A narrative review of the clinical approach to subsolid pulmonary nodules

Introduction

Lung cancer is the leading cause of cancer-related mortality, and its incidence is increasing worldwide (1,2). The National Lung Screening Trial demonstrated the utility of low-dose helical computed tomography (LDCT) for the early detection of lung cancer and improvement of lung cancer-specific mortality (3,4). Chest LDCT is becoming widely used for lung cancer screening in high-risk groups (3,5) and in some low-risk groups (e.g., never-smokers and women) (6,7). The widespread use of LDCT has increased the detection of pulmonary nodules, including subsolid nodules (SSNs). SSNs comprise a large proportion of pulmonary nodules and are characterized by ground-glass opacity (GGO), which exhibits higher attenuation than normal lung tissue without the obliteration of vascular and bronchial margins (8). SSNs are classified as part-solid nodules (PSNs) or mixed ground-glass nodules (GGNs) and nonsolid nodules or pure GGNs (8). SSNs may be transient or persistent; compared with transient SSNs, persistent SSNs are more likely to be premalignant or malignant (9). Although SSNs usually have indolent progression (10), their management is complicated by variable growth rates (11) and the need for long-term follow-up with repeated CT scans.

This review discusses the characteristics, natural history, and genetic features of SSNs. It also addresses the surveillance and management of SSNs. We present the following article in accordance with the Narrative Review reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5246/rc).

Methods

PubMed and Google Scholar were searched to identify relevant articles published in English using the following keywords: “subsolid nodule”, “ground-glass nodule (GGN)”, and “part-solid nodule (PSN)” (Table 1).

Differential diagnosis and pathology

Multiple differential diagnoses should be considered before SSN is diagnosed, including transient lesions such as inflammation, focal pneumonia, hemorrhage, or pulmonary infiltration with eosinophilia (12). The differential diagnoses of SSNs that persist for >3 months include focal fibrosis and premalignant or malignant lesions, such as atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA) (13,14).

Transient or benign lesions

Among newly detected SSNs, 40–63% resolved during follow-up (10,15-17). In the NELSON study cohort, 63% of SSNs had resolved by the 1-, 3-, and 5.5-year follow-up screening (15). Therefore, the persistence of newly detected SSNs should be ascertained before biopsy or surgical resection.

Pulmonary infiltration with eosinophilia is characterized by asymptomatic migrating pulmonary infiltrates, with an increased number of peripheral blood eosinophils and spontaneous resolution (18) (Figure 1). This condition is the result of parasitic infections or drug use. Toxocariasis is a helminthozoonosis caused by Toxocara canis or Toxocara catis. Humans are infected through the ingestion of embryonated eggs or consumption of raw meat from paratenic hosts, such as chickens, lambs, rabbits, or cows (19). Toxocara-induced visceral larva migrans may cause pulmonary infiltrates. Raw meat and uncooked cow liver are popular dishes in South Korea. In a previous study, we found that blood eosinophilia and Toxocara seropositivity were associated with transient and migratory pulmonary infiltrates, including SSNs, on chest CT (20). Therefore, pulmonary toxocariasis is an important differential diagnosis of new pulmonary infiltrates, including SSNs, in patients with a history of raw meat intake.

Figure 1 Pulmonary infiltration with eosinophilia. A 47-year-old man with a history of raw cow liver intake had a peripheral blood eosinophil proportion of 9.7% at the initial visit. The patient had positive findings in a Toxocara canis enzyme-linked immunosorbent assay. At the 3-month follow-up visit, the patient’s multiple SSN lesions had improved without any treatment. The red arrows indicate the change from initial finding to follow-up. SSN, subsolid nodule.

Premalignant or malignant lesions

The 2011 classification of lung adenocarcinoma introduced the concepts of AIS and MIA while omitting terms such as bronchioloalveolar carcinoma and mixed subtype adenocarcinoma (21). AAH is characterized by small (≤5 mm) localized foci of proliferating mild-to-moderate atypical type II pneumocytes and/or club cells that line the alveolar walls and respiratory bronchioles (21). AIS has a predominantly lepidic pattern of ≤3 cm neoplastic cell growth along the alveolar walls without stromal, vascular, or pleural invasion. MIA is characterized by a small solitary adenocarcinoma with ≤5 mm of invasion and ≤3 cm overall size in a lepidic background (21). IA is characterized by >5 mm invasion and classified as lepidic, acinar, papillary, micropapillary, or solid predominant (21,22).

There are no reliable correlations between histopathological findings and radiological appearance. Approximately 25–50% of resected pure GGNs have invasive components (23-27). Ichinose et al. (25) reported that MIA and IA comprised 31% and 4% of 180 resected pure GGNs, respectively. Additionally, a higher maximum CT attenuation value (≥−300 Hounsfield units) was a useful predictor of histological invasiveness.

Natural history of SSNs

An understanding of the natural history of SSNs may improve their management. However, it has not been fully elucidated because they were first described <30 years ago (i.e., in the mid-1990s) (28,29). In this section, we summarize the results of studies concerning the long-term course of SSNs.

Natural courses of pure GGNs and PSNs

Table 2 presents recent studies concerning the natural history of SSNs (10,15,26,30-39). The type (pure GGNs or PSNs) and size of included nodules, as well as the follow-up duration, varied among studies. Nodule growth was most commonly defined as an increase in diameter of ≥2 mm and/or the development of a new solid portion (Table 2). However, one study defined nodule growth as a volume increase of ≥25% (15). The existing literature suggests that pure GGNs have an indolent natural course, whereas PSNs have a less indolent course.

In a previous study, we explored the natural history of 122 pure GGNs for a median follow-up interval of 59 months; we found per-person and per-nodule growth rates of 13.5% (12/89) and 9.8% (12/122), respectively (10). The volume doubling time (VDT) is defined as the time required for a growing nodule to double its volume (40). In this study, we calculated VDT according to a modified method of the Schwartz formula (41). The median volume VDT of the 12 growing SSNs was 769 days (range, 330–3,031 days). Therefore, almost 90% of pure GGNs did not grow during a median follow-up interval of 5 years, and the growing pure GGNs had slow growth rates (VDT >330 days) (10). Matsuguma et al. (31) investigated the natural courses of 98 pure GGNs (nonsolid nodule) and 76 PSNs. The respective 2- and 5-year cumulative growth rates were 13% and 23% in patients with pure GGNs, whereas they were 38% and 55% in patients with PSNs (31). In 2016, a Japanese group performed a prospective multicenter study to record the natural history of 1,229 SSNs (accrual period: 2009–2011; mean follow-up duration: 4.3 years) (33). The 2- and 5-year probabilities of growth were 2% and 14%, 12% and 24%, and 17% and 48% for pure GGNs, heterogeneous GGNs, and PSNs, respectively. Sawada et al. (36) found that all patients with a consolidation tumor ratio (C/T ratio) >0 exhibited tumor growth within 3 years; however, in 16% of patients with a C/T ratio of 0 (pure GGN), >3 years of follow-up was necessary to identify tumor growth. C/T ratio was defined as the proportion of the maximum consolidation diameter divided by the maximum tumor diameter (36). Cho et al. (32) found that, among SSNs that had remained stable during the initial 3 years, the rate of subsequent growth was 3.3%. Therefore, the proportion of growth and the time to growth are higher and shorter, respectively, in PSNs than in pure GGNs.

Natural course of SSNs after stability for 5 years

In 2 recent studies analyzing nodules that remained stable for 5 years after detection, some SSNs demonstrated growth after >5 years of follow-up (37,38). In 2019, Lee et al. (37) analyzed 208 SSNs with a median follow-up interval of 136 months. They reported that 13.0% of SSNs grew during follow-up after remaining stable for the initial 5 years. Approximately 70% of growing nodules had a size ≤6 mm at the time of detection. In 2020, another study evaluated 235 SSNs with a size ≥6 mm that had remained stable for 5 years (38); in that study, 5 (2.1%) nodules grew during a median follow-up interval of 112 months. Three of the five growing SSNs showed a change in clinical stage during follow-up: one from Tis to T1mi and two from T1mi to T1a. The results of these two studies support a longer follow-up duration (i.e., >5 years) for SSNs than the duration suggested by current guidelines. Further studies are needed to determine the optimal follow-up duration for SSNs.

Risk factors for SSN growth

Multiple studies have identified risk factors for SSN growth, including a large size (>10 mm) at the time of detection (10,26,31-35,42), history of lung cancer (31,32,34,35), smoking (43), the presence of a solid component (10,26,32,34,35,37), the presence of bubble lucency or air-bronchogram (32,37), male sex (26), the presence of EGFR mutation (11), and age ≥65 years (32,44). Although SSNs generally exhibit continuous slow growth, SSN size may paradoxically decrease when a solid component appears. Kaneda et al. (45) found that 47% of resected SSNs with adenocarcinoma showed a decrease in size during progression; the decrease in size usually coincided with the appearance of a solid component. Therefore, a mild decrease in SSN size suggests progression to IA and the need for careful follow-up.

Natural course of newly detected SSNs

Multiple recent studies have evaluated the course of SSNs that were absent at the initial evaluation and detected during follow-up. SSNs identified on follow-up rounds are more likely to resolve, compared with SSNs identified at baseline. In the International Early Lung Cancer Action Project, 66% of new GGNs and 70% of new PSNs decreased or resolved (46,47). In the NELSON trial, <1% of LDCT lung cancer screening participants developed a new SSN after the baseline evaluation. New SSNs that appear on follow-up examinations in patients without malignancy are more likely to be transient, considering the indolent nature of SSNs and long VDTs. In contrast to new solid nodules (48), new SSNs may not require more aggressive follow-up (49). A Korean study analyzed 6,725 screening-detected SSNs (5,241 SSNs detected at baseline screening and 1,484 newly detected SSNs on follow-up scans) (50). The authors found that newly observed SSNs during follow-up had a significantly lower probability of overall nodule growth [odds ratio =0.39, 95% confidence interval (CI) =0.26–0.59] and higher probability of resolution (odds ratio =6.30, 95% CI =5.09–7.81), compared with SSNs detected at baseline. Newly found SSNs also had a lower risk of undergoing biopsy (hazard ratio =0.39, 95% CI =0.26–0.51) and receiving a diagnosis of lung cancer (hazard ratio =0.31, 95% CI =0.19–0.51), compared with SSNs found at baseline. The authors of that study attributed these findings to the inflammatory nature of SSNs. Based on the results of recent studies, less aggressive follow-up and management may be appropriate for newly detected SSNs.

Genetic alterations in lung adenocarcinoma manifesting as SSNs

In previous studies of genetic alterations in lung adenocarcinoma manifesting as SSNs, EGFR mutations were the major driver mutations (frequency of 36–89%) (11,51-55). The differences in EGFR mutation frequency among these studies may be partly explained by differences in study populations (Asian vs. Caucasian), detection methods (polymerase chain reaction vs. next generation sequencing), and nodule subtypes (pure GGNs vs. PSNs). Other genetic alterations identified in lung adenocarcinoma manifesting as SSNs included KRAS mutations, HER2 mutations, BRAF mutations, ALK rearrangement, and ROS1 rearrangement (11,53-58).

The expression of programmed death ligand-1 (PD-L1) is low in SSNs (59,60). Suda et al. (59,60) found that the frequency of PD-L1 positivity was significantly higher in pure-solid lung adenocarcinomas than in part-solid lung adenocarcinomas (25% vs. 4%, P<0.01). Toyokawa et al. (60) reported that the frequency of PD-L1 positivity was significantly lower in lung adenocarcinomas with surrounding GGOs than in lung adenocarcinomas without surrounding GGOs (10% vs. 29%, P<0.01).

Preoperative evaluation of SSNs

Surgical resection is the preferred treatment for SSNs. In this section, we summarize the need for preoperative evaluation before surgical resection of SSNs.

PET/CT and brain magnetic resonance imaging (MRI)

¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has limited utility in the diagnosis and staging of SSNs, compared with other solid nodules. Kim et al. (61) reported a high false-negative rate when using FDG-PET for the detection of bronchioloalveolar carcinoma, now known as AIS. In another study, Chun et al. (62) compared the maximum standardized uptake (SUV_max) values of inflammation and malignancy that manifested as GGN on chest CT. In mixed GGNs (PSNs), the SUV_max was significantly higher in inflammatory lesions (2.00±1.18) than in malignancies (1.26±0.71). However, in pure GGNs, both inflammation and malignancy showed similar SUV_max values of <1.0. Therefore, PET/CT is not recommended for the diagnosis of SSNs.

Cho et al. (63) evaluated the utilities of preoperative PET/CT and MRI in 164 lung adenocarcinomas with pure GGNs; they didn’t find mediastinal or distant metastasis. We also evaluated the utilities of preoperative PET/CT and brain MRI in 35 pure GGNs and 39 PSNs; we found no mediastinal or distant metastases (64). Therefore, preoperative PET/CT and brain MRI are not useful for patients with pure GGNs. However, large-scale prospective studies are needed to determine the utilities of preoperative PET/CT and brain MRI in patients with PSNs, considering its more aggressive course.

CT-guided biopsy

A meta-analysis showed that CT-guided percutaneous biopsy for SSNs had high diagnostic sensitivity (92%, 95% CI =84–98%) and specificity (94%, 95% CI =84–98%), although sample sizes were small (n<90) in the included studies (n=6) (65). However, the diagnostic performance was lower for SSNs with a size <10 mm and a greater proportion of ground-glass components (66). CT-guided percutaneous biopsy is associated with various complications, such as hemoptysis, pneumothorax, and air embolism (67). Additionally, a negative biopsy result does not exclude the possibility of malignancy. The Fleischner Society guidelines address that the appropriate use of invasive diagnostic and therapeutic procedures for pulmonary nodules is vitally important but depends greatly on available resources and expertise (68). Therefore, considering the potential limitations of CT-guided biopsy for SSNs such as inadequate sampling and false-negative results, in our institution surgical resection for peripheral SSNs is preferred over CT-guided biopsy.

Bronchoscopy

We previously evaluated the utility of preoperative flexible bronchoscopy in 264 patients with 296 SSNs; only 3 (1%) SSNs were preoperatively identified as malignant according to bronchial washing cytology (69). Therefore, bronchial washing is not recommended for diagnosis because of its low diagnostic yield. Preoperative flexible bronchoscopy has limited value for peripheral SSNs, which could be easily removed by sublobar resection.

Transbronchial lung biopsy with radial probe endobronchial ultrasound or virtual bronchoscopic navigation may be considered for the preoperative histological confirmation of SSNs that are located in the centers of lobes and require lobectomy. In previous meta-analyses, the pooled diagnostic yield of transbronchial lung biopsy was 75–81% (70-72).

Clinical guidelines for the surveillance of incidentally detected and screening-detected SSNs

Current guidelines regarding the management of SSNs include guidelines for incidentally detected nodules from the American College of Chest Physicians (ACCP) (73,74), British Thoracic Society (BTS) (75), and the Fleischner Society (68,76), as well as National Comprehensive Cancer Network (NCCN) guidelines for non-small cell lung cancer (NSCLC) (77) (Table 3). Additionally, the guidelines for screening-detected nodules include guidelines from the Japanese Society for CT Screening (78), lung imaging reporting and data system (Lung-RADS) (79), and NCCN guidelines for lung cancer screening (80) (Table 3).

Because 60–70% of SSNs may be transient, the ACCP, BTS, and Fleischner Society guidelines recommend confirming that SSNs are persistent (68,73,75). The ACCP Consensus Asian Guidelines suggest that empirical antibiotics may be appropriate for PSNs with a size >8 mm (74).

Nodule growth is defined as a change in size of ≥2 mm in the BTS guidelines (75) and ≥1.5 mm in Lung-RADS 2022 (79) and NCCN guidelines (80). Nodule progression may manifest as a new or increasing solid component, or a uniform increase in attenuation (81). All guidelines recommend active surveillance and intervention for SSNs with interval progression.

Incidentally detected SSNs

According to the ACCP and BTS guidelines, follow-up is recommended for incidentally detected SSNs with a size >5 mm (73,75). However, the ACCP clinical practice consensus guidelines for Asia recommend surveillance for SSNs of all sizes because of the increased risk of malignancy in this population (74). The BTS guidelines recommend resection or nonsurgical treatment for SSNs that exhibit growth or altered morphology, including a new or increased solid component at the 3-month surveillance visit; the guidelines also recommend CT surveillance, image-guided biopsy, resection, or nonsurgical treatment for SSNs that are unchanged at the 3-month surveillance visit and have a high risk of malignancy (>10%) on the basis the Brock risk prediction model, which was also validated for SSNs (75,82).

Screening-detected SSNs

In contrast to the incidentally detected SSNs, there is no size threshold for follow-up of screening-detected SSNs (78-80). In Lung-RADS (version 1.1), a pure GGN with a size ≥30 mm that is unchanged or growing slowly is classified as category 2 (i.e., malignancy risk of <1%) (79). As previously discussed, 25–50% of resected pure GGNs exhibit invasive component in the histopathology (23-27). Therefore, Lung-RADS (version 1.1) underestimates the malignancy risk for slow-growing pure GGNs with a size ≥30 mm and makes no recommendations regarding tissue sampling for pure GGNs. However, the NCCN guidelines recommend biopsy or surgical excision for ≥20 mm pure GGNs that exhibit growth of >1.5 mm (80). Lung-RADS (version 1.1) and the NCCN guidelines recommend PET/CT and/or tissue sampling for PSNs with solid component size ≥6 mm and new/growing (>1.5 mm in solid component) PSNs with solid component size ≥4 mm (79,80). The Japanese Society for CT Screening guidelines (version 3) recommend surgical resection or nonsurgical biopsy for pure GGNs or PSNs with a size ≥15 mm and for PSNs of all sizes with a solid component size >5 mm (78). Notably, the Japanese Society for CT Screening guidelines recommend biopsy or surgery for smaller PSNs (even if the solid component is ≤5 mm) based on the physician’s discretion, presumably because of the greater risk of SSN malignancy in the East Asian population (83).

Surveillance endpoint for stable SSNs

Table 3 summarizes the surveillance endpoint for stable SSNs. For stable incidental SSNs, the 2013 ACCP guidelines recommend ≥3 years of surveillance (73); however, the recent Fleischner Society guidelines recommend ≥5 years of surveillance (68). However, for screening-detected SSNs, the NCCN guidelines recommend surveillance until the patient is no longer a candidate for definitive treatment (77). Overall, long-term follow-up studies (i.e., >15 years) are needed to determine the optimal follow-up duration for stable SSNs.

Our institutional surveillance guidelines for pure GGNs and PSNs

Our multidisciplinary pulmonary nodule management team, which includes pulmonologists, radiologists, and thoracic surgeons, developed institutional guidelines for SSNs in 2018 (Table 3, Figures 2,3). Our institutional guidelines make same recommendations for both screening- and incidentally detected SSNs. Considering the high prevalence of pulmonary toxocariasis in our country (20), newly detected SSNs are followed up with a 3-month chest CT, blood serology (Toxocara enzyme-linked immunosorbent assay), and questions regarding raw meat intake. We do not use a minimum size threshold for follow-up because of our experience concerning pure GGNs with a baseline size of 4–5 mm that grew during long-term follow-up and were finally diagnosed as adenocarcinoma (10). Similar to the Japanese Society for CT Screening guidelines, our institutional guidelines recommend a total size threshold of ≥15 mm, rather than ≥20 mm, for the surgical resection of persistent pure GGNs, based on the extent of sublobar lung resection, as well as radiation exposure and patient anxiety during CT surveillance (Figure 2). Surgery is also indicated for growing (>1.5 mm) pure GGN with a total size of ≥15 mm or pure GGN with a new solid component during follow-up. Additionally, a study conducted at our institution revealed that GGNs with a nodule size >16.4 mm were associated with IA (23). Surgery is indicated for persistent PSNs with a total size of ≥15 mm or solid component size of ≥6 mm (Figure 3). Furthermore, surgery is indicated for PSNs with a solid component size ≥4 mm that exhibit solid component growth of >1.5 mm and for growing PSNs with total size of ≥15 mm during follow-up. We also recommend ≥5 years of follow-up for both pure GGNs and PSNs.

Figure 2 Samsung Medical Center guidelines for the surveillance of pure GGNs. Bold lines indicate preferred options. GGN, ground-glass nodule; CT, computed tomography; ELISA, enzyme-linked immunosorbent assay.

Figure 3 Samsung Medical Center guidelines for the surveillance of PSNs. Bold lines indicate preferred options. PSN, part-solid nodule; CT, computed tomography; ELISA, enzyme-linked immunosorbent assay.

Role of artificial intelligence (AI) tools in SSNs

AI is computer science concerned with developing systems that can perform tasks that typically require human intelligence, such as problem-solving, reasoning, and perception (84,85). These days, AI technology has developed and is also applied in many medical fields. AI advancements might help physicians detect and diagnose pulmonary nodules (86). Many deep learning algorithms showed high sensitivity (around 70–91%), and all physicians showed improvement in lung nodule detection performance with the assistance of these algorithms (87,88). Some studies suggested that diagnostic models could be developed to differentiate benignancy and malignancy in GGNs (89-91). They reported that several models showed different diagnostic performances; however, their best models showed an area under the curve (AUC) value around 0.73–0.92 to differentiate benign and malignant GGNs (89-91). They also suggested that deep learning models can assist radiologists in determining benign and malignant GGNs (89). Our group also investigated the possibility of deep learning analysis to predict EGFR mutation status in lung adenocarcinoma manifesting as pGGNs (92). In our study, the AUC of the clinical only and deep learning with clinical models to predict EGFR mutations were 0.50 and 0.85, respectively. We suggested that a deep learning approach of CT images combined with clinical factors can predict EGFR mutations in pGGNs.

Surgical treatment of SSNs

Table 4 presents the results of studies concerning overall survival (OS) and relapse-free survival (RFS) in patients with SSNs (93-99). Multiple retrospective studies have demonstrated excellent outcomes of surgical resection for SSNs, with a 5-year survival rate >95%. In a previous study conducted at our institution, the GGO-dominant clinical stage IA lung adenocarcinoma (pure GGO group) had an excellent prognosis after wedge resection (95). Radiological noninvasiveness (C/T ratio ≤0.25) was a good indicator of suitability for sublobar resection in patients with early-stage lung cancer. However, wedge resection should be carefully considered for patients with mixed GGNs (PSNs) (C/T ratio >0.25) because of the high recurrence rate (95). A recent Japanese single-arm study showed that sublobar surgical resection, including both wedge resection and segmentectomy, with a sufficient surgical margin was feasible and effective for the treatment of GGO-dominant peripheral lung cancer with a size ≤2 cm and C/T ratio ≤0.25 (JCOG0804/WJOG4507L) (98). The 5-year RFS was 99.7% and there were no instances of recurrence (98). Another recent Japanese multicenter, phase 3, randomized, controlled, noninferiority trial (JCOG0802/WJOG4607L) showed improved OS after segmentectomy, compared with lobectomy, for patients who had small peripheral NSCLCs with a diameter ≤2 cm and C/T ratio >0.5 (99). During a median follow-up interval of 7.3 years, the 5-year OS rates were 94.3% for segmentectomy and 91.1% for lobectomy. The 5-year RFS rates were 88.0% for segmentectomy and 87.9% for lobectomy. Although 51% of the patients had solid nodules with a C/T ratio of 1, the results suggest that segmentectomy should be the standard surgical procedure for small peripheral tumors with a diameter ≤2 cm and C/T ratio >0.5. Most recently, results of the CALGB 140503 trial have been announced (100). CALGB 140503 trial is a multicenter international non-inferiority phase III trial in which NSCLC patients clinically staged as T1aN0 with tumor size ≤2 cm were randomly assigned to sublobar or lobar resection. This trial show that for patients with peripheral NSCLC with 2 cm or less in tumor size who have pathologically confirmed node-negative disease, sublobar resection is non-inferior to lobectomy. For RFS, the stratified HR was 0.999 (95% CI, 0.784–1.272). For OS the stratified HR was 0.930 (95% CI, 0.695–1.243).

Nonsurgical treatment options for SSNs

Multiple nonsurgical treatment options are available for SSNs. Combinations of surgical and nonsurgical treatment are also useful, particularly for multifocal SSNs.

Stereotactic body radiotherapy (SBRT)

SBRT is an alternative treatment option for SSNs, particularly in older patients with multiple comorbidities (101). If a growing PSN is located centrally and lobectomy is necessary in an older patient with multiple comorbidities, SBRT should be considered because the rate of lobectomy-related mortality is approximately 2–4% in patients aged >70 years (102-104). Although SBRT is commonly performed as treatment for SSNs, data regarding SBRT are scarce. Hammer et al. (105) recommended the use of SBRT for nonsolid Lung-RADS 4B/4X nodules in patients aged >77 years and the use of surgery for such nodules in patients aged ≤77 years. SBRT was associated with the longest OS (80%), followed by surgery (79%; 49,139 of 62,559 patients) and no treatment (74%, P<0.01). Therefore, in the situations where surgical risk is high (for example, older patients with multiple comorbidities who need lobectomy, patients with reduced pulmonary function due to severe chronic obstructive pulmonary disease or diffuse interstitial lung disease, etc.), the treatment decision of SBRT vs. surgery needs to be made after multidisciplinary team discussion.

Radiofrequency ablation (RFA)

RFA is used for the ablation of solid organs and is a newer treatment option for medically inoperable primary lung cancer. RFA is regarded as an alternative treatment option for SSNs. Iguchi et al. (106) reported the clinical outcomes of RFA for 16 patients with lung cancer and a GGO component of >50%. Although there were no major complications, pneumothorax occurred during 15 of 20 RFA sessions. During a median follow-up interval of 61.5 months, the 5-year OS and 5-year RFS rates were 93.3% and 100%, respectively (106). RFA was performed under local anesthesia in the outpatient setting, rather than under general anesthesia. However, lesions >3 cm should not be managed with RFA; the lesion location is also important because of the risk of damage to adjacent structures (e.g., esophagus and trachea) (107,108). Endobronchial ultrasound-guided bipolar RFA has also been described recently (109). Further studies are needed to identify good candidates for RFA treatment of SSNs and to identify the optimal delivery method for RFA (extrathoracic or endobronchial).

Medical treatments

Several medical treatment options for SSNs were previously evaluated. Lu et al. (110) evaluated the impact of platinum-based chemotherapy (cisplatin or carboplatin) on GGNs that persisted for ≥3 months. During follow-up, on a per-nodule basis, 86 (94.5%) GGNs had an unchanged size, and 5 (5.5%) GGNs increased in size. Considering the natural course of GGNs, chemotherapy had no effect on their growth (110). We hypothesized that lung adenocarcinoma with SSNs may respond to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) because of the high frequency of EGFR mutations (89%) (54). Therefore, we investigated the impact of EGFR-TKIs (gefitinib or erlotinib) on concurrent SSNs in patients with stage IV NSCLC (111). In our retrospective study, almost 20% of concurrent SSNs with stage IV NSCLC shrank after EGFR-TKI treatment. Therefore, EGFR-TKI therapy may affect the natural course of SSNs. However, no study has directly evaluated the use of EGFR-TKIs in the treatment of SSNs, except for SSNs in patients with stage IV NSCLC. In situations where surgery or radiation therapy is not feasible because of multiplicity, location (lobe center), old age, multiple comorbidities, or patient refusal, EGFR-TKIs may be an appropriate therapeutic option for multiple growing SSNs. Further prospective studies are needed to determine the utility of EGFR-TKIs in the management of SSNs. An Italian group performed a phase IIb multicenter randomized study to assess the efficacy of low-dose aspirin in reducing SSN size (112), based on the successful use of aspirin in cancer prevention. The previous study showed an almost 30% reduction in lung cancer-related mortality after 5 years of aspirin treatment and 20 years of follow-up (113). However, in the Italian study, there was no change in the sum of the longest diameters of the target nodules in the placebo and low-dose aspirin groups after 12 months of treatment. The investigators suggested that the null result could be explained by the small study population and short study duration.

Management of multifocal SSNs

Multiple persistent SSNs often represent synchronous or metachronous lung primary cancer, rather than intrapulmonary metastases (114,115). Multiple SSNs often occur in women, never-smokers, and North American and Asian populations (115). Each lesion should be managed individually with intervention or surveillance, depending on the changes in overall size and solid component size over time. The Fleischner Society guidelines recommend follow-up CT at 3–6 months for multiple incidental SSNs with a size ≥6 mm; subsequent management should be based on the most suspicious nodule(s) (76).

Wang et al. (116) evaluated the clinical and pathological characteristics of 99 patients with single GGNs and 102 patients with multiple GGNs (>3 nodules). All patients with >10 nodules showed bilateral pulmonary nodules and presented with both pure and mixed GGNs. However, the proportions of mixed GGNs and malignant nodules significantly decreased as the total number of lesions increased (116). Sato et al. (35) investigated the natural history and clinical characteristics of multiple SSNs; they observed progression in 32% of patients at 36 months and 5% of patients after 36 months. Among patients with multiple SSNs who exhibited growth of a single SSN, 41% experienced residual SSN growth (35).

Kim et al. (117) reported the clinical outcomes of multiple pure GGNs after surgical resection. Five patients underwent resection of all GGNs, whereas 18 patients underwent resection of some GGNs and serial CT for the remaining lesions. No GGNs increased in size and no new solid component developed during a median follow-up interval of 40.3 months (range, 22–110 months) in 18 patients. The investigators suggested that, when it is unfeasible to resect all GGNs, CT-based close follow-up is an alternative to surgical resection. Hattori et al. (118) reported the outcomes of 53 patients who underwent surgical resection for multifocal SSNs (C/T ratio: 0–0.5). Regarding surgical managements for multifocal SSNs, the 5-year OS rates of multiple synchronous or staged limited resection alone vs. anatomical resection with or without additional limited resection were similar. There were 278 resected multifocal SSNs, most of which had adenocarcinoma or AAH/AIS. Unresected or newly developed SSNs occurred in almost 36% of patients, and all of these SSNs remained stable as pure GGNs of size <10 mm without any intervention. The 5-year OS rates of multifocal SSNs and solid lesions were 94.4% and 80.6%, respectively, over a median follow-up interval of 60 months (118). Therefore, considering the outcomes of surgery for multiple SSNs, a reasonable approach may comprise lung-sparing limited resection for the most dominant lesion(s) and periodic CT surveillance for SSNs that remain after surgery.

Conclusions

The differential diagnoses of SSNs include benign and malignant lesions. Because a substantial proportion of SSNs tend to disappear, there is a need to confirm that SSNs are persistent before performing any invasive procedures. Even in patients with precancerous or cancerous lesions, the natural course of SSNs is generally indolent and the clinical outcomes are often favorable. However, PSNs may have a less indolent clinical course compared with pure GGNs; therefore, careful follow-up is necessary. Periodic CT surveillance and surgery are the main strategies for the management of persistent SSNs. For the preoperative evaluation of SSNs, PET/CT, brain MRI, and bronchoscopy have limited utility. The size, solidity, location, and number of SSNs are important factors in determining the need for surveillance, biopsy, and surgical resection, as well as the duration of follow-up. For SSNs, sublobar resection with sufficient surgical margins based on the C/T ratio is feasible and effective. Nonsurgical treatment options for SSNs include SBRT and RFA. The need for CT surveillance and surgical treatment of multifocal SSNs should be determined on the basis of the most dominant SSN(s). Combinations of surgical and nonsurgical treatment may also be useful, particularly for multifocal SSNs. Practice guidelines for the management of incidentally detected and screening-detected SSNs should be updated based on the accumulated knowledge regarding SSNs. Since the SSN is a heterogeneous disease, a personalized medicine approach is needed in the future. To this end, future studies of the SSNs should focus on their natural history, optimal follow-up duration, genetic features, surgical methods and nonsurgical treatments. All these information will pave the way to the personalized medicine approach for the SSNs.

Acknowledgments

Funding: This work was supported by the National Research Foundation of Korea grant funded by the Korea government (MSIT; No. 2020R1A2C2006282).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-22-5246/rc

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5246/coif). SWU serves as an unpaid editorial board member of Annals of Translational Medicine from September 2022 to August 2024. The other author has no conflicts of interest to declare.

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