A 59-year-old woman presents to your clinic with severe abdominal pain. After exhausting other measures, you order an abdominal CT, which is unremarkable other than a small 5 mm pulmonary nodule in the base of the left lower lobe. Her abdominal pain spontaneously resolves; however, she has concerns about the pulmonary nodule. What do you tell her?
Pulmonary nodules are a common finding on chest radiograph and CT imaging. The widespread use of CT scans has seemingly spurred an epidemic of pulmonary nodules, leaving clinicians to determine whether they represent harmless spots or worrisome tumors. Various institutions have released guidelines to help clinicians manage nodules by using clinical and radiographic features and establishing algorithms for CT surveillance and treatment pathways. Physician assistants (PAs) must be aware of best practices, as pulmonary nodules are frequently found incidentally on CT imaging. Furthermore, the discovery of nodules is expected to rise as the use of CT increases, in particular for lung cancer screening.
Lung cancer is the second most common malignancy in the United States and has the highest mortality among cancers. Understandably, many patients will be anxious if a spot is discovered in the lung.1 Most nodules, however, are benign. PAs are patient advocates who can effectively manage small pulmonary nodules, offer and understand the appropriate diagnostic plan for larger nodules, and provide much needed patient education to assuage patients' fears.
DEFINITION, INCIDENCE, AND PREVALENCE
A pulmonary nodule is a rounded opacity that is well or poorly defined, measuring up to 3 cm in diameter.2 Anything larger is called a mass. A radiologist may discover nodules as small as 6 mm on a chest radiograph, but generally they must be at least 1 cm to be well-visualized. CT resolution can detect a nodule as small as 2 mm. Due to the subjective measurements between radiologists, a subcentimeter nodule is considered to be 8 to 10 mm in diameter or less.3
A well-defined nodule is usually wholly solid and clearly visible on CT. Nodules that are partly translucent (through which the lung parenchyma, surrounding vessels, or airways can be seen) are described as subsolid or ground-glass.4
Pulmonary nodules are a frequent chief complaint in the pulmonary department. One study found that up to 96% of incidental nodules are less than 10 mm in size and often more than one is reported.5 Nodules are discovered on 8% to 51% of all chest CTs, in smokers and nonsmokers alike. Nodules have been found in up to 60% of CTs in studies for lung cancer screening.3 Nodules are also detected incidentally on cardiac and calcium-scoring CTs and in the lung bases of abdominal CTs.
Possible causes of pulmonary nodules include many benign etiologic factors. Smaller nodules may represent postinfectious scars, intrapulmonary lymph nodes, or small inflammatory lesions.5 Many incidental, indeterminate, subcentimeter nodules are nonspecific granulomas or infectious granulomas that are the sequelae of a past infection with an endemic fungal disease such as histoplasmosis or coccidiomycosis. Larger nodules may represent granulomas, organizing pneumonias, or hamartomas (fat density tumors). Some other causes of pulmonary nodules, which will often present with other chest findings or systemic complaints, include active infections, inflammatory lesions from systemic conditions such as rheumatoid arthritis or Crohn disease, sarcoidosis, and metastatic disease. For any pulmonary nodule, however, the leading concern is primary neoplasm.6
The overall prevalence of cancer in a nodule discovered during lung cancer screening trials was 1.1% to 12%, according to a literature review.7 Further defining by size, the risk of malignancy in a nodule smaller than 5 mm was less than 1%. For nodules 5 to 10 mm, 6% to 28% were found to be cancer. The prevalence of malignancy over 20% may be explained by the patient population (those at high risk for lung cancer: heavy smokers, older age) and the grouping of nodules ranging from 5 mm to 10 mm, which also has a significant difference in terms of risk. Other US trials have found the prevalence of malignancy to be as low as 2.3% in nodules in the 5 to 9 mm size group. Among larger nodules (those greater than 20 mm), 64% to 82% were found to be malignant.7,8
In a study of more than 12,000 abdominal CTs, 362 (3%) reported lung nodules. Of those, only 16 were malignant and all had a history of preexisting or newly diagnosed abdominal organ cancers from that initial abdominal CT.9
The initial assessment begins with a history and physical examination to determine the patient's overall health and risk for developing lung cancer, and to help the clinician form the differential diagnosis of the nodule or nodules. Careful review of the CT report and actual images is imperative as the radiographic features and descriptors aid in diagnosis and follow-up.10
Patient factors Certain patient factors can act as risk predictors in determining a malignant versus benign nodule. Older age is directly related to a person's lung cancer risk.6 Lung cancer is uncommon in patients under age 40 years and rare in patients under age 35 years (less than 1% of cases).11 More than 60% of patients with lung cancer are between ages 65 and 84 years.
Tobacco use has been linked to bronchogenic cancer for decades. Active and former smokers are much more likely to have a malignant nodule over a patient who has never smoked. The amount and duration of cigarette smoking directly affect risk.4,8,9,11 A recent study of the past 50 years of cigarette smoking in the United States found that smokers' risk for developing lung cancer is about 25 times higher than that of patients who have never smoked.12 Cigar smoking also is an independent risk factor for lung cancer. Other risk factors for lung cancer include exposure to secondhand smoke, having a first-degree relative with lung cancer, and exposure to asbestos, silica, arsenic, radon, or uranium. However, cigarette smoking is still the leading risk factor.11
In patients with a personal history of cancer, multiple lung nodules may represent lung metastases. These patients fall outside the standard guidelines and should be referred to a pulmonologist. Decision making is guided by the type of cancer and the time since the initial diagnosis.11 Patients with previous malignancies also are at greater risk for developing other cancers. In particular, patients with a history of aerodigestive malignancies (affecting the respiratory and upper gastrointestinal tracts) and those who have had previous chest radiation therapy are at greater risk for developing a primary lung cancer.6
Patient factors that may help corroborate a benign cause for a pulmonary nodule include symptoms of a recent respiratory infection, history of systemic inflammatory or connective tissue diseases, residence in or travel to an endemic fungal area, working in a barn, exposure to bird droppings, or engaging in unusual hobbies such as spelunking.5,6,13 A lung nodule itself will not cause any symptoms unless it is large enough to obstruct an airway, in which case the person may have a persistent cough.
Imaging characteristics The size of a nodule influences its risk for malignancy. As a nodule increases in size, so does its chance of being malignant.3–9,11–13 Most malignant nodules double in size (based on volume not diameter) every 20 to 400 days. This is called the doubling time.3 A nodule that has rapidly grown in size over the course of several days or weeks is more than likely to be an infectious process. A solid nodule that has not grown or changed in shape in 2 years is deemed benign. One study of patients at high risk for lung cancer used volumetric measurements of nodules discovered on screening CTs.14 The researchers found that patients with indeterminate, solid nodules (ranging in size from 4.6 mm to 9.8 mm) with a doubling time of more than 400 days had a 99.9% chance of not having cancer.
When initially interviewing patients, ask about old CTs or chest radiographs (if the nodule is visible on radiograph) and obtain these for comparison.15,16 If the nodule was present on a CT from several years ago and is unchanged in size or shape, it is benign, and no further workup or tests are needed.
The makeup or density of a nodule provides clues to its origin. A dense, central, and uniform calcification pattern is a very reliable predictor of a benign nodule. Using the density measure (greater than 164 Hounsfield units) and comparing the nodule to surrounding bone can confirm the presence of calcium (Figure 1). A laminated calcification pattern also is indicative of a granulomatous response. Hamartomas will have the density of fat and may contain “popcorn” calcification. However, calcium deposits do not always denote a benign process. Punctate calcifications may be visible in carcinoid tumors and primary lung cancers.5
Many subcentimeter nodules are difficult to characterize due to their small size. Suggested features of benign small nodules include subpleural, flat, or polygonal shaped nodules in small clusters. These nodules are usually located in the bases or lung periphery. Tiny nodules within the fissures usually represent benign intrapulmonary lymph nodes (Figure 2).5 Smooth or rounded borders are associated with benign causes but many cancers also present this way.
Nodules greater than 8 mm with spiculated edges and an irregular shape or lobulated appearance are concerning for cancer (Figure 3).8,9 Larger nodules located centrally or in the upper lobes are also more suspicious for cancer.6
The subsolid lesion or ground-glass nodule may be described as pure ground glass or contain a part-solid component (Figure 4). These subtle characteristics play a role in management. Ground-glass nodules have a higher likelihood of being cancer compared with solid nodules, and have a different disease evolution process.4,8,9
ENACTING THE PLAN
Not all nodules can be grouped together in a basic definition in terms of diagnosis and treatment. The plan is developed based on the risk of malignancy as determined by clinical and radiographic features. The approach to a 3-mm nodule versus a 23-mm nodule, a solid versus subsolid nodule, and a patient who smokes versus one who has never smoked will be different.
The only situations in which clinicians may be confident in a benign cause for a nodule is if:
- the nodule is densely and uniformly calcified
- the nodule is less than 4 mm and the patient is healthy and has never smoked
- the small solid nodule has been present and unchanged for 2 years or more (remember to always obtain old imaging, if possible)
- the nodule is small and solid and the patient is otherwise healthy and under age 30 years.
All other nodules require further attention.4,8–10
Subcentimeter nodules Management for subcentimeter nodules consists of CT surveillance over 2 years. Follow-up CT scans of the chest should be performed without contrast unless otherwise indicated by the radiologist (Table 1).
Going back to the clinical scenario, if the 59-year-old patient has never smoked, she would be advised to have a follow-up CT in 1 year. If she is a current or former smoker, she would be advised to have a CT follow-up in 6 to 12 months.11 Discuss smoking cessation with active smokers at every visit, as quitting smoking at any age is beneficial.17
Some patients will feel disconcerted by this active surveillance or “watchful waiting” approach.18 Provide detailed patient education, explaining the risks and low yield of intervention, and the low likelihood of cancer.14 A common response from a patient may be: “Why can't you just cut it out of me?” Acknowledge the patient's concern and address the downfalls of intervention. Subcentimeter nodules are often not amenable to biopsy and too small to be felt by a surgeon during a procedure. Because most of these nodules are benign, patients should not be subjected to unnecessary surgery and the accompanying risks of respiratory complications, chronic pain, and (rarely) death. Inform the patient that if the nodule grows during surveillance, it will have been caught early and will be more aggressively managed. Table 2 specifies recommendations for discussing pulmonary nodules with patients and addressing patient concerns and anxiety.18,19
Another common concern is the risk of radiation exposure from continued CT follow-up. Using complex statistical analysis and modeling, some researchers have been able to assign lifetime risk for cancer from CT exposure. From one study, a 60-year-old woman would have to undergo 1,090 chest CTs without contrast to develop a radiation-induced cancer (compared with 2,080 CTs for a 60-year-old man and 390 CTs for a 20-year-old woman).20 To put this in perspective, any individual's lifetime risk for developing cancer is about 40%.1
Overall, the risk from CT exposure is quite low, but patients should be adequately informed. The Fleischner Society recommendations are only for patients over age 35 years. CTs must be used cautiously in younger patients (especially young women) whose tissues are more radiosensitive; younger patients also have longer life expectancies. For patients under age 35 years, one CT follow-up in 6 to 12 months may be considered.11,20
The bottom line is that the vast majority of pulmonary nodules are benign.7 For patients who present with small pulmonary nodules, estimate the likelihood of cancer, provide reassurance, and follow the guidelines listed in Table 1. In cases where the patient or clinician is uncomfortable with CT surveillance, or the patient is at high risk for lung cancer, refer the patient for a pulmonary consultation.
Larger nodules (8 to 30 mm) With a wide gray area, any nodule 8 mm or larger requires attention and referral to pulmonology and/or thoracic surgery for further assessment and intervention.3,11 However, 8 mm is not a magic number. Regardless of the size of the nodule, the decision for referral should be guided by the clinical picture, the likelihood for cancer in the nodule, and other risk factors. Tertiary care medical centers commonly offer advanced diagnostics, interventional pulmonary services, studies and trials, a multidisciplinary approach, and specialist pulmonary nodule clinics.21
Guidelines suggest that clinicians first estimate the likelihood of malignancy of these larger nodules using clinical judgment or validated models.10 One such model, the solitary pulmonary nodule (SPN) calculator, is available online at http://www.chestx-ray.com, under the Calculators tab.6 Another helpful source (http://www.brocku.ca/lung-cancer-risk-calculator) lets providers download a free probability calculator.22 The calculations must be used in combination with the clinical situation and other predictors. Establishing the probability of cancer helps clinicians choose which tests and/or intervention are most appropriate for each patient.
Positron emission testing (PET) can assist in diagnosing a cancerous nodule. PET scans use a radioactive dye, usually fluorine-18-fluorodeoxyglucose (FDG), to assess metabolic activity. Cancers are metabolically active and so will “light up” on the scan measured in the standardized uptake value (Figure 5). A standardized uptake value greater than 2.5 is generally considered positive but this varies between machines and scans. Evidence has shown that the use of PET scans has reduced the number of resections for benign nodules. The sensitivity of PET scanning for revealing a malignant nodule is 80% to 100%.7 However, there are drawbacks.
The specificity of PET is variable, with reports of specificity ranging from 40% to 100%.7 Active infections or inflammation may also appear as positive on PET scan. Nodules smaller than 8 mm should not be evaluated by PET scan, as they are below the resolution and could be false-negative. PET scans should not be used for ground-glass nodules, which are less dense and less metabolically active. Carcinoid tumors also will be negative. Furthermore, PET scans are expensive. To be covered by most insurers and to fit the appropriate clinical criteria, the situation should consist of a solitary pulmonary nodule between 10 and 30 mm in size.15,23
Biopsy is generally required for a larger pulmonary nodule. The nodule's size and location will determine the best course for obtaining tissue. Transthoracic needle biopsy may be attempted for nodules close to the chest wall. For nodules centrally located near an airway, standard bronchoscopy may be sufficient. Newer advanced bronchoscopy techniques such as electromagnetic guidance and radial probe ultrasound allow greater sampling and higher yield for peripheral and smaller nodules.3,24
An otherwise healthy patient may proceed straight to surgical resection without biopsy if, based on clinical indicators, a nodule is suspicious for a stage IA lung cancer with no other spread of disease evident on PET or CT scan. If the nodule is proven to be malignant on frozen section during surgery, a lobectomy is performed. Surgical resection of an early-stage lung cancer provides the best chance for cure, so close attention to a suspicious nodule is crucial.10 Guidelines for lung cancer resection surgery are complex and may be found elsewhere in the literature.25
Bottom line: Estimate the likelihood of malignancy in patients presenting with larger nodules. Consider a PET scan based on the patient's risk for lung cancer. Refer all patients with larger nodules for pulmonary and thoracic surgery consultations.
Subsolid lesions Many ground-glass nodules and subsolid lesions are caused by infectious or inflammatory processes and resolve within 3 months. However, persistent ground-glass nodules may represent early adenocarcinomas. This disease process was once called bronchioalveolar carcinoma, but a new classification system reveals a wide spectrum of pulmonary adenocarcinoma, from premalignant lesions to invasive disease.26 Morphologically and histologically, the ground-glass nodule that represents an adenocarcinoma in situ is markedly different from the more common and aggressive forms of non–small cell lung cancer.
These neoplasms may develop in younger patients who have never smoked, and are more common in women. They are slow-growing, so the standard 2-year follow-up is not sufficient. See Table 3 for an algorithm for managing subsolid lesions. Pure ground-glass nodules that persist beyond 3 months have a greater likelihood of being malignant. Mixed-density lesions (ground-glass with a solid part) and ground-glass nodules that become more dense or evolve into developing solid components over time are also highly suspicious.4,16
Bottom line: For patients with a ground-glass nodule or subsolid lesion, perform a chest CT in 3 months or as dictated in Table 3. Refer the patient to a pulmonologist upfront or if the lesion persists on the 3-month scan.
ON THE HORIZON
The findings of the National Lung Cancer Screening Trial showed a 20% reduction in lung cancer mortality using a low-dose chest CT for high-risk patients.27 Several journals and societies have issued guidelines for lung cancer screening based on these findings and evidence from the literature. Many institutions offer lung cancer screening CTs for a nominal fee, as this service is not covered by most insurers, including Medicare. However, this is expected to change in the near future because the US Preventive Services Task Force recently issued recommendations for screening high-risk populations with low-dose CT.28 When selecting patients for screening, choose only those who fit the appropriate criteria:
- age 55 to 74 years
- current smoker of 30 pack years or more, or former smoker of 30 pack years or more who has quit within the last 15 years.21,27,29,30
As CT screening increases so will the incidence of pulmonary nodules. The lung cancer screening studies have proven that indeterminate pulmonary nodules (or “false positives”) are inevitable.30 This highlights the need for understanding pulmonary nodule management and the effort to decrease patient anxiety and the risk of unnecessary biopsy and surgery.
Noninvasive tests may aid in determining a benign versus malignant nodule. However, very few of these tests are used in clinical practice. Biomarkers, such as serum antibodies, protein profiles, or genetic changes, show promise as risk predictors for lung cancer, but these blood tests must be used in accordance with other clinical predictors.31 Recent studies of exhaled breath analysis of volatile organic compounds have found moderate accuracy in distinguishing lung cancer from controls. Breath biosignatures can also predict lung cancer histology and even the stage. Breath testing with an “electronic nose” is still in the research phase and not available in the clinical setting.32
Pulmonary nodules are a common occurrence and frequent complaint to the pulmonary department. Because lung cancer remains the deadliest malignancy, clinicians must understand the management of nodules and the effect they have on patients.1 As low-dose CT lung cancer screening becomes more accepted, pulmonary nodules are more likely to be discovered. Most subcentimeter pulmonary nodules are benign and require CT follow-up according to published guidelines. Larger pulmonary nodules generally require referral to pulmonology and/or thoracic surgery for further intervention.
CLINICAL SCENARIO OUTCOME
The woman in the opening clinical scenario had a 5-mm nodule in the very base of her left lower lobe. The nodule was round and solid. The patient had a 20-pack-year smoking history but quit about 15 years ago. She denied other significant past medical history or history of cancers. Because she had been a smoker, she was considered high-risk. After discussing the benign features of the nodule (very small, round, and in the base), the low likelihood of malignancy, and the rationale and duration of a CT surveillance plan, the patient and clinician opted for a 12-month follow-up with a chest CT per guidelines listed in Table 1.
On the 12-month follow-up scan, the nodule was stable and unchanged. However, as often happens, the full-chest CT revealed another nodule in the left lung that was not visualized on the abdominal CT. This nodule was 3 mm in size. Another CT was performed 1 year later and showed both nodules to be stable. At that point, the clinician told the patient that the nodules were benign and most likely represented noncalcified granulomas. She did not need further CT surveillance. The patient felt reassured that the nodules were tiny scars and was glad “to give up the worry.”
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Keywords:© 2014 American Academy of Physician Assistants.
pulmonary nodules; lung cancer; subcentimeter; screening; incidental; ground-glass