The Solitary Pulmonary Nodule

What every physician needs to know:

The solitary pulmonary nodule (SPN) is a spherical radiographic opacity that measures less than 3 cm in diameter and is completely surrounded by lung tissue. The popular but misleading term “coin lesion” should be discouraged, as most SPNs are spherical, not round and flat. Patients with SPNs are usually asymptomatic, so most SPNs are detected incidentally on radiographic studies, including chest X-ray (CXR) and computed-tomography (CT) of the neck, chest, or abdomen. The widespread use of CT to investigate respiratory symptoms has markedly increased the detection of SPNs and made them a common clinical problem.

The differential diagnosis of the SPN includes malignancy, benign tumor, active granulomatous infection, healed granuloma, and scar. The work-up should focus on assessing the radiographic characteristics of the nodule and determining the growth rate of the nodule (if old radiographic studies exist).

The cornerstone of SPN management relies on the clinical assessment of the likelihood of malignancy in a specific nodule. The discovery of SPNs that are likely to be malignant should prompt surgical resection because malignant SPNs represent early-stage lung cancer, and resection offers the best chance of survival. SPNs that are likely to be benign can be followed with serial radiographic studies.

Some SPNs fall into the indeterminate category when various characteristics fail to assign cancer risk to the nodule with any confidence; optimal management in this situation requires a discussion between the physician and the patient, with careful consideration of the benefits and risks of each approach. Surgical resection of all SPNs encountered, although definitive, will result in many unnecessary surgeries with their attendant cost implications and potential for morbidity and mortality.

Classification:

Pulmonary nodules can be solitary or multiple. Solitary pulmonary nodules usually have no accompanying abnormalities in the chest, while multiple pulmonary nodules are often a manifestation of a systemic disease, including collagen vascular diseases (rheumatoid arthritis), vasculitis (granulomatosis with polyangiitis), granulomatous disease (sarcoidosis), infections (bacterial septic emboli, fungal or mycobacterial infection), malignancy (lung cancer or metastases from extrathoracic malignancies), or deposition diseases (amyloidosis). Patients are typically symptomatic with these diseases and may require systemic treatment.

Are you sure your patient has a solitary pulmonary nodule? What should you expect to find?

Most patients with SPNs are asymptomatic, but occasionally they have systemic symptoms like fever, chills, night sweats, or weight loss because of infectious or inflammatory causes. Respiratory symptoms like cough, hemoptysis, shortness of breath, and chest pain are uncommon.

Beware: there are other diseases that can mimic a solitary pulmonary nodule:

Structures outside the lungs can masquerade as pulmonary nodules on CXRs. These can be nipple shadows, various articular surfaces of bones in the thoracic cavity, or objects external to the body. Structures located within the lungs are usually seen in more than one radiographic view, in which case a CXR PA and lateral should be obtained and reviewed. Special projection X-rays may be recommended by the radiologist in selected cases. If doubt still exists after careful review of the CXR, a chest CT should be obtained.

How and/or why did the patient develop a solitary pulmonary nodule?

Malignant SPNs are related to well-known risk factors for cancer, particularly lung cancer. These risk factors include smoking, second-hand smoking, occupational exposure to asbestos, and exposure to radon (a natural gas that comes from rocks and dirt and that can become trapped in houses and buildings).

Some benign SPNs caused by fungal infection can be linked to environmental exposure (soil) or to dwelling in endemic areas (histoplasmosis in the Ohio River Valley and the Mississippi River Valley, or coccidiodomycosis in the desert region of the southwestern United States).

Which individuals are at greatest risk of developing a solitary pulmonary nodule?

Before ordering additional imaging studies or biopsy procedures for a patient with a SPN, the clinician should elicit factors related to patient characteristics and nodule characteristics that determine the pre-test likelihood of malignancy in the nodule.

Patient characteristics:

Advanced age – The risk of malignancy increases with age.
Tobacco use – Active smokers have a higher risk of lung cancer than non-smokers do, and the risk of cancer increases with increasing duration and quantity of smoking.
History of previous malignancy – Any history of prior thoracic or extrathoracic cancer should raise the possibility of recurrent cancer with metastases to the chest.

Nodule characteristics:

Size – The risk of malignancy increases proportionately with the diameter of the nodule. While the prevalence of malignancy is low (<1%) in nodules that measure less than 5 mm in diameter, it escalates to 64-82 percent in nodules larger than 20 mm in diameter.
Borders – Nodules with smooth margins have a lower risk of malignancy than those with irregular, lobulated, or spiculated borders do.
Morphology – Lung nodules can be qualified on chest CT images as solid, partly-solid, or ground-glass opacities. Ground-glass opacity is defined as hazy opacity that does not obscure underlying bronchial structures or pulmonary vessels. Nodules that have a pure ground-glass structure are more likely to be malignant than solid nodules are.
Calcification – Calcifications can be seen in both benign and malignant lesions. In some instances, calcification patterns can be highly suggestive of a benign cause of the nodule, prompting no further work-up in selected patients. These patterns include diffuse, central, laminated, or popcorn calcification patterns, the last of which is suggestive of benign hamartoma.

Once these data elements are collected, an estimate of the probability of malignancy can be formed using clinical judgment, a validated statistical model, or both. These quantitative models use multiple logistic regressions models from large studies on SPNs to create independent predictors of malignancy. The clinician can put the patient’s factors into the data fields and obtain a numerical value of the likelihood of malignancy in this particular patient. An example is the “SPN calculator,” which can be found at www.chestx-ray.com/index.php/calculators/spn-calculator

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Laboratory studies are not usually helpful in determining the etiology of the SPN. On rare occasions, when infectious or inflammatory conditions are suspected, selected serological tests–sedimentation rate, antibodies for specific inflammatory diseases (ANCA for granulomatosis with polyangiitis, RF for rheumatoid arthritis), or serological tests for fungal pathogens–may be part of the evaluation.

What imaging studies will be helpful in making or excluding the diagnosis of a solitary pulmonary nodule?

CXR: Nodules that are small or located behind superimposing structures can be missed on CXRs even by experienced specialists. CXR can be helpful in the initial characterization of the nodule’s size, morphology, and calcification, as well as other findings that can aid in the diagnosis, such as additional nodules, pleural effusion, and mediastinal or hilar adenopathy. The comparison of current CXRs to previous CXRs is particularly important, so the physician should make every effort to obtain old films that might have been performed in other institutions. Nodules that are stable for over two years are unlikely to be malignant.

Nodule growth is usually measured in volume-doubling time (VDT), the interval needed for the nodule to double in volume. Because of the spherical shape of nodules, one that doubles in volume has increased its diameter by 26 percent. (For example, a nodule that increases in diameter from 1 mm to 1.25 mm over a year has doubled in volume.) VDT for malignant nodules is estimated to range at 20-200 days: hence the recommendation for a two-year radiographic surveillance and declaration of nodule benignity if no change occurs in a two-year period. The exception to this rule is ground-glass nodules, which are often a slow-growing type of adenocarcinoma (bronchioalveolar cell carcinoma) that can have long VDT. A longer period of observation is recommended for these nodules.

Chest CT: A chest CT should be obtained on every nodule detected on CXR to increase the accuracy of the nodule’s size, borders, and morphology. CT can also reveal additional subtle abnormalities (other parenchymal abnormalities, adenopathy, or invasion of the nodule into surrounding structures) that can clue the physician into the underlying cause of the nodule. As with CXRs, comparison of CT findings to old CT studies provides invaluable information.

PET (positron emission tomography) scan: PET is a functional imaging study that displays the metabolic activity of various structures. The sensitivity of PET in identifying the malignancy in SPNs is comparatively high (87%), but the specificity is low (82%). False positive are seen in patients with infectious or inflammatory conditions like fungal and mycobacterial infection or rheumatoid nodules. False negatives are seen in certain types of malignancy, including bronchioalveolar carcinoma and carcinoid, as well as in nodules smaller than 10 mm in diameter. Therefore, PET imaging is not recommended in these small nodules.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of a solitary pulmonary nodule?

Non-invasive pulmonary diagnostic studies are not helpful in the diagnosis of SPN. However, they are indicated if surgical resection of the nodule is contemplated. Tests like the pulmonary function test and arterial blood gas can help determine the candidacy of the patient for surgery.

What diagnostic procedures will be helpful in making or excluding the diagnosis of a solitary pulmonary nodule?

Diagnostic procedures include transthoracic needle aspiration (TTNA), bronchoscopy, and surgical resection.

Transthoracic needle aspiration: In TTNA, which is usually performed by radiologists, percutaneous sampling of the nodule is performed under fluoroscopy, ultrasound, or CT guidance, the last of which is the most common guidance tool. The modality is most suitable when the nodule is peripheral, decreasing the amount of lung tissue that must be traversed to access the nodule. The sensitivity of TTNA in detecting malignancy in SPNs, which depends on the size and location of the nodule, ranges between 82 percent and 100 percent. While the specificity of TTNA is excellent (100% in most studies), the major limitation of TTNA is the incidence of pneumothorax after the procedure (15-43% of patients), although only approximately 5 percent of these pneumothoraces require placement of a chest tube.

Bronchoscopy: Bronchoscopy can be helpful in sampling SPN via instruments that can be extended from the distal end of the bronchoscope into the periphery of lung. The sensitivity of bronchoscopy in detecting malignancy in SPN has varied greatly (11%-82%), with higher yields obtained in larger and more central lesions and when a bronchial branch extends directly into the lesion on chest CT (“bronchus sign”). However, two new bronchoscopic technologies with improved diagnostic yield in SPNs are now available: endobronchial ultrasound (EBUS) and electromagnetic navigation bronchoscopy (ENB).

Radial EBUS is a miniature ultrasound probe that can be placed through the working channel of a bronchoscope and extended through bronchial branches into the lesion. An ultrasound image is displayed on a monitor, giving the operator feedback on the correct location of the lesion so sampling can be pursued with increased certainty. A recent meta-analysis showed that radial EBUS sensitivity and specificity for detecting malignancy in SPNs are 73 percent and 100 percent, respectively.

Similarly, ENB is a novel technology that couples CT images with bronchoscopic landmarks to create a road map to the peripheral lung nodule with real-time feedback to the operator on the location of a sensor tip relative to the target nodule. The experience with this technology is still limited, but the diagnostic yield in sampling SPN is approximately 70 percent. Although these novel bronchoscopic technologies have a lower yield than TTNA does, their incidence of pneumothorax is much lower (<7%).

A non-diagnostic sample obtained via any of the sampling modalities above would never rule out malignancy with absolute certainty, so these procedures should be followed by either surgical resection or clinical and radiographic surveillance based on the clinical situation.

Surgery: For patients with high likelihood of malignancy and those who prefer to undergo a definitive procedure over sampling modalities or radiographic surveillance, surgical resection can be pursued for both diagnostic and therapeutic purposes. Video-assisted thoracoscopic surgery (VATS) is the preferred surgical technique for sampling peripheral nodules with sensitivity and specificity close to 100 percent and a mortality rate of 1 percent. VATS resection of nodules smaller than 5 mm in diameter is fraught with difficulty and requires expertise. Various localizing techniques have been used with varying levels of success to assist the surgeon in finding smaller lesions.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of a solitary pulmonary nodule?

All cytological and histological samples obtained from SPNs should be examined by a pathologist with appropriate training to determine the underlying etiology. Additional fresh samples should be submitted for fungal and mycobacterial culture (based on clinical suspicion) at the time of sampling.

Recent research in the pathogenesis of non-small-cell lung cancer has revealed unique gene mutations, such as the epidermal growth factor receptor (EGFR) gene, which can be targeted with specific chemotherapy agents and lead to a marked improvement in patient survival rates. Gene mutation testing is now an essential part of the diagnosis of lung cancer. The clinician who is ordering sampling tests of SPN should ask that these tests be performed.

If you decide the patient has a solitary pulmonary nodule, how should the patient be managed?

The first step in the management of SPN is the careful assessment of all clinical and radiological aspects of the case, including review of old CXRs and CTs, evaluation of radiographic characteristics of the nodules, and review of the patient’s clinical history. If there is evidence of at least two years of radiographic stability of the nodule, then no further interventions are required–except for ground-glass nodules, which require longer follow-up.

If no old imaging studies are available, the clinician should assess the clinical probability of cancer and a management strategy based on whether there is a low, high, or indeterminate probability of cancer.

Radiographic surveillance with serial noncontrast, thin slice (1 mm), low-dose radiation chest CTs is most appropriate for cases in which there is a low probability of cancer. Intervals between imaging studies vary based on the size and characteristics of the nodule.

Solid nodules greater than 8 mm warrant surveillance CT scans at 3-6 months, 9-12 months, and then 18-24 months if unchanged. For solid nodules less than or equal to 8 mm, the size of the nodules and the individual’s risk factors dictate the recommendation for follow-up.

In patients with low risk:

Solid nodules less than or equal to 4 mm do not require follow-up.
Solid nodules 4 to 6 mm should be followed up at 12 months.
Solid nodules 6 to 8 mm should have 6- to 12-month follow-up and then, if unchanged, 18- to 24-month follow-up.

In higher-risk patients:

Solid nodules less than or equal to 4 mm should have 12 month follow-up.
Solid nodules 4 to 6 mm should be followed at 6- to 12-months and then at 18- to 24-months if unchanged.
Solid nodules 6 to 8 mm should have follow-up at 3 to 6 months, 9 to 12 months, and then at 24 months if unchanged.

Ground-glass (also called nonsolid) nodules: Due to their potential for representing more indolent malignancy, these nodules have different recommendations for surveillance. Ground-glass nodules less than or equal to 5 mm require no further evaluation, whereas ground glass nodules greater than 5 mm should be followed by annual CT scans for at least 3 years.

Part-solid nodules: Part-solid nodules less than or equal to 8 mm should be followed at 3 months, 12 months, 24 months, then annually for an additional 1 to 3 years. Part-solid nodules greater than 8 mm should be followed at 3 months, then by functional testing (PET-CT) or tissue biopsy.

Nodules >10 mm: In general, evaluation of nodules of any quality larger than 10 mm should include a discussion about biopsy or resection.

Of note, these recommendations are based on data published by the Fleischner Society and by the American College of Chest Physicians. In 2017, the Fleischner Society is publishing updated guidelines. The new recommendations will, among other things, increase the threshold for following nodules to 6 mm and broaden time intervals for follow-up of nodules in order to provide more flexibility for physicians to individualize recommendations.

If the clinician’s pre-test probability of malignancy is high and the patient is a good surgical candidate, referral to surgical resection is the most appropriate management. In this scenario, sampling of the nodule prior to surgery is discouraged; both positive and negative diagnosis of malignancy will lead to surgical resection, as the negative result may be the result of a sampling error and does not rule out malignancy.

Surgical resection in high-probability cases should be pursued.. If a diagnosis of lung cancer is obtained by a pathologist via intra-operative frozen-section analysis, the surgeon usually proceeds to mediastinal staging, followed by a complete resection of the involved lobe or wedge resection. If the patient is not a candidate for surgical resection, a tissue diagnosis of cancer is required prior to delivery of treatment via TTNA or bronchoscopy. Treatment options include external radiation therapy, stereotactic radiosurgery, and percutaneous radio-frequency ablation.

The probability of cancer may be indeterminate when there is a divergence between clinical judgment and radiographic studies or when there is a reasonable suspicion of an entity other than cancer (e.g., a fungal infection). In this situation it is appropriate to obtain a tissue diagnosis via TTNA, bronchoscopy, or surgery. Alternatively, watchful waiting with clinical and radiographic follow-up may be reasonable, but the clinician should spend ample time with the patient to explain the benefits and drawbacks of various approaches and determine the patient’s preferences.

What are the recommended institutional strategies for screening for lung cancer and monitoring lung nodules?

Much of the current data surrounding screening for lung cancer derive from the National Lung Screening Trial (NLST), a large controlled trial that showed a mortality benefit to lung cancer screening using low-dose chest CT scans. Consequently, individuals between ages 55 and 80 with at least a 30 pack-year smoking history, smokers within the past 15 years, or other individuals whose overall health would improve from diagnosis and treatment of lung cancer are all recommended to undergo annual lung cancer screening.

Moreover, it is now widely recognized that an interdisciplinary team is necessary in the management of lung cancer screening and the follow-up of lung nodules. Critical members of this team include primary care physicians, radiologists, pulmonologists, thoracic surgeons, oncologists, and many other administrative and support staff who can help coordinate care. Providers should engage in a shared-decision-making model along with their patients in order to identify those who would benefit from screening, to perform the screening in a timely fashion, and to refer to the appropriate specialists for evaluation of abnormal findings.

There are several other institution-wide adjustments that can improve the success rate of a lung cancer screening program. Using a high-quality, standardized reporting system such as the American College of Radiology’s Lung Imaging Reporting and Data System (Lung-RADS) is one such example. Keeping careful registries of patients with lung nodules and comprehensive modes of communication to patients and primary care physicians can help to prevent loss to follow-up. Lastly, the importance of ongoing smoking cessation efforts cannot be overstated.

What is the prognosis for patients managed in the recommended ways?

The prognosis of SPN follows the prognosis of the underlying disease. Infectious or inflammatory diseases carry a more favorable diagnosis, while lung cancer or metastases from extra-thoracic malignancies carry a modest to poor prognosis. Despite advances in the treatment of lung cancer, the five-year survival rates of stage I and II non-small-cell lung cancer (reflecting the likely stages of SPNs) are approximately 60 percent and 30 percent, respectively.

What other considerations exist for patients with a solitary pulmonary nodule?

The discovery of a lung nodule, with the possibility of a cancer diagnosis generates a tremendous amount of fear and anxiety in most patients. Clinicians should be sensitive to the mental well-being of their patients and spend adequate time explaining the nature of their condition and the risks and benefits of the diverse range of diagnostic and therapeutic approaches available.

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