Ground-Glass Opacity Lung Nodules in the Era of Lung Cancer CT Screening: Radiology, Pathology, and Clinical Management

The advent of computed tomography screening for lung cancer will increase the incidence of ground-glass opacity (GGO) nodules detected and referred for diagnostic evaluation and management. GGO nodules remain a diagnostic challenge; therefore, a more systematic approach is necessary to ensure correct diagnosis and optimal management. Here we present the latest advances in the radiologic imaging and pathology of GGO nodules, demonstrating that radiologic features are increasingly predictive of the pathology of GGO nodules. We review the current guidelines from the Fleischner Society, the National Comprehensive Cancer Network, and the British Thoracic Society. In addition, we discuss the management and follow-up of GGO nodules in the light of experience from screening trials. Minimally invasive tissue biopsies and the marking of GGO nodules for surgery are new and rapidly developing fields that will yield improvements in both diagnosis and treatment. The standard-of-care surgical treatment of early lung cancer is still minimally invasive lobectomy with systematic lymph node dissection. However, recent research has shown that some GGO lesions may be treated with sublobar resections; these findings may expand the surgical treatment options available in the future.

Introduction

Low-dose computed tomography (LDCT) is accepted as an effective screening method in high-risk individuals for the purpose of reducing lung cancer mortality. Following the results of the National Lung Screening Trial (NLST) in the United States,[1] LDCT screening for lung cancer is being implemented in the United States and China[2,3] and is under consideration in many other countries. The management of screen-detected nodules, which must include methods for distinguishing between malignant and benign nodules, is crucial to the success of a screening program. Nodules that demonstrate ground-glass opacity (GGO) on CT are particularly challenging on account of their malignant potential and heterogeneous characteristics.[4] This review focuses on the radiologic and pathologic features of GGO nodules, along with the clinical management of these lesions.

Radiologic Features of GGO Nodules

GGO nodules are defined radiologically as focal areas of slightly increased CT attenuation through which the normal lung parenchyma structures, airways, and vessels are visually preserved; in fact, airways are often recognized more clearly because of the increased contrast between intraluminal air, which appears very black, and the surrounding abnormal lung parenchyma, which has increased density. Increased lung opacity occurs when the amount of air in the airspaces and in the lumen of the airways decreases and when the soft-tissue structures increase in size and/or amount. Thus, a reduction in the volume of the airspaces, as well as a partial or total replacement of the air in the airspaces by cells or fluid, will result in increased opacity.[5] In GGO nodules, airspace volume reduction is only partial, and the alveolar lumen is only moderately filled with cells and fluid, to a degree where complete consolidation of the lung parenchyma does not occur.

GGO nodules, also referred to as subsolid nodules, are radiologically divided into two categories: 1) pure GGO nodules, which contain no solid component (Figure 1A), and 2) part-solid GGO nodules, which contain both a pure GGO region and a consolidated region (Figure 1B).[6] These part-solid nodules are also called mixed GGO nodules. In malignant part-solid GGO nodules, the solid part histologically represents invasion, whereas the pure GGO areas are considered adenocarcinoma in situ (AIS). Solid transformation of GGO nodules is thus considered a strong indicator of malignancy.[7] A study showed that, based on the proportion of the solid component, called the consolidation/tumor (C/T) ratio, it may be possible to differentiate between invasive and noninvasive malignant disease.[8] GGO nodules are often slow-growing, and if malignant transformation from carcinoma in situ does occur, the process may take years-which is why longer follow-up time is necessary (see section on management).

It is important to keep in mind that “GGO” is a rather unspecific radiologic feature seen in a number of clinical conditions involving different pathologic processes. GGO on images may represent alveolar changes, but also interstitial changes, with increased cellularity and fluid within the alveolar wall. Apart from malignant disease, which is often a focal finding, GGO changes can represent lung infections (which may be visualized as patchy findings scattered throughout the parenchyma), lung edema with fluid in the interstitium, patchy increased parenchymal perfusion (ie, mosaic perfusion), or interstitial diseases (where GGO can represent disease activity and may precede irreversible changes, including the development of fibrosis).[9] Knowledge of these pathologies, along with a patient history and observation via repeat scans, is therefore necessary in the diagnostic workup of GGO nodules.

Pathology of GGO Nodules

According to the recent World Health Organization (WHO) classification,[10] adenocarcinoma and its precursors are classified into preinvasive lesions (including atypical adenomatous hyperplasia [AAH] and AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma. A detailed review of the pathologies of these three groups is outside the scope of this review.

In general, lung adenocarcinomas are thought to follow a linear multistep progression in which AAH progresses to AIS, which in turn is followed by invasive adenocarcinoma.

AAH is a localized small (less than 5 mm) proliferation of atypical type II pneumocytes and/or Clara cells lining the alveolar walls and respiratory bronchioles. AIS is a small (3 cm or less) solitary adenocarcinoma that demonstrates pure lepidic growth without stromal, vascular, or pleural invasion (Figure 2). The cell type is mostly nonmucinous (but may rarely be mucinous), and nuclear atypia is absent or inconspicuous.

MIA is a small (3 cm or less) solitary adenocarcinoma with a predominantly lepidic pattern and invasion of 5 mm or less at the largest dimension. If any histologic subtype other than lepidic is predominant, it should be regarded-and measured-as the invasive component.[11] However, the measurement of invasion size can be challenging if multiple foci of invasion are present.[12] If there is doubt about the tumor size, correlation with CT should be done. MIA does not invade lymphatics, blood vessels, or the pleura; contains no necrosis; and does not spread through air spaces. The prognosis is excellent for patients who undergo complete resection for AIS and MIA, as 5-year disease-free survival is close to 100%.

AIS and MIA should not be diagnosed in small biopsies or cytology specimens, as the whole tumor must be evaluated in order to rule out invasion for AIS and to measure the size of the whole invasion for MIA. If a noninvasive pattern is present in a small biopsy, it should be referred to as a lepidic growth pattern of adenocarcinoma, with a comment added that this could represent AIS, MIA, or invasive adenocarcinoma with a lepidic component.

For tumors with a semisolid pattern on CT, the site for obtaining the biopsy is critical and very important for the final diagnosis. In the peripheral part of the tumor, the biopsy will show a lepidic pattern only, whereas in the more central/solid part, the biopsy may show a lepidic as well as an invasive pattern.

Correlation with CT findings can help determine the most likely final diagnosis. For example, if a biopsy shows a lepidic pattern and CT shows a pure GGO nodule, this would favor a diagnosis of AIS, or possibly MIA, and would make a diagnosis of lepidic-predominant adenocarcinoma less likely, while if a mostly GGO nodule also had a solid component measuring more than 5 mm, this would favor a diagnosis of lepidic-predominant adenocarcinoma.[7,13,14] However, as mentioned previously, the final diagnosis of AIS or MIA requires a resection specimen, as these entities cannot be diagnosed in small biopsy specimens. It is reasonable to sample possible AIS or MIA lesions and to freeze the tissue samples obtained for possible later use; however, the pathology findings should also be correlated with the CT findings to make sure there are no solid areas suspicious for invasion. If suspicious areas are seen on CT and they are not represented on the histology slides, the frozen samples may need to be processed for histologic examination in order to reach a definitive diagnosis.

Invasive adenocarcinomas are classified into different subtypes according to pattern of growth: lepidic-predominant, papillary-predominant, micropapillary-predominant, acinar-predominant, or solid-predominant. The classification of invasive adenocarcinomas should be determined on the basis of the predominant subtype, with the proportion of all subtypes present measured in 5% increments. This subclassification has prognostic import, since solid and micropapillary adenocarcinomas have a poor prognosis, papillary and acinar adenocarcinomas have an intermediate prognosis, and lepidic adenocarcinomas have a favorable prognosis.[15-17] Invasive mucinous adenocarcinoma with lepidic pattern, formerly classified as mucinous bronchioloalveolar carcinoma, has been added as another specific subgroup.

The reproducibility of this classification has been evaluated by pathologists.[18,19] In pulmonary adenocarcinomas with classic morphology, there is good reproducibility for the identification of a predominant pattern and fair reproducibility for distinguishing invasive from in situ patterns. However, education in interpretation is needed to improve recognition of purely in situ disease, since this is an area of increasing importance.

In the multistep progression model, AIS is an intermediate step between AAH and MIA. KRAS and EGFR mutations have been demonstrated in up to one-third of AAH, suggesting that these mutations are early events of peripheral adenocarcinomas. These rates of mutation are only slightly different from those seen in AIS, MIA, and invasive adenocarcinomas.[20-22] However, because the definitions of AIS and MIA were established recently, the data on the rates of mutations in these lesions are sparse.

The association between mutations in driver genes such as EGFR, ALK, and KRAS and the presence of GGO has been studied to some extent. Some studies have demonstrated a significant association between EGFR mutation and air bronchogram. In a recent paper, 60% of tumors with GGO harbored the EGFR mutation, while only 35% of tumors with GGO were wild-type.[23] In other studies, such correlation was not demonstrated. In a study by Sugano et al, no significant association was found between GGO and EGFR mutations (P = .07). However, EGFR mutations occurred more frequently in male patients with GGO than in men without GGO (P = .04).[24] In a study by Ko et al, EGFR mutation status was not correlated to GGO proportion of nodules.[25] Pure GGO seems to be a significantly less common finding in patients with ALK mutations than it is in those with EGFR mutations, and the same is true for patients with KRAS mutations.[23,26,27] Ko et al also demonstrated that ALK rearrangement is rare in lung cancer with pure GGO nodules.[25] Finally, in a recent study, GGO nodules negative for four driver mutations (EGFR, KRAS, ALK, and HER2) were associated with no growth, whereas EGFR mutation–positive GGO nodules demonstrated a correlation with growth.[28] Prospective studies are required to further validate the association between GGO nodules and the presence of driver mutations.

Management of GGO Nodules

The increasing use of low-dose chest CT scans and implementation of CT screening for lung cancer have made it increasingly important to have available updated algorithms on the management of such findings as GGO lesions. Several sets of guidelines are already available for the management of subsolid nodules found on CT scans or via CT screening.

In 2013, the Fleischner Society (FS) published their recommendations for the management of subsolid pulmonary nodules detected on CT.[6] These complemented the 2005 FS guidelines on small pulmonary nodules detected on LDCT scans,[29] and together with data from NLST[30] and International Early Lung and Cardiac Action Program (I-ELCAP) protocol guidelines[31] form the basis for the recommendations from the National Comprehensive Cancer Network (NCCN).[32]

Recently, the British Thoracic Society (BTS) also published guidelines for investigation of pulmonary nodules.[33] The guidelines were based on a comprehensive review of the literature and on evidence from case series and reports that each included 50 or more GGO nodules, and from large CT screening trials; predominantly thin-section CT scans were included.

The following is a summary of the guideline recommendations for the management of subsolid nodules, along with the evidence supporting these recommendations.

Scan intervals and length of follow-up

With regard to short-term follow-up, the BTS guidelines suggest an initial follow-up CT scan 3 months after detection; the FS guidelines make the same recommendation (however, in both sets of guidelines, this recommendation only applies in GGO nodules of more than 5 mm). The recommendation is based on retrospectively collected data that support 3 months as being an appropriate interval to wait before measuring to determine resolution or growth of a GGO nodule.[34] NCCN recommends yearly follow-up of GGO nodules smaller than 5 mm and initial follow-up in 6 months if nodule size is greater than 5 mm-up through 10 mm.

Pertinent to the issue of long-term follow-up of persistent GGO nodules, studies have shown a significant increase in size (2 mm or more in longest diameter) after the nodules had been stable for more than 2 years.[34] Furthermore, some studies suggest that significant growth can be seen in about one out of four nodules after a median interval of approximately 4 years.[35,36] Thus, the BTS guidelines recommend that GGO nodules be followed for at least 4 years.[33] The FS guidelines recommend annual surveillance CT scans for a minimum of 3 years.[6] The NCCN guidelines recommend annual surveillance for a minimum of 2 years or until the patient is no longer a candidate for definitive treatment (Figure 3).

Size and growth measures predictive of malignancy

Growth in linear measures. Most studies have used linear measurements. An increase of 2 mm or more in the maximum diameter of a GGO nodule was considered significant and suggestive of malignancy. Nodules whose initial size was smaller than 5 mm in maximum diameter were considered benign and required no follow-up.[37]

The NCCN guidelines, however, define nodule growth differently, in a manner dependent on nodule size. For nodules 15 mm or smaller, growth is defined as an increase in the mean diameter of 2 mm or more in any nodule or in the solid portion of a part-solid nodule when compared with the baseline scan. For nodules 15 mm or larger, growth is defined as an increase of 15% in mean diameter when compared with the baseline scan.[32]

Growth in volume. GGO nodules are often slow-growing nodules with higher volume doubling times than are seen in solid nodules. The mean volume doubling time for growing GGO nodules was 769 days in one study and 1,041 days in another.[38,39] Currently, neither the NCCN nor the FS has addressed volumetric analysis or calculations based on volume doubling time.

Growth in mass. A study from the Dutch-Belgian NELSON trial suggests that measurements of the mass of GGO nodules can detect growth earlier than linear and volumetric measures and are subject to less interobserver variability.[38] The mass of a nodule can be derived from the CT image by using the nodule Hounsfield unit value, which is a density measurement; from this value, the mass can be calculated.

The role of PET-CT

Some studies have shown that the use of F18-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT to discriminate between benign and malignant GGO nodules is inappropriate, especially in the case of pure GGO nodules.[39,40] The BTS guidelines suggest that PET/CT may have a role in management if standardized uptake value (SUV) thresholds are lowered. A single study that included 64 pure GGO nodules showed an increase in the accuracy of FDG-PET/CT when the SUV threshold was lowered to 0.8.[41] PET has low sensitivity for nodules with a solid component of less than 8 mm.[32]

Nodule risk prediction model

The BTS guidelines were the first to include risk prediction models in the nodule management algorithms. Because of its high area under the curve for small nodules (under 10 mm), use of the Brock model is recommended.[37] The model has been thoroughly validated in a UK population[42] and with data from the Danish Lung Cancer Screening Trial (DLCST).[43] The model is based on data from the low-dose CT screening trial in Canada (Pan-Canadian Early Detection of Lung Cancer Study [PanCan]) and on validation datasets from chemoprevention studies conducted by the British Columbia Cancer Agency (BCCA). A combined 12,029 nodules (144 malignant) were included. In the original PanCan study, predictors for malignancy were nodule size, advanced age, lung cancer in the family, location in the upper lobe, part-solid nodule type, lower nodule count, and spiculation. Female sex and the presence of visually detected emphysema on CT were also considered malignancy predictors; however, these were not validated in the validation study from DLCST, in which male sex was associated with a greater risk of malignancy and emphysema was not found to be a useful predictor of nodule malignancy. The Brock model is available free of charge at http://www.brocku.ca/lung-cancer-risk-calculator (choose full model).

The BTS guidelines recommend the use of the Brock risk prediction tool if a GGO nodule 5 mm or larger in size is stable after 3 months. If the risk of malignancy is low (less than 10%), imaging follow-up is recommended.[33] However, if the risk is higher (greater than 10%), consideration of a more invasive diagnostic approach is recommended.

Results from the Dutch-Belgian NELSON trial

In 2014, researchers from the Dutch-Belgian NELSON trial analyzed the way in which they had used low-dose CT in evaluating and handling the GGO nodules in the study population of this large lung cancer screening trial.[44] Included in the analysis were 7,135 participants from the screening group. During the trial, 264 GGO nodules were registered, of which 117 persisted after 3 months of follow-up. Of these, 69 were pure GGO nodules and 48 were part-solid GGO nodules. Twenty of the pure GGO nodules developed into part-solid GGO nodules. A total of 33 GGO nodules were resected (11 pure GGO nodules and 22 part-solid GGO nodules); 28 (85%) were AIS or invasive carcinoma. Eighty-four of the nonresected GGO nodules (51 pure GGO nodules and 33 part-solid GGO nodules) were followed in accordance with the study protocol algorithm.[45] None of the unresected GGO nodules developed into symptomatic lung cancer; however, six participants died of pulmonary adenocarcinoma diagnosed in a solid nodule elsewhere in the lung parenchyma. The median follow-up period in the patients with unresected GGO nodules was 95 months. The research group found that their strategy-which involved close follow-up and a cutoff level for further investigation of 30% increase in volume of the solid component-could be considered safe.

Natural history of GGO nodules

Growth and solid transformation of GGO nodules are indicators of malignancy; however, most GGO nodules remain unchanged, and this is one of the reasons why the management of GGO nodules can be challenging. A study consisting of 122 screen-detected GGO nodules showed that 90% of nodules did not grow during long-term follow-up (median follow-up, 59 months).[46] Most GGO nodules thus have an indolent clinical course[47]; this is especially true in screening settings, where the participants are without symptoms. Selective surgery and longer (over 4 years) follow-up of GGO nodules is thus crucial to insure optimal, safe management.[36]

Localization, Marking, and Surgical Management of GGO Nodules

Suspicious GGO nodules may have to be surgically removed via video-assisted thoracoscopic surgery (VATS) for diagnostic or therapeutic reasons. However, GGO nodules are often difficult to locate due to their size and morphology. The preferred surgical procedure is VATS in combination with a marking of the GGO nodule. Most of the evidence regarding markers is derived from studies of peripherally located solid nodules smaller than 15 mm. It is generally assumed that the techniques used in the latter setting will also be effective in cases of GGO nodules.[48] The marking consists of CT-guided injection of 0.2 mL of methylene blue at the periphery of the nodule in combination with a small amount of dye at the subpleural region at the level of the nodule to serve as guidance for the surgeon.[49] In a recent prospective randomized trial, CT-guided percutaneous placement of microcoil markers in combination with fluoroscopic-guided VATS resection was significantly better than procedures in which nodule localization was via finger palpation only in small (mean nodule diameter, 12 mm) solid and subsolid nodules (93% vs 48%; P < .01).[48] Other techniques available are intraoperative ultrasonography,[50] hook wire placement,[51] injection of lipiodol,[52] and injection of radioisotope.[53] Centrally located GGO lesions are more difficult to resect and may in rare cases require a diagnostic lobectomy, even though this should be the diagnostic approach of last resort.[54]

The current guidelines recommend lobectomy with systematic lymph node dissection as the minimal resection in cases of stage I/II invasive carcinoma.[55] In recent years, improvements in CT scanning resolution, combined with increased use of CT screening, has led to the increased detection of GGO lesions that represent noninvasive or MIA types of lung cancer with a favorable prognosis.[8,56] In a CT screening context, the indication for surgery should always be carefully considered, and the decision should be made by a multidisciplinary board.[57] This is a necessary precaution in order to avoid resection of nonmalignant lesions, which if left alone might have regressed/disappeared and could in principle represent instances of the overdiagnosis of lung cancer. However, when a malignant diagnosis has been made, surgery is the primary curative treatment option. In some cases, sublobar resection may offer the same long-term survival as lobectomy, and without an increase in the likelihood of local recurrence.[58,59] In the past, sublobar resection has primarily been reserved for operable but high-risk patients in whom the optimal surgical approach must be modified. However, in recent years, especially in Japan, considerable research has gone into the evaluation of sublobar resections in non–high-risk patients.[60] The potential benefits of sublobar resection would be to spare healthy lung tissue, making for better respiratory capacity, and to allow for the possibility of future surgical treatment in the event of a new primary lung cancer.

It is possible to use radiologic criteria to identify an early noninvasive adenocarcinoma-eg, when the GGO nodule size is less than 2 cm and the C/T ratio is below 0.25 (cT1a), or when the C/T ratio is below 0.5 in a GGO nodule less than 3 cm in size (cTa-b).[8] In these patients, wide wedge resection is being compared with segmentectomy in an ongoing prospective, randomized trial conducted by the Japan Clinical Oncology Group (Table).[60] For radiologically invasive lung tumors (cTaN0M0) 2 cm or less in diameter and a C/T ratio greater than 0.5, lobectomy vs segmentectomy is being investigated in another randomized trial conducted by the Japan Clinical Oncology Group (Table).[61] In the United States, the Cancer and Leukemia Group B 140503 trial (ClinicalTrials.gov identifier: NCT00499330) is comparing lobectomy vs wedge resection or segmentectomy. With more extensive use of CT screening, it is expected that more GGO lesions will be detected, and hence the indications for sublobar resection will need to be considered more often. However, it is important that the oncologic benefit of the surgical procedure be monitored by conducting adequate follow-up and registering results, to make possible the systematic evaluation of the procedures used. Segmentectomy is oncologically superior to a wedge resection, since it provides wider resection margins and a lower local recurrence rate.[62] If a wedge resection is performed, it should be done with a resection margin greater than 2 cm, or greater than the maximal tumor diameter.[63,64]

Conclusions

GGO nodules remain a diagnostic challenge, and therefore a more systematic approach is necessary to ensure an optimal workup. Persisting GGO nodules larger than 5 mm should be followed for at least 4 years. PET/CT has limited value in the diagnostic workup of GGO nodules. Growth of more than 2 mm in maximal diameter is considered significant. Development of a solid component in a pure GGO nodule, or growth of a pre-existing solid component in a part-solid GGO nodule, is predictive of invasive malignancy. In such cases, invasive techniques such as CT-guided biopsy or nodule removal by VATS should be considered. The current standard of care for surgical treatment of early lung cancer (cT1a-bN0M0) is still VATS lobectomy. Recent research has shown that some GGO lesions with low C/T ratios may be treated by sublobar resection. However, final recommendations with regard to this must await the results of ongoing randomized trials in the United States and Japan.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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