Evaluation and management of incidentally discovered thyroid nodules

3.1. Radiation 

Radiation to the head and neck region has been given for a variety of reasons such as acne, tuberculous lymphadenoapthy, lymphoma, tonsillar enlargement, thymic enlargement, chronic otitis media and other skin conditions, such as squamous cell carcinoma. The relationship between radiation and thyroid malignancy was reported as a Chicago endemic [10]. Radiation exposures in Chernobyl have also lead to an increase in number of thyroid malignancies. Higher doses used for cancer treatment produce cell death and are less likely to induce carcinogenesis as compared to low dose radiation. There are two large case control studies reported, one for enlarged thymus [11] and the other for tinea capitus [12]. Both show an increased incidence of benign thyroid nodules as well as thyroid carcinoma. Thyroid cancer is 18 times more common in survivors of treatment for Hodgkin's disease than in the general population [13]. A radiation dose of 2500cGy or more and male sex was an independent risk factors for thyroid nodules.

3.2. Autoimmune disease 

Patients who present with Graves disease and a nodule should be evaluated to rule out malignancy. A multicenter, retrospective review of 557 patients with Graves disease showed that 25.1% of patients had nodules; 15% of these nodules were malignant. Four patients with thyroid carcinoma had a palpable nodule with the diameter ranging from 2 to 25mm [14], [15].

4.1. Nodules 

Autonomous functioning nodules comprise 12% of all thyroid nodules [16]. The majority of these nodules are due to activating mutations in the thyroid stimulating hormone (TSH) receptor. This leads to adenylate cyclase activation in the absence of TSH [17], [18], [19]. TSH receptor gene mutations are seen in 5–80% of autonomously functioning nodules. H-RAS, K-RAS, N-RAS proto-oncogene point mutations have been seen in both follicular adenoma and carcinoma [1].

The molecular basis for most cold nodules remains unknown.

4.2. Papillary thyroid carcinoma 

There is an association of at least two transmembrane genes not usually expressed in thyroid epithelial cells; namely RET and NTKRI. Both are associated with tyrosine kinase activity. These are found in 40–80% of papillary thyroid carcinomas [20]. Rearrangement of both genes, such as exposure after radiation, leads to activation of tyrosine kinase activity and neoplastic transformation.

4.3. Follicular thyroid carcinoma 

There are no cases of familial follicular thyroid carcinoma. Thyroid transcription factor PAX8 domain binds to peroxisome proliferators-activated receptor (PPAR) γ1 in a subset of thyroid follicular carcinoma [21].

4.4. Environmental iodine 

Iodine deficiency has been known to cause thyroid nodules. The mechanism is associated with an increase in serum TSH, which in turn increases thyroid cell replication and mutations [20]. Iodized salt has been utilized to reduce the incidence of endemic goiters.

8.1. Thyroid scintigraphy 

Technetium pertechnate or iodine 123 or 131 has been used widely. I123 has a low dose of radiation (0.04cGy) and a short half-life. Technetium has a shorter scanning time and a radiation dose of 0.07cGy. When the uptake is absent, the nodule is described as “cold”; when it is equivalent to the surrounding thyroid tissue, the nodule is “warm” and if the uptake is more than the surrounding thyroid tissue, the nodule is “hot”. Eighty percent of thyroid nodules are cold with an incidence of malignancy of 20%. Ten percent of the nodules are warm with a 10% incidence of malignancy. Finally, 10% of the nodules are hot, with a 5% incidence of malignancy. Given the above values, thyroid scintigraphy is not much value in making a diagnosis of malignancy. It is useful in diagnosing autonomous toxic nodules for patients with hyperthyroidism. These nodules appear hot on the scan. The scans are also helpful in diagnosing ectopic thyroid tissue, such as lingual thyroid. Thallium-201, Sestamibi and PET scans have also been used in the evaluation of thyroid nodules.

8.2. Needle biopsy of the thyroid 

FNA is the mainstay of the initial evaluation in the management of the thyroid nodule. It has significantly reduced surgery on benign nodules; at the same time increasing the percentage of malignant diagnosis requiring surgery for thyroid nodules. The technique involves preparing smears from the thyroid nodules. Use of salicylates does not preclude doing the biopsy. FNA has reduced the number of thyroidectomies by 50%, increasing the number of malignancies in the operated specimens; thus reducing the cost by 25% as compared to surgery alone based on clinical findings [32].

There are four results from FNA: (1) malignant, (2) benign, (3) suspicious and (4) inadequate. Approximately 4% of the aspirates are malignant, 70% benign, 10% suspicious, and 17% inadequate for diagnosis [33] (Table 3). The diagnoses which can be made with some certainty are papillary carcinoma (Fig. 1), lymphoma, colloid nodule, medullary carcinoma, anaplastic carcinoma and thyroiditis.

Table 3. Fine needle aspirate of the thyroid

	Malignant
	1.Papillary 2.Follicular 3.Anaplastic 4.Metastatic carcinoma
	Suspicious
	1.Follicular neoplasm 2.Hurthle cell neoplasm 3.Lymphoma
	Benign
	1.Colloid goiter 2.Thyroiditis
	Inadequate
	1.Degenerative nodule 2.Technical

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Fig. 1. Fine needle cytology of papillary carcinoma of the thyroid showing nuclei with inclusions.

The diagnosis which by far creates a management dilemma is follicular neoplasm. This cannot distinguish follicular adenoma from carcinoma since vascular invasion and capsular invasion are a key component in the diagnosis. Follicular neoplasm includes hyperplastic nodules, follicular adenomas, follicular carcinomas, and follicular variant of papillary carcinomas [34]. Predictors of malignancy based on FNA results have been studied, but results are not encouraging. Electron microscopy, flow cytometry, immunohistochemistry and genetic markers [35] have been evaluated, but overall results are disappointing. Two markers, human bone marrow endothelial cell (HBME-1) and galectin-3 have shown promise [36]. Hurthle cell neoplasms create a similar problem where it is not easy to distinguish malignant from benign on FNA.

The technique of FNA has been well described. It consists of two–three passes with the needle, followed by preparing smears and cell blocks. Criteria to consider a specimen vary adequately among Institutions. However, commonly accepted criteria is six or more groups of 10–20 well-preserved follicular epithelial cells per group on at least two slides [36]. Suspicious cytologies should be subjected to surgery as there is a high incidence of malignancy. A hypocellular specimen is the most common cause of an inadequate specimen, contaminated with blood make interpretation difficult. A study from The Mayo Clinic reported a false negative rate of 0.7% and a false positive rate of 0% [37]. FNA is performed with ultrasound guidance for non-palpable nodules.

Tru-cut biopsy is an alternative procedure to FNA, but is rarely appropriate. This involves sampling a core of the nodule. It does carry more morbidity such as bleeding, pain, recurrent laryngeal injury and tracheal injury. In a cystic lesion or a complex lesion, needle biopsy should be aimed at the solid component of the lesion since the incidence of malignancy is similar to a solid nodule [38], [39].

8.3. Ultrasonography 

Sonography of the neck is useful in differentiating solid from cystic nodules. It is not able to distinguish benign from malignant [40]. With the help of sonography, nodules as small as 0.3cm can be diagnosed. Ultrasound characteristics which are suspicious for malignancy include irregular margin, central microcalcification, increased vascularity, hypoechogenecity and cervical adenopathy (Table 4) (Fig. 2). Ultrasound is also very useful for follow up of previously diagnosed nodules over time with serial examinations.

Table 4. Ultrasound features suggesting malignancy

	Irregular margin
	Fine calcifications
	Extraglandular extension
	Solid or hypoechogenecity

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Fig. 2. Ultrasound of the thyroid showing a solitary hypoechoic, heterogenous solid nodule. Needle aspiration (Fig. 1) showed papillary carcinoma.

10.1. Levothyroxine 

Nodules which have been evaluated with ultrasound and needle biopsy and are deemed to be benign have been treated with thyroxine. The dose is usually tailored to achieve levels of TSH below 0.3mU per liter. A recent study showed that there was no significant difference between patients in a period of 6–12 months with and without thyroxine; however, it did show that a significant number of nodules were reduced by 50% [44]. There was a higher incidence of size decrease if the levels of TSH were closer to 0.1mU per liter. Once levothyroxine was stopped, the nodules regrew. There is an increased incidence of atrial fibrillation, cardiac abnormalities and reduced bone density with such high doses of levothyroxine [45], [46], [47]. The current recommendation is to observe rather than suppress cytologically benign nodules [48].

10.2. Thyroid cysts 

The majority of thyroid cysts are benign with an incidence of malignancy from 7% to 17% [4]. Papillary carcinoma is the most common cancer associated with the cysts. Aspiration of the cyst is usually all that is necessary. Surgery should be recommended if the cyst recurs after two aspirations, bloody aspirate, palpable mass after aspiration or malignant cells in the cytology. Hemorrhage into a cyst leads to a presentation of a tender nodule and sudden increase in the size of the nodule. Sclerotherapy with ethanol has been tried to avoid recurrence of the cyst.

11.1. Surgery 

Treatment of the thyroid nodule involves a multidisciplinary team approach, which includes radiologists, cytologists and endocrine surgeons.

During the procedure, the side of the nodule is mobilized. Minimum surgery is thyroid lobectomy, isthmectomy and excision of the pyramidal lobe if present. The other lobe should be examined through the strap muscles without mobilization. The recurrent laryngeal nerve, external branch of the superior laryngeal nerve and parathyroid glands should all be preserved. Removal of the complete lobe with the nodule helps in preservation of the important structures. Frozen section is utilized selectively.

When performed by a specialist, the incidence of surgical complications is low. Hemithyroidectomy may preserve thyroid function. It also has a lower incidence of recurrent laryngeal nerve and parathyroid gland injury. After hemithyroidectomy, post-operative administration of levothyroxine is indicated only in cases of hypothyroidism [49].

There has been considerable debate between hemi-thyroidectomy and total thyroidectomy for the treatment of differentiated thyroid carcinoma. A randomized clinical trial is difficult as it would have to be a very long-term study with a large number of patients. Overall, the majority of patients with well-differentiated thyroid cancer do well, irrespective of hemithyroidectomy or total thyroidectomy. Utilizing the risk stratification, patients who fall into the low-risk category, do well with hemithyroidectomy. Patients with high-risk would require total thyroidectomy. Partial removal of the lobe or nodulectomy is to be discouraged as it has a higher incidence of local recurrence and operative morbidity.

Patients with a solitary thyroid nodule undergoing hemi-thyroidectomy with a frozen section suggesting ‘follicular neoplasm’ present a challenging problem. Invasive carcinomas diagnosed on permanent section may require completion thyroidectomy in a few days or 2–3 months later. The decision is based on the risks criteria already established which include age and sex of the patient, size of the cancer and extrathyroidal extension. Lesions larger than 4cm with a suspicious histology are more likely to be malignant and hence can be treated by total thyroidectomy. Also, prior radiation therapy can lead to multifocal disease and consideration to perform a total thyroidectomy.

Papillary microcarcinomas are being increasingly diagnosed. This is because of high-resolution ultrasound. The prevalence of occult papillary carcinoma has been reported to be 36% [50]. In a study of 162 patients with FNA diagnosis of papillary microcarcinoma who were followed without surgical intervention, 70% of the tumors did not change in size over a period of 5 years [51]. Most types of microcarcinoma may never become clinically apparent. Hence, to perform a total thyroidectomy after papillary microcarcinoma still remains controversial.

Advantages of total thyroidectomy for malignancy include a whole body survey and treatment of distant metastatic disease with Iodine 131.

11.2. Radioactive iodine 

Radioactive iodine dosimetry and ablation is used post-operatively to ablate residual thyroid cells and to look for metastatic disease. This is only possible in patients who have undergone total thyroidectomy. Post-operatively, patients are made hypothyroid for 4–6 weeks. This increases thyrotropin levels more than 25mU per liter. Clearly this state of hypothyroidism is not tolerated well by the patients. Some patients now receive T3 or recombinant TSH. After the radioactive iodine scan, patients undergo ablation of the residual thyroid cells in the neck. This is followed by another scan to document the ablation. The role of adjuvant radioactive ablation is to destroy any residual microscopic foci, to improve the value of serum Thyroglobulin as a tumor marker and to increase the sensitivity of iodine 131 scanning for metastatic disease.

11.3. External beam radiation 

Few patients are candidates for external beam radiation. These include anaplastic thyroid cancer, medullary thyroid cancer with extensive nodal, mediastinal or residual disease, high-risk differentiated thyroid cancer with invasion in the central compartment and patients with metastatic disease.

11.4. Medullary thyroid cancer 

The overall incidence of medullary thyroid cancer is 5–7% of all thyroid cancer. They can be sporadic or a part of the familial MEN syndrome. Patients should be worked up for pheochromocytoma before surgery. The operative procedure includes total thyroidectomy. Central nodal clearance and a modified neck dissection is performed for nodal involvement. Follow-up is done with calcitonin, and families should also be screened for medullary thyroid cancer with the RET protooncogene. Prophylactic thyroidectomy may be indicated in family members who are positive for the RET mutation.

11.5. Anaplastic thyroid carcinoma 

This is a very aggressive form of neoplasm. The incidence is 2–5% of all thyroid malignancies. It presents as a rapidly enlarging mass in the thyroid gland. It commonly presents in an elderly patient with compression symptoms such as hoarseness of voice and difficulty in breathing. The diagnostic work up includes FNA or tru-cut biopsy for pathology. Surgery has a limited role since at the time of presentation there is usually extra-thyroidal extension. A tracheostomy may be required for clearance of the airway. Treatment includes chemo radiation with doxorubicin. The average overall survival is 6–9 months.