Goiter, Nontoxic Multinodular

Definition and Etiology Top

Nontoxic multinodular goiter (MNG) is a disease of the thyroid gland characterized by the presence of thyroid nodules (dominant focal structural lesions) without biochemical abnormalities of the thyroid gland. The etiology of nontoxic MNG is multifactorial, with the important factors including, among others, iodine deficiency (initially manifesting as a simple goiter), genetic predisposition, goitrogens, exposure to ionizing radiation, and history of thyroiditis.

A goiter is defined as an enlarged thyroid gland. A precise cutoff value for the size on physical examination or the volume measured by ultrasonography is controversial and difficult to provide given the expected differences due to age, sex, and presence of iodine deficiency in patients from different populations.

A simple goiter refers to an enlarged thyroid gland with no structural echographic abnormalities, which most frequently develops as a result of iodine deficiency in children and adolescents. It is a risk factor for the development of MNG in adults. A substernal goiter is an enlarged thyroid gland with more than one-third of the thyroid volume located below the upper margin of the jugular notch. It may remain undiagnosed until compression symptoms develop.

A nontoxic goiter is a goiter in a euthyroid patient. Euthyroid status refers to normal function of the thyroid gland with no abnormal findings in history and on clinical examination, which has been confirmed by normal results of thyroid hormone tests.

An incidental thyroid nodule is a nodule not suspected clinically that is identified during an imaging study performed for other clinical reasons.

Clinical Features and Natural History Top

Nontoxic goiter develops slowly and often remains undiagnosed for years; it is not accompanied by biochemical abnormalities of the thyroid gland. The enlarged thyroid gland with nodular hypertrophy may be evident through an increased neck circumference and its visible asymmetry. In rare cases it may present with dyspnea, cough, or dysphagia resulting from the compression of adjacent tissues by a large or retrosternal goiter.

Diagnosis Top

Diagnostic Tests

1. Laboratory tests: Serum thyroid-stimulating hormone (TSH) levels are usually obtained to rule out biochemical thyroid abnormalities; normal results usually exclude abnormal thyroid function without the need for the determination of free thyroid hormone levels.

2. Imaging studies: Thyroid ultrasonography is used for the evaluation and monitoring of the thyroid size and nodules, including their location, size (3-dimensional), echogenicity (iso-, hyper-, or hypoechogenic solid nodules; nonechogenic cysts), internal structure (homogeneous or heterogeneous), borders (clearly demarcated or fuzzy and irregular), calcifications (microcalcifications or macrocalcifications), blood supply (vascularity) of the whole parenchyma and nodules (color Doppler or power Doppler). Ultrasonography cannot reliably differentiate nonmalignant from malignant nodules, but it may detect an increased risk of malignancy (see below). Thyroid ultrasonography is recommended in all patients with suspected thyroid nodules and for the initial evaluation of thyroid nodules discovered through other modalities.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of intervention). Quality of Evidence lowered due to the lack of comparative studies against other modalities (with ultrasonography being accurate, accessible, and low-cost compared to other imaging techniques).Smith-Bindman R, Lebda P, Feldstein VA, et al. Risk of thyroid cancer based on thyroid ultrasound imaging characteristics: results of a population-based study. JAMA Intern Med. 2013 Oct 28;173(19):1788-96. doi: 10.1001/jamainternmed.2013.9245. PubMed PMID: 23978950; PubMed Central PMCID: PMC3936789. Brito JP, Gionfriddo MR, Al Nofal A, et al. The accuracy of thyroid nodule ultrasound to predict thyroid cancer: systematic review and meta-analysis. J Clin Endocrinol Metab. 2014 Apr;99(4):1253-63. doi: 10.1210/jc.2013-2928. Epub 2013 Nov 25. Review. PubMed PMID: 24276450; PubMed Central PMCID: PMC3973781. Radionuclide thyroid imaging has limited use in the diagnosis of nontoxic goiter and should not be routinely used for this purpose (however, it is useful in the evaluation of patients with hyperthyroidism, as it can help distinguish between toxic multinodular goiter and Graves disease).

3. Fine-needle aspiration biopsy (FNB) and cytologic examination is an extremely useful technique in the evaluation of thyroid nodules. It helps guide clinical management and evaluate the need for surgery. One of the most commonly used cytology-reporting classifications is the Bethesda classification; it has 6 diagnostic categories (Table 1). FNB allows the cytologic diagnosis of papillary thyroid cancer but does not differentiate benign lesions (hyperplastic nodule, thyroiditis, or follicular adenoma [nonmalignant neoplasm]) from malignant follicular carcinoma, where only histologic examination of surgical specimens is conclusive. Therefore, the diagnosis of “follicular neoplasm” has been replaced with “suspicious for follicular neoplasm” and the respective oxyphilic variant. Molecular testing of the aspirate, if available, allows better classification and risk prediction.

Indications for FNB of a thyroid nodule include (but are not limited to):

1) A nodule of any size with the presence of suspicious cervical lymphadenopathy assessed clinically or with imaging studies.

2) A nodule >1 cm with ultrasound features associated with a high risk of malignancy.

3) A nodule with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) avidity.

Features of a thyroid nodule associated with a high risk of malignancy:

1) Clinical: Worrisome clinical lymphadenopathy, rapidly increasing nodule size, hoarseness (due to laryngeal nerve palsy), metastases from an unknown primary lesion, previous neck or chest irradiation, family history of thyroid cancer, age <18 years.

2) Ultrasonography: Internal microcalcifications, hypoechogenicity, increased central blood flow, infiltrative margins, taller than wider nodules, features suggestive of lymph node metastases, features of infiltration of the thyroid capsule or adjacent tissues. Suspicious cervical adenopathy (microcalcifications, loss of the hilum, and a round shape) strongly suggests the presence of a metastatic disease. FDG-PET–avid thyroid nodules are more likely to be malignant than FDG-PET–negative thyroid nodules (the study is usually performed for other reasons).

Diagnostic Criteria

Diagnostic criteria for nontoxic MNG:

1) At least 1 clinically evident thyroid nodule (regardless of the total volume of the thyroid gland) or an enlarged thyroid gland on ultrasonography with focal abnormalities of the echogenic structure lesions >1 cm in diameter.

2) Normal serum TSH levels.

Follow-Up Investigations to Exclude Thyroid Cancer

FNB should be considered in every case of MNG. The criteria for selection of nodules to perform FNB are based on clinical and ultrasound features (see above). In patients with multiple nodules, each nodule should be assessed independently.

1. If the initial FNB yields no features of malignancy of the examined nodules (“benign” nodule; Table 1) and the study is reliable, the biopsy does not need to be repeated and a follow-up ultrasonography of the thyroid gland is sufficient. If the clinical suspicion is high and follow-up imaging reveals findings suspicious of malignancy, repeat FNB should be performed.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). The strong rather than weak recommendation based on low Quality of Evidence reflects the high value placed on the detection of missed cases of thyroid cancer.Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and heterogeneity. Kwak JY, Koo H, Youk JH, et al. Value of US correlation of a thyroid nodule with initially benign cytologic results. Radiology. 2010 Jan;254(1):292-300. doi: 10.1148/radiol.2541090460. Epub 2009 Dec 17. PubMed PMID: 20019136. Rosário PW, Purisch S. Ultrasonographic characteristics as a criterion for repeat cytology in benign thyroid nodules. Arq Bras Endocrinol Metabol. 2010 Feb;54(1):52-5. PubMed PMID: 20414548. Nou E, Kwong N, Alexander LK, Cibas ES, Marqusee E, Alexander EK. Determination of the optimal time interval for repeat evaluation after a benign thyroid nodule aspiration. J Clin Endocrinol Metab. 2014 Feb;99(2):510-6. doi: 10.1210/jc.2013-3160. Epub 2013 Nov 25. Erratum in: J Clin Endocrinol Metab. 2015 Jun;100(6):2502. PubMed PMID: 24276452; PubMed Central PMCID: PMC4413457. Of note, the initial clinical suspicion appears more relevant than, for example, the rate of growth.

2. If the initial FNB result indicates a “follicular lesion of undetermined significance,” repeat the FNB at 3 to 12 months depending on the degree of clinical suspicion of malignancy.

Treatment Top

Advantages and disadvantages of individual treatment modalities: Table 2.

Surgical Treatment

A surgical approach for thyroid nodules is recommended as a treatment modality in cases where the clinical evaluation (ultrasound features, FNB) demonstrates a high risk of malignancy. In addition, surgery might be recommended as both a diagnostic and treatment modality in cases where the clinical evaluation is suggestive of malignancy. In cases of benign nodules surgery can be performed in the setting of compressive symptoms or for cosmetic concerns.

Indications:

1) Cytologic diagnosis of a “malignant” or “suspicious for malignancy” nodule (Table 1) denoting suspicion of thyroid cancer or insufficient data for its exclusion (an absolute indication). The diagnosis of “suspicious for oxyphilic neoplasm” is associated with a 15% to 20% risk of cancer and can be an important indication for surgery. The diagnosis of “suspicious for follicular neoplasm” is a relative indication for surgery, as the risk of cancer is ~5% (the decision is taken on a case-by-case basis, depending on the size of the nodule and presence of risk factors; surgery is mandatory in nodules >4 cm in diameter).

2) A large goiter causing airway compression.

3) A retrosternal goiter (regardless of airway compression).

Nonsurgical Treatment

Nonsurgical treatment may be considered in cases where both the FNB findings and clinical features do not suggest thyroid cancer (Table 2).

Prognosis Top

If the FNB is correctly performed and interpreted, the risk of overlooking a malignant thyroid nodule ranges between <1% and 10%, according to center. A benign nodule may increase in size and cause compression symptoms during follow-up; there is also some risk of gradual development of hyperthyroidism (see Thyrotoxicosis; see Figure 2 in Graves Disease).

TablesTop