodules—Italian study looked at 402 participants with thyroid nodules <1.5 cm (8-15 mm) and value of 4 US features in
predicting whether thyroid nodule malignant; irregular margins, vascular pattern, and microcalcification more predictive;
tumor size itself not predictive of malignancy; rates of benign, suspicious, and malignant nodules similar to those seen in
palpable nodules; if one US feature present, need to perform 10 FNA biopsies to detect one cancer (if no features present,
need 23 FNA biopsies); one-third of those with occult papillary thyroid cancer had extrathyroidal invasion (poor prognostic
marker) and 20% had lymph node metastases (none had distant metastases); if thyroid nodule >1.0 to 1.5 cm, perform
FNA biopsy (unclear whether to biopsy if nodule <1.0-1.5 cm); rationale that even if nodule that small ends up
being cancer, more likely papillary thyroid cancer (good life expectancy and low risk for recurrent disease); guidelines
developed; any solitary thyroid nodule >1 cm, with suspicious features on US, should be biopsied; if cervical lymphadenopathy
present, biopsy lymph node; also biopsy if size increased (under US guidance, if nodule in posterior portion of
lobe); if multiple nodules, same criteria applied to each nodule >1 cm
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| US-guided FNA biopsy: question of whether necessary to perform routinely; most studies compared US-guided biopsy to biopsy
done under palpation; failure or nondiagnostic rate decreases when US guidance used; also improves sensitivity and
specificity of FNA biopsy and interpretation, leading to higher rate of malignancy when thyroidectomy performed; no level
1 clinical evidence (ie, no randomized controlled trials); indications—complex nodule with cystic and solid components;
small thyroid nodules <2 cm (to obtain representative portion of nodule); nodules in posterior location; previous nondiagnostic
biopsy; when results of FNA biopsy of thyroid nodule indeterminate—30% of FNA biopsy results; number of thyroidectomies
performed for thyroid cancer lower than number of diagnostic thyroidectomies; issues include determining
risk for malignancy, predicting who is more likely to have malignant tumor, surgical approach to use, and how to reliably
determine whether tumor malignant; several studies addressing these issues; rate of follicular neoplasm being cancerous,
13% to 47% (largely dependent on cytopathologist); malignancy more common in older and very young patients and in
men; no consistent predictor across all studies; FNA cytologic features of follicular cancer and follicular adenoma indistinguishable
(remove gland where thyroid nodule located; pathologist must see capsular or vascular invasion); summary—in
initial work-up, obtain good history and make sure patient has no risk factors; check TSH; use FNA biopsy results to guide
management; radioiodine scan obsolete, unless patient hyperthyroid; US-guided FNA biopsy decreases nondiagnostic rate;
patients with indeterminate FNA biopsy need diagnostic thyroidectomy
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Medullary Thyroid Cancer
| Introduction: relatively rare; accounts for 3% to 7% of all thyroid cancers; originates from parafollicular cells (endocrine
in origin; also called C cells) that secrete calcitonin (marker); 2000 to 3000 cases annually; has hereditary component
with hyperparathyroidism, pheochromocytoma, and multiple endocrine neoplasia type 2 (MEN2) syndrome; calcitonin
used as screening test for MTC in early 1970s; hereditary MTC found to have component of C-cell hyperplasia (premalignant
lesion to MTC); chromosome 10 locus identified as responsible for hereditary cases of MTC; RET (formerly
MEN2A, MEN2B) proto-oncogene germline mutation responsible; findings led to early diagnosis with improved outcome
and implementation of prophylactic thyroidectomy
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| Clinical presentation: most patients present with thyroid nodule or cervical lymph node metastasis and rarely with distant
metastasis (often mistakenly worked up for inflammatory bowel disease); in speaker’s cohort of patients, those with hereditary
disease diagnosed earlier (one-third of all presentations); due to genetic testing, more patients diagnosed even before
developing cancer; sporadic MTC accounts for 75% of cases, and of those, 8% to 12% hereditary MTC; 25%
hereditary MTC (isolated, familial, or part of MEN2 syndrome); RET proto-oncogene—transmembrane tyrosine kinase
receptor; specific genetic mutations in specific codons predict patient phenotype; in MEN2B, most mutations occur in tyrosine
kinase domain; MEN2B genotypes different; distinction between isolated familial MTC and MEN2A less clear
due to significant overlap in specific codon mutations (most occur in extracellular membrane); question of when to intervene
in patient with RET proto-oncogene but no thyroid nodule and normal calcitonin; 9 mo earliest identified age at onset
(hereditary); tend to be patients with MEN2B; categorized as level 3 codon mutation; requires intervention as soon as
possible; MEN2A has level 2 mutation (refers to degree of aggressiveness of MTC, based on age at onset and extent of
cancer); isolated familial MTC has level 1 mutation (earliest identified age at onset, 6 yr); syndromes of hereditary MTC
and MEN2B have typical phenotypes, therefore genetic testing not necessary (patients have mucosal neuromas, tongue
nodules, ganglioneuromatosis, and Marfanoid body habitus; ≈70% have pheochromocytoma); distinction between isolated
familial MTC and MEN2A—patients with MEN2A develop hyperparathyroidism and pheochromocytomas; distinction
seen only after long-term follow-up; intervention with prophylactic thyroidectomy should be based on specific
codon mutation; FNA biopsy accurate diagnostic method; if cytology demonstrates MTC, check calcitonin and carcinoembryonic
antigen (CEA) preoperatively; if calcitonin >1000 pg/mL and CEA >12 ng/mL, metastatic disease likely; also
perform neck US (assume cervical lymph node metastasis present) for appropriate lymph node dissection
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| Treatment: one of few thyroid cancers in which consensus exists on appropriate extent of thyroidectomy and lymph node
dissection; for clinically evident disease—thyroid nodule or cervical lymph node disease; perform total or near-total thyroidectomy
with central neck node and functional lateral neck node dissection; if contralateral thyroid nodule present, or
if cervical lymph nodes positive on contralateral central neck, perform contralateral lateral neck node dissection; if no evidence
of disease and diagnosed by genetic testing, perform prophylactic total thyroidectomy and ensure calcitonin not
elevated; also make sure US not positive for thyroid nodules
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| Anatomy: central neck nodes (within carotid sheath up to hyoid bone and down to innominate vessels), level 6; in lateral
neck, upper jugular nodes, level 2; midjugular nodes, level 3; lower jugular nodes, level 4; posterior triangle, level 5; upper
and anterior mediastinal nodes, level 7; lateral neck dissection includes levels 2, 3, 4, and 5; in central neck dissection,
include level 7 lymph nodes in patients with MTC, including doing cervical thymectomy; prophylactic cervical
lymph node dissection performed because occult metastases almost always present in patients whose primary tumor >1
cm; data on prophylactic lymph node dissection show that approximately two-thirds have central neck lymph node metastases;
two-thirds have lateral neck lymph node metastases on side of primary tumor, and one-third have contralateral
neck lymph node metastases; prophylactic lymph node dissections should be performed on initial surgery
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| National practice patterns: data show <50% of patients had total or near-total thyroidectomy; MTC multicentric and bilateral,
so patients require initial surgery of total or near-total thyroidectomy; only 21% of patients seen had lymph node dissection
(number increasing)
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| Management issues: parathyroid glands—if normal, leave in situ; if ischemic, autotransplant to forearm in patients with
MEN2A (risk of developing hypoparathyroidism) and to neck (sternocleidomastoid muscle) in patients with MEN2B;
pheochromocytoma—must screen; 8% to 12% of cases hereditary (at risk); specific mutation more likely associated
with pheochromocytoma in patients with MEN2A; assume that every case hereditary; genetic testing available
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| Outcome: poor (accounts for 20% of thyroid cancer mortalities); 75% of patients alive at 10-yr follow-up; prognostic
factors—stage (those with metastatic disease usually not alive >10 yr; those with cervical lymph node metastases do
slightly worse than those without); age (≈15% difference in mortality rate between patients <45 yr of age and those ≥45
yr of age); check calcitonin and CEA postoperatively (wait 2-3 wk [half-life of calcitonin]); if calcitonin detectable or elevated,
recognize as recurrent or persistent MTC and follow patient closely; >50% of patients have recurrent or persistent
MTC, so perform definitive procedure in initial setting; all patients need long-term follow-up
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| Treatment options for recurrent or persistent MTC: external beam irradiation and standard chemotherapy ineffective; if
seen postoperatively with elevated calcitonin, question whether patient had adequate initial operation (total thyroidectomy
with central and lateral neck node dissection); if not, opportunity to biochemically treat patient; if so, look for metastatic
disease; methods of localizing tumors in patients with recurrent or persistent MTC—US appropriate for neck; computed
tomography (CT) or magnetic resonance imaging (MRI) used routinely for anterior mediastinum and chest (MRI slightly
better); if calcitonin doubles in 6 mo, possibility of rapidly progressive disease; venous sampling helps lateralize location
of tumor; positron emission tomography (PET) often used when all other imaging studies exhausted; reoperative
surgery—indications include increasing calcitonin in localized disease; also as palliation for local symptoms or if widely
metastatic disease present; systemic symptoms of elevated calcitonin include diarrhea and flushing; if octreotide ineffective
for symptoms, tumor debulking useful; calcitonin decreases >50% in only ≈20% of patients; patients whose calcitonin
drops >50% after reoperation less likely to develop distant metastases, compared to patients in whom drop <50%
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| Algorithm: if calcitonin elevated, determine whether initial complete operation performed; if not, reoperate on compartment
not yet removed; if calcitonin still elevated, work up with neck US, MRI for anterior mediastimum or anterior chest,
or abdominal CT; if localized tumor found, resect; if metastatic, refer patient to emerging clinical trials; if all negative but
calcitonin extremely elevated or doubling in <6 mo, PET and venous sampling may help identify tumors; if calcitonin undetectable
after reoperation, follow patient long term; genetic testing imperative; distinct genotype-phenotype associations
dictate intervention; persistent or recurrent MTC common, and only way to reduce is by performing complete initial
operation; any patient with clinically evident tumor should have total or near-total thyroidectomy with central and ipsilateral
lateral neck node compartment dissection; palliative surgery helpful in those with local and systemic symptoms (reduces
tumor burden and calcitonin level)
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Suggested Reading
Bajaj Y et al: Fine needle aspiration cytology in the diagnosis and management of thyroid disease. J Laryngol Otol
120:467, 2006; Boi F et al: Calcitonin measurement in wash-out fluid from fine needle aspiration of neck masses in patients
with primary and metastatic medullary thyroid carcinoma. J Clin Endocrinol Metab 92:2115, 2007; Castro MR et al:
Continuing controversies in the management of thyroid nodules. Ann Intern Med 142:926, 2005; Gibelin H et al: Increased
calcitonin level in thyroid nodules without medullary carcinoma. Br J Surg 92:574, 2005; Karanikas G et al: Frequency
and relevance of elevated calcitonin levels in patients with neoplastic and nonneoplastic thyroid disease and in healthy subjects.
J Clin Endocrinol Metab 89:515, 2004; Kouvaraki MA et al: Role of preoperative ultrasonography in the surgical
management of patients with thyroid cancer. Surgery 134:946, 2003; Machens A et al: Contralateral cervical and mediastinal
lymph node metastasis in medullary thyroid cancer: systemic disease?. Surgery 139:28, 2006; Machens A et al: Prospects
of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab 90:2029,
2005; McAuliffe PF et al: Preemptive surgery. Surgery 140:1, 2006; Miller B et al: Prevalence of malignancy within cytologically
indeterminate thyroid nodules. Am J Surg 188:459, 2004; Silver RJ et al: Management of thyroid incidentalomas.
Surg Clin North Am 84:907, 2004; Skinner MA et al: Prophylactic thyroidectomy in multiple endocrine neoplasia
type 2A. N Engl J Med 353:1105, 2005; Tan YY et al: Does routine consultation of thyroid fine-needle aspiration cytology
change surgical management? J Am Coll Surg 205:8, 2007; Tischler AS et al: Prophylactic thyroidectomy in multiple endocrine
neoplasia type 2A. N Engl J Med 353:2817, 2005.
Educational Objectives
| The goal of this program is to improve the management of thyroid nodules and medullary thyroid cancer (MTC). After
hearing and assimilating this program, the clinician will be better able to:
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 | 1. Perform a thorough work-up of a patient with a thyroid nodule.
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| 2. Utilize ultrasonography in evaluating a thyroid nodule.
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| 3. Recognize the importance of genetic testing in patients with MTC.
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| 4. Prescribe appropriate treatment for patients with clinically evident MTC and those who have no evidence of disease but
are diagnosed by genetic testing.
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| 5. Review the indications for reoperative surgery for MTC.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and planning committe
members to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of
interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and
not a proprietary business or commercial interest. For this program, the faculty reported nothing to disclose.
Acknowledgments
Dr. Kebebew was recorded at the 35th Annual Phoenix Surgical Symposium, held February 14-17, 2007, in Phoenix, AZ,
and sponsored by Banner Health and the Phoenix Surgical Society. The Audio-Digest Foundation thanks Dr. Kebebew and
the sponsors for their cooperation in the production of this program.
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