Thyroid Cancer: Treating the Tough Ones

Educational Objectives

The goal of this program is to improve the management of difficult cases of thyroid cancer. After hearing and assimi­lating this program, the participant will be better able to:

1.   Choose the appropriate surgical treatment for substernal goiter, tracheal deviation, thyroid cancer, and extra­thyroidal cancer.

2.   Identify the features of locally aggressive thyroid cancer and assign levels of risk to patients with thyroid can­cer.

3.   Describe the stages of severity comprising the spectrum of thyroid cancer.

4.   Summarize the prevalence and natural history of papillary carcinoma.

5.   Compare and contrast the treatment options and prognoses for patients with multifocal, bilateral, and extrathy­roidal disease and for those with and without nodal involvement and distant metastases.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee 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 and planning committee reported nothing to disclose.

Acknowledgements

Dr. Shaha spoke at Management of the Thyroid, held March 2, 2009, in Chicago, IL, and presented by the Chicago Laryn­gological and Otological Society. Dr. Ross  lectured at Surgery of the Thyroid and Parathyroid Glands, held November 7, 2008, in Boston, MA, and presented by Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, and Har­vard Medical School. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the pro­duction of this program.

The Difficult Thyroid

Ashok R. Shaha, MD, Professor of Surgery, Weill Cornell Medical College, and Attending Surgeon, Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY

Background: incidence of thyroid cancer in United States has increased from 8000 in 1975 to 35,000, probably be­cause of improved diagnosis and interest in incidentalomas; mortality from thyroid cancer unchanged in 30 yr; »1000 deaths occur annually, usually from anaplastic or medullary but rarely from well-differentiated thyroid can­cer; incidence of thyroid cancer increased »30-fold in region near Chernobyl between 1986 and 1990

Incidentalomas: best evaluated with ultrasonography (US) and ultrasound-guided needle biopsy, but cannot rule out thyroid cancer; positron emission tomography (PET) often detects neoplasms in thyroid known as PET-associated incidental neoplasms (PAIN); categorized as those with focal or diffuse uptake; focal uptake form has 50% chance of malignancy, with many tall cell or insular tumors

Substernal goiter and tracheal deviation: only »10% to 12% malignant, and most come out easily through neck (sternal split required for <1%); assistance of thoracic surgeon probably unnecessary unless carina deviated; intubation  —  not difficult; larynx found in normal position in these patients; intubation performed using small (<#6.5) tube; thyroid cork   —located in bony confines of thoracic inlet where trachea and esophagus become com­pressed; lower portion of thyroid possibly much larger

Locally aggressive thyroid cancer: extrathyroidal extension most important clinical prognostic feature in all thyroid cancers; patients without extrathyroidal extension have excellent survival; those with extrathyroidal extension have decreased survival; good local resection needed to prevent recurrence in central compartment; mortality after local recurrence approaches 50%

Risk groups: low-risk group consists of young patients with low-risk tumors; high-risk group comprises older pa­tients with high-risk cancers; intermediate-risk group consists of young patients with high-risk cancer and old pa­tients with low-risk cancer; risk group predicts survival; 48% incidence of local recurrence in patients with extrathyroidal extension; 42% incidence of local and 37% incidence of distant metastases

Spectrum of severity: 99% rate of survival seen in patients with papillary vs 99% mortality in those with anaplastic thyroid cancer; ranking in order of increasing severity, papillary tall cell,  moderately differentiated,  poorly differ­entiated, and anaplastic thyroid cancer; radioactive iodine (RAI) avidity decreases and PET positivity increases with disease severity; PET useful in moderately and poorly differentiated forms

Surgery: aggressive surgery improves survival in some patients with aggressive tumors; important to know status of vocal cords preoperatively; if nerve already damaged, more aggressive surgery appropriate, and more care needed to avoid injuring nerve on opposite side; nodal metastases   —  usually not problematic in thyroid cancer, except in older patients and those with aggressive histology; total laryngectomy may be indicated; patients die of distant me­tastases, rather than local recurrence; destruction of cricoid cartilage  —  total laryngectomy as well as total thyroid­ectomy required; primary total laryngectomy also required when tumor in subglottic area

Sites of recurrent extrathyroidal extension: strap muscles most common, followed by nerve, tracheal wall, and esophagus

Management of extrathyroidal cancer: attempt to remove all cancer and preserve functioning structures; most pa­tients need adjuvant RAI; consider  postoperative external radiation therapy if tumor solid or if stuck to or invading cartilage; intensity modulated radiation therapy (IMRT) reduces complications from external irradiation

Vocal cords: important to examine vocal cords by laryngoscopy before thyroid surgery to determine function of ret­ropharyngeal nerve; do not sacrifice functioning nerve without examining nerve on other side; laryngoplasty can improve voice function after surgery; usually possible to remove tumors from larynx without laryngectomy unless patient has subglottic extension, destruction of cricoid cartilage, or paralyzed nerve; primary total laryngectomy rare, but selected patients do well with procedure

Management of trachea: crucial to determine whether to shave tumor off or dissect trachea; possible to sacrifice tra­chea by 4 to 5 rings; dissect 5 to 6 rings of trachea, bend neck, perform laryngeal drop, and cut strap muscles; lar­ynx moves by »3 cm; primary anastomosis then performed

Levels of tumor invasion: type 1, tumor stuck to trachea and easily shaved off; type 2, slight damage to trachea present, yet still possible to remove by shaving tumor without reducing rate of survival; type 3, massive submu­cosal or intraluminal disease requires tracheal dissection; if tumor appears fixed in central compartment, perform imaging, laryngoscopy, and tracheoscopy to search for intraluminal or submucosal disease, which indicate tra­cheal dissection required

Tracheal dissection: important to determine distance between vocal cord and carina; if tumor close to carina or vo­cal cord, resection cannot be done; in ideal case, large distance between tumor and carina, and tumor below cri­coid cartilage; dissect tracheal rings; if tumor stuck to esophagus, remove musculature; make sure no holes exist in esophageal mucosa; availability of electrocautery important; during surgery, go around trachea and open at lowermost portion of tumor; cut posterior wall and place stitch to prevent trachea from disappearing into medias­tinum (especially in obese patients); pull trachea up and perform upper resection, avoiding damage to nerve; re­move entire tumor and take specimen for frozen sections; examine endotracheal tube again, remove it to pull specimen out, then reinsert; perform anastomosis; perform laryngeal drop by cutting muscles attached to hyoid cartilage; do posterior anastomosis first, using interrupted sutures, then anterior anastomosis; place stitch be­tween chest and chin (so neck bent and trachea and anastomosis not extended)

Management of esophagus: usually sufficient to peel tumor off esophageal mucosa and sacrifice musculature; rarely necessary to perform esophagectomy, unless tumor invades esophagus or trachea; rarely necessary to resect carotid Management of neck: after total thyroidectomy and RAI therapy, surgical intervention in paratracheal area (eg, when small positive lymph node found) may carry more risk than disease itself; radical neck surgery does not help patients, but availability of new diagnostic methods has led to increased rate of repeat neck dissections

External radiation therapy: rarely used for well-differentiated papillary cancer; used primarily for older patients and those with gross residual tumor, or poor histology; histology report critical to determine management of thy­roid cancer

Management of airway: cricothyrotomy preferable to tracheostomy in patients with anaplastic thyroid cancer and airway distress

Imaging: PET useful for following patients with elevated thyroglobulin; patients with positive PET have poor sur­vival, compared to those with negative PET; survival poor if >10 lesions detected by PET; survival good if <2 le­sions detected by PET; in small study, standard uptake value >13 predicted poor survival

Future developments: genetic analysis  —  1q21 (MUC1) gene and BRAF mutation under study, but better tumor markers needed; targeted therapies under development

Malpractice in thyroid surgery: most of 30 malpractice suits analyzed involved patients who had poor outcomes (eg, respiratory event; patient with hematoma who could not be intubated)

Complications: experienced surgeons (>30 surgeries per year) have fewest complications; injury to nerve in tracheo­esophageal groove generally occurs in any of 3 sites (near Berry’s ligament most common site because of traction or attempts to control bleeding); superior laryngeal most important nerve during thyroid surgery

Voice changes: acoustic analysis of voice often changes after thyroid surgery

Postthyroidectomy central compartment syndrome: scarring and fibrosis may cause discomfort in neck or sensa­tion of choking in 5% to 10% of patients

Papillary Microcarcinoma

Douglas S. Ross, MD, Associate Professor of Medicine, Harvard Medical School, and Co-Director, Thyroid As­sociates, Massachusetts General Hospital, Boston

Background: World Health Organization (WHO) defines microcarcinoma as papillary carcinoma £10 mm in diame­ter

Prevalence: 0.5% to 13% prevalence of micropapillary carcinoma (MPC) found by autopsy in United States; 36% prevalence in Finland; in Spain, prevalence of papillary thyroid carcinoma (PTC) 5.3% using routine methods at autopsy but 22% after more careful analysis; incidence of PTC independent of age; rate of incidental findings of MPC during thyroidectomy ranges from 2% to 24%; National Cancer Institute reported »23,600 new cases of all thyroid cancers per year, »1460 deaths per year, and observed prevalence of »327,000

Increase in prevalence: incidence of PTC has increased because of high-resolution ultrasonography (US), but death rate has not; in Hong Kong, MPC represented 5% of thyroid cancer specimens between 1960 and 1980; by 2000, MPC represented 21.7%; in 2006, Universities of Wisconsin and Ferrara (Italy) reported MPC represented >40% of thyroid cancer specimens

Natural history: <2% of MPC seen clinically, suggesting tumors indolent

Clinical Trial Results

Observational trial: 211 patients with MPC followed by US for mean of 4 yr; found >60% of tumors remained un­changed in size, 12% to 13% regressed, and 25% grew; 9% grew to >10 mm (some of these patients had surgery, as did those who developed lateral nodes); comparison of patients with initial vs late surgery showed no difference in rates of nodal metastasis, multifocality, or distant metastases; results support argument against performing biopsy on small thyroid nodules (<10 mm)

Mayo Clinic trial: 535 patients with papillary carcinomas followed for 17.5 yr; 13% incidental MPCs; 20% had mul­tifocality, 10% bilateral, 2% extrathyroidal, 33% had nodal metastases; few patients had distant metastases; only 2 patients died (both had nodal involvement, and 1 had lung metastases); recurrence rates  —  nodal rates stable after 10 yr, but local recurrence increased up to 30 yr; rates higher if nodes positive initially or if patient had lobectomy rather than bilateral (subtotal or total) surgery

French study: included patients with small follicular cancers; long follow-up; 67% incidental cancers; higher inci­dence of multifocality but similar incidence of bilateral cancer; 15% extrathyroidal cancer; observed high rates of nodal metastases (43%); distant metastases (2.8%), including 6 PTCs; found lower rates of nodal and local recur­rence; recurrence more likely in multifocal disease and in patients with lobectomy only; no benefit from RAI after surgery

Japanese study: large number of patients (some with follicular cancer) and long follow-up; most patients had inci­dental MPCs; lower rates of nodal metastases; 3.6% rate of nodes with capsular invasion, and 5% of these palpable; low mortality rates; 1.8% overall rate of recurrence

Hong Kong study: 203 patients followed for 8 yr; nodal metastases and multifocality associated with increased risk for recurrence; study demonstrated benefit of RAI for MPC, but result derived from small number of patients; larger tumors (>5 mm) had higher rates of extrathyroidal extension, but no difference in rates of nodal and distant metastases, multifocality, and nodal or local recurrence

National Thyroid Cancer Treatment Cooperative Study Group: prospectively enrolled 710 patients with MPC; when patients with extrathyroidal extension and distant metastases excluded, 611 patients remained free of disease after initial therapy at average follow-up of 4 yr; 6.2% overall rate of recurrence (2.8% in thyroid bed, 2.3% in nodes, 2 mediastinal, and 1 distant recurrence); extent of thyroidectomy  —  patients with MPC who received near-to­tal or total thyroidectomy had similar prognoses, whether disease multifocal or unifocal; patients who had less than near-total thyroidectomy and multifocal disease had higher rate of recurrence; results support argument for per­forming at least near-total thyroidectomy in patients with multifocal disease; no benefit observed for RAI in pa­tients with multifocal MPC; nodal status  —  patients with node-positive disease had higher rate of recurrence, regardless of treatment with RAI

Summary: wide range in proportion of incidental tumors among MPCs; multifocality occurred in »33%, bilateral disease in »15%, extrathyroidal disease in 2% to 15%, nodal metastases in »33%, and distant metastases in 0.2% to 0.4%; nodal recurrence occurred in 2.5% to 5%, local recurrence in 1% to 4%; death extremely uncommon

Treatment: surgery  —  study of 414 patients who received therapeutic node dissection if nodes palpable, prophylactic node dissection otherwise, and no node dissection if tumors discovered incidentally; low rates of recurrence found, with no significant difference among treatments; RAI  —  studies show no benefit in stage 1 MPC disease, if tumor <1 cm, or in patients at low risk; indicated in patients with stage 2 through 4 MPCs; in stage 2 (distant metastases) if patient <45 yr of age; stages 3 (nodal metastases) and 4 if patient >45 yr of age; recommendations  —  total thy­roidectomy; therapeutic node dissection; completion thyroidectomy after lobectomy for stages 2 to 4; RIA for all patients with stage 4; consider RIA for stages 2 and 3; RIA for stage 1 remains controversial

Suggested Reading

Adjadj E et al: Germ-line DNA polymorphisms and susceptibility to differentiated thyroid cancer. Lancet Oncol 10:181, 2009; Arora N et al: Papillary thyroid carcinoma and microcarcinoma: is there a need to distinguish the two? Thyroid 19:473, 2009; Arora N et al: Extrathyroidal extension is not all equal: Implications of macroscopic versus microscopic extent in papillary thyroid carci­noma. Surgery 144:942, 2009; Chisholm EF et al: Systematic review and meta-analysis of the adverse effects of thyroidectomy combined with central neck dissection as compared with thyroidectomy alone. Laryngoscope 119:1135, 2009; Davidson BJ et al: Adopting the operating microscope in thyroid surgery: Safety, efficiency, and ergonomics. Head Neck June 17, 2009 [Epub ahead of print]; Foroulis CN et al: Primary intrathoracic goiter: a rare and potentially serious entity. Thyroid 19:213, 2009; Grodski S, Del­bridge L: An update on papillary microcarcinoma. Curr Opin Oncol 21:1, 2009; Katz SC, Shaha A: PET-associated incidental neo­plasms of the thyroid. J Am Coll Surg 207:259, 2008; Knauf JA, Fagin JA: Role of MAPK pathway oncoproteins in thyroid cancer pathogenesis and as drug targets. Curr Opin Cell Biol 21:296, 2009; Lin JD et al: High recurrent Rate of Multicentric Papillary Thy­roid Carcinoma. Ann Surg Oncol June 16, 2009 {Epub ahead of print]; Mehanna HM et al: Investigating the thyroid nodule. BMJ 338:b733, 2009; Mercante G et al: Prognostic Factors Affecting Neck Lymph Node Recurrence and Distant Metastasis in Papillary Microcarcinoma of the Thyroid: Results of a Study in 445 Patients. Thyroid Apr 6, 2009 [Epub ahead of print]; Orlov S et al: Influ­ence of age and primary tumor size on the risk for residual/recurrent well-differentiated thyroid carcinoma. Head Neck 31:782, 2009; Price DL et al: Invasive thyroid cancer: management of the trachea and esophagus. Otolaryngol Clin North Am 41:1155, 2008; Rosenbaum MA, McHenry CR: Contemporary management of papillary carcinoma of the thyroid gland. Expert Reve Anticancer Ther 9:317, 2009;Rotstein L: The role of lymphadenectomy in the management of papillary carcinoma of the thyroid. J Surg Oncol 99:186, 2009; Shaw GY, Pierce E: Malpractice litigation involving iatrogenic surgical vocal fold paralysis: a closed-claims review with recommendations for prevention and management. Ann Otol Rhinol Laryngol 118:6, 2009; Smallridge RC et al: Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies. Endocr Relat Cancer 16:17, 2009; Stang MT, Carty SE: Recent de­velopments in predicting thyroid malignancy. Curr Opin Oncol 21:11, 2009; Xing M et al: BRAF mutation testing of thyroid fine-needle aspiration biopsy specimens for preoperative risk stratification in papillary thyroid cancer. J Clin Oncol 27:2977, 2009.