Demystifying the risk stratification of pulmonary and thyroid nodules (2023)

Insurance for pulmonary nodules and thyroid nodules has always been a separate challenge.

Pulmonary nodules are one of the most common incidental changes on a chest X-ray or computed tomography (CT) scan. On the other hand, thyroid nodules are mostly detected by ultrasound and are believed to affect more than half of the world's population. In this two-part article, our goal is to provide insight into the two types of bumps that can help simplify insurance challenges, identifying factors that can help quantify risk and provide accurate and relevant guidance.

Part I: Lung nodules

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Pulmonary nodules are characterized by rounded or irregular focal opacity and dimensions <3 cm. They may be well or poorly defined, are usually surrounded by lung parenchyma, and are not associated with atelectasis (collapse), lymphadenopathy, or pleural effusion.¹

A study published in 2015 that tracked trends in random lung nodules in the United States reported that of the 4.8 million study participants who had a computed tomography (CT) scan between 2006 and 2012, one-third (1.57 million) of a nodule lung was accidentally detected. Furthermore, of those 1.57 million, approximately 4% developed lung cancer within two years of initial discovery.²

Evolution of the ability to detect and diagnose single lung nodules

Historically, chest radiography has been the most common method of detection and diagnosis of random pulmonary nodules. However, the advent of CT scans has led to more accurate and accurate diagnoses as it allows smaller or indistinct lung nodules to be more accurately detected and identified. The increasing global frequency of CT scans has contributed to a significant increase in incidental diagnoses of pulmonary nodules over the past two decades.

Studies indicate that the incidence of malignant pulmonary nodules can vary greatly depending on how they are detected. Initial lung screening such as CT scan gives a rate for incidentally detected nodules between 2% and 24%, while for malignant nodules, the rate is between 2% and 13%. Advanced or follow-up tests such as positron emission tomography (PET) have a much higher detection rate (46% to 82%).^3,4

Classification of risk of malignancy

Several charts have been developed to classify the risk of malignancy from pulmonary nodules.

The American College of Chest Physicians (ACCP) guidelines, first published in 2007 and then revised in 2013, use a computational method developed by researchers at the Mayo Clinic as a method of assessing nodule malignancy risk. It takes into account factors such as age, smoking, location and diameter of the nodule, presence of spiculations and history of cancer.^4,5

In 2015, the British Thoracic Society (BTS) published a set of commonly used guidelines from which risk calculators were developed to determine the risk of malignancy from pulmonary nodules.⁶

The Fleischner Society recommendations, first published in 2005 and revised in 2013 and 2017, are currently the most accepted guidelines for grading the risk of a pulmonary nodule.⁷

Fleischner Society guidelines are based on the following factors:

• A type of lump
  Various types of random lung nodules can be found on chest X-rays or CT scans. Figure 1 shows the three main types of pulmonary nodules - peridiaphragmatic, solid and subsolid - and the two types of subsolid nodules (pure ground glass and semisolid nodule). It is important to understand and distinguish each of these types, as each has its own impact on a candidate's cancer risk.
• Periapical nodules (PFN): These well-defined nodules usually have smooth margins and are located close to pulmonary fissures. There is usually no risk of malignancy associated with these nodules.
• solid nodules: these are the most common types of lung nodules found on chest X-rays or CT scans. These nodules completely cover the lung parenchyma. They present the most pronounced insurance challenge in assessing malignancy risk, as the assessment depends on the characteristics of the nodule and associated risk factors.

Figure 1
Classification of types of pulmonary nodules

• subsolid nodulesA: These nodules have two subtypes - transparent and semi-solid ground glass. They are less common than solid nodules and both carry a higher risk of malignancy than solid nodules (odds ratio [OR] 1.4).

  • Clear ground-glass nodules are non-opaque nodules that do not obscure the structure of the bronchi or pulmonary vessels. They usually grow slowly over many years.

  • Semi-solid nodes contain matte and solid elements. Part of the nodule may completely obscure the lung parenchyma.

  • Partially solid subsolid nodules have the highest risk of malignancy of all types of nodules. Its malignancy rate was 63%, while the rate of pure opaque nodules was 18%.^{3,6, 7, 8, 9}

• the size of the pitLung nodule size plays an equally important role in determining the likelihood of malignancy, with larger nodules indicating greater risk of malignancy.

  The incidence of malignant lung nodules can vary greatly depending on how they are detected.

  For example, according to Fleischner Society guidelines, a solid nodule less than 6 mm in diameter and associated with factors considered to be low risk (see Table 1 below) is usually benign and does not require further supervision or follow-up. In contrast, a solid nodule larger than 8 mm in diameter may have a worse prognosis and require more frequent surveillance, depending on the associated risk category.⁷

• Number of nodules found
  Multiple pulmonary nodules are also common incidental findings on radiographs or CT scans. The risk of malignancy is not necessarily greater if multiple nodules are found. However, in some cases, more careful follow-up may be required based on the identified "dominant" nodule. A dominant nodule is one that can mean a higher risk of malignancy. It may not always be the biggest lump.

  Fleischner's guidelines recommend close observation of the dominant nodule, especially when different types and sizes are a mixture of multiple pulmonary nodules. For example, if both a solid nodule and a semisolid nodule are found, the risk assessment should include the semisolid nodule as the dominant nodule because of the higher risk of malignancy, even if the solid nodule is slightly larger.⁷

• Other risk factors
  There are other risk factors that can play a significant role in modifying the likelihood of malignancy from a lung nodule. For example, a smaller nodule associated with the high risk factors listed in Table 1 (below) would require more supervision and monitoring as it is more likely to become malignant.⁷

Table 1
Risk factors for pulmonary nodules

*Between 40 and 50 years old is considered moderate risk.

Bonus Points for Considering Insurance

In addition to the main risk modifiers for pulmonary nodules described above, the presence of the following secondary risk factors should not be ignored:

• selected professions, for example workers in the asbestos industry or people working with radioactive substances

• the presence of other lung diseases, such as emphysema, infections, or fibrosis

• intermittent growth of nodule(s) seen on chest X-rays or CT scans during follow-up

The presence of these additional risk factors further increases the risk of malignancy. These cases would require complete and detailed updated node reports for possible consideration at the insurance stage.

On the other hand, a benign nodule usually has all or most of the following characteristics:

• diffuse calcifications (hamartomas, popcorn calcifications), with smooth edges
• no high risk factors
• no nodule growth for two years
• complete absence of any change in the nodule that would indicate an increased risk of malignancy

Application

Lung nodule insurance remains a challenge for insurers. Although a significant proportion of lung nodules are benign, the fact that lung cancer has one of the highest mortality rates of any cancer remains a major cause for concern. Therefore, a prudent approach to selective risk quantification based on the aggregate characteristics of each nodule and its associated risk factors is recommended.

Part 2: Thyroid nodules

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Thyroid nodules are solid or fluid-filled masses that form within the thyroid gland. They are one of the most common types of nodules found in the human body, and estimates suggest that around half of the world's population is likely to develop a thyroid nodule in their lifetime. Estimated worldwide prevalence ranges from 19% to 67% by ultrasonography (US), depending on geographic region.^{10,11, 12}

Risk classification methodologies

In the case of insurance companies, reports of accidental thyroid nodules detected on ultrasound are frequent. However, assessing the prognosis of these nodules from a single ultrasound report remains a challenge for insurers. A methodical approach to malignancy risk assessment would be most beneficial.

Several groups have tried to classify thyroid nodules based on their characteristics. A recent study reported differences in the relative risk of thyroid nodules comparing three sets of guidelines: the 2016 guidelines from the American Association of Clinical Endocrinologists (AACE), the American College of Endocrinology (ACE), and the Associazione Medici Endocrinologi. AM); the 2015 American Thyroid Association (ATA) guidelines for the management of thyroid nodules and differentiated cancer; and the 2014 British Thyroid Society (BTA) guidelines for the treatment of thyroid cancer.¹⁰

The study analyzed thyroid nodules based on the characteristics found on ultrasound and classified them as:

• Low-risk thyroid lesions (benign or low-suspicion malignancy)
• Intermediate-risk thyroid lesions (suspected intermediate or unspecified malignancy)
• High-risk thyroid lesions (high suspicion of malignancy or malignancy)

Today, however, the American College of Radiology's Thyroid Imaging Data and Reporting System, known as the ACR TI-RADS (or simply TI-RADS), is one of the most accepted methods for classifying the risk of thyroid nodules.

ACR TI-RADS: a new chapter in thyroid nodule risk classification

The risk grading framework for thyroid nodules is not a new development. Several of them, including the European EU-TIRADS published by the European Thyroid Association in 2017 and the Korean Society of Thyroid Radiology (KSThR) K-TIRADS published in 2016, assessed the risk of malignancy based on the characteristics of the nodules.^14,15

In 2017, the ACR TI-RADS model was introduced, paving the way for a new scoring framework that focused on assigning score values ​​to nodular features and using these to calculate a holistic risk score to predict malignancy.¹⁶

Table 2 (below) provides an overview of the ACR TI-RADS risk scoring method.

Table 2
ACR TI-RADS scoring system for classifying thyroid nodules based on ultrasound images

*Table adapted from ACR TI-RADS, Reporting and Data System (TI-RADS): ACR TI-RADS Committee White Paper.¹⁶

Each component in the table was given a specific score value, with higher scores given to more suspicious features. For example, a solid hypoechoic nodule with peripheral calcifications would have a much higher risk of malignancy than a smooth cystic nodule, which is usually benign. Thus, each component - solid, hypoechoic and marginal calcifications - would have an individual score higher than the cystic and smooth components.

The aim is then to calculate a cumulative risk score for each nodule based on the presence of features indicative of a given TI-RADS category, thus allowing a more accurate assessment of the nodule's potential risk of malignancy. TI-RADS categories can range from 0 to 5, with 0 being a benign nodule and 5 being the highest risk of malignancy. For example, a cumulative risk score of 2 would indicate TI-RADS 2, a relatively benign prognosis, while a cumulative risk score of 7 or more would indicate TI-RADS 5, a more malignant condition.

The role of fine needle aspiration in the diagnosis of thyroid nodules

The Bethesda System for Reporting Thyroid Cytopathology 2017, a version of the system first introduced in 2007, has been widely adopted as the grading system for thyroid nodules after evaluation by fine needle aspiration (FNA).

Table 3 (below) lists the different diagnostic categories of FNA results and illustrates the corresponding malignancy risk using common management strategies.¹⁷

Table 3
Bethesda system for classifying thyroid nodules based on FNAB results

*Adapted from 2017 Bethesda Thyroid Cytopathology Reporting System: Cibas A, et al.¹⁷

Note that there are several predefined criteria for taking FNA tests. Clinicians usually rely on a combination of TI-RADS score and nodule size to determine if FNAB is needed. For example, an FNA may be recommended for an EU-TIRADS 5 nodule greater than or equal to 1 cm in size. However, EU-TIRADS 4 nodule can be considered for ANF if the nodule is 1.5 cm or larger and EU-TIRADS 3 nodule can be considered for ANF if the nodule is 2 cm or larger. If multiple nodules are found, FNAB is recommended for a maximum of three nodules, according to risk and size criteria.¹⁴

risk modifiers

The factors listed below can be used in conjunction with ACR TI-RADS and FNA scores, if available, to determine the prognosis of a nodule. The presence of any of these factors can lead to a worse prognosis, which indicates a prudent insurance approach.¹⁰

• Age of onset, especially in adolescence or older age (>70 years)
• Family history of first-degree medullary thyroid cancer, type 2 multiple endocrine tumors, or papillary thyroid cancer
• Intermittent nodule(s) growth, i.e. nodule growth seen on follow-up ultrasound or PET scan
• Associated symptoms such as persistent dysphonia, dysphagia, or shortness of breath
• Personal history of head and neck irradiation, particularly in childhood and/or adolescence
• The presence of cervical adenopathy

There is an ongoing debate about whether intranodal vascularity is a determinant of the malignant potential of a thyroid nodule. A 2017 US study based on more than 20 years of follow-up of 698 people showed that hypervascularity within nodules is associated with adenomatous/adenomatous (benign) thyroid nodules, whereas lack of vascularity is indicative of thyroid cancer.¹⁸

Another study, performed on 1,024 hospitalized patients in South Korea, found that vascularity detected on ultrasound, alone or in combination with grayscale ultrasound features, was not useful for predicting thyroid cancer. Intranodular vascularity was present in 31% of those with benign nodules compared to 17% with malignant nodules.¹⁹

From these studies, the use of intranodular vascularity as a predictor of malignant thyroid nodules may not always be accurate and remains controversial. More research is needed to explore this aspect.

The role of other tests in the evaluation of thyroid nodules

The process of diagnosing thyroid nodules can often include additional tests. Here are some of them and their implications.

• Thyroid function tests(TSH, T4) are commonly performed during examination of the thyroid nodule(s). An overactive nodule is less likely to be malignant.

• Blood thyroglobulin testsare not clinically recommended for the evaluation of thyroid nodules, as their reliability in predicting malignancy remains controversial. In fact, it was observed that in some cases an increase in thyroglobulin was found in the presence of occasional benign nodules.

• Presenceand calcitonin, which is produced by perifollicular (C) cells, is considered more reliable as a serum marker for medullary thyroid carcinoma, but may not necessarily play a role in the initial clinical evaluation of a thyroid nodule.²⁰

• The diagnosis of nonspecific thyroid changes is a constant challenge for most radiologists and cytologists. The mere evaluation of morphological characteristics is not always enough. Applicationadditional molecular testsfor unspecified thyroid FNAB samples, provided better stratification and segregation in some of these cases. Research continues to refine and improve molecular tests, making them more accurate and less expensive, and it is anticipated that they may serve as a basis for resolving some of the challenges associated with these types of nodules.²¹

Application

Thyroid nodules are one of the most common accidental findings seen in insurance. Although the characteristics of a nodule play a significant role in determining its risk of malignancy, it is important not to underestimate the associated risk factors, as they also serve as potential risk factors for malignancy. Judicious guidance supported by research-based insurance tools will help the insurer classify and assess the risk of nodule malignancy and ensure prudent decision-making.