This comprehensive review explains that thyroid nodules are extremely common, found in up to 70% of people through ultrasound, with only 7-15% being cancerous. The article details a systematic approach to evaluation involving clinical assessment, TSH blood tests, ultrasound imaging, and fine-needle aspiration (FNA) biopsy when needed. Key recommendations include that routine cancer screening isn't beneficial for most people, molecular testing can help clarify uncertain biopsy results, and treatment decisions should be personalized based on cancer risk factors and patient preferences.

Understanding Thyroid Nodules: Diagnosis and Management for Patients

Table of Contents

• Introduction: What Are Thyroid Nodules?
• How Common Are Thyroid Nodules?
• Thyroid Cancer Risk Factors
• Comprehensive Evaluation Approach
• Medical History and Physical Examination
• Laboratory Testing
• Imaging Studies
• Fine-Needle Aspiration (FNA) Biopsy
• Molecular Testing Advances
• Treatment and Management Options
• Long-Term Monitoring and Follow-up
• Study Limitations and Considerations
• Patient Recommendations
• Source Information

Introduction: What Are Thyroid Nodules?

Thyroid nodules represent a very common medical condition where abnormal growths form within the thyroid gland, which is located at the base of your neck. These nodules can be solid or filled with fluid, and they range dramatically in how they present—some people can feel them, while others discover them accidentally during imaging tests for unrelated conditions.

The primary importance of identifying thyroid nodules lies in the need to assess thyroid function, evaluate whether they're causing physical symptoms by pressing on surrounding structures, and most importantly, to exclude the possibility of thyroid cancer. While the vast majority of thyroid nodules are benign (non-cancerous), approximately 7-15% do turn out to be malignant, making proper evaluation essential.

How Common Are Thyroid Nodules?

Thyroid nodules are exceptionally common in the general population. Approximately 5% of people have nodules that can be felt during a physical examination (palpable nodules). However, when using ultrasound technology, which is much more sensitive than physical touch, doctors find thyroid nodules in up to 70% of people.

The prevalence of thyroid nodules increases with age, with older patients more likely to have them. Interestingly, when nodules are discovered incidentally during positron emission tomography (PET) scans performed for other reasons, they carry a 35% probability of being malignant, which is significantly higher than nodules found through other methods.

Most thyroid nodules develop from thyroid follicular cells. Benign follicular nodules, whether solitary or as part of a multinodular goiter (enlarged thyroid with multiple nodules), represent the most common type. The different types of thyroid cancer include papillary thyroid cancer (about 85% of cases), follicular thyroid cancer including Hürthle cell variant (about 12%), medullary thyroid cancer (2%), and anaplastic thyroid cancer (less than 1%).

Thyroid Cancer Risk Factors

Certain factors significantly increase the risk that a thyroid nodule might be cancerous. These risk factors include:

• Radiation exposure: Childhood head and neck irradiation, whole body radiation for bone marrow transplantation, radiation fallout, or other radiation exposures (such as treatment for acne or birthmarks, or occupational exposure)
• Family history: Thyroid cancer in a first-degree relative or inherited genetic syndromes associated with thyroid cancer (Cowden syndrome, Carney complex, multiple endocrine neoplasia type 2, Werner syndrome, familial polyposis)
• Nodule characteristics: Enlarging nodules or rapid nodule growth
• Demographic factors: Male sex, age younger than 20 or older than 70 years
• Physical exam findings: Cervical lymphadenopathy (swollen neck lymph nodes), hoarseness, craggy/hard nodules, nodules fixed to surrounding tissue
• Test results: TSH in upper normal or elevated range, suspicious ultrasound features, positive PET scan, or serum calcitonin levels above 50-100 pg/mL

Despite these risk factors, it's important to recognize that thyroid cancer generally has an excellent prognosis. The 5-year overall survival rate is 96.1%, and for patients who survive one year after diagnosis, the 5-year survival rate improves to 98.2%. This favorable outlook is largely driven by papillary thyroid carcinoma, which is the most common and most treatable form.

Comprehensive Evaluation Approach

The evaluation of thyroid nodules involves four key components that work together to provide a complete picture:

1. Clinical history and physical examination
2. Serum thyroid stimulating hormone (TSH) measurement
3. Thyroid ultrasound performed by a specialist with expertise in thyroid sonography
4. Fine-needle aspiration (FNA) biopsy when indicated based on nodule size and characteristics

If the serum TSH level is suppressed (low), doctors may recommend a thyroid scan using technetium-99 (99Tc) to distinguish between different types of nodules. This scan can identify "hot" nodules (which are rarely cancerous), toxic multinodular goiter, or less commonly, thyroiditis or Graves' disease occurring alongside thyroid nodules.

It's important to note that routine thyroid cancer screening is not recommended for the general population. The United States Preventive Services Task Force specifically recommends against thyroid cancer screening in asymptomatic adults, except for high-risk individuals such as those with history of radiation exposure in childhood or adolescence or with inherited genetic syndromes associated with thyroid cancer.

Medical History and Physical Examination

When you have a thyroid nodule, your doctor will conduct a thorough history and physical examination. Neck examination including palpation of the thyroid and cervical lymph nodes should be part of the routine physical examination for patients with thyroid nodules.

Most typically, thyroid cancer presents as a painless nodule. Patients may not even be aware of its growth pattern. Recent rapid growth of a thyroid nodule may indicate aggressive cancer and can be associated with pain. This scenario needs to be differentiated from subacute nodular thyroiditis, which is commonly associated with systemic features like fever.

Sudden enlargement, especially if accompanied by sudden onset of pain, suggests hemorrhage into a nodule, which is rarely associated with malignancy. Hoarseness suggests possible infiltration of the recurrent laryngeal nerve by thyroid cancer. Symptoms of mass effect might include dysphagia (difficulty swallowing); neck discomfort in certain positions, such as recumbency at night; and rarely, dyspnea (shortness of breath) or wheeze.

During the physical examination, doctors characterize thyroid nodules for size, location, and texture. Evidence of nodule firmness, fixation, dysphonia, and cervical lymphadenopathy suggest malignancy. However, more commonly, thyroid cancer does not manifest overtly malignant clinical features.

Laboratory Testing

Serum thyroid stimulating hormone (TSH) should be measured in all patients with a thyroid nodule. Most individuals will have a normal TSH level. A low or suppressed TSH level may suggest a hyperfunctioning nodule or a toxic goiter, and free thyroxine (fT4) and/or free triiodothyronine (fT3) levels should be measured in these cases.

Uncommonly, Graves' disease can occur in the context of a multinodular goiter. A persistently suppressed TSH with normal fT4 and fT3 levels defines subclinical hyperthyroidism—a condition associated with an increased risk of atrial fibrillation and bone loss, particularly in postmenopausal women, and of developing overt thyrotoxicosis.

Hashimoto thyroiditis, which can present with a transient hyperthyroid phase, is the usual cause of elevated TSH or hypothyroidism. TSH elevation or TSH within the upper normal range has been reported to be associated with an increased risk of malignancy within a thyroid nodule.

Measurement of TSH receptor antibody or thyroperoxidase antibody is not indicated unless autoimmune thyroid disease is suspected. Routine serum calcitonin measurement is not recommended, except for family members with multiple endocrine neoplasia syndrome type 2 and patients with suspicious imaging and cytology not consistent with papillary thyroid carcinoma.

Imaging Studies

All patients with palpable thyroid nodules or nodules detected by other imaging modalities should have a thyroid ultrasound performed by a specialist with expertise in thyroid sonography. A thyroid ultrasound allows documentation of thyroid size, location and characteristics of individual nodules and commonly detects additional nodules not apparent on physical examination.

Nodular characteristics suspicious for malignancy include being solid or predominantly solid, taller than wide, hypoechoic (darker than surrounding tissue), irregular margins, microcalcifications, absent halo, and increased vascularity. Nodules are very likely to be benign if they are purely cystic, have typical colloid echoes of ring down or comet tail artifact, or are spongiform (multicystic components occupy more than 50% of nodule volume).

Based on these characteristics, the American Thyroid Association (ATA) classifies nodules into risk categories to aid in selection of nodules for FNA. Some Australian radiology providers have begun to adopt the American College of Radiology Thyroid Imaging, Reporting and Data System (TI-RADS) for standardized reporting.

In contrast to neck ultrasound that allows structural assessment, a radionuclide (technetium-99, 99Tc) thyroid scan provides functional assessment of a nodule. It should only be performed when TSH is suppressed to diagnose a hyperfunctioning ("hot") nodule or a toxic multinodular goiter. This type of scan should not be performed if the TSH level is normal or elevated.

When a multinodular goiter is present with compressive symptoms, a non-contrast computed tomography (CT) thyroid scan is useful to assess the degree of retrosternal extension, tracheal deviation and calibre of the tracheal lumen. The use of intravenous contrast is contentious as it provides better structural resolution but will delay the timing of radioactive iodine therapy after thyroidectomy for about 2 months.

Fine-Needle Aspiration (FNA) Biopsy

FNA provides a cytological assessment of thyroid nodules, and its main purpose is to reduce the risk of unnecessary surgery and to facilitate single rather than multiple operations for papillary and medullary thyroid carcinoma. The 2015 ATA guidelines recommend the use of FNA for nodules 1.5 cm or larger, or for nodules 1.0 cm or larger if they have high or intermediate risk sonographic characteristics.

There is no evidence that routine investigation of suspicious nodules smaller than 1.0 cm improves outcomes. Suspicious lymph nodes should undergo FNA for cytology and needle washings should be taken for thyroglobulin measurement. A normal lymph node does not contain thyroglobulin, and a measurable concentration is suspicious of metastatic thyroid cancer.

In the case of very low risk sonographic features, such as spongiform or purely cystic appearance, FNA may be limited to nodules sized 2.0 cm or larger; alternatively, very low risk nodules could be monitored for clinical or sonographic change. Monitoring may also be appropriate for patients with limited life expectancy or unacceptably high surgical risk.

If a multinodular goiter is present, each nodule should be assessed for FNA on the basis of the above criteria. In most cases, either no nodule warrants FNA or only few of the many nodules may warrant FNA. Where no FNA is indicated, a repeat thyroid ultrasound may be considered in 12-24 months.

Thyroid cytopathology should be reported according to the Bethesda Classification System. Benign cytology is found in about 70% of all FNAs, indeterminate cytology (follicular lesion/atypia of undetermined significance [FLUS/AUS] and follicular neoplasm/suspicious for follicular neoplasm [FN/SFN]) in 10-15%, and non-diagnostic or unsatisfactory smears in about 15%.

The rate of non-diagnostic or unsatisfactory results may be reduced by appropriate selection of nodules that warrant FNA, performing FNA under ultrasound guidance, undertaking two to five needle passes, targeting the solid components of a cystic nodule, immediate check of the material to ensure adequate sampling, and evaluation by an experienced thyroid cytopathologist.

Molecular Testing Advances

Molecular analysis of FNA material—not yet widely available in Australia—is likely to improve nodule selection for surgery by evaluation either for the absence or presence of mutations associated with thyroid carcinoma. These advanced tests analyze genetic markers that can help distinguish between benign and malignant nodules when cytology results are uncertain.

The Afirma Gene Expression Classifier analyzes mRNA expression of 167 genes, providing a high negative predictive value of 94-95% in nodules with indeterminate cytology, making it a useful rule-out test for malignancy that can obviate the need for immediate surgery. Another test, ThyGenX, uses next generation sequencing to identify alterations across eight thyroid cancer-associated genes, together with RNA translocation fusion markers with a negative predictive value of 94% and a positive predictive value of 74%.

ThyroSeq v2 uses next generation sequencing to analyze a larger array of gene mutations and RNA fusion proteins than ThyGenX and may offer better negative and positive predictive values, although further studies are required. While promising, it is not known whether the performance characteristics of these molecular tools developed at tertiary specialist centres will be the same if used during routine clinical care, thus further validation is needed.

Treatment and Management Options

A solitary hot nodule or a toxic multinodular goiter with a persistently suppressed TSH should usually be treated with radioactive iodine (131I). If a preceding course of antithyroid medication is necessary, 131I should be given while the TSH is still suppressed, as this protects non-autonomous thyroid tissue from 131I uptake and reduces the risk of hypothyroidism. Surgery may be preferred for large toxic lesions, for those individuals with suspicious imaging characteristics, and for young patients.

A total thyroidectomy is usually indicated for FNA cytology that is either diagnostic of or suspicious for malignancy. It may also be considered for indeterminate FNA cytology (FLUS/AUS and FN/SFN) in the setting of high risk clinical factors, or if molecular markers are predictive for malignancy.

Total thyroidectomy has been the usual management in Australia for nearly all thyroid cancer. The latest ATA guidelines allow for consideration of hemithyroidectomy for low risk thyroid carcinomas up to 4.0 cm. However, given the absence of definitive evidence to support this recommendation, the guidelines state that "the treatment should be individualised."

For example, of 1465 Japanese patients with papillary thyroid carcinoma smaller than 1.0 cm followed prospectively for 10 years, less than 10% progressed and there were no deaths from papillary thyroid carcinoma. Minimally invasive follicular thyroid carcinoma smaller than 4.0 cm may also be managed by hemithyroidectomy—this is widely accepted practice.

Compartment-oriented lymph node dissection is necessary for involved nodes, usually in papillary thyroid carcinoma and medullary thyroid carcinoma but occasionally for follicular thyroid carcinoma and Hürthle cell carcinoma. Prophylactic lymph node dissection remains controversial. Surgical clearance of cancer remains the best option when possible, and it may entail partial excision of contiguous structures when invaded and in the absence of distant metastases.

Long-Term Monitoring and Follow-up

A diagnostic lobectomy may be warranted when there is diagnostic uncertainty or patient preference. A conservative approach is reasonable if there is poor surgical risk or short life expectancy. If a nodule with an indeterminate FNA is to be monitored, a repeat thyroid ultrasound should be performed in 6-12 months, and a repeat FNA is recommended if there is a 50% increase in nodule volume or a 20% increase in at least two nodule dimensions of at least 2 mm.

When the patient is younger and the nodule is larger or growing, it may be practical to consider surgery for an apparently benign nodule rather than continue close observation and rebiopsy, particularly if future removal seems highly probable.

Another area of controversy relates to whether surgery should be offered for nodules larger than 4.0 cm that return a benign FNA. A retrospective cohort analysis of 7348 nodules, of which 927 (13%) were cancerous, showed that while 10.5% of nodules 1.0-1.9 cm were cancerous, 15% of nodules larger than 2.0 cm were cancerous. A prospective study of 382 nodules larger than 4.0 cm reported a thyroid cancer rate of 22% and a false-negative cytology rate of 10.4%.

There is still uncertainty as to the appropriate frequency of follow-up of nodules with benign FNA findings when the risk of malignancy is 0-3%. However, it is reasonable to repeat the thyroid ultrasound after 12-24 months. If the nodule has grown by the dimensions given above, FNA should be repeated. If the cytology is once again benign, it may not be necessary to have further ultrasounds unless there are sonographically suspicious features or there is clinical change on nodule palpation.

Thyroxine suppression therapy to slow nodule growth is not recommended as it has not been shown to be effective and is associated with adverse effects.

Study Limitations and Considerations

This review acknowledges several important limitations in our current understanding of thyroid nodules. Despite the fact that thyroid nodules are very common, there is a scarcity of randomized controlled clinical trial data to guide clinical decision making, in part due to the usually good prognosis of thyroid cancer.

Instead, recommendations in societal guidelines such as those from the American Thyroid Association (ATA) are largely based on observational studies and expert opinion. The main challenge in managing thyroid nodules is to identify those that are malignant, while avoiding inappropriate excess use of thyroid sonography, FNA and surgery.

Achieving this balance should be considered in the context of recent evidence from the US, the United Kingdom and Australia, suggesting that the increased incidence of thyroid cancer over the past three decades is not purely due to overdiagnosis but also to a true increase in its incidence. Reasons for this greater incidence may include increased exposure to potentially modifiable factors, including obesity and environmental influences other than the known effect of ionising radiation, such as chemical exposures.

Patient Recommendations

Based on this comprehensive review, patients with thyroid nodules should:

1. Ensure proper evaluation with all four components: clinical history/exam, TSH testing, specialist ultrasound, and FNA when indicated
2. Understand that most nodules are benign, with only 7-15% being cancerous
3. Recognize that thyroid cancer generally has an excellent prognosis with proper treatment
4. Discuss personal risk factors with their healthcare provider
5. Consider molecular testing if they have indeterminate biopsy results
6. Participate actively in treatment decisions, which should be individualized based on their specific situation
7. Adhere to recommended follow-up schedules for monitoring
8. Avoid unnecessary thyroid cancer screening unless they have specific high-risk factors

Patients should maintain open communication with their healthcare team and seek care from specialists experienced in thyroid disorders when needed.

Source Information

Original Article Title: Thyroid nodules: diagnosis and management

Authors: Rosemary Wong, Stephen G. Farrell, Mathis Grossmann

Publication: Medical Journal of Australia

Note: This patient-friendly article is based on peer-reviewed research published in the Medical Journal of Australia and represents a comprehensive translation of the original scientific content for educational purposes.