Continuing Education Activity

A solitary pulmonary nodule (SPN) is a single lung nodule measuring less than 3 cm. Even though most cases are benign, it is essential to determine the underlying cause because lung cancer is the leading cause of oncological death in the U.S. This activity reviews the evaluation and treatment of an SPN and highlights the interprofessional team's role in evaluating and treating patients with this finding.

Objectives:

• Review the diagnostic criteria for a solitary pulmonary nodule.
• Summarize the different ways in which a patient may present with a solitary pulmonary nodule.
• Outline the various methods of managing a solitary pulmonary nodule.
• Describe interprofessional team strategies for improving care coordination and communication to advance the management of a solitary pulmonary nodule and improve outcomes.

Introduction

Solitary pulmonary nodule (SPN) is defined as a single lung opacity of size less than 3 cm. It is usually discrete and does not attach to the lung border or pleura. Associated lymphadenopathy is characteristically absent. Though most of the SPNs are benign in nature, these nodules pose diagnostic challenges for the physicians, especially when they are incidentally discovered during routine CT scans of the chest in relatively asymptomatic patients. Differentiating the benign and malignant nature of these nodules could be very challenging in the absence of biopsy. With the complications associated with the biopsies or repeated "unnecessary" CT scans of the chest, a systematic approach becomes essential in evaluating these nodules. Since its initial publication in 2005, Fleischner Society guidelines (updated in 2017) are utilized by most clinicians worldwide to evaluate the SPN and other pulmonary nodules.[1] The Fleischner Society is an international, interprofessional approach to the diagnosis and management of diseases of the chest. In this activity, the SPN is discussed in detail.

Etiology

Solitary pulmonary nodules (SPNs) are generally nonmalignant though there is always the concern for malignant neoplasms. Differential diagnoses for benign SPN include infectious, inflammatory, congenital nodules of the lung. Granulomatous infections like tuberculosis, fungal infections including Histoplasmosis, Cocciodiomycosis, parasites like Echinococcus causing pulmonary hydatid cyst, Paragonimus westermani, also known as Chinese lung fluke, cause solitary lung opacities. Bacterial pneumonia is a rare cause of solitary lung opacities and can represent an abscess. Scars as a sequela of previous infections could cause an SPN. Noninfectious granulomas like sarcoidosis, other inflammatory disorders like rheumatoid arthritis, granulomatosis with polyangiitis (GPA) are examples of inflammatory etiologies for SPN. Bronchogenic cysts and arteriovenous malformation are present since birth and would be incidentally found even in asymptomatic individuals. Other benign causes that could present as solitary pulmonary nodule would also include mucus plugging, rounded atelectasis, pulmonary infarction, fibromas, and hamartomas. On the other hand, SPNs may present as a wide variety of malignant neoplasms, including bronchogenic carcinoma (both small cell and non-small cell carcinomas), metastatic cancers, carcinoids, lymphomas, and sarcomas.

Epidemiology

In the general population, solitary pulmonary nodules (SPNs) are found incidentally on 0.1% to 0.2% of chest x-rays and 13% on CT scans. Those with a high risk for malignancy, such as those with a smoking history or previous malignancy, have an increased incidental finding of an SPN on 9% of chest X-rays and 33% on low dose CT scans.[2] It is estimated that the prevalence of SPN found in the general population is 2% to 24% and is 17% to 53% in those who are screened due to having more risk factors for occult malignancy. The risk factors that lead to an increased incidence of SPN include being a current or previous smoker, a diagnosis of chronic obstructive pulmonary disease, and advanced age.[3] An SPN tends to be found more often in men than women using screening CT scans, 18.8% and 16.3%, respectively. When using a chest x-ray for screening, men still had increased findings of SPN over women with an incidence of 2.5% and 1.6%, respectively. On the other hand, women did have a higher incidence than men to have an SPN in the nonsmoking population. This leads to a higher incidence of pulmonary adenocarcinoma for women.[4]

History and Physical

Around 95% of patients who are found to have an incidental SPN found on imaging are asymptomatic. Those patients that do present with symptoms usually have symptoms related to the underlying etiology of the SPN. It is essential to evaluate patients for high-risk malignancy and obtain a detailed history and physical to help determine your management of the SPN. Obtain information on smoking status, previous malignancies, personal and family history of cancer, especially lung cancer, and current lung condition such as chronic obstructive pulmonary disease (COPD), emphysema, and interstitial lung disease to help rule out malignant SPN. Auscultate both lungs to help uncover the underlying condition. It is also essential to obtain travel history when infectious etiologies are suspected, especially if the patient has been to areas with endemic tuberculosis. Also, inquire about the history of rheumatoid arthritis, granulomatosis with polyangiitis, or other autoimmune disorders. Most of the time, physical findings of an SPN will be absent, and one must rely on history and imaging.[2]

Evaluation

A chest CT scan is a modality that is most likely to pick up a solitary pulmonary nodule (SPN). It is also used as the first-line when observing the nodule as it can detect changes in the size of 1 to 2 mm, which is often an integral part of determining nodule etiology. If the SPN is larger (>8 mm)or the patient is at higher risk for malignancy, a Positron emission tomography scan may be used for further evaluation. Chest x-rays are not the best imaging modality to pick up an SPN, but they are the most commonly performed. They, therefore, can identify a large number of asymptomatic patients with an SPN. MRIs are more expensive than CTs and do not have any increased use when evaluating a solid SPN. If the nodule is cystic or ground glass in appearance, then the MRI may be of more use.[5] Electromagnetic navigation bronchoscopy offers a noninvasive means of evaluation but is limited by its cost and is usually only used if other means are impossible or unsuccessful.[6] Tumor markers such as CEA, FR positive circulating tumor cells, LG3BP, and C163A may also aid in evaluating SPN when distinguishing between benign versus malignant.[7] The ultimate test to evaluate for the cause of the nodule is a biopsy. This may be performed by fine-needle aspiration, liquid biopsy, or excisional biopsy, depending on location. The tissue sample can then be examined histologically.[8] Biopsies of the tumor itself or enlarged lymph nodes may be obtained by CT-guided transthoracic needle aspiration or through the use of bronchoscopy. Multiple variations of bronchoscopic techniques, including radial probe endobronchial ultrasound (RP-EBUS), thin/ultrathin bronchoscopes, virtual navigation bronchoscopy (VBN), robotic bronchoscopy, and electromagnetic navigation bronchoscopy (ENB) may be used to help aid with the biopsy. Bronchoscopic biopsy carries a lower risk of adverse events than transthoracic biopsy, but it also has an overall lower diagnostic yield.[9]

Whenever a patient is found to have an SPN, it is essential to determine the patient's risk for malignancy. Lung imaging reporting and data system (Lung-RADS) is a classification tool used to evaluate findings on a low dose CT scan when screening for lung cancer. A category 0 (incomplete) is used if there is prior CT imaging that is not available for comparison or if the lungs are not completely imaged. Category 1 (negative) is when there are no lung nodules found or nodules carrying high favorability to be benign (complete/centra/concentric ring/popcorn calcifications or fat-containing nodules.) This carries a less than 1% chance of malignancy. Category 2 (benign appearance) is for solid nodules <6 mm, new solid nodules <4 mm, subsolid nodules <6 mm, or ground glass nodules <30 mm and carries a <1% chance of malignancy. Category 3 (probably benign) is for solid nodules >6 mm but <8 mm, new solid nodules >4 mm but <6 mm, subsolid nodules >6 mm with solid component <6 mm, new subsolid nodules <6 mm, or ground glass nodules >30 mm and carries a 1% to 2% chance of malignancy. Category 4A (probably suspicious) is for solid nodules >8 mm but <15 mm, growing nodules <8 mm, new solid nodules 6mm to <8 mm, subsolid nodules >6 mm with solid component >6 mm but <8 mm, new/growing subsolid nodules with a <4 mm solid component, or an endobronchial nodule and carries a 5 to 15% chance of malignancy. Category 4B (suspicious) is for solid nodules >5 mm, new or growing solid nodules >8 mm, subsolid nodules with solid component >8 mm, or new/growing subsolid nodules with >4 mm solid component and carries a >15% chance of malignancy. Category 4X (suspicious) is either category 3 or 4 with other features suspicious for malignancy, including spiculation, ground-glass nodules that double in 1 year, and enlarged regional lymph nodes.

In addition to the Lung-RADS classification system, two calculators help to determine the malignancy probability. The Mayo Clinic Calculator (1997) utilizes certain criteria to help estimate the malignancy risk. These are increased age, upper lobe location of the nodule, nodule diameter in mm, spiculation, smoking, and extra-thoracic cancer >5 years. Another risk calculator is the Brock University calculator (2013), which takes a few more variables into account. It still uses increased age, upper lobe location, nodule diameter in mm, and speculation, but it also adds emphysema, ground-glass opacity, subsolid nodule, female sex, number of nodules, and family history of lung cancer. Notably, it does not take into account smoking status.[2] Both of these calculators will produce a percentage that indicates the likelihood of the SPN to be malignant. It was recently found that Lung-RADS categories 2 and 3 were underreporting the risk of malignancy and that the Brock risk calculator was a more accurate tool.[10] Nonetheless, all of these are valuable tools physicians can utilize to determine their next step as far as management.

Treatment / Management

The management of a solitary pulmonary nodule is best performed by using an interprofessional approach. Assessing for nodule size, appearance, patient risk factors, and patient preference are integral in treating SPNs. The following is a summary of the 2017 Fleischner Society Guidelines.

Solid nodules: <6 mm in a low-risk patient do not need any routine to follow up; if it is a high-risk patient, then a repeat CT scan at 12 months is optional. If between 6 to 8 mm, regardless of the patient's risk, a repeat CT in 6 to 12 months and again at 18 to 24 months is warranted. If the nodule is >8 mm, consider repeating CT at 3 months versus obtaining a PET/CT or tissue sample. If high risk, a diagnostic biopsy is essential to distinguish the nodule's etiology.[11]

Gound glass nodules: <6 mm require no routine follow up. If >6 mm, then repeat CT at 6 to 12 months, then every 2 years for a total of 5 years. If parts of the nodule are solid, consider resection.

Partly solid nodules: <6 mm require no routine follow up. If >6 mm, the repeat CT at 3 to 6 months, if nodule continues to grow or has persistent solid component >6 mm, the patient is deemed high risk, and resection should be considered. A CT should be performed annually for 5 years if the nodule is unchanged from a prior and solid component <6 mm.

If multiple nodules, repeat CT at 3 to 6 months. Refer to the above information for further management of individual nodules.[3][8]

In 2013, the American College of Chest Physicians (ACCP) came out with its guidelines for SPNs. It states that CT imaging should be utilized if a nodule is found on a chest x-ray. These need to be compared to old images to evaluate for any change. If a nodule has been stable for 2 years, then no more testing is needed.

Solid nodules <8 mm are more likely to be benign and are divided into two groups: those with or without risk for malignancy. If there is no risk for malignancy and the nodule is <4 mm, follow up is optional. For nodules 4 to 6 mm, follow-up CT at 12 months. For nodules 6-8 mm, follow up at 6 to 12 months and then again at 18 to 24 months. Patients with risk factors for malignancy and nodules <4 mm should have repeat CT at 12 months. If the nodule is 4 to 6 mm, follow up CT at 6 to 12 months and again at 18-24 months. For nodules of 6 to 8 mm, follow up with repeat CT at 3 to 6 months, 9 to 12 months, and again at 24 months.

Solid nodules between 8 and 30 mm are be divided into three groups: low, moderate, and high pretest probability. Low pretest probability should have low dose CT at 3 to 6 months, 9 to 12 months, and 18 to 24 months. Moderate pretest probability should have PET or serial CT scans. High pretest probability should go straight to surgical diagnosis with either biopsy or surgical excision.

Part-solid nodules should have repeat CT imaging at 3 months. If at 3 months, the solid component is <5 mm, then annual CT imaging is recommended for at least 3 years. If it is >5 mm at 3 months, then a biopsy or surgical excision is warranted.

Non-solid nodules <5 mm need no further evaluation. Those >5 mm should get annual CT scans for 3 years. If the non-solid nodule is >1 cm, repeat imaging at 3 months, biopsy, or surgical excision is warranted.

Ground glass nodules <5 mm should have a repeat CT in 2-3 years. In those >5 mm, a repeat CT in 3 months with subsequent CTs up to 3 years if the nodule continues to persist. If the nodule persists at 3 years, then a biopsy or surgical excision is recommended.

Nodules classified as a Lung-RADS category 0 need to be compared to the previous imaging or need complete lung imaging before they can be classified. Category 1 and 2 findings may continue with yearly low dose CT. Category 3 findings should be followed up with a low dose CT at 6 months. Category 4A findings should be followed up with low dose CT in 3 months or PET/CT if there is a >8 mm solid component. Category 4B and 4X should get a full dose chest CT with/without contrast, PET/CT, biopsy, or repeat low dose CT at 1 month.

Of course, with all incidental findings of an SPN, there is a risk for malignancy. Due to this, it is important to discuss with the patient about other options, including surgical resection either by open thoracotomy, VATS (video-assisted thoracic surgery), or RATS (robotic-assisted thoracoscopic surgery). Overall 3-year survival is the same for all three surgical options, but VATS and RATS have improved morbidity compared to open. SBRT (stereotactic body radiotherapy) is another form of treatment that is recommended only for poor surgical candidates with stage I non-small cell lung cancer. The 5-year survival for patients undergoing SBRT is 37% versus 68% of the patients who received a VATS lobectomy. Surgical candidates need to be evaluated for preoperative functional status with pulmonary function tests in addition to the standard presurgical testing to determine the risk to a patient following a wedge resection or lobectomy.[2] Patients may also require chemotherapy depending on the diagnosis of the SPN. Nodules may progress to or present as a respiratory obstruction requiring a bronchoscopy or surgery to open the airways.[12]

Differential Diagnosis

When attempting to determine the cause of an SPN, one first needs to look at the location and characteristics of the nodule. This is best done with a CT scan. Malignancy, which only comprises about 5% of incidental SPNs, tends to be located in the upper lobes. Other malignancy characteristics are increased size, spiculated margin (sunburst or corona radiata sign), nodule enhancement after injection of IV contrast, and high growth rate.[2] Benign lesions tend to be smaller in size, are slow-growing (stable at 2 years), are located in the lower lobes, or are located adjacent to the pleural fissure, low-density attenuation, cavitation with thin regular walls, and central/laminated/diffuse calcification.[3] Differentials for benign lesions include carcinoid, sarcoidosis, amyloid, hamartomas, infections (TB and non-TB mycobacteria), round atelectasis, granulomatosis with polyangiitis, rheumatoid arthritis, vasculitis, arteriovenous malformations, and intrapulmonary lymph nodes.[13][14][15][16][17][18]

It is important to consider any pulmonary nodule to be malignant, but here are some examples of benign nodules and how they present on CT imaging. Tuberculosis, which is a granulomatous infection by Mycobacterium tuberculosis, may present with tree in bud opacities, cavitary lesions with a thick wall, and central hypo-enhancing necrotic nodules on CT. Organizing pneumonia presents with granulation tissue causing a consolidation or nodule with spindle-shaped margins and central necrosis. Sarcoidosis, which can affect any organ system, presents as noncaseating granulomas, bilateral perihilar opacities, honeycomb-like cysts, and fibrotic changes in a peri-bronchovascular distribution. Aspergillosis, which is a mycotic infection by Aspergillus, colonizes a preexisting cavity to form an aspergilloma. This is seen as a nodule or consolidation with either the crescent or halo signs. The crescent sign is radiolucency within the nodule, and the halo sign is when a zone of low attenuation surrounds the nodule. Another fungal infection, mucormycosis, also presents with a halo sign and crescent sign in the later stages of the disease. Granulomatosis with polyangiitis is a necrotizing vasculitis that presents as waxing and waning parenchymal nodules with or without the halo sign and may have associated ground-glass opacities, circumferential tracheobronchial thickening, and pleural effusions. Pulmonary sequestration is a rare congenital malformation of nonfunctioning lung tissue typically seen as a heterogeneous or homogeneous soft-tissue mass. Schwannoma, a benign mesenchymal tumor in Schwann cells, presents as homogeneous or heterogeneous enhancement with cystic degeneration or hemorrhage. Hamartoma, a benign mesenchymal neoplasm, presents a well-defined, smooth, round, or lobulated nodule with popcorn calcifications or central calcifications and fatty attenuation. Inflammatory myofibroblastic tumor, which is a tumor of spindle myofibroblasts that presents as an enhancing, well-defined nodule in the peripheral lung fields as well as an endobronchial lesion. A solitary fibrous tumor is a tumor of spindle cells presenting as a hyperdense, well-defined heterogeneous mass that forms obtuse angles with the pleura. Perivascular epithelial cell tumors (PEComas) are rare mesenchymal neoplasms that present as a well-defined solitary peripheral lung nodule without calcifications or cavitation. Pleomorphic adenoma is a common benign neoplasm of the salivary gland but may be found in the lung. It presents with a homogeneous, smooth, circular, soft-tissue density in the peripheral lung field. Carcinoid, a neuroendocrine tumor, presents as a well-defined homogeneous sphere that may cause narrowing or obstruction of the bronchus. Castleman disease, also known as angiofollicular hyperplasia and giant lymph node hyperplasia, presents as a well-circumscribed homogeneous mass commonly found in the hilum.[19]

• Amyloidosis
• Aspergillosis
• Arteriovenous malformation
• Castleman disease
• Carcinoid
• Granulomatosis with polyangiitis
• Hamartoma
• Inflammatory myofibroblastic tumor
• Intrapulmonary lymph nodes
• Mucormycosis
• Perivascular epithelial cell tumor
• Pleomorphic adenoma
• Pulmonary sequestration
• Rheumatoid arthritis
• Round atelectasis
• Sarcoidosis
• Schwannoma
• Tuberculosis

Surgical Oncology

Biopsy of an SPN with fine-needle aspiration biopsy (FNAB), either transthoracic or endobronchial, may help with the diagnosis. Most of the time, biopsies are obtained to determine if the nodule is benign or malignant. If the biopsy is positive, then one has the diagnosis and can treat accordingly, but what if the results are negative? The negative predictive value of an FNAB is around 89.4%.[20] More commonly seen factors in patients with a false negative biopsy are age >60 years, nodule size >13.5 mm, increased FDG uptake on PET imaging, and nodules with subsolid lesion characteristics.[21] It is important to evaluate all of the different risk factors and the tissue samples obtained when determining the etiology of an SPN.

Prognosis

The overall prevalence of malignancy in a patient with a solitary pulmonary nodule (SPN) is from 2% to 23%.[3] The prognosis of patients with an SPN depends primarily on the characteristics of the SPN. As stated above, an SPN is most commonly benign and does not necessarily require treatment. Of course, those with multiple risk factors and malignant features on imaging have a poorer prognosis.

Complications

Complications usually arise when more invasive treatment options are taken, such as surgical resection. Common surgery complications include hemorrhage, pulmonary embolism, infections (empyema, pneumonia, surgical site), pleural effusions, pneumothorax, myocardial infarction, and central neurological event.[22] If providers can work together to screen high-risk patients and follow the Fleischner Society Guidelines, the risk of death from an SPN greatly decreases. This will help to decrease unnecessary procedures, imaging, or medicines. Discuss the risks and benefits of any treatment or observation modality with the patient. 

Deterrence and Patient Education

Patients should be educated on the differential diagnosis and overall prognosis of an SPN. They should be an integral part of deciding what direction the medical management will go. They should be encouraged to stop smoking if they are and report any new symptoms to their physician, as this may aid in diagnosing the SPN.

Enhancing Healthcare Team Outcomes

Patients with a solitary pulmonary nodule (SPN) are typically asymptomatic when they are diagnosed. Those that are symptomatic usually present with signs and symptoms of the underlying cause of the SPN. An interprofessional approach is required to evaluate and manage an SPN, whether found incidentally or during a screening process due to the myriad of differential diagnoses, which include infection, malignancy, autoimmune diseases, vasculitis, and intrapulmonary lymph nodes. [Level 5] 

Pulmonologists are usually the main decision-makers when taking care of patients with an SPN, but they need help from other members of the interprofessional healthcare team, including surgeons, hospitalists, radiologists, oncologists, primary care physicians (PCPs), pharmacists, psychiatrists, nurses, and family members. Everybody plays a vital role in the overall care of any patient. The surgeon is needed to help biopsy or surgically remove the nodule, which is both diagnostic and therapeutic. Radiologists help aid in the diagnosis of the SPN. Oncologists will help in management and treatment if the nodule is found to be malignant. Pharmacists aid in managing patient's medications to ensure the greatest efficacy with the lowest side effect profile. Psychiatrists may help any patient who has increased stress, anxiety, or depression due to the finding of an SPN. Primary care providers help coordinate care between all different specialties while also managing other medical conditions. Nurses are also vital to the care as they usually spend the most time with the patient. They are able to tell if a patient starts to have any new symptoms like cough, chest pain, or respiratory distress, which helps determine which direction the medical management will take. The main strategy for diagnosing and managing an SPN is dictated by the Brock University risk model 2013, the Mayo Clinic model 1997, and the Fleischner Society Guidelines 2017.[3][23] [Level 1]

 The cause of the SPN and how promptly diagnosis and management are utilized ultimately determines the patient's outcome. It takes an entire interprofessional team working together effectively to decrease morbidity and mortality for these patients.