see also: Thyroidectomy and Thyroid Lobectomy and I131 sialadenitis (Radioiodine Sialadenitis)

see also: Thyroid nodule evaluation

and: Thyroid Hormone Replacement TSH free T4

"It is imprudent to be dogmatic in discussing the management of thyroid cancer. The literature is controversial and confusing, and support can be found for almost any modality of treatment."
--P Ward, MD 
but 
"It is helpful to have general guidelines."
--H Hoffman, MD, et al

INITIAL EVALUATION

1. History
   1. Identify symptoms of hyperthyroid or hypothyroid state.
   2. Identify symptoms related to neck mass.
      1. Pressure on adjacent structures: dysphagia/airway obstruction
      2. Hoarseness or dysphagia secondary to laryngeal paralysis
      3. Pain
   3. Identify family history of thyroid cancer
      1. Medullary carcinoma
         1. Familial medullary thyroid cancer (MTC)
         2. MEN type 2 syndrome
      2. Papillary thyroid cancer
         1. No clear familial association other than with syndromes
         2. Cowden's syndrome
         3. Gardner's syndrome
   4. Identify prior exposure to irradiation
2. Physical
   1. Laryngeal exam for vocal cord mobility
   2. Neck exam: measure size of thyroid nodule(s)
   3. Identify fixation of mass to adjacent soft tissue
   4. Palpate for nodal disease
   5. Check for and note presence of positive Chvostek's sign
   6. Identify if patient is one of the 5% of the population with normal calcium and positive Chvostek's sign (for postoperative monitoring).
3. Fine Needle Aspiration (FNA)
   1. Following a history and physical, this evaluation is usually the next step and may be used to direct the remainder of the evaluation.
   2. FNA is not necessary for all thyroid nodules. Clinical suspicion of malignancy (associated laryngeal paralysis), compression of aerodigestive system, and cosmetic disfigurement are indications for surgical treatment regardless of FNA results. Nodules greater than 3 cm in diameter are not adequately sampled by FNA and may be removed based on size criteria alone.
4. Blood Studies
   1. All cases of thyroid nodularity
      1. Do TSH and free T 4.
      2. If TSH is suppressed, then obtain T 3.
      3. There is no value in obtaining a preoperative thyroglobulin level.
   2. Medullary thyroid cancer
      1. Serum calcium (ionized calcium is more expensive, but easier to interpret)
      2. Calcitonin
      3. Consider carcinoembryonic antigen (CEA)
         1. CEA is nonspecific, but it is a marker that can be followed along with calcitonin levels.
      4. RET proto-oncogene genetic testing
         1. Testing for codons associated with Multiple Endocrine Neoplasia (MEN) 2A or MEN 2B or familial MTC
         2. 75-80% of MTC cases are sporatic mutations;  20-25% MTC are inherited and associated with MEN
         3. MEN2A is autosomal dominant and characterized by:
            1. MTC
            2. Pheochromocytoma
            3. Primary hyperparathyroidism
         4. Most common codon mutations in MEN2A are 609, 611, 618, 620 and 634
         5. If mutations are found associated with MEN syndromes, family members should be tested
      5. Pheochromocytoma work up (not necessary if RET gene analysis is negative for MEN syndromes)
         1. Plasma free metanephrines or normetanephrines
         2. 24 hour urine metanephrines and normetanephrines
5. Chest X-Ray
   1. For all cases of thyroid cancer
   2. For all cases of thyroid nodularity that are to undergo surgical treatment
6. Other
   1. Neck and chest MRI or CT if mediastinal involvement, suggestion of fixation to adjacent structures (eg, larynx), or palpable cervical adenopathy. Note: Contrast-enhanced CT may (theoretically) give a large dose of iodine that could interfere with subsequent radioactive iodine imaging and treatment. The newer contrast agents make this concern less tenable.
   2. I 123, I 131, Tc 99 thyroid scans
      1. Their general use is controversial, but we feel they are rarely helpful in a decision-making process as to whether an operation is advised for a thyroid mass suspicious for cancer.
      2. These nuclear medicine scans are beneficial in cases in which the TSH is depressed.
   3. Ultrasound Thyroid
      1. Beneficial in helping with difficult FNA (ultrasound guided FNA)
      2. Helpful as an objective measure of thyroid size if the patient chooses to forego definitive surgical therapy in favor of observation either on or off suppressive therapy
   4. Observation with medical therapy to suppression TSH stimulation
      1. We do not recommend suppression because
         1. Suppression is generally ineffective in diminishing nodule size
         2. Malignant and benign nodules may shrink on suppression
         3. Potential morbidity from the hyperthyroid state may result
      2. Others recommend treatment with T 4 to suppress serum TSH levels to less than 0.1 mIU per L for 6 to 12 months.
7. Pathological Considerations
   1. Hürthle cell neoplasms and carcinomas were formerly both treated as a carcinoma because of the difficulty in predicting clinical behavior histologically. More recently, absence of invasion (capsular or vascular) is adequate to predict a benign course; hence total thyroidectomy is not needed for Hürthle cell adenomas.
   2. Mixed papillary and follicular carcinomas are classified and treated as papillary carcinomas.
   3. Tall cell variant of papillary thyroid cancer is particularly aggressive.
8. Consultations
   1. Endocrinology consult to help with preoperative preparation and postoperative care
   2. Thoracic surgery if sternotomy is a possibility

SURGICAL TREATMENT DECISIONS

1. Lobectomy and Isthmusectomy: Indications
   1. FNA demonstrates follicular neoplasm (broadly interpreted: 20% chance carcinoma; 80% chance benign)
   2. FNA inconclusive but clinically worrisome for carcinoma (enlarging mass despite suppression; association of mass with laryngeal paralysis)
   3. Size greater than 3 cm (large sampling error with FNA); evaluate with frozen section at time of surgery
      1. If papillary or follicular carcinoma is identified
         1. remove contralateral lobe to perform total thyroidectomy.
      2. If frozen section analysis demonstrates benign disease or is inconclusive:
         1. contralateral lobe is not removed.
         2. completion thyroidectomy is performed if final review of pathology shows cancer.
   4. Anaplastic thyroid cancer
      1. Consider treatment with a tracheotomy after performing a biopsy.
      2. Occasionally anaplastic thyroid cancer may be diagnosed at an early stage to permit a meaningful resection of the entire tumor.
   5. Medullary thyroid cancer: There is no role for less than a total thyroidectomy. Patients diagnosed with MTC should have relatives screened for RET germline mutations. Patients with the MEN 2B mutation (ATA-D) should undergo prophylactic thyroidectomy prior to age 1. Those with MEN 2A mutations (ATA-C) should have prophylactic thyroidecotmy prior to age 5.
   6. Lymphoma: A conservative resection is performed to provide material adequate for diagnosis.
2. Total Thyroidectomy: Indications
   1. Papillary and follicular thyroid cancer
      1. The majority of cases receive treatment with total thyroidectomy to:
         1. Permit use of I 131 postoperatively (both for diagnostic and therapeutic purposes).
         2. Permit monitoring of serum thyroglobulin levels to assess for tumor recurrence.
      2. Exceptions
         1. Occult thyroid cancers
         2. Controversial: Strong support for less than total thyroidectomy exists for the treatment of papillary or follicular cancers less than 3 cm in size with favorable prognostic features.
   2. Anaplastic carcinoma
   3. The rare case amenable to meaningful resection may be treated with a lobectomy if this resection is sufficient to encompass the tumor. Alternatively, a more aggressive resection may be performed if the tumor is readily encompassed.
   4. Other cancers that may mimic anaplastic thyroid cancer:
   5. (1) Small cell (primary thyroid lymphoma) that is responsive to chemotherapy and XRT and does not require a thyroidectomy
   6. (2) Insular thyroid carcinoma treated with total thyroidectomy with postoperative I 131
   7. Medullary thyroid cancer
3. Extent of Cervical Lymphadenectomy
   1. Papillary and follicular thyroid cancer
      1. Central nodal clean-out (Level VI) for all papillary carcinoma
      2. Additional Selective Neck Dissection for palpable disease
      3. Sternocleidomastoid muscle and internal jugular vein preserved unless involved with cancer
      4. Predominately follicular thyroid cancer on final pathologic review may contain papillary elements and hence be considered papillary thyroid cancer
   2. Medullary thyroid cancer
      1. Sporadic
         1. Total thyroidectomy with central (Level VI) nodal dissection
         2. Ipsilateral lymphadenectomy (comprehensive) is usually indicated
         3. The presence of bilateral disease warrants bilateral dissection
      2. Familial
         1. Same as for sporadic if gross cancer identifiable intrathyroid or in nodal metastases
         2. Total thyroidectomy done without cervical lymphadenectomy only if the diagnosis is established on the basis of screening before clinical evidence of disease is apparent
   3. Anaplastic thyroid cancer
      1. Lymph node dissection is generally limited to clearance of disease around the trachea as much as is reasonable to maintain an adequate airway. Maintenance of an airway is often achieved through a tracheotomy.
      2. Occasionally total thyroidectomy with neck dissection may permit meaningful removal of disease.
   4. Lymphoma: Removal of nodal disease is performed only if necessary for staging or other diagnostic purposes.

NONSURGICAL TREATMENT

1. Papillary and follicular thyroid cancer 
   1. Thyroid replacement
      1. All patients treated for well-differentiated thyroid cancer receive long-term suppressive doses of T 4.
      2. Synthroid (T 4) is most commonly administered after total laryngectomy at a dose between 100 to 200 g per day.
      3. Clinical judgment is required to balance complete suppression of TSH with potential for negative effects of a chronically hyperthyroid state.
      4. An endocrinology consultation preoperatively is helpful to direct thyroid replacement postoperatively.
   2. Radioactive iodide scan
      1. The need for I 131 postoperative diagnostic scan (and possible ablation) is determined by risk factors and discussion at tumor board upon review of the excised specimen.
      2. For those patients to receive an I 131 scan, Cytomel (T 3) at 25 µg PO BID is administered for three of four weeks then discontinued for two or three more weeks.
      3. A low iodine diet is instituted.
      4. An I 131 scan (usually with 2 to 5 millicuries [mCi]) is done after the sixth postoperative week.
      5. The dose of I 131 is determined by amount of residual or metastatic disease demonstrated, generally between 100 to 150 mCi.
      6. Every patient receiving I 131 ablation for residual disease identified on a diagnostic scan should have at least one negative scan performed subsequently. Timing of scans varies according to the patient. In general, a follow-up scan at 6 months after initial treatment and then again in several years are broad guidelines.
   3. External beam irradiation (XRT)
      1. XRT is potentially useful for unresectable recurrences of differentiated thyroid carcinoma that have not shown response to I 131.
      2. XRT is of questionable benefit for residual thyroid cancer that has extended through lymph node or thyroid capsule into surrounding soft tissue, even when the lesion does concentrate iodine.
2. Medullary thyroid cancer  
   1. Surgical treatment remains the mainstay of treatment for medullary thyroid cancer.
3. Anaplastic thyroid cancer  
   1. The focus is on supportive care
      1. Maintain an adequate airway (tracheotomy when necessary)
      2. Maintain adequate pain control and nutrition
   2. External beam irradiation
      1. To the thyroid bed and adjacent neck are offered as elective treatment.
      2. Palliative irradiation to distant metastases may be offered.
   3. Chemotherapy for palliation in selected cases may be offered.
4. Thyroid Lymphoma
   1. The surgical management of lymphoma is generally restricted to establishing a diagnosis through an adequate biopsy. Care of these patients should be managed by an experienced team, usually led by a medical oncologist.

LONG-TERM MANAGEMENT

1. Papillary and follicular thyroid cancer 
   1. Risk
      1. There are several ways to quantify risk from well-differentiated thyroid cancer. One is termed the AMES scale. This is based on the Age of the patient, the presence of Metastases, the Extent of the primary tumor, and the Size of the primary tumor.
      2. Through this simplified scheme, patients may be segregated into a low-risk or a high-risk group. The low-risk group includes 89% of patients, 1.8% mortality.
         1. Women younger than 51 years and men younger than 41 years without evidence of distant metastases
         2. Older patients with tumors less than 5 cm and intrathyroidal (papillary) or lack of gross capsular invasion (follicular) and without distant metastases
      3. High-risk group includes 11% of patients, 46% mortality; those not included in "low-risk group."
      4. Employ more intense follow-up for high risk and less intense for low risk.
   2. Suppression with L-Thyroxine (Synthroid)
      1. The great majority of patients who have been treated with total (or subtotal) thyroidectomy will require replacement therapy. Nearly all patients with well-differentiated thyroid cancer should be treated with suppression. The degree of TSH suppression obtained in each individual patient requires clinical judgment based on risk of recurrence versus risk of complications of aggressive suppression (arrhythmia, angina, osteoporosis).
      2. Follow TSH and free T 4 level. Observe a seven-week interval (minimal interval) between adjusting dose and evaluation with blood studies to permit equilibration.
   3. Thyroglobulin measurements
      1. No role for serum thyroglobulin in initial evaluation. This measurement is useful only after ablation of thyroid theoretically rendering thyroglobulin level undetectable.
      2. Sensitivity of this evaluation is greatest if levels are drawn prior to I 131 imaging or ablation when TSH is maximally elevated.
      3. Interpretation of levels is done in the context of an assay for antithyroglobulin antibodies.
   4. Yearly chest x-ray
   5. Consider more advanced imaging of the neck if high risk or suspicious for recurrence.
      1. Ultrasound (with or without FNA)
      2. CT or MRI
   6. Follow-up is lifelong.
2. Medullary thyroid cancer 
   1. Thyroid replacement (not suppression) with L-thyroxine (Synthroid) to euthyroid state
   2. Follow calcitonin
      1. Non-stimulated
      2. Stimulated calcitonin (with pentagastrin or calcium) may detect low level disease in background of normal non-stimulated calcitonin
         1. current recommendation is to not obtain stimulated calcitonin 
   3. Follow CEA
   4. Yearly chest x-ray
   5. Consider imaging studies: ultrasound/MRI/CT if serologic evidence for persistence or recurrence.
      1. Usually defined as a rising caclitonin of >20-100% baseline
   6. Anaplastic thyroid cancer Identify opportunity for interventions to improve quality of life
3. Lymphoma
   1. Directed by medical oncologist

CONTROVERSY

1. There is published support (Ward 1986) for considering use of systemic steroids post-operatively to help restore recurrent laryngeal nerve function if a paralysis is identified after thyroidectomy.

REFERENCES

Blair E, Goepfert H. Thyroid nodule. In: Gates GA, ed. Current Therapy in Otolaryngology Head and Neck Surgery. 6th ed. St. Louis, Mo: CV Mosby; 1998: 302-307.

Cady B, Rossi RL. Surgery of the Thyroid and Parathyroid Glands. 3rd ed. Philadelphia, Pa: WB Saunders Co; 1991.

Falk SA. Thyroid Disease. 2nd ed. Philadelphia, Pa: Lippincott-Raven; 1997.

Grebe SKG, Hay ID. Clinical evaluation of thyroid tumors. In: Thawley SE, Panje WR, eds. Comprehensive Management of Head and Neck Tumors. Philadelphia, Pa: WB Saunders Co; 1999.

Hoffman HT, et al. Iowa Head and Neck Surgical Protocols. Head and Neck Cancer and Reconstructive Surgery Course 1992.

Hoffman HT, Rojeski M, Funk GF, McCulloch TM. Solitary thyroid nodule. In: Gates' Current Therapy. 5th ed. St. Louis, Mo: CV Mosby; 1994.

Kloos RT et al. Medullary Thyroid Cancer: Mangement Guidelines of the American Thyroid Associated, Thyroid 2009;  19 (6) 565-612

Ward PH. The surgical treatment of thyroid cancer. Arch Otolaryngol Head Neck Surg. 1986;112:1204-1206.