key: cord-0853131-pz3jeycd
authors: Azour, Lea; Ko, Jane P.; Naidich, David P.; Moore, William H.
title: Shades of Gray: Subsolid Nodule Considerations and Management
date: 2020-10-05
journal: Chest
DOI: 10.1016/j.chest.2020.09.252
sha: f79cb2611e6bb2b51f66a2c856aa214807f7f551
doc_id: 853131
cord_uid: pz3jeycd

Subsolid nodules are common on chest CT and may be either benign or malignant. Their varied features, and broad differential diagnoses present management challenges. While subsolid nodules often represent lung adenocarcinomas, other possibilities are common, and influence management. Practice guidelines exist for subsolid nodule management for both incidentally and screening-detected nodules, incorporating patient and nodule characteristics. This review will highlight similarities and differences amongst these algorithms, with the intent of providing a resource for comparison, and aid in choosing management options.

Subsolid nodules (SSNs) include both pure groundglass (GGNs) and part-solid nodules (PSNs), and are increasingly detected on chest CT scans [1] [2] [3] . In addition to the spectrum of primary adenocarcinoma of the lung, potential diagnoses include a number of alternate malignancies as well as benign lesions.

A range of imaging techniques and clinical concerns need to be considered when constructing differential diagnoses and establishing management guidelines. Of particular concern is the correlation among various morphologic CT appearances, including attenuation, shape, and internal complexity, in characterization and serial assessment for potential growth. In this regard, technical factors may profoundly influence nodule detection and encourage consistency in nodule assessment and reporting.

To date, multiple management algorithms have been developed to address these challenges, in both screening and non-screening populations. These include those of the American College of Chest Physicians (ACCP) 4,5 , British Thoracic Society (BTS) 6 , Fleischner Society 7 , American College of Radiology (ACR) 8 , and National Comprehensive Cancer Network (NCCN) 9 .

Despite considerable overlap, including prioritization of shared decision-making, no one algorithm -either for screen-detected or incidentally identified nodules -is universally accepted. This review will compare and contrast these algorithms, providing a resource for comparison, which may aid in choosing management options.

Current algorithms for lung nodules share essential CT acquisition and reporting considerations, regarding slice thickness, reconstruction algorithm, display windows, and value of multi-planar reformatted images (Table 1) .

Applying consistent CT parameters enables reliable comparison across serial exams. Full inspiratory images are universally recommended for lung nodule evaluation 9,10 , with use of the lowest possible radiation exposure 6, 8, 10 . Contrast-enhancement is unnecessary 4, 9 . The presence of contrast increases dose, and increases measured volume, mass and mean attenuation of SSNs 11 .

Contiguous thin-section images improve nodule detection and feature evaluation 6,7 , with management algorithms recommending 1 mm slice thickness, and evaluation on lung windows at thinnest collimation. Mediastinal soft tissue display windows may aid in determining the presence of solid components within a subsolid nodule 12, 13 .

Sagittal and coronal image reconstruction aids SSN detection 6, 7 , which may be challenging in the setting of interstitial or smoking-related lung disease. Lung cancers in interstitial lung disease most often develop adjacent to or within regions of fibrosis 14 , and review of non-axial reconstructions may exclude nodularity or identify convexities typical for scarring in regions of parenchymal abnormality, like paravertebral or apical fibrosis (Figure 1 ).

Maximum and minimum intensity projection images may improve solid and subsolid nodule detection, respectively 6, 15 . Volume rendering 6,9 and computer aided diagnosis (CAD) 9 are additional tools. CAD has higher sensitivity for SSNs than visual detection, 88.4% versus 34.2%, in 2303 baseline screening exams from the Multicenter Italian Lung Detection trial 16 .

Ultimately, nodule size is fundamental when deciding on a management approach-all nodule aspects are included in overall measurement, preferably on the high-frequency, sharp reconstruction algorithm, with reporting of size in the plane of maximal dimension 10 .

Practice guidelines addressing subsolid nodule management include those for incidentally detected nodules from the ACCP, BTS, and Fleischner Society, and those for screening-detected nodules from the ACR (Lung-RADS) and NCCN ( Table 2 ). These algorithms specify applicable patient populations, and incorporate patient and nodule-specific risk factors for lung cancer.

Risk of malignancy is a major consideration affecting nodule management guidelines, and is often based on clinical judgement. The ACCP guidelines define high (>65%), intermediate (5-65%), and low (<5%) malignancy risk categories incorporating clinical factors of age, smoking history, and prior cancer, and nodule features including size, margin, upper lobe location, imaging behavior (PET and serial CT) and nonsurgical histopathology results 4 . The ACCP risk categories are incorporated in the Fleischner guidelines, which recommend risk assignment based on the ACCP low risk category, and grouping of the intermediate and high risk categories 7 . The BTS and NCCN also consider both clinical risk factors and radiologic nodule features.

Qualitative risk prediction, based on clinician judgement, or quantitative, model-based risk prediction are encouraged by the ACCP guidelines 4 . There are several models, or probability calculators, synthesizing clinical and imaging features, such as the BIMC (Bayesian Inference Malignancy Calculator), Brock, Herder, Mayo Clinic, TREAT (Thoracic Research Evaluation and Treatment), and VA (Department of Veteran's Affairs) models 17 .

Each of the models is derived from specific patient populations 17 . Model performance is optimal when applied to populations similar to those from which the model was derived 4,17 . For this reason, separate ACCP consensus guidelines for Asia were developed indicating that diagnostic risk calculators may not apply to Asian patients due to the higher rate of lung cancer in women, and higher prevalence of tuberculosis and environmental exposures 5 .

The ACCP recommends the Mayo Clinic probability model in the US population, developed and validated from a patient cohort with incidentally-detected nodules on chest radiography 18 . The VA model is similarly based on incidentally-detected nodules, albeit in the higher-risk veteran population 19 . Screening data informs the Brock model, synonymous with PanCan or Vancouver models, in reference to the screening cohorts 2 .

Risk assessment models can be applied at multiple points in nodule management. For example, the BTS guidelines suggest risk prediction at two separate junctures along the management algorithm, initially using the Brock calculator to determine if malignancy risk is greater than 10% 6 . When malignancy risk is estimated to be less than 10%, BTS guidelines advise CT surveillance over biopsy or resection for SSNs. For patients who undergo further evaluation with PET/CT, the BTS guidelines suggest using the Herder risk assessment model, which incorporates FDG activity with Mayo-predicted probability 20 , to guide subsequent management.

For screen-detected nodules, Lung-RADS categorizes findings and standardizes management, and recommends the Brock calculator for risk stratifying patients with category 4B or 4X (very suspicious) lesions 8 . Brock model inputs include age, sex, family history, emphysema, nodule size, nodule spiculation, number of nodules, lobar location, and nodule attenuation (solid, partially solid, or nonsolid) 2 .

The Brock model is the only validated model incorporating nodule attenuation, and thus subsolid nodules. Of note, the Brock model is based on a screening population (50 to 75 years of age) with smoking history, which may affect its performance when applied to female nonsmokers, in whom a higher incidence of subsolid nodules/indolent lung adenocarcinomas are reported 21 . Studies have evaluated the efficacy of models when applied to differing populations and roles 22,23 , and knowledge of their performance in these scenarios is important. A future role may exist for model-based patient selection for lung cancer screening 24 . Management of small nodules may also be aided by the application of models 25 .

Some clinical factors associated with higher lung cancer risk are not reflected in risk models. As noted in the NCCN guidelines 9 , COPD and ILD are risk factors for lung cancer, but not specifically included in the Brock model. The incidence of lung cancer in patients with ILD and COPD is nearly threefold higher than in patients with COPD alone 26 . In the NLST cohort of over 25,000 participants, those with asymptomatic interstitial abnormalities (e.g. baseline reticulonodular opacities, honeycombing, fibrosis and scarring) had higher incidence of and mortality from lung cancer 27 .

Family history is included in both the NCCN and Brock model risk assessments. In a pooled analysis from the International Lung Cancer Consortium, having a first degree relative with lung cancer conferred 1.5 times increased risk, after adjustment for smoking and additional risk factors 28 .

The risk for malignancy is low in younger patients. The incidence of all cancers in adolescents and young adults is only approximately 75.5 per 100,000, with lung cancer among neither the most common nor most deadly cancers for patients under age 40 29 . However, certain clinical and radiologic features may render particular nodules more suspicious, warranting closer follow-up regardless of age. The Fleischner, BTS and ACCP guidelines address incidentally detected nodules, with BTS guidelines applicable to adults 18 and older, and Fleischner applicable to individuals 35 years or older. In patients younger than 35 years presenting with subsolid nodules, recommendations are therefore based on the clinical scenario.

Guidelines for incidentally detected nodules are not intended for patients with known primary neoplasms in whom metastatic disease would be a consideration 7 . This rationale applies more for solid nodules, however subsolid nodules may uncommonly represent metastases, in which case their behavior and neoplastic potential depends on the type and grade of the primary malignancy.

Lymphomas, mucinous gastrointestinal neoplasms, extra-pulmonary adenocarcinomas, and tumors associated with hemorrhage creating groundglass opacity may all present as subsolid nodules 30 . Groundglass attenuation produced by metastases is infrequently due to the lepidic growth 31,32 that characterizes most lung adenocarcinoma spectrum lesions. Metastatic lesions initially presenting as subsolid nodules may demonstrate aggressive rather than indolent behavior 32, 33 . Therefore, close followup is prudent in oncology patients with new subsolid nodules.

Surveillance recommendations for subsolid nodules are guided by the main cause for persistent subsolid nodules: lesions on the spectrum of lung adenocarcinoma. Lung adenocarcinoma spectrum lesions are currently classified pathologically by the International Association for the Study of Lung Cancer (IASLC) system, which has been integrated into the WHO TNM staging (Table 3, Figure 2 ). This classification applies to small, < 3cm, non-mucinous lung adenocarcinomas with groundglass attenuation, and lepidic growth patterns on pathology. The algorithms direct surveillance primarily based on nodule size and groundglass or part-solid density.

For incidentally detected subsolid nodules, size threshold necessitating follow-up is typically 5mm 4-7 . This reflects that nodules 5mm and smaller correspond to atypical adenomatous hyperplasia. The ACCP consensus guidelines for Asia recommend considering surveillance for even small SSNs, recognizing increased risk in this population 5 . The Fleischner guidelines also suggest that CT follow-up at 2 and 4 years may be obtained in Asian populations 7 for solitary nodules 5 mm and smaller, as these may represent pre-invasive lesions.

Part-solid nodules are managed differently than nonsolid nodules due to their association with invasive lung adenocarcinoma. The Fleischner guidelines note a potential limitation in discerning small solid aspects of already-small nodules, thus generally considering all PSNs to be at least 6 mm in size 7 . Though follow-up is not precluded for smaller nodules if morphologically suspicious, or the patient is high risk 7 . A multiplicity of nodules, irrespective of size and/or pure groundglass density, would be followed in 3-6 months as per the Fleischner guidelines 7 . Multiple subsolid nodules, when persistent, most often represent synchronous or metachronous lung primaries rather than intra-pulmonary metastasis 34, 35 . This pattern most often occurs in female nonsmokers, in both North American and Asian groups 36 .

Decisions regarding surveillance versus treatment for persisting subsolid nodules require evaluating each nodule individually 4 , such as in terms of overall and solid component size. The most suspicious nodule may not be the largest nodule 7 .

Persistence of a nodule has significant implications upon differential diagnosis (Table 4) , including malignant (Figures 2 and 3 ) and benign causes (Figure 4) . Establishing persistence of a subsolid lesion is recommended by the ACCP, BTS, and Fleischner Guidelines, because up to 70% of subsolid nodules may be transient 37 . The ACCP Consensus Asian Guidelines further suggest empiric antimicrobials may be appropriate for PSNs >8mm in size 5 .

For participants of the International Early Lung Cancer Action Project (IELCAP), nearly 20% of part-solid nodules 38 and 26% of nonsolid nodules 39 identified on baseline decreased in size or resolved. Comparably, in 622 part-solid and groundglass nodules from the NLST cohort, 28% resolved on followup imaging 3 . And, in 264 SSNs from the Dutch Belgian Lung Cancer Screening trial (NELSON) cohort, 63% resolved on follow-up 40 . Subsolid nodules identified on follow-up rounds as compared to baseline are more likely to resolve: in IELCAP, 66% of new nonsolid nodules and 70% of new part-solid nodules decreased in size or resolved 38, 39 . Given the likely transience for new SSNs on subsequent screening exams, Lung-RADS version 1.1 suggests new large nodules may be surveilled at a short 1-month interval rather than proceeding to further work-up 8 . Similarly, the NCCN algorithm for a newly detected SSN on follow-up first asks whether there is suspected infection/inflammation, and if so, recommends low-dose CT in 1-3 months 9 .

New subsolid nodules on follow-up exams in patients without malignancy are favored to be transient given the indolent nature of subsolid nodules, with reported volume doubling times of 457-568 days for PSNs, and 469-813 days for GGNs 41, 42 . Similar to IELCAP findings, data from the NELSON trial showed that 67% of newly detected subsolid nodules (on 1, 3, and 5.5 year incidence screening rounds) resolved, and new SSNs after baseline occurred in less than 1% of participants 43 . Though 3 of 16 nonresolving newly-detected SSNs were malignant in NELSON (AIS in two nodules, and stage 1A invasive adenocarcinoma in one nodule), favorable staging of these lesions despite protracted referral after one year did not support the need for more aggressive management 43 . 46 , and large solid component 45 are more often associated with subsolid nodule transience, as are polygonal shape (as opposed to round), mixed density (rather than pure groundglass), and larger size 47 . In contrast, pleural retraction and "bubble" lucencies are more common in persisting subsolid nodules 44 .

Overall nodule size and solid component size are associated with pathologic staging as well as outcomes for lung adenocarcinoma spectrum lesions 48, 49 . Establishing nodule growth is based on change in size of 2mm or greater as per the Fleischner and BTS guidelines 6,50 , and >1.5 mm as per the ACR's Lung-RADS version 1.1 8 , as smaller changes are within measurement error. Volumetric growth is an additional parameter included in both the BTS and Lung-RADS algorithms 6,8 , and may facilitate earlier lung cancer diagnosis 51 . The NELSON trial classified screen-detected nodules into growth and subsequent management categories based on volume doubling time; in subsolid nodules, volumetric segmentation was applied to the solid portion and diameter for the overall nodule 52 . This method recognizes challenges in defining subsolid nodules, which can contribute to inaccurate segmentations 11,53-55 .

Nodule progression may also manifest as new or increasing solid component, or uniform increase in attenuation. Nodule mass, incorporating both attenuation and volume, is associated with less intra-and inter-observer variability compared to either diameter or volume alone, and an earlier indicator of nodule growth for subsolid nodules 56 . A change in this measure would reflect increase in nodule size and/or density. Nodule mass assessment is recommended in the BTS guidelines, though it requires volumetric segmentation, and may be more broadly recommended in the future.

Accurate assessment of growth on CT may be more difficult because of nodule attenuation, shape, location, and scan interval 6 . Lesions adjacent the mediastinum or lung base may be affected by cardiac or inspiratory motion, and greater inspiratory effort inversely affects volume of solid nodules 57 . Growth is more evident when comparing exams separated by longer intervals 6,10 , highlighting the need for comparison to baseline studies in addition to immediate prior imaging-especially useful for lesions with indolent behavior ( Figure 5 ). Growth-rate precision also increases with greater time interval between scans 51 .

Contracting nodules are an uncommonly encountered pitfall, as nodules may at times decrease in size at points in their growth curve 58 . Progressing nodules may contract in one or both dimensions with increasing soft tissue, related to fibrotic alveolar collapse, or increasing invasive components 59, 60 . Spurious contraction may be due to inflammatory components of cancers, which can be misinterpreted in absence of continued follow-up imaging or investigation (Figure 6 ).

Larger size in pure groundglass nodules is associated with higher probability of invasive adenocarcinoma 61 62 . Nevertheless, the malignancy potential of stable or slowly growing non-solid nodules >30mm is classified as Lung-RADS category 2, which implies risk of malignancy estimate of <1%.

Recent risk-based stratification models suggest the probability of malignancy for subsolid nodules currently assigned to Lung-RADS categories 2 and 3 may be higher, 3% and 13% respectively, versus current risk prediction of <1% and 1-2% 3 . Future iterations may consider further size-based risk stratification, given Lung-RADS category 2 groundglass nodules that are greater than 10mm in size have greater malignancy risk than subcentimeter groundglass nodules 3 . Current ACCP guidelines state biopsy or resection may be considered for pure GGNs larger than 10 mm, and the BTS guidelines even for stable persistent GGNs where malignancy risk is >10%. The BTS guidelines also suggest resection and non-surgical treatment may be considered for GGNs increasing in size by 2 mm or greater. Lung-RADS has no recommendation for tissue sampling for pure groundglass nodules, though category 4x may suggest tissue sampling for GGNs >30. These lesions may have indolent behavior, and it is unclear if aggressive management translates into improved outcomes.

The purpose of follow-up is to guide decision making in the patient's best interest. This includes an emphasis on shared decision-making.

The choice between surveillance and action is influenced by an increase in nodule size; new or increasing solid component; and pace of growth as indicated by surveillance intervals. Biopsy, resection, or non-surgical treatment can also be pursued for subsolid lesions in the setting of >10% malignancy risk per the BTS guidelines.

The appropriate length of imaging surveillance for non-screening patients with stable subsolid nodules is an unanswered question. Subsolid nodules may demonstrate lengthy volume doubling times, consistent with their often-indolent behavior. For example, in a retrospective cohort of 97 patients with subsolid nodules, median volume doubling times ranged from 759-1832 days, with more rapid volume doubling time for those nodules with solid components >5 mm 64 . In this cohort, upper limits of median volume doubling time for groundglass lesions reached over 12 years 64 .

For stable subsolid nodules, the ACCP recommends a minimum follow-up duration of 3 years, BTS 4 years, and Fleischner 5 years. The ACCP Clinical Practice Consensus Guidelines for Asia encourage consideration of ongoing surveillance beyond 3 years 5 . A reasonable endpoint for surveillance of stable subsolid nodules in non-screening populations includes patient counseling, such as whether or not diagnosis and treatment would be pursued for progressing nodules 65 . ACR and NCCN screening guidelines similarly suggest cessation of follow-up if patients are no longer candidates for definitive treatment, have life-limiting comorbidities, or would defer eventual treatment.

PET/CT is not recommended to characterize GGNs or other subsolid nodules with small solid components 4 . FDG-avidity is nonspecific and both false positives and false negatives may occur 66,67 (Figure 7) . Infectious/inflammatory processes may result in false positives for subsolid opacities 68, 69 . False negatives in SSNs may be due to lower metabolism of indolent lesions, lesions or solid components below the threshold for PET-CT spatial resolution, mucinous lesions, or location mis-registration 66, 70 . PET is also of limited utility for pre-operative staging of T1 SSNs 71 .

The rate of benign diagnoses for SSNs after biopsy ranges from 6-39% [72] [73] [74] [75] , and may be affected by differing indications, referral patterns and patient preferences-including desire for diagnostic certitude and level of risk-tolerance 4 . Benign diagnoses included fibrosis, organizing pneumonia, or presumed infection/inflammation. Biopsy of subsolid lesions has been associated with lower diagnostic accuracy in comparison to solid lesions 76 , which may be due to lower cellularity 72 . However, others have shown comparable diagnostic accuracy for malignancy comparing subsolid and solid nodules 77 , and up to 97% diagnostic accuracy in a series of 67 patients with groundglass lesions sampled by percutaneous core needle biopsy 73 .

For primary invasive lung cancers in which definitive local therapy is possible, the NCCN and BTS favor parenchymal-sparing surgical resection. Radiotherapy and ablative therapies are additional local treatment options 78 . For GGNs, localization may be necessary prior to surgical resection. Options for localization include CT-guided wire or marker placement, percutaneous injection of dye, radiotracer or other material (Figure 8) , or navigational bronchoscopic localization 79 .

Radiation and other ablative therapies are most often pursued in non-surgical candidates 6 , and increasingly as a lung-sparing treatment option, in surgical candidates. This is especially relevant for patients presenting with multiple synchronous primary lesions. Simulation modeling has suggested superior outcomes with SBRT in comparison to lobectomy or non-therapy for subsolid nodules 80 , however trials comparing these treatments to establish non-inferiority of ablative options have failed to accrue participants. The gold standard remains surgical resection for patients who are surgical candidates.

While there are overlapping and distinct aspects to the various algorithms for incidentally and screen-detected subsolid nodules, all algorithms highlight shared decision-making and patient counseling to reach practical management approaches. The side-by-side presentation of these guidelines may help prioritize the management options, with the understanding that ongoing research will refine recommendations 81 . Lesion, patient, and even local epidemiologic factors are considerations needed to arrive at balanced management decisions. Future guidelines, such as from the ACCP, BTS, and Fleischner Society, will continue to evolve in step with knowledge of subsolid nodule behavior and management. Table 1  Guidelines for Subsolid Nodule Reporting  Parameter Current Recommendations Slice thickness  Contiguous thin section slices 4 : Fleischner < 1.5 mm 10 , BTS < 1.25 mm 6 , and NCCN < 1 mm preferred 9 , particularly for nodules less than 10 mm 7,10 Reconstruction algorithm  High-frequency, sharp reconstruction algorithms 10 Display window  Lung windows; attenuation of nonsolid components may not meet attenuation threshold to be displayed on soft tissue mediastinal windows 10  Mediastinal display windows may aid qualitative assessment for presence or change in nodule density/solid components 12,13

Multi-planar reformatted images  Measurement should be made in plane of largest dimension 10

Reporting of nodule size  Include all components, including cystic and groundglass, in overall nodule size 10  Long and short axis measurements should be perpendicular and in same plane 10 o Lung-RADS, NCCN: report nodule mean diameter 8,9 o Fleischner: mean diameter for SSNs <10mm; bidirectional measures for SSNs >10mm 10  Long-axis dimension of the largest solid component should be reported, rather than summing/estimating percent solid components 10,48  Report to nearest millimeter 10 thought to represent fibrosis. Coronal image (B) demonstrates ovoid convex shape, atypical for scarring, and fissural tethering which has been described with malignant lesions. C, D) On imaging 8 years later, the lesion has progressed in size and is now solid, with round shape in the axial plane (C), and increased fissural bowing in the coronal plane (D). The lesion was invasive adenocarcinoma on resection. E, F) Periosteophyte fibrosis may appear nodular in the axial plane (E). Coronal images show crandiocaudal distribution of fibrosis to better advantage (F). in situ on resection. C) MIA: 76-year-old woman with 11 mm subsolid right middle lobe nodule; while there is no discrete solid component on imaging, the nodule is denser than groundglass in attenuation, and was a minimally invasive adenocarcinoma on resection. Inset demonstrates the lesion in mediastinal windowing, confirming small solid aspects. D) Invasive adenocarcinoma: 66-year-old man with predominately solid right upper lobe nodule, found to be adenocarcinoma, acinar pattern predominant with lepidic, papillary, and focally solid patterns. E) Mucinous adenocarcinoma: 46-year-old woman with 9 mm subsolid right upper lobe nodule with coursing air bronchogram, found to be mucinous adenocarcinoma on percutaneous core biopsy. Invasive mucinous adenocarcinoma is a less common and distinct histopathologic subtype of lung adenocarcinoma. A) 73-year-old woman with brain mass found to have a 2.4 cm right upper lobe nodule, with very mild surrounding groundglass. Biopsy was requested prior to inpatient neurosurgery. 4 days later, the lesion decreased to 1.5 cm in size. Percutaneous core biopsy revealed invasive adenocarcinoma. The decrease in nodule size was attributed to the high dose steroids administered for cerebral edema. B) 85-year-old woman with multiple lung adenocarcinomas, and a right lung subsolid nodule (2.2 x 1.7 cm) that contracted over 18 months (1.3 x 1 cm), as solid density increased. 

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