Goiter, Nontoxic Multinodular

Definition and EtiologyTop

Nontoxic multinodular goiter (MNG) is a disease of the thyroid gland characterized by the presence of ≥2 thyroid nodules (dominant focal structural lesions) with normal thyroid function. From an anatomic perspective, a goiter may be classified as diffuse (encompassing the entire thyroid gland) or multinodular (consisting of discrete but multiple lesions). It may also be further subdivided into being obstructive (compressing surrounding structures causing clinical symptoms) or nonobstructive. From a biochemical standpoint, goiters may be associated with normal or abnormal thyroid hormone production.

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

Notably, most thyroid nodules are benign and the general risk of thyroid cancer in a patient with MNG ranges between 7% and 15%, depending on clinical and ultrasonographic risk factors.

The most common cause of goiter throughout the world is iodine deficiency. However, in iodine-replete areas, such as Canada and the United States, the most common etiologies include autoimmune thyroid disease (Hashimoto thyroiditis and Graves disease) as well as radiation exposure and genetics.

Solitary thyroid nodules or nontoxic MNG may be due to a thyroid cyst, colloid nodule, hyperplastic nodule, follicular adenoma, and multiple forms of thyroid malignancy (discussed briefly below). Malignancy more often arises from a single solitary nodule.

Clinical Features and Natural HistoryTop

Clinically, thyroid nodules may be palpated on physical examination in 5% to 7% of the general population, while the prevalence of thyroid nodularity in the general population ranges between 20% and 50%, depending on the population studied (eg, ultrasound-detected or autopsy-based studies), and increases with age. Usually a nontoxic goiter develops slowly and often remains undiagnosed for years, especially since nontoxic MNG implies no biochemical abnormalities.

The enlarged thyroid gland with nodular hypertrophy may be evident by an increased neck circumference and visible asymmetry. In rare cases it may present with dyspnea, cough, dysphagia, or hemoptysis resulting from the compression of adjacent structures by a large or retrosternal goiter

DiagnosisTop

Diagnostic Tests

1. Laboratory tests: The first step in the evaluation of an MNG is to measure a serum thyroid-stimulating hormone (TSH) level to exclude biochemical thyroid abnormalities. Normal TSH level confirms normal thyroid function, and there is no indication for measuring free hormones (free thyroxine [FT4] or free triiodothyronine [FT3]).

2. Imaging studies: Thyroid ultrasonography is the imaging modality of choice for the evaluation and monitoring of MNG and nodules. Ultrasonography is also recommended when nodules are discovered through other imaging 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. PMID: 23978950; 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. PMID: 24276450; PMCID: PMC3973781. It is important to note that ultrasonography alone cannot reliably distinguish between nonmalignant and malignant nodules, but it may detect an increased risk of malignancy based on specific nodule characteristics and various classification systems. One of the most commonly used ultrasonographic criteria to risk-stratify thyroid nodules is the American College of Radiology Thyroid Imaging and Reporting System (ACR-TIRADS; Table 6.7-1). These criteria assign points based on high-risk imaging features and in conjunction with nodule size, and recommend observation or biopsy. If nodules are noted on ultrasonography, most radiologists will assign a TIRADS score to each nodule in their report. TIRADS scoring is a valuable tool to guide clinical decision making; however, this should be individualized to each patient, taking into consideration patient preference and risk factors for malignancy (eg, radiation exposure, family history):

1) Composition: Solid nodules carry a higher risk for malignancy as compared with cystic or spongiform nodules (2-0 points).

2) Echogenicity: Hypoechoic nodules carry a higher risk of malignancy as compared with isoechoic or hyperechoic nodules (3-0 points).

3) Shape: Taller-than-wide nodules carry a much higher risk of malignancy as compared with wider-than-tall nodules due to their association with an aggressive variant of papillary thyroid cancer (3 vs 0 points).

4) Margin: Irregular margins (2 points) or extrathyroidal extension nodules (3 points) carry a higher risk of malignancy as compared with smooth or ill-defined margins (0 points).

5) Echogenic foci: Peripheral rim calcifications (2 points) or microcalcifications (3 points) carry a higher risk of malignancy as compared with macrocalcifications (1 point) or no calcifications (0 points).

Radionuclide thyroid imaging has limited use in the evaluation of nontoxic goiter and should not be routinely used for this purpose (however, it is useful in the evaluation of patients with hyperthyroidism or low TSH levels, as it can help distinguish between toxic/hot MNG, toxic/hot nodule, and Graves disease) and identify cold nodules in this setting. Hot/toxic nodules are rarely malignant and usually fine-needle aspiration biopsy (FNAB) is not needed.

3. FNAB and cytologic examination: If the nodule is classified as higher risk according to the ACR-TIRADS ultrasonography criteria described above, the next best step is to perform a FNAB, the most commonly used biopsy mode for thyroid nodules. FNAB 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 6.7-2). FNAB allows for the cytologic diagnosis of papillary thyroid cancer molecular testing of the aspirate, if available, provides further risk stratification and is particularly useful in the setting of cytologically indeterminate nodules.

Indications for FNAB 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 with ultrasound features associated with a higher risk of malignancy, as per the ACR-TIRADS criteria, using specific size criteria depending on risk.

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, hard or fixed nodule, dysphagia, hoarseness (due to laryngeal nerve palsy), metastases from an unknown primary lesion, previous neck or chest irradiation, family history of thyroid cancer, personal or family history of genetic syndromes associated with 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 extrathyroidal extension. Suspicious cervical adenopathy (microcalcifications, loss of fatty hilum, and a round shape) strongly suggests the presence of a malignant 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.

2) Normal serum TSH levels.

Follow-Up Investigations to Exclude Thyroid Cancer

FNAB should be considered in every case of MNG with suspicious findings on thyroid ultrasonography. The criteria for selection of nodules to perform FNAB are based on clinical and ultrasound features (see above). In patients with multiple nodules, each nodule should be assessed independently. The risk of thyroid cancer in patients with a solitary nodule and those with multiple nodules is similar. Next steps after FNAB depend on cytology results:

1) Benign: The biopsy does not generally need to be repeated and a follow-up ultrasonography of the thyroid gland, initially 12 months and then at progressively increasing intervals if no changes are noted, is sufficient. The risk of false-negative cytology results in apparently benign lesions is low. The exception to this would be a TIRADS-5 nodule with a benign biopsy result. As these higher-risk nodules require 2 benign biopsies, FNAB should be repeated following the first benign FNAB result. If follow-up imaging demonstrates significant growth (as defined by 50% increase in nodule volume or 20% increase in diameter with an increase in ≥2 dimensions of ≥2 mm) or new suspicious characteristics, a repeat FNAB should be considered.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. 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. 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. PMID: 24276452; PMCID: PMC4413457.

2) Nondiagnostic: If the nondiagnostic result is due to inadequate sampling, a repeat FNAB should be performed.

3) Atypia of undetermined significance (AUS): If molecular testing is not available, one can either repeat FNAB and continue with close ultrasound surveillance, or refer the patient for diagnostic lobectomy. If molecular testing is available, it can help further risk-stratify patients into low- or high-risk categories.

4) If the initial FNAB result indicates follicular neoplasm, the risk for malignancy is slightly higher than for AUS. If molecular testing is not available, continue with close ultrasound surveillance or refer the patient for diagnostic lobectomy.

5) Suspicious for malignancy or malignant: The patient should be referred for surgical management. In some cases, there is an option for active surveillance for malignant nodules <1 cm in size if the patient meets criteria, and this can be discussed with their surgeon or specialist.

TreatmentTop

Surgical Treatment

A surgical approach for thyroid nodules is recommended in all cases where cytology is suggestive of malignancy. In cases of cytologically benign nodules, surgery may be considered in the setting of compressive symptoms or for cosmetic purposes. Advantages and disadvantages of individual treatment modalities: Table 6.7-3.

Indications:

1) Cytologic diagnosis of a “malignant” or “suspicious for malignancy” nodule (Table 6.7-2).

2) AUS is a relative indication, usually undertaken if nodules are >4 cm in diameter.

3) Follicular neoplasm carries a slightly higher risk of malignancy than AUS and is also a relative indication for surgery, particularly with large nodules (>4 cm in diameter).

4) A large goiter causing airway compression.

Nonsurgical Treatment

Nonsurgical treatment may be considered in cases where neither the FNAB findings nor clinical features suggest thyroid cancer.

PrognosisTop

If the FNAB is correctly performed and interpreted, the risk of overlooking a malignant thyroid nodule ranges between <1% and 10%. A benign nodule may increase in size and cause compressive symptoms during follow-up; there is also some risk of gradual development of hyperthyroidism (see Thyrotoxicosis; see Figure 6.7-2).

Another possible entity, noninvasive encapsulated follicular variant of papillary thyroid cancer [NIFTP], is a diagnosis made on pathology and implies that there is no evidence of either vascular or tumor capsule invasion. NIFTP is effectively cured with lobectomy and no other therapies (eg, radioactive iodine) are required.

TablesTop