Hospital Medicine

Solitary lung nodule

Solitary lung nodule

1. Introduction and definition

Solitary lung nodule (SLN) is defined as a single, relatively spherical radiological opacity that measures up to 3 cm in size and is surrounded by aerated lung parenchyma. Also, there should be no other associated abnormality including atelectasis, hilar enlargement or pleural effusion.

Focal pulmonary lesions which are larger in size (>3 cm) are classified as lung masses. They are considered malignant until proven otherwise.

Nodules less than 8–10 mm in size are classified as ‘small’ or ‘sub-centimeter’ lung nodules. They have to be approached differently as their malignant potential is very minimal when compared to larger nodules.

Nodules are further classified as solid or subsolid or nonsolid based on CT attenuation. Solid nodule is a nodule that completely obscures the entire lung parenchyma within it. Subsolid nodules are those having sections that are solid, and nonsolid nodules are those with no solid parts. Subsolid and nonsolid nodules have a higher likelihood of being malignant when compared with solid nodules.

2. Epidemiology

SLN is a common incidental finding in chest radiographs. Earlier reported incidences were based on chest X-rays (CXR). The incidence is increasing dramatically with increasing use of computed tomography (CT) of the chest, especially when smaller nodules detectable only on CT scan are included. Some studies report that up to 50% of smokers aged 50 years or older may have pulmonary nodules on CT scan of the chest.

Interestingly, many solitary pulmonary nodules noted on chest radiographs may be false positive findings. In one study which included subcentimeter nodules, more than half of the nodules found on CXR were not confirmed on low-dose CT scans.

In a study conducted between 2006 and 2012 at a large integrated health care system, there was an increase in the annual frequency of chest CT imaging from 1.3% to 1.9% for all adult members. The frequency of nodule identification increased from 24% to 31% for all scans performed. While the annual rate of chest CT increased from 15.4 to 20.7 per 1,000 person-years, the rate of nodule identification increased from 3.9 to 6.6 per 1,000 person-years. However, the rate of a new lung cancer diagnosis remained stable. This study estimates that more than 1.5 million adult Americans will have a pulmonary nodule identified each year. More frequent nodule identification has not been accompanied by increases in the diagnosis of cancerous nodules.

3. Significance of lung nodules

The possibility of solitary lung nodule being a potentially curable form of bronchogenic carcinoma makes it extremely significant. Five-year survival rates for resected malignant SLN may be up to 80%, but extremely low for inoperable bronchogenic carcinoma. This makes earlier diagnoses extremely important. Incidence of malignancy among SLN varies widely; however, data from studies suggests that the majority of lung nodules discovered on computed tomography (CT) scans are benign. One of the main determinants is the size of the lesion.

Most common causes of benign lung nodules are infectious granulomas (like tuberculosis, histoplasmosis, etc.), nonspecific granulomas, hamartomas, etc. Multiple other, less common, causes like fibrosis and atelectasis have been described in literature as causes of benign nodules.

Most common causes of malignant lung nodules are adenocarcinoma, squamous cell carcinoma and solitary metastasis.

4. Factors predicting the possibility of malignancy

One of the first steps in evaluating solitary pulmonary nodules is estimating the "pretest" probability. Multiple clinical and radiological factors help clinicians in predicting the possibility of malignancy. Multiple prediction models are available to estimate the risk of malignancy in lung nodules. Clinical judgment is an alternate way to estimate pretest probability.

CT scan of chest is needed to exclude mimics of lung nodule on chest X-ray (like nipple shadows, rib lesions, etc.) and to clearly define the important radiological variables. CT with contrast is preferred as it may help in determining the enhancement of the nodule and better evaluation of mediastinum. If biopsy is advised, CT will help in determining the approach.

Important predictors of malignant potential of solitary pulmonary nodule are discussed below:

Age

Clinically, age is one of the independent predictors of malignancy. Hence, nodules in older patients are more likely to be malignant than younger patients.

History of smoking

It is well known that smokers are at a higher risk of lung malignancy when compared to non smokers. The longer the time since quitting smoking, lesser is the possibility of malignancy.

History of cancer

History of extrathoracic cancer in the past has been found to be an independent predictor in predicting the malignant potential.

Size

Radiologically, size is one of the most important predictors. Lesions more than 3 cm in diameter have very high malignant potential and hence should be considered malignant until proven otherwise. Lesions smaller than 1 cm have lower malignant potential and Fleischner society has issued separate guidelines for management of such ’small’ nodules.

Location

Location of nodules in the lung is another important predictor as nodules on the upper lobes are more likely to be malignant. Although etiology of this predilection is unclear, higher concentration of inhaled carcinogens could be a possibility.

Calcification

Calcification of the nodule is one of the important radiological signs of benign nature, but only when the pattern is characteristic. Calcifications are better evaluated by CT scan rather than chest radiography as its sensitivity is very low.

Pattern of calcification

Diffuse, central and laminar pattern suggests benign lesion, while popcorn pattern of calcification suggests hamartomas. On the other hand, punctuate, stippled or eccentric pattern of calcification doesn’t exclude malignancy.

Growth rate

Another very important predicting factor is the growth rate. Never start evaluating a pulmonary nodule without comparing it in previous radiological images. This holds true for most incidentally diagnosed radiological abnormalities.

Doubling time

Doubling time of most malignant lesions are between 20–300 days. The volume of the lesion doubles first before the size. The general rule of thumb is if the size of the pulmonary nodule is stable for more than two years, it is benign. But very rarely, there may be exceptions.

Lesion characteristics

Nodules with smooth contour favors benign lesions, while lobulated or spiculated margin is highly suggestive of malignancy. Air bronchograms are not only seen in pneumonias, but also in malignant nodules. Enhancement after intravenous contrast is characteristic of malignant nodules due to their high vascularity.

Wall thickness

In a true cavitatory lesion, the probability of malignancy is more than 80% when maximum wall thickness is more than 15mm.

4. Models for predicting malignancy risk

Using above explained risk factors, multiple models have been created to estimate the malignant potential of lung nodules. Two models worth mentioning, and the main predictors used in these models, are:

Mayo clinic model

  • History of extrathoracic cancer

  • Spiculated morphology

  • Current or past smoking

  • Location - upper lung

  • Diameter of the nodule

  • Age

Veterans Affairs model

  • Current or past smoking

  • Age

  • Diameter of the module

  • Time since quitting smoking

Brock university model

  • Age

  • Sex

  • Family history of cancer

  • Emphysema

  • Nodule size

  • Nodule type (nonsolid, partly solid vs solid)

  • Location of nodule

  • Number of nodule

  • Spiculation

There was no statistically significant difference between the areas under the receiver operating characteristic curve for both models, making them equally accurate in predicting the likelihood of malignancy.

5. Differential diagnosis

The differential diagnosis of SLN is wide and can be broadly divided into malignant and benign categories.

Malignant causes

1. Primary lung malignancy: The most worrisome possibility of SLN is primary lung malignancy. Following are the causes of malignant SLN in decreasing frequencies - adenocarcinoma (accounts for almost half of all malignant SLN), squamous cell carcinoma, undifferentiated non-small cell carcinoma, small cell lung cancer and bronchoalveolar carcinoma.

2. Metastasis: Solitary metastasis would account for approximately 10% of malignant SLN. Sarcomas, breast cancer, colon cancer, renal cell carcinoma and malignant melanomas are among the common malignancies which cause lung metastasis.

3. Rare tumors: Carcinoid tumors, teratomas, lymphomas are other possibilities.

Benign causes

1. Infectious causes: Infectious granulomas account for majority of benign SLN. The common infectious causes of SLN are tuberculosis, histoplasmosis, nocardiosis, fungal mycetomas and round pneumonia.

2. Benign tumors: Hamartoma is one of the benign tumors which may cause SLN.

3. Inflammatory causes: Sarcoidosis, rheumatoid arthritis and Wegner’s granulomatosis are among the inflammatory diseases which cause SLN.

6. Diagnostic evaluation

Multiple radiological investigations are available to evaluate solitary pulmonary nodule and have got different characteristics.

Chest radiography

The first step in diagnosis is careful review of the chest radiography, if possible, with a radiologist. Two views are recommended although lateral projection may miss nodules. Always be aware of artifacts like nipple shadows. Multiple studies have shown that many solitary nodules can be missed by chest radiography.

Dual energy subtraction radiography

This new technique increased the ability of radiography to detect nodules markedly. But this digital radiography system is not widely available yet.

Computed tomography of the chest

CT scan is more sensitive and more specific than chest X-ray. The thinner the slice thickness, the higher the likelihood of nodule detection. Previous radiological images of the chest must always be compared to new images when a nodule is detected. CT scans provide more specific information about the nodule location and characteristics.

Computed tomography densitometry:

This is a sensitive technique, but not specific. This technique however is no longer used.

Magnetic resonance imaging

Not currently recommended for SLN evaluation.

FDG-PET

This is one of the commonly used tests in the world of oncology now. This is a non-invasive functional test. FDG is an analog of glucose which is selectively taken up by malignant cells. FDG accumulates within these cells and start emitting photons as FDG is a positron-emitting radionuclide. These photons are detected by PET scanner and the computer software localizes the abnormality using that information.

Uncontrolled hypoglycemia could cause false negative finding, but this is not widely accepted. Some malignancies like carcinoid tumors, mucinous adenocarcinoma could cause false negative finding as well.

PET scan is recommended in patients with low to intermediate pretest probability of malignancy and NOT recommended in patients with high pretest probability of malignancy.

Following are the invasive diagnostic approaches available in management of SLN:

Transthoracic needle biopsy

Usually transthoracic biopsy is CT guided, but can be done under the guidance of fluoroscopy as well. Although the sensitivity of needle biopsy is dependent on multiple factors, CT guidance seems to have higher sensitivity than fluoroscopic guidance in multiple studies. One of the common complications is pneumothorax, but large ones requiring interventions happen only in about 5% of cases. Another important point is that nondiagnostic biopsies do not exclude malignancy.

Bronchoscopy

Although many factors influence the choice between bronchoscopy and transthoracic biopsy, most important ones are proximity to the trachea and other major central airways, size of the lesion and operator preference.

7. Approach to management of solitary lung nodule

Management of solitary pulmonary nodule depends on choosing between following strategies:

  1. Watchful waiting with close follow-up

  2. Nonsurgical biopsy, which includes CT-guided transthoracic and bronchoscopic biopsy

  3. Surgery

According to the 2013 ACCP Guidelines, SLNs are divided into the following groups:

  1. 8 mm or larger

  2. Lesions smaller than 8 mm

  3. Nonsolid

  4. Part solid (>50% ground glass)

  5. Multiple subsolid nodule

Eight millimeters is used as a cut-off as the risk of malignancy increases markedly when the size of the lesion is 8 mm or larger.

General approach to lung nodules:

  1. If the nodule is identified on CXR, then CT of the chest should be performed (preferably with thin sections through the nodule) to help characterize the nodule.

  2. CXR or CT scan should be compared with prior imaging if available. If the nodule has been stable for at least 2 years, no additional diagnostic evaluation needs to be performed. Also if the lesion shows a benign pattern of calcification there is no need for further intervention.

Solitary solid pulmonary nodules of size between 8 mm to 30 mm

  1. Estimate pretest probability preferably by using validated models and categorize pretest probability as low, moderate, or high based on score <5%, 5%–65%, or >65%, respectively.

  2. Nodule with low pretest probability: serial surveillance with low-dose, thin sections, noncontrast CT scans should be performed at 3 to 6, 9 to 12, and 18 to 24 months.

  3. Nodules with low to moderate pretest probability of malignancy (5%–65%): functional imaging, preferably with PET, should be performed to characterize the nodule. Surveillance with serial CT scans is recommended if clinical probability is low (<30%–40%) and results of a functional imaging test such as PET or dynamic CT are negative, or when a fully informed patient prefers this nonaggressive management approach.

  4. In nodules with a high pretest probability of malignancy (>65%): functional imaging should not be performed to characterize the nodule, rather a surgical diagnosis should be pursued. (See Figure 1).

Figure 1.

Subcentimeter solitary pulmonary nodules (less than or equal to 8 mm)

Management is based on two major points: size of the nodule and presence of risk factors for malignancy.

1. Patients with NO risk factors for malignancy

  • Less than or equal to 4 mm - Follow-up is optional.

  • More than 4 mm to 6 mm - Follow-up at 12 months. If stable, no further follow-up recommended.

  • More than 6 mm to 8 mm - Follow-up recommended between 6–12 months. If stable, follow-up between 18–24 months is recommended.

2. Patients WITH risk factors for malignancy

  • Less than or equal to 4 mm - Follow-up at 12 months. If stable, no further follow-up is recommended.

  • More than 4 mm to 6 mm - Follow-up recommended between 6 and 12 months. If stable, follow-up between 18–24 months is recommended.

  • More than 6 mm to 8 mm - Follow-up at 3–6 months, second follow-up at 9–12 months and third follow-up at 24 months.

Non-solid nodules:

  • Nonsolid nodules that are <5 mm in diameter do not require further evaluation.

  • Nonsolid (pure ground glass) nodule measuring >5 mm in diameter, annual surveillance with chest CT for at least 3 years is recommended.

  • Nonsolid nodules >1 cm, may require early follow-up at 3 months, followed by nonsurgical biopsy and/or surgical resection for nodules that persist.

Part-solid nodules:

  • In individuals with a part-solid nodule measuring, a CT scan should be repeated at 3 months to confirm the persistence of the nodule. If the nodule persists and has a solid component <5 mm, then an annual CT scan for minimum 3 years is recommended. If a persisted nodule has a solid component ≥5 mm, then a biopsy or surgical resection is recommended.

Multiple subsolid nodules:

Ground glass nodules ≤5 mm: Follow-up CT scan at years 2 and 4.

Ground glass nodules >5 mm without a dominant lesion: Confirm persistence of the nodules by repeating CT scan at 3 months. If persistent, then follow up with an annual CT scan up to 3 years.

Dominant nodule with part solid or solid component: Confirm persistence of the nodules by repeating CT scan at 3 months. If persistent, then a biopsy or surgical resection is recommended.

Conclusion

A solitary pulmonary nodule is one of the common incidental radiological abnormality. The incidence is expected to rise with the increasing use of CT scan in the current era. Although SLN could represent lung malignancy where early intervention could be life saving, most SLN are benign. Differentiating malignant from benign nodules is complex and is based on multiple factors as discussed above. Nodules less than, or equal to, 8 mm are dealt with differently due to the low probability of malignancy.

Our recommendations are based on the 2013 ACCP guidelines, which are the current major medical guidelines concerning SLN.

What’s the Evidence?

Gould, MK, Fletcher, J, Iannettoni, MD. "American College of Chest Physicians: Evaluation of patients with pulmonary nodules: When is it lung cancer?: ACCP evidence-based clinical practice guidelines (2nd edition)". Chest. vol. 132. 2007. pp. 108S-130S.

MacMahon, H, Austin, JH, Gamsu, G. "Guidelines for management of small pulmonary nodules detected on CT scans: A statement from the Fleischner society". Radiology. vol. 237. 2005. pp. 395-400.

Khan, A. "ACR appropriateness criteria on solitary pulmonary nodule". J Am Coll Radiol. vol. 4. 2007. pp. 152-155.

Gould, MK. "Recent trends in the identification of incidental pulmonary nodules". American Journal of Respiratory and Critical Care Medicine. vol. 192. 2015. pp. 1208-1214.

McWilliams, A. "Probability of cancer in pulmonary nodules detected on first screening CT". New England Journal of Medicine. vol. 369. 2013. pp. 910-919.

Henschke, CI. "CT screening for lung cancer: frequency and significance of part-solid and nonsolid nodules". American Journal of Roentgenology. vol. 178. 2002. pp. 1053-1057.

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