3.1. Etiology

There are various possible etiologies for a non-toxic goiter including:

1. Iodine deficiency (defined as intake < 50 mcg per day). This is not uncommon in the US, as about 1 in 4 women over 40 years old may have moderate iodide deficiency.
2. Iodine excess in glands with pre-existing inflammation
3. Goitrogens are substances that can cause a goiter. Goitrogens can be divided into:
   • Drugs such as lithium (inhibits release of thyroid hormone causing hypothyroidism and secondary goiter) or amiodarone (high iodide content may cause inhibition of thyroid hormone synthesis. Amiodarone may also induce inflammatory destruction of the thyroid)
   • Foods such as the Brassica family of vegetables, soy bean and cassava
4. Dyshormonogenesis: inherited defect in the thyroid hormone biosynthetic pathway will cause a secondary (compensatory) goiter.
5. Radiation. Exposure to radiation at a young age increases risk for goiter, nodules and cancer as well as hypothyroidism. Abnormal thyroid structure and function may appear many years (10-20) after exposure to radiation.
6. Unknown. In most cases of goiter, a readily identifiable cause is not found. It is believed that genetic predisposition under the influence of unknown environmental factors may lead to formation of goiter.

3.2. Pathophysiology

The histopathology varies with the etiology and duration of the goiter. Initially, there is a uniform hyperplasia but as the disorder persists, the thyroid architecture loses its uniformity with development of areas of involution or fibrosis interspersed with areas of focal hyperplasia resulting in multiple nodules and the formation of a multinodular goiter (MNG). Many diffusely enlarged goiters are composed of multiple soft nodules which cannot be palpated individually. Accumulation of colloid may also contribute to the nodularity of the goiter. Hemorrhage or cystic degeneration of a hyperplastic nodule can result in a sudden focal increase in size of a goiter. In areas of growth, regression and hemorrhage, irregular calcifications can occur. The evolution of this multinodular stage is accompanied by the development of "hot" (hyper-functioning) and "cold" (non-functional) nodules on thyroid nuclear scan (Technicium 99m pertechnetate or I-123 radioiodine) with functional autonomy (see Figure 1).

Figure 1

Nodules within a MNG are due to a combination of monoclonal and polyclonal expansion. The natural history for goiters is a continuous accumulation of multiple autonomously functioning, or "hot" nodules leading to mild thyrotoxicosis after several decades (developing into a toxic multinodular goiter, see section on thyrotoxicosis).

3.3. Clinical Findings

Initially a small goiter is usually asymptomatic. As the goiter enlarges the patient may develop structural or functional problems:

3.4. Laboratory and Imaging Evaluation

To evaluate thyroid function (hypothyroidism or hyperthyroidism), TSH is measured. Thyroid autoantibodies (anti-Thyroid Peroxidase or anti-TPO) are often checked to determine risk for autoimmune thyroid disease. If a dominant nodule or a history of head and neck radiation is obtained, the patient should be evaluated for thyroid cancer (see below). To evaluate structure, often physical examination by an experienced thyroidologist is adequate. Occasionally, thyroid imaging, most often with an ultrasound, is done to define the size and nodularity of the goiter.

3.5. Treatment

Factors that are obviously linked with the goiter such as iodine deficiency should be treated.. If thyrotoxicosis or hypothyroidism are present, they need to be treated. Surgery is usually recommended if there is a suspicion of malignancy, local obstructive symptoms or for cosmetic reasons.

4.1. Clinical Findings

Thyroid nodules are very common. High resolution ultrasound and autopsy studies have shown that 50% of the population over 65 years old has at least one thyroid nodule. It is generally accepted that a nodule must reach a diameter of 1 cm to be detected by palpation. Therefore there are many small thyroid nodules that cannot be detected by physical exam. Palpable thyroid nodules are found in approximately 5% of the population, more common in women. About a third of patients thought to have a solitary nodule on physical exam have multiple nodules on an ultrasound consistent with a multinodular goiter. Benign thyroid nodules are more common in woman as they age, so that a solitary nodule in a child or a male should raise the suspicion of malignancy.

Clinical features that suggest carcinoma includes:

• Firm/hard nodule
• Fixation to local neck structures
• Recent and rapid growth
• Hoarseness (vocal cord involvement) but not with pain
• Unilateral adenopathy on the side of the thyroid nodule
• History of head and neck radiation

4.2. Etiology

The differential diagnosis of an apparent thyroid nodule includes a dominant or first nodule of a multinodular goiter, benign adenomas, thyroid cysts, focal thyroiditis and carcinoma. The nodules of a multinodular goiter are polyclonal and are not considered to have an increased risk of malignancy. The etiology of benign adenomas is unknown but are clearly monoclonal in origin. Thyroid adenoma may be hyperfunctioning causing thyrotoxicosis.

Approximately 5-10% of thyroid nodules contain thyroid carcinoma. Primary thyroid carcinoma are classified by whether it arises from the thyroid follicular epithelium, parafollicular or C cells or other cells (see Table 1).

Medullary thyroid carcinoma derives from the parafollicular C cells and occurs as a sporadic form (>80%) or part of a familial disorder including multiple endocrine neoplasia (MEN) type 2A and 2B. Many of the medullary thyroid carcinoma have RET-protooncogene mutations in cysteine residues close to the transmembrane region of the predicted protein product of the gene. Early screening of family members is done with a pentagastrin stimulation test with measurement of serum calcitonin levels. A positive pentagastrin test may detect C-cell hyperplasia before malignant transformation has occurred. MTC occurs in less than 0.5% of thyroid nodules and calcitonin testing is not routinely done in the initial evaluation of a thyroid nodule.

Carcinomas of thyroid follicular epithelium are composed for three main types (see Table 1): Papillary (75-85%), follicular (15-20%) and anaplastic carcinoma (~5%). Other carcinomas found in thyroid include primary thyroid lymphoma that often develops in patients with pre-existing Hashimoto's thyroiditis, carcinoma metastatic to the thyroid (breast, lung, renal cell, melanoma), and sarcoma. Although clinically significant thyroid carcinoma are uncommon with approximately 12,000 diagnosed each year, the incidental, less than 1 cm thyroid carcinomas are very common. In routine autopsy studies of subjects who die of causes unrelated to the thyroid, between 8 -12% of thyroids contained thyroid cancers.

Of patients with significant head and neck radiation with palpable thyroid nodules, approximately 1/3 will have thyroid carcinoma that is often multicentric. The nodules may not become apparent for 10-15 years after the radiation and the risk for carcinoma does not return to the levels of the normal population even > 30 years after the radiation exposure. Therefore a patient with a significant radiation risk and a solitary nodule is usually referred to surgery without further evaluation. The risk correlates with the younger age at exposure (i.e., less than 16 y.o.), female gender and radiation dose. The thyroid carcinoma seen after external beam radiation appear to be no different in type (papillary) or behavior (generally, benign with lymphatic spread to local lymph nodes). In contrast, the thyroid carcinoma being observed in the children exposed to the nuclear fall-out radiation from the Chernoybyl nuclear reactor accident has been associated with very large, bulky, papillary thyroid carcinoma that is particularly aggressive with local extension into normal tissues in less than 10 years after the accident. Oncogene analysis of the Chernobyl related papillary thyroid carcinoma but not in the sporadic papillary thyroid carcinoma has demonstrated an increase in a RET-protooncogene overexpression due to a mutation in the regulatory or promoter portion of the gene.

4.3. Laboratory and Imaging Evaluation

It is generally agreed that papillary thyroid carcinoma <<1 cm is "carcinoma in situ" and is unlikely to result in morbidity or mortality for the patient. Therefore, evaluation for carcinoma is often initiated for thyroid nodules > 1 cm in diameter or with recent growth. The evaluation of a thyroid nodule is shown in Table 2.

Laboratory tests are generally not helpful in differentiating malignant nodules from benign ones. Thyroid cancer usually is associated with a normal TSH. Generally, if the TSH is abnormal, medical treatment of the thyroid dysfunction should be performed before evaluation of the nodule for malignancy (see Table 2). Medullary thyroid carcinoma is associated with an elevated fasting calcitonin. It should be measured in patients with a thyroid nodule and a family history of MTC or MEN syndrome. Thyroglobulin can be elevated by benign and malignant thyroid disease. Thyroglobulin becomes a useful tumor marker for recurrence of differentiated thyroid cancer after removal of all normal thyroid tissue by thyroidectomy and radioactive iodine ablation therapy.

Imaging studies are not necessary in the evaluation of a nodule with a normal TSH as over 90% of all nodules appear "cold/cool" on Nuclear Medicine imaging. A hyperfunctioning "hot" nodule has very little risk for carcinoma and does not need further evaluation, but less than 5% of the nodules will be "hot". The vast majority of "hot" nodules can be identified by a suppressed TSH. If a TSH is suppressed, then nuclear imaging with I-123 is done to confirm the presence of a "hot" nodule.

Ultrasound cannot reliably differentiate between and malignant thyroid nodules. Ultrasound is very good at determining the size and number of thyroid nodules and in guiding biopsy.

The diagnostic procedure of choice to determine if a nodule contains cancer is fine needle aspiration (FNA), a relatively simple outpatient procedure. (see Table 2). The results of many published series of fine needle aspiration biopsies (FNA bx) of the thyroid show these results:

• 60-70% of biopsies are benign (macrofollicular multinodular goiter with abundant colloid, thyroiditis, subacute thyroiditis).
• 10% of biopsies contain insufficient number of cells for diagnosis.
• 15-20% of biopsies are considered indeterminate (hypercellular in a microfollicular pattern, with a variable degree of atypia). These nodules may represent either a benign follicular adenoma or a follicular carcinoma. Although follicular thyroid carcinoma cannot be detected on a FNA biopsy (it requires observing vascular and capsular invasion), the risk is as high as 10-20% in indeterminate biopsies.
• 5-10% of biopsies contain cancer.

5.1. Differentiated Thyroid Carcinoma

[95% of all thyroid cancers]

Both papillary and follicular thyroid carcinoma are slow growing. Papillary thyroid carcinoma tends to be multifocal (20%) and spreads early by lymphatics to local cervical lymph nodes. The presence of adenopathy does NOT predict an increased risk of mortality. Follicular thyroid carcinoma tends to metastasize hematogenously to distant sites and therefore is considered a more aggressive thyroid cancer. For both malignancies, distant spread is the best predictor for death (40-80% at 10 years). The general recommendation for papillary or follicular thyroid carcinoma is total thyroidectomy. All patients after a thyroidectomy should have a I-131 radioactive scan to detect any local or distant metastases that retain the ability to take up iodine. Patients with residual disease are treated as an in-patient with therapeutic doses of I-131 that have been shown to reduce recurrence rates from 25-30% to approximately 5% and decrease mortality. The overall mortality for papillary thyroid follicular thyroid carcinoma is excellent (<5%) if no distant metastases are detected. Following the I-131 ablation, patients are placed on suppressive doses of L-thyroxine such that the TSH is unmeasurable. Excess thyroid hormone reduces the growth of residual thyroid metastases. Repeat I-131 total body scanning and thyroglobulin levels are followed to detect tumor recurrence.

5.2. Medullary Thyroid Carcinoma (MTC)

[< 5% of all thyroid cancers]

After MEN II/IIA syndrome with pheochromocytoma is ruled out, the therapy for MTC is a total thyroidectomy and a central lymph node dissection (removal of all lymph nodes) because medullary thyroid carcinoma metastizes to local nodes very early. Radiation and chemotherapy have not been useful in the routine treatment of MTC. Although most metastases occur in the neck, metastases can be widespread. Nuclear medicine octreotide scans (radiolabeled somatostatin receptor analogue) have been useful in some cases to detect metastatic disease. The progression of disease can be followed by CEA and calcitonin levels. Five and 10 year survival is 80% and 60% respectively. The diarrhea and flushing that occur in ~ 1/3 of patients are difficult to treat. Agents that have worked occasionally include loperamide, diphenoxylate and the long-acting somatostatin analogue, octreotide.

5.3. Anaplastic Thyroid Carcinoma

[< 5% of all thyroid cancers]

The prognosis is generally very poor with life expectancy of less than 1 year. Total thyroidectomy should be done if clinically feasible. These tumors are so poorly differentiated that they do not take up radioactive iodine and therefore I-131 scan and therapy are not useful. Suppressive thyroid hormone therapy is not effective in reducing tumor growth. Chemotherapy with adriamycin and/or external radiation therapy are other modes of treatment but these tumors usually do not respond to these therapies.

5.4. Thyroid Lymphoma

[< 5% of all thyroid cancers]

Thyroid lymphomas are not derived from thyroid follicular cells and do not take up iodine or make thyroglobulin. Occurs almost always in patients with history of Hashimoto's thyroiditis. Treatment is determined by the stage of the disease. Surgical resection is indicated if the disease is localized only to the thyroid. If total removal is not possible, debulking will make subsequent radiation therapy more effective. Inoperable disease should be treated with combination chemotherapy that includes doxorubicin before radiation therapy. Five year survival is between 50-80%.