Nodular thyroid disease

Overview

 * In the Framingham study, 6.4% of females and 1.5% of males between 30 and 59 years old were found to have clinically apparent thyroid nodules. These numbers, however, underestimate the prevalence of nodules. When thyroids are examined with surgery, ultrasonography or at autopsy, the true prevalence is likely 10 times this. The prevalence of thyroid nodules increases with age, female gender (~ 2:1), and irradiation exposure.
 * Among patients with a single palpable nodule, ultrasound identifies additional nodules in 20-48%.

Risk Factors

 * Risk factors for malignancy include:
 * Age 60 years
 * Male gender (2:1)
 * History of neck irradiation
 * A family history of medullary or papillary thyroid cancer or familial polyposis also increases the likelihood of malignancy. Additionally, a hypofunctioning nodule in the presence of a diffusely enlarged thyroid gland (i.e. in Grave’s disease) is also worrisome.

Types of Nodules

 * Most thyroid nodules (~90%) are benign.
 * Multinodular goiter accounts for 42-77%, 15-40% are follicular adenomas, 15-20% are cystic and only 6-17% are carcinomas.
 * Multinodular goiters can, however, contain cancer in 1.5 – 3.6% of the cases.
 * They are generally hypofunctioning, and incompletely encapsulated. Fine needle aspiration--abundant colloid and benign follicular cells.
 * Follicular adenomas are usually single lesions with well-developed fibrous capsules. They are primarily classified according to size and degree of cellularity.
 * Microfollicular adenomas are distinguished from carcinomas by their lack of capsular or vascular invasion. Therefore, the diagnosis of follicular CIS does not exist.
 * Approximately 5% of microfollicular adenomas turn out to be malignant.
 * Macrofollicular adenomas are thought not to have malignant potential.
 * Other benign nodules include Hürthle-cell adenomas (of which 5% can turn out to be malignant), and cysts.
 * Even if a nodule is malignant, differentiated thyroid cancer (papillary and follicular), account for 80% of cases, and are associated with a good prognosis.
 * Sub-clinical thyroid cancer is common, with autopsy studies revealing that 6-13% of the population has occult papillary cancer.

Physical Examination

 * Most thyroid nodules are not detected by clinicians.
 * The physical findings suggestive of malignancy include a firm, non-mobile nodule with rapid growth.
 * Unfortunately, these findings are not sensitive or specific.
 * Hard nodules can be found in chronic thyroiditis, and soft nodules in cystic papillary cancer.
 * Vocal cord paralysis and enlarged lymph nodes may also be indicative of malignancy.

Laboratory Findings

 * The thyroid stimulating hormone (TSH) is the most important test, as it can identify patients with unsuspected thyrotoxicosis. The next step would likely be a scan. Serum calcitonin should be measured when medullary carcinoma is suspected, however this is controversial and expensive.

Echocardiography or Ultrasound

 * Ultrasonography is not able to differentiate benign from malignant nodules. It can, however, determine the presence of additional nodules, the size of nodules, and the consistency (solid or cystic) of the nodules. It is most helpful in following growth of benign nodules.

Scintigraphy

 * Radionucleotide scanning is most helpful in the work-up of indeterminate FNAs. Hot nodules are almost always benign, whereas warm or cold nodules should likely be removed.
 * Alternatively, a ‘suppression scan’ can be obtained. Thyroxine is given in a dose sufficient to suppress TSH secretion and a second scan is done. Uptake will be low or undetectable in nonautonomous tissue (bad), but persist in autonomous tissue (good). If the uptake corresponds to the palpable nodule, it can be presumed benign and the patient can be followed.

Fine Needle Aspiration

 * Fine needle aspiration (FNA) should otherwise be the first step in the evaluation of a thyroid nodule, and its use has halved the number of patients undergoing surgery. It costs ~ $350 (1995) dollars, compared with $400 for an ultrasound, and $600 for a scan. The results are usually reported as benign, malignant or indeterminate (suspicious).
 * Most results (~ 70 - 80%) do not reveal malignancy (however ~ 11% are indeterminate, and ~11% are inadequate).
 * These patients can be followed clinically with ultrasound and repeat FNA in 6 months to 1 year. The rate of false negatives is ~ 1-6% and results from sampling errors or inadequate specimens (repeat biopsy is adequate in 50% of these cases).
 * Hashimoto’s thyroiditis is the most common cause of the 4-6% false positive rate.
 * ~ 20% of indeterminate biopsies turn out to be malignant (usually follicular cancer).

Acute Pharmacotherapies

 * Radioiodine (I-131) is as effective as surgery for the treatment of toxic multinodular goiter, however has a more prolonged reversal of hyperthyroidism after therapy. It has also been used for the treatment of non-toxic multinodular goiter.
 * Antithyroid drugs, such as propylthiouracil (PTU) or methimazole are not 1st line agents in treating nodular thyroid disease when overt hyperthyroidism is present. This is primarily due to the fact that this treatment would be lifelong.  These drugs are mainly used prior to surgery, as they have been shown to lower the operative risk.  Additionally, when given prior to radioiodine therapy, they have been shown to achieve a state of euthyroidism more rapidly, and decrease the exacerbations of hyperthyroidism.
 * Recent studies, however, report no significant difference between thyroxine and placebo for the treatment of benign nodules.
 * If a nodule grows, with or without replacement, surgery is indicated.

Surgery and Device Based Therapy

 * The extent of surgery is also controversial. Some surgeons advocate lobectomy and isthmectomy for papillary cancers < 2cm confined to one lobe, whereas others prefer complete thyroidectomy. Larger, multicentric or locally metastatic tumors are best managed with total thyroidectomy, regional lymph node and radical neck dissection.
 * For nontoxic multinodular goiter, bilateral subtotal thyroidectomy is the standard of care.
 * Lifelong thyroxine replacement has been shown to reduce tumor recurrence rate. The optimal range of suppression is not clear however.  If the tumor is completely removed, most authors recommend keeping the TSH ~ 0.1 ug/ml, and even lower in metastatic disease.
 * The use of thyroid hormone replacement to shrink or suppress the growth of a benign nodule is controversial. Reported effectiveness is between 0 – 68%, and it seems to work better in multinodular disease.
 * A recent study from the Annals suggests that only 10-20% of nodules shrink in response to therapy. Additionally, they report that post-op replacement therapy does not prevent recurrence, except in patients with a history of radiation therapy.  As thyroid replacement is associated with an increased risk of osteoporosis and heart disease, they do not recommend suppressive therapy.
 * For cystic lesions, FNA can be curative, whereas thyroxine replacement will usually not change the cyst at all.

Indications for Surgery

 * The indications for surgery vary widely between institutions, with rates primarily determined by the accuracy of FNA, the threshold of individual surgeons, and differing views on whether all indeterminate FNA should be removed.

Acknowledgements
The content on this page was first contributed by: David Feller-Kopman, M.D.