SURGERY FOR THYROID CANCER
From the University of California, San Francisco, School of Medicine’s Symposium on Head and Neck Endocrine
Surgery
Well-Differentiated Thyroid Cancer
| SURGICAL MANAGEMENT —Gregory W. Randolph, MD, Associate Professor, Otolaryngology–Head and Neck
Surgery, Harvard Medical School, Director, Thyroid Surgical Division, Massachusetts Eye and Ear Infirmary, and
Member, Division of Endocrine Surgery and Division of Surgical Oncology, Massachusetts General Hospital, Boston
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| Types: papillary—multifocal; intraglandular; early and robust lymphatic spread with microscopic nodal disease in ipsilateral
neck in 60% to 70% of cases; follicular—solitary lesion that grows by direct extension; large invasive lesions;
early hematogenous spread by large-caliber veins that invade capsule; rate of distant metastasis ≤16% (must
determine whether rate high enough to warrant total thyroidectomy)
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| Rising incidence: more cases being detected with ultrasonography; nuclear accident at Chernobyl also factor; incidence
in United States has increased 2.4 times over past 20 to 30 yr, all in papillary form; however, mortality has remained
stable, probably thanks to earlier diagnosis; similar increase seen in northern and western Europe, due to
Chernobyl, mostly in people who were young at that time; cases formerly deemed follicular now considered follicular
variants of papillary carcinoma; pathologists perhaps now labeling lesions formerly considered benign as cancer
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| Surgery: prognostic factors include age, degree of invasiveness (key), presence of distant metastases; patient’s sex; size
of lesion
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 | American Joint Committee on Cancer staging criteria: cover size, degree of extrathyroidal extension, presence of regional
nodes, distant metastases, and age
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| Considerations in determining extent of thyroidectomy: cancer-positive needle biopsy; sex; age >45 yr; size of lesion; results
of chest x-ray or computed tomography (CT; distant metastases suggest high-risk patient); result of preoperative
laryngoscopy most important (vocal cord paralysis as important as malignancy on fine-needle aspiration biopsy)
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| Physical examination and work-up: look for fixation to airway and presence of regional lymphadenopathy; laryngoscopy
to look for paralysis; have low threshold for obtaining neck CT (with contrast if preferred; surgeon must know
if airway or lymph nodes require resection); ultrasonography (US) plus physical examination and contrast-enhanced
CT helpful for all patients with papillary carcinoma; chest CT or x-ray to look for mediastinal lymphadenopathy and
chest disease; consider endoscopy at time of thyroidectomy to permit surgeon and patient to plan for additional surgery
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| T4 disease: poor prognosis; high risk for regional recurrence; marker for regional lymph node disease; treatment problems
local, regional, and distant; complete resection improves prognosis; prognosis good with papillary carcinoma,
regardless of extent of surgery; speaker performs total thyroidectomy for lesions >6 mm; tailor treatment to individual
patient; in low-risk patient with negative contralateral lobe on US, removal of involved lobe and isthmus may be
sufficient; even with high-risk patients, preserving some thyroid tissue (near-total thyroidectomy) spares parathyroid
function and enables use of thyroglobulin as indicator of distant metastases
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| Total thyroidectomy: required by 20% to 60% of patients; some patients have oddly shaped thyroids that preclude removal
of entire gland; first surgery should encompass gross disease in thyroid and neck; microscopic disease often
occurs in contralateral lobe and ipsilateral neck, but clinical significance negligible (should not be surgical target);
20% to 30% of patients have gross nodal disease; no current recommendations for preoperative radiographic work-
up for these patients
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| NECK 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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| Thyroid lymphatic system: intraglandular—each lobe communicates pericapsularly with other; cancer sometimes
spreads via these vessels, but some foci independent clones rather than intraglandular metastases; central neck compartment
primary drainage site; secondary drainage occurs into lateral neck nodes; skip metastases infrequent; glandular
vasculature parallels lymphatics; knowledge of lymphatic anatomy essential for accurate evaluation of neck,
anticipation of lymphatic involvement, and appropriate treatment and drainage; extraglandular—lymphatics occur
superiorly to Delphian lymph nodes (levels II and III in high jugular chain); laterally to levels III and IV in lower jugular
chain; inferiorly to pre- and paratracheal nodes (level III), and to anterior and suprerior mediastinal nodes; they
rarely occur posteriorly to retropharyngeal or parapharyngeal nodes
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| Incidence of nodal metastases: papillary carcinoma—40% to 50% at time of presentation; likelihood usually correlates
with primary tumor diameter, but smaller tumors also associated with metastases (10%-30% incidence with papillary
microcarcinoma [<1 cm in diameter]); higher frequency of nodal metastases in pediatric patients, extrathyroidal
spread, and gland multicentricity; follicular carcinoma—risk for metastases lower (percent incidence in low teens);
usually associated with advanced local disease and invasion; Hurthle cell carcinoma—incidence slightly higher than
with follicular; metastases infrequently 131 I-avid (makes surgical removal even more crucial)
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| Routine neck dissection: incidence of metastases higher with therapeutic than with elective neck dissection, but also
depends on thoroughness of surgeon and pathologist; central neck most commonly involved (most solitary metastases
found here; patients usually <20 yr of age); in lateral neck, metastases most likely to occur in mid and lower
jugular chains, and central compartment; levels II to IV most often involved (≈10% of thyroid carcinomas show
level I involvement); skip metastases uncommon
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| Level II: divided into IIa (below spinal accessory nerve) and IIb (above nerve); dissect all way up jugular chain in area
of spinal accessory nerve
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| Bilateral nodal metastases: infrequent; seen with bilateral primary tumors, isthmus primaries, recurrent tumors, and
multilevel nodal involvement
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| Impact of nodal metastases on recurrence and survival: papillary carcinoma—higher incidence of recurrence,
even with postoperative 131 I ablation in older patients, but true impact of nodal metastases on survival unknown; if patient
has bilateral nodes, nodal fixation, or extrathryoidal extension of primary tumor, nodal metastases have negative
effect on survival; follicular carcinoma—impact unclear; retrospective studies show no or negative impact
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| Evaluation and staging: patients <45 yr of age with nodal metastases assigned to stage I; those >45 yr of age placed in
stage III; sentinel node identification— intraoperative palpation and inspection (often does not correlate with presence of
metastases); frozen sections—immunohistochemical staining increases detection; routine US—detects previously unsuspected
metastases in about one third of patients; magnetic resonance imaging—good for imaging parapharyngeal, retropharyngeal,
paratracheal, and mediastinal nodes
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| Impact of surgical resection of nodal disease: difficult to show survival benefit because of 1) indolent nature of disease,
2) retrospective nonrandomized nature of studies, 3) inconsistencies in adjuvant therapy, 4) more extensive
surgery for more advanced disease; no proven benefit in literature for elective dissection of stage N0 neck; medical
management usually effective for occult nodes; removal preferred for gross nodes, followed by postoperative adjuvant
chemotherapy; routine “plucking” of enlarged nodes not recommended (violates neck; causes scarring; makes
subsequent surgery more problematic; usually leaves residual nodal disease; higher incidence of recurrence; no difference
in survival)
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| Central neck dissection: defined as nodes between carotid sheaths, and from anterior mediastinum to hyoid bone;
some surgeons perform routinely, despite lack of evidence of benefit to patient; some experts recommend against it
due to higher incidence of permanent hypoparathyroidism; dissection may be appropriate if clinical nodal involvement
present; inspect nodes during surgery (usually not above inferior thyroid artery, so superior parathyroid gland
less at risk; some surgeons routinely dissect area thoroughly and autotransplant inferior parathyroid gland)
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| Radical neck dissection: not recommended; no benefit over selective neck dissection
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| Complications of neck dissection: central—concerns similar to those associated with thyroidectomy; lateral—
chylous fistula; hemorrhage; seroma
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| Postoperative care: adjuvant therapy; external beam irradiation (if risk for local recurrence high)
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| Management of neck recurrence: central reoperation much harder and more dangerous than lateral reoperation;
nerve monitoring useful; when reoperating on central neck, be prepared to manage invasive tumor; with lateral recurrences,
plan incision carefully; extend previous incisions or use separate but parallel incision; provide adequate exposure
and “get the job done completely”
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| Papillary carcinoma found during dissection for tumor in upper aerodigestive tract: occurs in ≈1% of neck
dissections; manage primary head and neck carcinoma first; image thyroid with US; perform interval total thyroidectomy,
followed by 131 I and suppression therapy; head and neck primary determines prognosis
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Medullary Thyroid Cancer
| SURGICAL MANAGEMENT —Ann Gillenwater, MD, Associate Professor, Head and Neck Surgery, University of
Texas MD Anderson Cancer Center, Houston
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| Medullary thyroid carcinoma (MTC): arises from parafollicular (“C”) cells that secrete calcitonin; mostly found in
upper two thirds of lateral lobes; if nodule in that location difficult to identify, consider MTC (may be too poorly
differentiated to display amyloid or calcitonin staining); comprises 3% to 10% of thyroid cancers; aggressiveness
intermediate between that of well-differentiated (papillary, follicular) and anaplastic tumors; accounts for 13% of
deaths from thyroid cancer; 10-yr survival also intermediate; 25% of cases congenital
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| Presentation: initially, as neck or thyroid mass; may involve airway; if systemic metastases present, may see watery
diarrhea and flushing (unique to MTC); sporadic cases usually appear in fifth or sixth decade; genetic screening detects
familial cases
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| Inherited MTC syndromes: associated with 2 multiple endocrine neoplasia (MEN) syndromes; third form (familial
MTC) not associated with MEN; MEN 2A—high penetrance of MTC (occurs in 70% of cases); incidence of parathyroid
hyperplasia much lower; ≈50% of patients also have pheochromocytomas; MTCs usually occur in upper two-
thirds of gland and are often bilateral and multifocal (tipoff to MEN 2A); pheochromocytomas usually associated with
medullary hyperplasia (another tipoff to genetic syndrome); MEN 2B—much more aggressive than MEN 2A; MTC
occurs in nearly 100% of cases; incidence of pheochromocytoma 50%; hyperparathyroidism rare; often see mucosal
neuromas on lips, eyelids, and tongue; gastrointestinal dysfunction (megacolon) also common with MEN 2B; rare
subsyndromes associated with Hirschsprung’s disease or cutaneous lichenoid amyloidosis; patients have Marfenoid
habitus; can diagnose by watching patient walk across room; familial MTC—no other associated endocrine abnormalities;
less aggressive than MEN 2B, and occurs later in life
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| Causes of MTC: hereditary—autosomal dominant mutation that causes gain of function in RET proto-oncogene; somatic
mutation of RET proto-oncogene seen within tumor in 40% to 70% of cases; prognosis correlates with nature
of mutation
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| RET proto-oncogene: codes for transmembrane tyrosine kinase receptor; needed for sympathetic and parasympathetic
neural development; activates several downstream molecular pathways
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Treatment
| Preoperative assessment: measure calcitonin (very high levels suggest metastasis) and carcinoembryonic antigen
(CEA); exclude pheochromocytoma; check calcium levels for hyperparathyroidism; CT with iodine; further imaging
studies because of possibility of mediastinal vascular involvement or aerodigestive tract invasion; test for
RET mutation
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| Surgery: total thyroidectomy, with total neck dissection if palpable disease found; consider adjuvant therapy; incidence
of nodal metastases correlates with tumor size; identify drainage patterns
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| Neck management: total thyroidectomy, central compartment resection, and at least ipsilateral nodal dissection for
palpable disease; dissect bilaterally if preoperative imaging shows bilateral disease; if mediastinum involved, dissect
it too
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| Prophylactic thyroidectomy: MEN 2A—patients with RET mutation have high risk of developing MTC before 10 yr
of age; consider thyroidectomy before 6 yr of age, before palpable disease occurs; MEN 2B—more aggressive; thyroidectomy
recommended at time of diagnosis of RET mutation, even if patient <1 yr of age
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| Adjuvant therapy: radioactive iodine not helpful because not taken up by C cells; postoperative radiation therapy controversial;
may be indicated for locally aggressive disease (especially if aerodigestive tract involved), or for palliation;
chemotherapy cannot cure but may palliate; supportive care includes antidiarrheal medication and esophageal
stents; consider experimental approaches
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| Approaches to distant metastases and unresectable disease: observation or “brush fire” approach recommended
(limit treatment to sites most likely to cause patient trouble); example—ignore lateral neck node if it causes no
problems; focus on nodes near trachea or airway, which are more likely to be symptomatic); palliate symptoms;
chemotherapy—most common agents dacarbazine (DTIC) and 5-fluorouracil; may improve quality of life
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| Experimental approaches: radioimmunotherapy; RET inhibition; gene therapy
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| Prognosis: must follow patients >2 yr; risk for recurrence high; rate of biochemical persistence also high (calcitonin
levels remain high after surgery); prognostic factors include tumor stage, patient’s age at presentation, treatment received,
specific RET mutation, nodal status, number of nodal metastases, and extrathyroidal extension
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| Postoperative monitoring: most important to check calcitonin level immediately after surgery and every 6 to 12 mo;
(elevated levels signal persistent disease; sudden elevation after stability indicates progression); sudden rise in CEA
suggests colon cancer or distant metastases; some surgeons dissect neck to manage high levels of calcitonin (abdominal
venous sampling to rule out liver metastases); cervical, mediastinal nodes most common disease sites; re-exploration
of neck not recommended unless disease source found (no evidence that normalizing calcitonin alone improves
survival or quality of life)
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Suggested Reading
Caron NR, Clark OH: Papillary thyroid cancer: surgical management of lymph node metastases. Curr Treat Options
Oncol 6: 311, 2005; Cohen MS, Moley JF: Surgical treatment of medullary thyroid carcinoma. J Intern Med 253: 616,
2003; Cohen R et al: Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization
in medullary thyroid carcinoma. Groupe d’Etudes des Tumeurs a Calcitonine (GETC). J Clin Endocrinol Metab 85:
919, 2000; Cuccuru G et al: Cellular effects and antitumor activity of RET inhibitor RPI-1 on MEN2A-associated medullary
thyroid carcinoma. J Natl Cancer Inst 96: 1006, 2004; de Groot JW et al: Determinants of life expectancy in
medullary thyroid cancer: age does not matter. Clin Endocrinol 65:729, 2006; Ito Y, Miyauchi A: A therapeutic strategy
for incidentally detected papillary microcarcinoma of the thyroid. Nat Clin Pract Endocrinol Metab 3: 240, 2007;
Lang BH et al: Staging systems for papillary thyroid carcinoma: a review and comparison. Ann Surg 245: 366, 2007;
Lee JH et al: Ultrasonographic findings of a newly detected nodule on the thyroid bed in postoperative patients for thyroid
carcinoma: correlation with the results of ultrasonography-guided fine-needle aspiration biopsy. Clin Imaging 31:
109, 2007; Lin JD: Papillary thyroid carcinoma with lymph node metastases. Growth Factors 25:41, 2007; Morton RP,
Ahmad Z: Thyroid cancer invasion of neck structures: epidemiology, evaluation, staging and management. Curr Opin
Otolaryngol Head Neck Surg 15: 89, 2007; Pelizzo MR et al: Papillary thyroid carcinoma: 35-year outcomes and prognostic
factors in 1858 patients. Clin Nucl Med 32: 440, 2007; Roh JL et al: Total thyroidectomy plus neck dissection in
differentiated papillary thyroid carcinoma patients: pattern of nodal metastasis, morbidity, recurrence, and postoperative
levels of serum parathyroid hormone. Ann Surg 245: 604, 2007; Slough CM, Randolph GW: Workup of well-differentiated
thyroid carcinoma. Cancer Control 13:99, 2006; Tan LG et al: Health-related quality of life in thyroid cancer survivors.
Laryngoscope 117: 507, 2007.
Educational Objectives
| The goal of this program is to improve the surgical management of thyroid cancer. After hearing and assimilating this
program, the clinician will be better able to:
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| 1. Explain the differences between papillary and follicular thyroid carcinoma.
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| 2. List the factors to consider when determining the extent of thyroidectomy for well-differentiated cancer.
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| 3. Discuss methods of neck management for these patients.
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| 4. Describe the 3 types of medullary thyroid cancer.
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| 5. Recognize the indications for prophylactic thyroidectomy.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty 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.
Acknowledgements
This program was recorded at Head and Neck Endocrine Surgery, held October 27-28, 2006, in San Francisco, CA, and
sponsored by the Department of Otolaryngology–Head and Neck Surgery of the University of California, San Francisco,
School of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsor for their cooperation in the production
of this program.
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