Are you sure the patient has a thyroid nodule?
Thyroid nodules are common and most often benign. However, 8-15% of all nodules can prove to be cancerous. There are ~50,000 new cases of thyroid cancer annually in the United States. In most low-risk individuals, thyroid nodules become clinically relevant when their diameter exceeds 1cm. Because of this, nodules smaller than 1cm are most often followed conservatively with periodic monitoring, unless either of the following high risk factors are present: head & neck exposure to ionizing radiation before age 16years; a family history of thyroid carcinoma in a 1st degree relative.
Thyroid nodules can be solid (or cellular), cystic (fluid filled), or a combination of both. Purely cystic lesions carry a much lower risk of malignancy, and a more conservative approach is usually warranted. Some have described the use of sterile ethanol injection into pure cysts to provide definitive sclerosis of the problem, though this is rarely performed. A cystic lesion can also represent a parathyroid adenoma when located in the posterior portion of the gland.
Most thyroid nodules >1cm are asymptomatic. This remains true even when nodules are as large as 3-4cm. Thyroid nodules are often detected incidentally during a physical examination or during an imaging test (such as ultrasound, computer assisted tomographic scan (CT), or magnetic resonance imaging (MRI)) performed for another indication, including imaging of the carotid arteries, cervical/thoracic spine, and chest. When symptoms are present, however (e.g. anterior neck discomfort, hoarseness of voice, or neck tightness), they should be taken seriously, as the risk of malignancy is increased.
A painless thyroid mass which is mobile with swallowing is the most common physical examination finding. More than one thyroid nodule can often be palpated. Rarely, voice hoarseness, fixation of the nodule to surrounding tissue, and/or a firm, immobile mass is palpated. When these signs are present, they increase concern that a thyroid nodule will prove to be malignant.
Key laboratory findings
Most thyroid nodules do not affect thyroid function or cause abnormal laboratory findings. However, a serum TSH should be obtained in all affected patients, as 5-10% of thyroid nodules can autonomously produce thyroid hormone, resulting in a suppressed serum TSH and often slight elevations in serum free T4 and/or total T3 concentrations. These are often called toxic (or “hot”) nodules and are almost always benign. Separately, 2 retrospective analyses have suggested that slight elevations or values in the upper range in serum TSH may be more likely to be associated with thyroid cancer than values in the mid or low-normal range.
What else could the patient have?
Thyroid nodule palpation is insensitive and nonspecific. Therefore, a patient with signs and symptoms of a possible thyroid nodule could have another local problem. For example, some patients thought to have a thyroid nodule on examination prove to have asymmetric, though otherwise normal, thyroid tissue. Thyroid ultrasound is the most sensitive means of imaging the thyroid and should be performed whenever a nodule is suspected. Hashimoto’s disease (chronic lymphocytic thyroiditis) can also cause thyroid gland asymmetry and enlargement and therefore mimic a nodule. Lymph nodes may also present as a neck mass. Unlike thyroid nodules, however, lymph nodes do not move upwards with swallowing. A midline mass superior to the thyroid or cricoid cartilage may represent a thyroglossal duct cyst. Thyroglossal duct cysts are uniformly midline in the neck and move upwards with swallowing or tongue protrusion.
Key laboratory and imaging tests
Serum TSH should be assessed in all patients with a solitary nodule or multiple nodules larger than 1cm in diameter. This is because some nodules (5-10%) can produce excess thyroid hormone. Such nodules may cause hyperthyroidism (which requires treatment), but are highly likely to be non-malignant. Therefore a patient with a suppressed TSH and a thyroid nodule >1cm should have measurement of circulating thyroid hormones and a radionuclide (I123) thyroid scan.
Serum calcitonin has been postulated as a useful adjunctive diagnostic marker for patients with thyroid nodules. When significantly elevated, this finding signals a high risk of medullary thyroid carcinoma. Prospective, non-randomized trials have demonstrated the utility of serum calcitonin measurement in European populations. In the United States, however, most physicians have found limited usefulness to such an approach, including the cost of the assay.
Ultrasound of the thyroid and anterior neck should be performed in all patients with a suspected or known thyroid nodule >1cm. Ultrasound is the optimal imaging technique for thyroid assessment (Figure 1) and provides precise measurement of size, as well as assessment of certain sonographic features which may help predict benign or malignant disease. These features include: solid vs. cystic content, the presence of microcalcifications, excess vascularity, the presence of irregular nodule borders, and/or marked hypoechogenicity of the nodular parenchyma (compared to normal thyroid tissue).
Other tests that may prove helpful diagnostically
In a euthyroid patient, ultrasound-guided fine needle aspiration (FNA) is generally recommended for any thyroid nodule larger than 1cm in diameter (Figure 2). Thyroid nodule FNA is a low-risk, minimally invasive procedure that is performed in an ambulatory setting and does not require general anesthesia. Samples obtained from FNA are analyzed for their cytologic appearance and cellular characteristics. This has proven valuable because ~60-70% of thyroid nodule aspirates will demonstrate benign cytology. Benign cytology is highly predictive and confirms the absence of malignancy. Such thyroid nodules can then be followed conservatively, perhaps with occasional ultrasounds, without need for other intervention or treatment. In contrast, 5-8% of thyroid nodule aspirates will demonstrate cytology positive for papillary carcinoma.
Approximately 20-25% of thyroid nodule aspirates will have indeterminate cytology. Such samples are sufficient in quantity, but demonstrate cellular abnormalities that raise suspicion of malignancy which are non-diagnostic. Traditionally, patients with such nodules are recommended for surgical resection and histopathologic assessment. More recently, however, repeat FNA can be performed and the sample sent for molecular analysis. Single gene mutations, when present, can signal a high likelihood of cancer. Alternatively, a gene expression classifier called Afirma can be used to signal the possibility that such cytologically indeterminate aspirates have a very low risk of being malignant.
Management and treatment of the disease
Most thyroid nodules can be evaluated in a non-emergent fashion. Rarely, a thyroid nodule may rapidly expand. Most often, this signals hemorrhage into a cystic nodule, which is a benign process that will self-resolve. Ultrasound examination can confirm this diagnosis. In very rare circumstances, rapid growth can signal the presence of an aggressive malignancy.
As previously mentioned, thyroid nodule FNA should be considered for all euthyroid patients with ultrasound-confirmed thyroid nodules larger than 1cm. A non-diagnostic FNA should be repeated. When FNA cytology is adequate and “benign”, most nodules are followed conservatively without further treatment. Followup and repeat ultrasound is often recommended 1 year later to monitor for growth. An exception to this approach applies to large thyroid nodules (>4cm). In a euthyroid patient, large thyroid nodules should be monitored more closely. Consideration should be given to surgical resection, even if they are cytologically benign, as structural problems can occur with continued growth, including tracheal deviation and esophageal compression. Some studies also suggest an increased risk of false negative aspirates in such nodules.
Thyroid nodule cytology that is ‘positive for papillary carcinoma’ signals malignancy with high reliability (>97%). These patients should be advised to pursue surgical resection of the malignant nodule and remaining thyroid tissue. Most often, a total or near-total thyroidectomy is recommended.
Indeterminate aspiration cytology is often labeled as one of three following categories: “suspicious for malignancy”; “suspicious for a follicular (or Hurthle cell) neoplasm”; or “atypical cells (or follicular lesion) of undetermined significance”. These categories generally impart a malignant risk of 60-70%, 20-35%, and 10-20%, respectively. Consideration should be given to surgical resection in such cases. Surgical removal allows for complete histologic diagnosis and is therapeutic for malignant lesions.
Recently, however, cytologically indeterminate nodules have also been analyzed for molecular markers in the hope that such markers may predict benign or malignant disease with greater accuracy pre-operatively. This may therefore modify subsequent care recommendations. Some of these molecular markers have proven useful, and can be readily performed on a repeat aspiration sample. Molecular markers with high positive predictive value include BRAF, PAX8:PPAR-gamma, and H-RAS, N-RAS, and K-RAS. In contrast, the Afirma gene expression classifier can also be performed on repeat aspirations and demonstrates a high negative predictive value. When considering surgery, it is therefore also reasonable to consider repeating the thyroid nodule FNA on cytologically indeterminate nodules, with the goal of performing molecular analysis and/or repeating the cytology.
There is no role for suppressive levothyroxine therapy in the treatment of thyroid nodules. This therapy increases the risk of osteoporosis and atrial fibrillation while having a minimal effect on inhibiting thyroid nodule growth.
Co-existing illness should be taken into consideration when providing patients with clinical care recommendations. For most patients with well-differentiated thyroid cancer, the prognosis remains excellent. Therefore, a conservative approach to nodule management (which may include recommending against surgery) can be reasonable when compared to patients with high operative risk and/or concurrent illnesses; multiple studies in these patients confirm a 2-10% risk of permanent operative morbidity.
If continued growth of a cytologically benign thyroid nodule is noted, repeat FNA should be performed. Even if the repeat FNA is benign on repeat aspiration, consideration should be given for surgical resection.
What’s the Evidence?/References
Frates, MC, Benson, CB, Doubilet, PM. “Prevalence and distribution of carcinoma in patients with solitary and multiple thyroid nodules on sonography”. J Clin Endocrinol Metab. vol. 91. 2006. pp. 3411(This study demonstrates that per patient malignant risk is similar whether one or more than one nodules are present in the gland, and supports the recommendation that all nodules over 1cm be considered for fine needle aspiration.)
Gharib, H, Goellner, JR. “Fine-needle aspiration of the Thyroid: An Appraisal”. Ann Int Med. vol. 118. 1993. pp. 282(This seminal article first demonstrated the ability of thyroid nodule FNA to reduce the proportion of unnecessary surgery.)
Alexander, EK, Heering, JP, Benson, CB. “Assessment of Nondiagnostic Fine Needle Aspirations of Thyroid Nodules”. J Clin Endocrinol Metab. vol. 87. 2002. pp. 4924(This study confirms that most non-diagnostic aspirates are related to cystic content. Repeat FNA is diagnostic up to 50% of the time.)
Cooper, DS, Doherty, GM, Haugen, BR. “Revised Management guidelines for patients with thyroid nodules and differentiated thyroid cancer”. Thyroid. vol. 19. 2009. pp. 1167(These guidelines outline care recommendations based on available literature.)
Marqusee, E, Benson, CB, Frates, MC. “Usefulness of Ultrasonography in the management of Nodular Thyroid Disease”. Ann Int Med. vol. 133. 2000. pp. 696(This study demonstrates the power of ultrasound to impact the clinical decision making of patients with thyroid nodules.)
Nikiforov, YE, Ohori, NP, Hodak, SP. “Impact of Mutational Testing on the Diagnosis and Management of Patients with Cytologically Indeterminate Thyroid Nodules: A Prospective Analysis of 1056 FNA Samples”. J Clin Endocrinol Metab. vol. 96. 2011. pp. 1945(This study shows the utility of testing aspiration samples for molecular markers.)
Alexander, EK, Kennedy, GC, Baloch, ZW, Cibas, ES, Chudova, D, Diggans, J, Friedman, L, Kloos, RT, LiVolsi, VA, Mandel, SJ, Raab, SS, Rosai, J, Steward, DL, Walsh, PS, Wilde, JI, Zeiger, MA, Lanman, RB, Haugen, BR. “Preoperative Diagnosis of Benign Thyroid Nodules with Indeterminate Cytology”. N Eng J Med. June 25, 2012. (This study demonstrated the power of a multigene classifier to assess indeterminate thyroid nodules.)
Yassa, L, Cibas, ES, Benson, CB, Frates, MC, Doubilet, PM, Gawande, AA, Moore, FD, Kim, BW, Nose, V, Marqusee, E, Larsen, PR, Alexander, EK. “Long-term assessment of a multidisciplinary approach to thyroid nodule diagnostic evaluation”. Cancer Cytopathol. vol. 111. 2007. pp. 508(This large case series provides excellent data on expected outcomes and distributions from a large referral practice.)
Cibas, ES, Ali, SZ. “The Bethesda system for reporting thyroid cytopathology”. Thyroid. vol. 19. 2009. pp. 1159-65. (This article provides expert consensus for thyroid FNA cytology terminology and reporting.)
Moon, WJ, Jung, SL, Lee, JH, Na, DG, Baek, JH, Lee, YH, Kim, J, Kim, HS, Byun, JS, Lee, DH. “Benign and Malignant thyroid nodules: US differentiation – multicenter retrospective study”. Radiology.. vol. 247. 2008. pp. 602-4. (This study demonstrates the utility of sonographic criteria to predict benign or malignant thyroid nodules.)
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