Thyroid Nodules and Thyroid Cancer

Thyroid Cancer

1. Incidence
• most common endocrine malignancy
• ~ 53,000 new cases/ year, with 2000 deaths
• incidence has been increasing at a higher rate than any other cancer in the U.S.


2. Pathogenesis
1. Ionizing Radiation
• only clear environmental factor associated with thyroid cancer
• patients who received external radiation for Hodgkin’s disease have a 30% - 35% chance of developing a thyroid nodule and cancer
• risk is much greater for papillary cancer than follicular cancer


2. Genetic Mutations
• specific mutations of the RET protooncogene, which encodes for a tyrosine kinase receptor, have been recognized in papillary cancer
• different, heritable, autosomal dominant mutations of a different part of the RET gene cause medullary cancer (MTC) in the familial MTC syndrome and MEN-II syndromes
• p53 mutations are associated with radiation exposure


3. Clinical Presentation and Diagnosis
• most thyroid cancers are asymptomatic, and the patients are euthyroid
• identified by observation or palpation of a thyroid nodule
• less common presentations include compressive symptoms such as difficulty swallowing or breathing, hoarseness, and enlarged cervical lymph nodes
• diagnosis is made by FNA
• heritable MTC may be diagnosed in at-risk patients before becoming clinically evident by genetic or biochemical testing


4. Papillary Cancer
1. Epidemiology
• accounts for 70% - 80% of thyroid cancers
• most common thyroid cancer in people exposed to ionizing radiation (85 - 90%)
• 2.5:1 female-to-male ratio
• mean age at presentation is 30 to 50 years
• 95% 10-year survival rate


2. Pathology
• may have a pure papillary pattern or a mixed pattern (papillary/follicular features)
• cells contain characteristic intranuclear inclusions (Orphan Annie nuclei)
• psammoma bodies (collections of necrotic, calcified cells) may also be present
• multicentricity is common
• may be definitively diagnosed by FNA


3. Clinical Manifestations
• metastasizes through lymphatics to the jugular and paratracheal nodes
• 40% of patients may have lymph node involvement at the time of diagnosis
• unlike most malignancies, the presence of lymph node metastases has no apparent effect on survival in patients younger than 55
• nodal involvement may be more apparent than the primary tumor (lateral aberrant thyroid)
• distant metastasis is uncommon at initial presentation
• 20% of patients ultimately develop distant disease, usually in the lungs


4. Prognostic Factors
1. Age
• most important prognostic factor for well-differentiated papillary and follicular cancers
• patients < 55 are stage I, regardless of their T and N stage; they are stage II if they have metastatic disease


2. Tumor Size
• high risk tumors are > 4 cm in size or invade into surrounding soft tissues


3. Lymph Node Metastasis
• only affects survival in patients > 55 years old


4. Distant metastasis
• patients with lung metastases have a 50% 10-year survival
• patients with brains metastases only have 50% 1-year survival


5. Surgical Treatment
1. Total Thyroidectomy
• should be used in all cases that require postoperative radioactive iodine (RAI) – tumors > 4 cm, soft tissue extension, nodal metastases
• also required if the patient has a history of head/neck radiation
• thyroglobulin becomes a useful postop marker
• local recurrence rates are very low
• redo thyroid and neck surgery are minimized
• safe operation in experienced hands


2. Thyroid Lobectomy
• reasonable option for tumors in which RAI is not planned
• most patients remain euthyroid
• lower complication rates than total thyroidectomy with equivalent oncologic outcomes
• if the final pathology demonstrates high-risk features like vascular or lymphatic invasion, then completion thyroidectomy will be required


3. Management of the Lymph Nodes
• patients must undergo a complete thyroid ultrasound exam of the central and lateral neck before resection
• FNA biopsy of suspicious nodes should be done prior to surgery


1. Central Neck Dissection
• should be performed if pathologic nodes are present
• some surgeons recommend routine prophylactic central neck dissection for high risk tumors
• extent of the dissection is from the carotid arteries laterally, hyoid bone superiorly, and the upper mediastinum inferiorly



2. Lateral Neck Dissection
• prophylactic node dissection should not be done
• biopsy-proven positive nodes require a therapeutic node dissection (levels II, III, IV)
• isolated resection of positive nodes (‘berry picking’) should not be done



4. Management of Occult Thyroid Cancer
• intrathyroidal cancers < 1.0 cm
• often found incidentally in thyroid lobes removed for other reasons
• general agreement that thyroid lobectomy is adequate treatment


6. Postoperative Management
1. Thyroid Hormone Replacement
• patients should be placed on supraphysiologic doses of thyroxine, even if they underwent only a partial thyroidectomy
• thyroxine suppresses TSH, reducing the growth stimulus for any remaining thyroid cancer cells
• TSH suppression reduces tumor recurrence rates
• recommended level of TSH suppression is determined by the risk level of the primary tumor


2. Radioiodine Therapy
• not necessary for low risk cancers
• all other patients should have radioiodine ablation of any residual thyroid tissue
• radiodine scanning is also used to detect metastatic disease and ablative doses may be used to treat metastases
• TSH levels must be high to have active uptake of RAI – thyroxine must be stopped for 3 to 4 weeks prior to RAI therapy


3. Thyroglobulin Measurement
• useful postop tumor marker in patients who have undergone a total thyroidectomy


5. Follicular Carcinoma
1. Epidemiology
• 10% - 15% of thyroid malignancies
• 3:1 female-to-male ratio
• average age at presentation is 50 years
• more frequent in iodine deficient areas
• not strongly associated with radiation exposure


2. Pathology
• cannot be diagnosed by FNA
• diagnosis requires vascular, capsular, or lymphatic invasion
• frozen section is not reliable in distinguishing benign from malignant lesions


3. Clinical Manifestations
• metastasizes hematogenously to the lung and bone, and occasionally to the brain
• lymph node metastasis occurs in < 10%


4. Surgical Strategy
• definitive preoperative diagnosis is usually not possible and frozen section is unreliable
• if gross local invasion or capsular invasion is present, many surgeons will proceed with total thyroidectomy
• if the lesion is encapsulated and less than 4 cm, then the operation is limited to a hemithyroidectomy since only 15 to 20% of these will prove to be malignant
• if permanent histology demonstrates a follicular cancer, then a decision will then have to be made about completion thyroidectomy
• if the lesion is encapsulated and greater than 4 cm, since ~ 80% of these prove to be malignant, many surgeons will perform a total or near-total thyroidectomy
• no advantage to prophylactic node dissections
• pathologic nodes will require a central or lateral node dissection


6. Hurthle Cell Carcinoma
1. Epidemiology
• 3% of all thyroid malignancies
• patients are older: 60 to 75


2. Pathology
• clinically distinct subgroup of follicular cancers
• derived from the oxyphilic cells of the thyroid, whose function is unknown
• 20% of Hurthle cell neoplasms are malignant
• diagnosis of cancer requires evidence of vascular or capsular invasion
• malignancy cannot be diagnosed preoperatively by FNA
• intraop frozen section is also unreliable


3. Clinical Manifestations
• differ from follicular cancers in several important respects:
• more often multifocal and bilateral
• more likely to metastasize to lymph nodes (25%)
• take up radioiodine in < 10% of cases


4. Surgical Strategy
• small, benign appearing neoplasms may be treated with unilateral lobectomy
• for tumors with gross infiltration, visible extension beyond the tumor capsule, diameter > 4 cm, or obvious lymph node metastases, then total thyroidectomy is recommended
• central compartment nodes should be removed routinely since RAI ablation is not possible
• modified neck dissection should be done for positive lateral nodes


7. Medullary Carcinoma (MTC)
1. Epidemiology
• 5% of thyroid carcinomas
• 80% are sporadic
• 20% are familial (MEN IIA, MEN IIB, familial MTC without other endocrinopathies)


2. Pathogenesis
• arises from the parafollicular, or C cells, of the thyroid
• C cells are concentrated in the superior poles laterally and this is where most medullary carcinomas develop
• C cells secrete calcitonin, which opposes the actions of parathyroid hormon
• in humans, calcitonin appears to have minimal physiologic effects


3. Clinical Manifestations
• in sporadic cases, age at presentation is usually between 50 and 60 years; in familial cases, age at presentation is much younger
• tumors may secrete a variety of peptides, including the ectopic production of ACTH (Cushing’s syndrome)
• kidney stones may occur in patients with hyperparathyroidism
• hypertension may be prominent in patients with pheochromocytoma
• tumors spread initially to local lymph nodes and later to distant sites such as the liver and lung


4. Familial Disease
1. MEN IIA
• syndrome characterized by MTC, pheochromocytoma, hyperparathyroidism
• bilateral pheochromocytomas are detectable in 50% of patients


2. MEN IIB
• MTC, pheochromocytoma, and mucosal ganglioneuromas
• patients have a characteristic facies with a thickened tongue and lips
• marfanoid features may also occur


5. Diagnosis
• made by history, physical exam, FNA of the thyroid mass, and raised calcitonin levels
• all patients should be screened for RET point mutations on chromosome 10
• all patients with MTC should be screened for pheochromocytoma by measuring 24-hour urine levels of catecholamines and metanephrines
• serum calcium should also be measured


6. Screening
• at-risk kindreds should be screened for RET mutations or serum calcitonin levels beginning in the first year of life
• prophylactic thyroidectomy is recommended for children or young adults with abnormal tests


7. Treatment
• in familial disease, pheochromocytomas should be addressed first; hyperparathyroidism can be addressed at the time of thyroidectomy
• prophylactic total thyroidectomy should be before age 1 in MEN2b, and before age 5 in MEN2a
• total thyroidectomy is standard for MTC
• central node dissection is routine
• modified neck dissection is indicated for involved lateral nodes
• because tumors are of C cell origin, radioiodine ablation and TSH suppression therapy (thyroxine) are not of value


8. Postop Management
• serum calcitonin should be monitored regularly


8. Anaplastic Carcinoma
1. Epidemiology
• 1% of thyroid cancers
• presents in the 7^th and 8^th decades of life
• arises from differentiated thyroid cancers
• highest prevalence is in areas of endemic goiter
• 100% fatal


2. Clinical Manifestations
• patients usually have a history of a long-standing goiter
• becomes rapidly enlarging and painful
• compressive symptoms are common
• tumor is hard and fixed to surrounding structures
• lymph node metastasis is usually present
• diagnosis is made by FNA


3. Treatment
• surgical resection is not possible because of extensive local invasion
• generally resistant to radioiodine or chemotherapy
• external radiation may reduce tumor volume for palliation
• palliative tumor debulking may alleviate compressive symptoms in some
• tracheostomy below the tumor may be helpful for patients with impending airway obstruction


9. Lymphoma
• 1% of thyroid malignancies
• usually non-Hodgkin’s B cell type
• usually develops in patients with Hashimoto’s thyroiditis
• diagnosis may be made by FNA, although open incisional biopsy may be required
• treatment consists of multiple agent chemotherapy and/or radiation


10. Complications of Total Thyroidectomy
1. Hypocalcemia
• to avoid devascularizing the parathyroid glands, the inferior thyroid artery should be divided close to the thyroid and not near its take off from the thyrocervical trunk
• transient hypocalcemia is common, and 80% of cases resolve within a year
• devascularized parathyroid glands should be reimplanted in the SCM muscle
• many surgeons routinely check a calcium and PTH level on the morning following surgery
• many surgeons also routinely send their patients home on oral calcium and vitamin D supplementation







2. Nerve Injury
1. Preoperative Evaluation
• quality of the voice should be assessed by the surgeon and patient preoperatively
• some surgeons routinely do mirror or flexible laryngoscopy before every thyroidectomy
• other surgeons only do laryngoscopy for high risk cases: preoperative voice changes, large goiter or tumor, bulky nodes, previous neck surgery


2. Superior Laryngeal Nerve (SLN)
• external branch of the SLN (EBSLN) is in close proximity to the superior thyroid artery
• EBSLN innervates the cricothyroid muscle
• superior thyroid artery vessels should be ligated close to the upper pole to avoid injury to the external branch of the SLN
• injury to the EBSLN results in voice fatigue, poor projection, inability to sing high notes


3. Recurrent Laryngeal Nerve (RLN)
• innervates the adductor and abductor muscles of the vocal cords
• transient hoarseness is common; permanent nerve injury is 2% to 5%
• exposure and visualization of the RLN is mandatory
• RLN is closely related to the inferior thyroid artery and runs superiorly in the tracheoesophageal groove
• the thyroid is anchored to the trachea by the ligament of Berry, and the RLN is easily injured in this area
• many thyroid surgeons use intraoperative nerve monitoring as an adjunct to visual nerve identification
• nerve monitoring is more accurate than visual inspection for identifying nerve injuries







3. Neck Hematoma
• can result in tracheal compression and airway obstruction
• surgical emergency
• bedside management includes opening the skin, platysma, and strap muscles
• endotracheal intubation is usually possible after the obstruction is relieved