Solitary Pulmonary Nodule

Etiology

SPNs are generally nonmalignant, though there is always concern for malignant neoplasms. Differential diagnoses for benign SPNs include infectious, inflammatory, and congenital lung nodules. Granulomatous infections like tuberculosis, fungal infections including histoplasmosis and coccidioidomycosis, 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, can cause an SPN. Noninfectious granulomas like sarcoidosis, other inflammatory disorders like rheumatoid arthritis, and granulomatosis with polyangiitis (GPA) are examples of inflammatory etiologies for SPN.

Bronchogenic cysts and arteriovenous malformations that may have been present since birth can be incidentally found even in asymptomatic individuals. Other benign causes that could present as SPNs include mucus plugging, rounded atelectasis, pulmonary infarction, fibromas, and hamartomas. SPNs also may present a wide variety of malignant neoplasms, including bronchogenic carcinoma (both small and non-small cell carcinomas), metastatic cancers, carcinoids, lymphomas, and sarcomas.[3]

Epidemiology

In the general population, SPNs are found incidentally on 0.1% to 0.2% of chest radiographs and 13% of CT scans. Those with a high risk for malignancy, such as individuals with a smoking history or previous malignancy, have an increased incidence of finding an SPN of 9% on chest radiographs and 33% on low-dose CT scans.[4] The estimated 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, having a diagnosis of chronic obstructive pulmonary disease, and being of advanced age.[5] 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 radiograph for screening, men still had increased findings of SPN over women, with an incidence of 2.5% and 1.6%, respectively. On the contrary, women did have a higher incidence than men of having an SPN in the nonsmoking population. This leads to a higher incidence of pulmonary adenocarcinoma for women.[6]

Pathophysiology

The pathophysiology of SPNs varies widely depending on their etiology. The development of an SPN involves cellular changes that lead to localized growth, which may be influenced by genetic mutations, environmental factors, and immune responses. Understanding the underlying pathophysiology is essential for determining the appropriate diagnostic and therapeutic approach.

History and Physical

Approximately 95% of patients who are found to have an incidental SPN on imaging are asymptomatic. Those patients who do present with symptoms usually have symptoms related to the underlying etiology of the SPN. Evaluating patients for high-risk malignancy and obtaining a detailed history and physical examination to help determine the management of the SPN is essential.

To help rule out malignant SPN, information should be obtained concerning smoking status, previous malignancies, personal and family history of cancer, especially lung cancer, and current lung conditions such as chronic obstructive pulmonary disease (COPD), emphysema, and interstitial lung disease. Obtaining a travel history when infectious etiologies are suspected, especially if the patient has been to areas with endemic tuberculosis, is essential. Also, the patient must be asked about a history of rheumatoid arthritis, granulomatosis with polyangiitis, or other autoimmune disorders. Both lungs should be auscultated to help uncover the underlying condition. Most of the time, the physical findings of a patient with an SPN will be unremarkable, and the history and imaging must be relied on alone.[4]

Evaluation

A chest CT scan is the imaging modality most likely to detect an SPN. CT scans are also used as the first-line modality when observing the nodule, as they can detect changes in 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 (PET) scan may be used for further evaluation.

Chest x-ray (CXR) is not the best imaging modality to use to pick up an SPN, but it is the most commonly performed imaging technique. CXR, therefore, identifies a large number of patients who are asymptomatic with an SPN. Magnetic resonance imaging (MRI) is more expensive than CTs and does 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.[7] 

Electromagnetic navigation bronchoscopy (ENB) offers a noninvasive means of evaluation but is limited by its cost and is usually only used if other means are not feasible or are unsuccessful.[8] Tumor markers such as carcinoembryonic antigen, folate receptor-positive circulating tumor cells, galectin-3-binding protein, and C163A may also aid in evaluating an SPN when distinguishing between benign versus malignant entities.[9] 

The ultimate test to evaluate for the etiology of the nodule is a biopsy. Depending on location, this may be performed by fine-needle aspiration, liquid biopsy, or excisional biopsy. The tissue sample can then be examined histologically.[10] 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 ENB, may be used to help aid with the biopsy. Bronchoscopic biopsy carries a lower risk of adverse events than transthoracic biopsy but has an overall lower diagnostic yield.[11]

When encountering an SPN, assessing the patient's risk for malignancy is crucial. The 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. The system classifies imaging findings as follows:

• Category 0 (incomplete) is used if prior CT imaging is not available for comparison or if the lungs are not completely imaged.                                                                                                                                  
• Category 1 (negative) is when no lung nodules are found, or nodules carrying a high favorability of being benign (complete/centra/concentric ring/popcorn calcifications or fat-containing nodules) are noted. This category carries a <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 between 6 mm and 8 mm, new solid nodules between 4 mm and 6 mm, subsolid nodules >6 mm with solid components <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 between 8 mm and 15 mm, growing nodules <8 mm, new solid nodules between 6 mm and 8 mm, subsolid nodules >6 mm with solid components between 6 mm and 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 >15 mm, new or growing solid nodules >8 mm, subsolid nodules with solid components >8 mm, or new/growing subsolid nodules with >4 mm solid components 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 within 1 year, and enlarged regional lymph nodes.

In addition to the Lung-RADS classification system, 2 calculators can help to determine the malignancy probability. The Mayo Clinic Calculator (1997) utilizes specific criteria to help estimate the malignancy risk, including increased patient age, upper lobe location of the nodule, nodule diameter in mm, spiculation, smoking status, and extra-thoracic malignancy diagnosed ≤5 years previously.

Another risk calculator is the Brock University calculator (2013), which considers a few additional variables which still utilizes increased age, upper lobe location, nodule diameter in mm, and spiculation. This calculator also adds emphysema, ground-glass opacity, subsolid nodules, female sex, number of nodules, and family history of lung cancer. Notably, it does not take into account smoking status.[4] These calculators will produce a percentage indicating the likelihood of an SPN being malignant. Recently, it was 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.[12] Nonetheless, physicians can utilize these valuable tools to determine their next management step.

Treatment / Management

An interprofessional approach is best for managing an SPN. Assessing nodule size, appearance, patient risk factors, and patient preference is 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 follow-up; if it is a high-risk patient, a repeat CT scan at 12 months is optional. If the SPN is between 6 mm 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.[13]                                                                             
• Ground-glass nodules: <6 mm require no routine follow-up. If >6 mm, CT should be repeated every 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, repeat CT at 3 to 6 months; if the nodule continues to grow or has a 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 prior imaging and the solid component is <6 mm.
(B3)

If multiple nodules are present, the patient is recommended to have a CT scan at 3 to 6 months.[5][10]

In 2013, the American College of Chest Physicians (ACCP) developed its guidelines for SPNs and states that CT imaging should be utilized if a nodule is found on a CXR. These findings must be compared to old images to evaluate any change.

• No more testing is required if a nodule has been stable for 2 years.                                                                              
• Solid nodules <8 mm are more likely to be benign and are divided into 2 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 mm to 6 mm, follow-up CT is performed at 12 months.                                                        
  • For nodules 6 mm to 8 mm, follow-up is done 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 mm to 6 mm and the patient has risk factors for malignancy, a follow-up CT scan at 6 to 12 months and again at 18 to 24 months is recommended.                                                                                                                                      
  • For patients with risk factors for malignancy and 6 mm to 8 mm nodules, follow-up with a repeat CT scan at 3 to 6 months, 9 to 12 months, and again at 24 months is suggested.                                                                                                     
• Solid nodules between 8 mm and 30 mm are divided into low, moderate, and high pretest probability groups.                                                                                                                                                             
  • Patients with a low pretest probability should have low-dose CT scans at 3 to 6 months, 9 to 12 months, and 18 to 24 months.                                                                                                                                                                                  
  • Those with a moderate pretest probability should have PET or serial CT scans.                                                                                                                                                                           
  • Individuals with a high pretest probability should go straight to surgical diagnosis with either biopsy or surgical excision.                                                                                                                                                                                                                  
• Patients with 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. A biopsy or surgical excision is warranted if it is >5 mm at 3 months.                                                                                                                                                            
• Those with non-solid nodules <5 mm need no further evaluation. Those  with >5 mm nodules 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.                                                                                                                                                          
• Individuals with ground-glass nodules <5 mm should have a repeat CT scan in 2 to 3 years, while for those with nodules >5 mm, a repeat CT scan in 3 months with subsequent CT scans for up to 3 years if the nodule persists is recommended. A biopsy or surgical excision is recommended if the nodule persists for 3 years.

Follow-up recommendations according to the Lungs-RADs classification are as follows:

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

Of course, with all incidental findings of an SPN, there is a risk for malignancy. Due to this, it is essential to discuss other options with the patient, 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 3 surgical options, but VATS and RATS have improved morbidity compared to the open technique.

Stereotactic body radiotherapy (SBRT) 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 rate for patients undergoing SBRT is 37% versus 68% for patients who received a VATS lobectomy. Surgical candidates need to be evaluated for preoperative functional status with pulmonary function tests and standard presurgical testing to determine the risk to a patient following a wedge resection or lobectomy.[4] 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.[14]

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 include increased size, spiculated margin (sunburst or corona radiata sign), nodule enhancement after intravenous contrast injection, and high growth rate.[4]

Benign pulmonary lesions typically exhibit distinct characteristics: they are often smaller in size, demonstrate slow growth (remaining stable over a 2-year period), tend to localize in the lower lobes or near pleural fissures, and show features such as low-density attenuation, cavitation with thin, regular walls, and central/laminated/diffuse calcifications.[5] Differentials for benign lesions include carcinoid, sarcoidosis, amyloid, hamartomas, infections (tuberclusosis [TB] and non-TB mycobacteria), round atelectasis, granulomatosis with polyangiitis, rheumatoid arthritis, vasculitis, arteriovenous malformations, and intrapulmonary lymph nodes.[15][16][17][18][19][20]

While it is crucial to approach every pulmonary nodule with caution regarding malignancy, there are distinctive characteristics of benign nodules as seen on CT imaging. Some benign entities and their corresponding imaging findings include the following:

• Tuberculosis, 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, 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 also 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 is a benign mesenchymal neoplasm that presents as a well-defined, smooth, round, or lobulated nodule with popcorn or central calcifications and fatty attenuation.                                                                     
• An inflammatory myofibroblastic tumor is a tumor of spindle myofibroblasts that presents as an enhancing, well-defined nodule in the peripheral lung fields and 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 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 that 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.[21]                                       

Other benign causes of an SPN include amyloidosis, arteriovenous malformation, intrapulmonary lymph nodes, rheumatoid arthritis, and round atelectasis.

Surgical Oncology

Biopsy of an SPN using fine-needle aspiration biopsy (FNAB), either transthoracic or endobronchial, can aid in diagnosis. Typically, biopsies are performed to determine whether the nodule is benign or malignant. A positive biopsy confirms malignancy, allowing for appropriate treatment. The negative predictive value of FNAB is approximately 89.4%.[22] Factors commonly associated with false-negative results include patient age over 60, nodule size >13.5 mm, increased fluorodeoxyglucose uptake on PET imaging, and subsolid lesion characteristics.[23] Considering all risk factors and thoroughly evaluate tissue samples to accurately determine the etiology of an SPN is esssential.

Prognosis

The overall prevalence of malignancy in a patient with an SPN ranges from 2% to 23%.[3] The prognosis of patients with an SPN depends primarily on its characteristics. An SPN is most commonly benign and does not necessarily require treatment. Of course, a patient with multiple risk factors and demonstrating a nodule with malignant features on imaging has a poorer prognosis.

Complications

Complications often arise with more invasive treatment options, such as surgical resection. Common surgical complications include hemorrhage, pulmonary embolism, infections (eg, empyema, pneumonia, surgical site infections), pleural effusions, pneumothorax, myocardial infarction, and central neurological events.[24] By collaborating to screen high-risk patients and adhering to the Fleischner Society guidelines, clinicians can significantly reduce the risk of death from an SPN. This approach minimizes unnecessary procedures, imaging, and medications. Discussing the risks and benefits of any treatment or observation strategy with the patient is essential.