Solitary pulmonary ground-glass opacity: is it time for new surgical guidelines?

Summary

As screening for lung cancer becomes more common around the world, so too does detection of pulmonary ground-glass opacities (GGOs). Although a number of guidelines have been published that cover the management of GGOs, they typically feature some common themes. These include basing management and surveillance on a limited number of computed tomography imaging criteria only, inadequate consideration of the pros and cons of non-surgical biopsy versus surgery, inadequate consideration of modern advances in surgery for GGOs and inadequate consideration of potential variations in pathology in different parts of the world. As GGOs become increasingly common in thoracic surgical practice, it may be appropriate to draft new guidelines for the clinical management GGOs that take a more distinctly surgical and international perspective.

It is difficult to overstate the impact that the National Lung Screening Trial has had on the management of lung cancer worldwide [1]. This first demonstration that modern computed tomography (CT) screening may reduce mortality from lung cancer has led to fervent interest in starting screening programmes in a number of countries around the world [2–6]. The object is of course to identify lung cancer at earlier stages of disease. However, as a by-product of the increased utilization of CT in asymptomatic populations, besides suspicious, solid solitary pulmonary nodules, larger numbers of ground-glass opacities (GGOs) are also being discovered [7–10].

These GGOs are defined as focal areas of slightly increased attenuation on CT through which normal lung parenchyma structures, airways and vessels are visually preserved. They are radiologically divided into 2 categories: pure GGOs that contain no solid component and part-solid GGOs that contain both a pure GGO region and a consolidated region [11]. Over the years, there has been a massive volume of clinical research conducted on the clinical significance of GGOs. It is well reported that size, proportion of solid content on CT and progression of the GGOs over time may all significantly impact the natural history of these lesions [9, 10, 12–16]. From the plentiful clinical data available, a number of national and international guidelines have already been published, detailing perceived best management strategies for pulmonary GGOs [17–22].

With such robust, respected guidelines already in place, it would seem churlish to suggest that yet another set of guidelines on GGO management is needed. However, closer scrutiny reveals that there remain issues or recent developments that current guidelines have not fully addressed. In particular, the potential influence of modern advances in thoracic surgery seems to have been relatively neglected [23, 24]. It is not unreasonable to ask whether a new surgery-focused set of GGO management guidelines may be appropriate today. This article aims to stimulate surgeons to ponder the limitations in current GGO management guidelines and to consider the need to design a dedicated set of guidelines by surgeons and for surgeons.

CURRENT GUIDELINES ON GROUND-GLASS OPACITY MANAGEMENT: AN OVERVIEW

The discovery of GGOs is virtually incidental during CT for screening or for investigation of other conditions. It is therefore logical to first consider guidelines for radiologists first encountering GGOs on CT. The Fleischner Society guidelines have hitherto been widely used by many clinicians [17]. GGOs are categorized according to whether they are pure or part-solid and whether they are up to 5 mm in diameter or larger. Small, pure GGOs require no follow-up, whereas all others require follow-up CT at various intervals. Biopsy or surgery is recommended only for GGOs that develop a solid component and become larger than 5 mm. The Fleischner guidelines favour CT surveillance as the primary course for most GGOs and relegate surgery to only a niche role. It is notable that the later versions of the Fleischner guidelines for GGOs no longer simplistically distinguish between high- and low-risk patients, whereas the older versions of the Fleischner guidelines do—reflecting the increasing sophistication of the radiological assessment of GGOs [25].

The Japanese Society for CT Screening has also produced GGO management guidelines from a radiology/CT perspective [18]. Again, the size and degree of solid component are the key factors. As opposed to the Fleischner guidelines, follow-up is recommended for all patients. All patients receive CT surveillance, with biopsy or surgery reserved for lesions that are larger than 15 mm, have grown at the follow-up visit or have developed a solid component larger than 5 mm. Intriguingly, these guidelines allow individual hospitals to proceed to biopsy or surgery of smaller part-solid GGOs even if the solid component is smaller than 5 mm—perhaps reflective of the greater concern over the probability of malignancy in GGOs in East Asia [5, 9, 15, 26]. Similar to the Fleischner guidelines, the radiology-centric Japanese guidelines also do not provide any detailed recommendations regarding the nature of the biopsy or surgery to be offered.

The American College of Chest Physicians guidelines provide a slightly more multidisciplinary perspective [19]. Again, overall size and existence of a solid component are the key factors, but for the latter, the American College of Chest Physicians guidelines only differentiate between GGOs that have a solid component lesser or greater than 50% of the GGO size. Pure GGOs 5 mm or smaller require no follow-up, but all others do. Biopsy or surgery is performed for GGOs that persist on follow-up and if they either are pure and larger than 10 mm or have >50% solid component and are larger than 8 mm. Biopsy or surgery may also be offered outright to patients whose part-solid GGOs are larger than 15 mm on presentation. Detailed consideration regarding surgery is not provided. Regarding non-surgical biopsy, there is a brief discussion with one conclusion being that ‘although TTNB appears to be less sensitive for sub-solid than for solid nodules, it is still potentially useful, particularly for individuals who are at higher risk for surgical complications and those who wish to confirm malignancy before undergoing surgical resection’. There is a presumption—not supported by any specific references—that the risks of surgery are so ‘high’ that they outweigh the lack of accuracy of non-surgical biopsy.

The National Comprehensive Cancer Network guidelines are possibly the most widely used or referenced and are drafted by an intentionally multidisciplinary panel [20]. For solitary pure GGOs, all patients receive CT surveillance at intervals determined by lesion size. Surgical excision is optional for pure GGOs up to 5 mm if they increase in size and for pure GGOs larger than 10 mm that remain stable but persistent. For pure GGOs larger than 5 mm, surgical excision (not biopsy) is mandatory, if there is increase in size or development of a solid component at follow-up. The specification of ‘excision’ is more explicit than in the aforementioned guidelines. The guidelines also specify that any solid component in a GGO requires management of the lesion according to the more aggressive recommendations for entirely solid lung nodules—again a notably interventionist approach.

The American Association for Thoracic Surgery guidelines are virtually identical to the National Comprehensive Cancer Network guidelines in most major aspects, except that they recommend management of part-solid GGOs alongside pure GGOs rather than solid lung nodules [21]. Despite originating from a surgical society, the American Association for Thoracic Surgery guidelines do not give any clearer specifications regarding surgery.

The British Thoracic Society (BTS) provides one of the more recent set of guidelines with the most detailed analysis of the evidence [22]. The BTS guidelines consider all part-solid GGOs alongside pure GGOs, regardless of the size of the solid component. GGOs smaller than 5 mm that are known to have been stable for over 4 years do not need follow-up, but all others require repeat CT at 3 months. GGOs that persist and have morphological features suggesting ‘high risk’ of malignancy are given the option of surgical excision. For GGOs that show growth or altered morphology, surgical resection is mandatory. For GGOs that receive surgery, the BTS guidelines place them on the same management algorithm as for solid pulmonary nodules or frank lung cancer. This is a clear, specific management algorithm but does not address any potential differences that may exist between GGOs and solid nodules in terms of optimal surgical management.

THEMES AND GAPS IN CURRENT GUIDELINES

From the overview of existing GGO management guidelines above, it is apparent that the existing guidelines are designed from the perspective of a number of specialties (notably radiology and pulmonology) but that the precise role of surgery in GGO management is relatively less well defined and detailed. It is perhaps appropriate now for guidelines written by surgeons and for surgeons—which may complement rather than completely replace existing guidelines. In particular, such surgical guidelines must address the pertinent clinical questions raised by the above overview of existing guidelines as follows:

1. Criteria for determining management: too unreliable, too few?

All guidelines focus on the same 2 main factors to determine how GGOs should be managed: size and solid component. This is only reasonable as these are the 2 factors where most evidence have been produced showing links to natural history [9, 10, 12–16]. However, there are concerns about the (over-)reliance on these factors by existing guidelines [26, 27]. First, there have been concerns over whether these factors—read from CT scans—may be subjective and hence unreliable [26]. Second, recent studies have suggested that these factors may not be as predictive of prognosis as previously believed [27]. Third, how these 2 factors may or may not influence surgical outcomes has not been studied. For example, do the size and solid component of GGOs correlate with different morbidity and survival outcomes following surgery using different access strategies and different extents of resection? Fourth, despite GGOs correlating most closely with the adenocarcinoma development pathway [12, 28], the driver gene mutations well recognized to be the primary drivers of adenocarcinoma prognosis have never been assessed by those designing GGO management guidelines [26, 29]. The authors also envisage that any future surgical guidelines may be extended to take into account the impact of multiple GGOs. This not uncommon finding is especially relevant to surgeons because operative strategies must then consider that bilateral and/or relatively extensive resections may be involved.

2. Is CT surveillance really the best choice?

The majority of patients with GGOs would receive CT surveillance as the mainstay of their management according to the above protocols. The rationale for this is that the majority of GGOs do not progress to malignancy, and even if they did, the ‘delay’ in surgery does not usually result in poorer survival [17, 19, 22]. In favouring CT surveillance over immediate surgery, there is also a presumption of ‘surgical risk’ and an anxiety over the possibility of ‘unnecessary’ surgery for benign disease [19, 22]. However, are such beliefs justified today? The very guidelines espousing CT surveillance acknowledge that the evidence does not completely preclude disease progression or compromised survival in all patients [16, 19, 22]. On the other hand, modern surgery is much safer than ever before, with much-reduced morbidity, thanks to advanced minimally invasive approaches [8, 23, 24, 30]. Furthermore, if good multidisciplinary team (MDT) tumour board management of patients with solitary pulmonary nodules and GGOs is implemented, aggressive early surgery without preoperative diagnosis yields low morbidity and low rates of operations on benign lesions [7]. Such collaborative management of GGO by standard MDT tumour boards is already practiced in some centres in Asia, and it should not be difficult to implement around the world as MDT tumour board management becomes the standard of care globally. If surgery can be offered for GGOs before they progress to full-blown invasive adenocarcinomas, long-term survival can reach 100% [8, 12, 31]. In light of these points, an argument could be framed for modern minimally invasive surgery taking on a greater role for early GGO intervention vis-à-vis CT surveillance only.

3. What are the relative roles of non-surgical biopsy versus surgery?

Following the above point, the role of modern surgery may have to be reviewed not only in relation to CT surveillance but also in relation to non-surgical biopsy. As said above, some guidelines view non-surgical biopsy as generally preferable to surgery [19]. This view may be outdated. Non-surgical biopsy is well recognized to have variable accuracy, and the poor reliability can occasionally have serious consequences such as failure to diagnose malignancy [30, 32–34]. On the other hand, surgery offers demonstrably better diagnostic accuracy [24, 30] while no longer constituting such a threat of postoperative pain and morbidity as before [23, 30].

4. Does surgical strategy make a difference in GGO management?

Advanced minimally invasive surgery is not aimed at merely improving the outcomes for individual patients but lowering thresholds for surgery for all patients [7, 23]. This has already been demonstrated in diagnostic surgery and lung cancer resection [30, 35]. Besides reducing access (wound) trauma, thoracic surgeons have also minimized the surgical impact on patients by developing techniques of sub-lobar resection [8]. By reducing the volume of lung removed, the compromise in patient respiration after surgery is reduced—yet survival may not be compromised for the pathologies presenting as GGOs [8, 12]. Almost all of the current GGO guidelines failed to consider the influence of modern surgical advances in management paradigms in any depth. The BTS guidelines mentioned the use of minimally invasive surgery yet failed to distinguish between the roles of minimally invasive surgery for solid lung masses and for GGOs [22]. The authors would further add that modern ‘minimally invasive’ surgery should not be taken lightly because lung tissue is still removed, albeit with minimal access trauma. This further highlights the need to develop guidelines that properly consider the role of such minimally invasive approaches in the overall strategy of treating GGOs and to minimize the risk of performing ‘unnecessary’ surgery (such as for obviously benign disease). As noted above, the authors would favour an MDT tumour board discussion of all patients considered for such surgery, to ensure that surgery is aimed at those lesions that are suspected of being potentially malignant.

5. Should GGO management be the same around the world?

It is interesting to note that most of the current guidelines that include recommendations on GGO management come from the West [17, 19–22], yet most of the evidence on which these are based come from Asia [22]. Given that GGOs largely represent lesions on the adenocarcinoma oncogenic pathway [12, 28, 29] and that patterns of driver gene mutations for adenocarcinoma are well known to vary considerably around the world [36–38], is it realistic to expect guidelines that are ‘one-size-fits-all’? GGO incidence already appears to be higher in Asia. Preliminary evidence from many Asian case series also seems to suggest a possibly higher rate of malignancy or malignant potential in GGOs from that continent [3–5, 7, 10, 14–16]. Management of GGOs in East Asia also tends to be slightly more aggressive in terms of offering surgery [5, 7, 18, 24], and this may possibly be influenced by local experiences with GGOs over time. With this in mind, would it be practical to consider modifications of GGO guidelines to suit geographical or racial patterns?

CONCLUSIONS

GGOs are undoubtedly becoming an important part of the workload for clinicians managing chest disease around the world. Modern screening strategies are detecting increasing numbers of patients with GGOs. At the same time, clinical research is producing sound data on these lesions at a prodigious rate, while surgical advances rapidly improve how we manage these patients. Together, this means that guidelines for GGO management may need updating or even complete replacement at an extraordinarily quick rate to stay abreast of developments. There are some signs that even the most respected current guidelines may be due for renewal soon—if not already—with tailoring to incorporate surgical and regional concerns a priority.

Conflictofinterest: none declared.

REFERENCES