More Opaque Than Clear: Reality Is Always Cloaked in Shades of Gray

March 15, 2016

Lung cancer exhibits a wide spectrum of behavior, from inconsequential to nonaggressive, typically aggressive, and very aggressive lung cancer. The proportion of “well-behaved” cancers has clearly been increased by the advent of CT screening.

The review by Pedersen and colleagues on ground-glass opacity (GGO) lung nodules[1] is timely, addressing a clinical scenario that clinicians are increasingly confronted with: how to appropriately manage the patient with an incidentally detected GGO nodule. I commend the authors for assembling a broad yet concise review of data that can help guide decision-making in this setting. However, I think that in reality, many of the concepts presented are not as clear-cut as depicted; we must be thoughtful and nuanced in our judgment when managing these patients.

The correlation between radiographic appearance and histologic diagnosis is far from reliable. Among resected pure GGO nodules, adenocarcinoma in situ (AIS) was diagnosed in 20% to 59%, minimally invasive adenocarcinoma (MIA) in 20% to 32%, and invasive adenocarcinoma in 39% to 48%.[2-4] Earlier studies of resected pure GGO nodules found that 10% to 30% were benign, 5% to 70% were atypical adenomatous hyperplasia, 20% to 70% were bronchioloalveolar carcinoma, and 10% to 30% were invasive adenocarcinoma.[5] There is moderate interobserver variability in the histologic classification: In a study evaluating the presence of invasion in 64 cases as assessed by 28 thoracic pathologists, complete agreement was seen in 10%, and less than 10% discordance in 29% (with use of a three-point scale: “probable and definite invasion,” “unclear,” “probably or definitely not invaded”).[6] Furthermore, radiographic appearance is significantly affected by many factors, such as CT section thickness, window settings, and radiation dose.[7] Thus, equating a pure GGO nodule with AIS and a part-solid GGO nodule that has a solid component of less than 5 mm with MIA is a gross oversimplification.

The underlying assumption in the review by Pedersen et al is that the diagnosis is black and white: benign or invasive lung cancer. Yet lung cancer exhibits a wide spectrum of behavior, from inconsequential to nonaggressive, typically aggressive, and very aggressive lung cancer. The proportion of “well-behaved” cancers has clearly been increased by the advent of CT screening.[8] The decision to treat must consider both the aggressiveness of the lung cancer and competing risks (comorbidities). Furthermore, the spectrum of nonaggressiveness/aggressiveness may confound the extent-of-resection data: for example, is survival after wedge resection for a pure GGO nodule good simply because the tumor was inconsequential anyhow? We have to learn to think of lung cancer in shades of gray rather than simply as malignant vs benign, or invasive vs noninvasive.

The view that it is only a matter of time until a GGO nodule progresses may not be correct. Kobayashi et al studied 108 GGO nodules that were followed for up to 10 years: only about one-third demonstrated progression (which manifested within 3 years in all cases).[9] Other research suggests that there may be two different populations of GGO nodules, with different mutational patterns; only about one-third are of the type that appears likely to progress.[10,11]

Observing a potentially nonaggressive lung cancer for a period of time is an appealing approach, since this allows the degree of change to guide management. However, small changes can be hard to assess. The appearance of a GGO nodule varies with the degree of inspiration and scanner parameters, and assessment is hampered by inter-/intraobserver variability. Even for solid tumors, data show that false-positive and false-negative assessments of growth are on the order of 10% to 50%,[12] and that inter- and intraobserver consistency are poor for size differences of less than 1.5 mm up to 2 mm.[13,14] GGO nodules are even more difficult to measure reproducibly, and volumetric programs generally do not work well (with interscan variability of ~35% and inter-/intraobserver variability of 20% to 40%).[15,16] Furthermore, growth must be evaluated in light of the time interval involved: Does a GGO nodule that has grown 1 to 2 mm over 5 years constitute a life-threatening lung cancer?

A growing body of data shows that prognosis correlates primarily with the solid component of a GGO nodule and with the invasive component of adenocarcinoma.[7,17-20] In fact, in the new (8th edition) American Joint Committee on Cancer staging system (due out in mid-2016), T will be determined by the solid (as determined by imaging)/invasive (as determined by pathology) component.[7] Thus, the development and the size of a solid component appear to be much more important than the GGO/lepidic component, calling into question the clinical importance of growth (typically slow) of a pure GGO nodule.

Data from CT screening show a marked increase in the proportion of patients with a long volume doubling time (VDT) compared with VDTs in patients with regularly detected lung cancers.[8] Among pure GGO lesions, 50% to 90% are tumors with a VDT of more than 400 days, and VDT is greater than 800 days in 20% to 50%.[8] Limited data are available regarding lung cancers incidentally detected on CT not associated with a screening program, but these data suggest a stage distribution and survival similar to the values seen in CT screening programs.[21,22]

In summary, I offer several thoughts regarding the management of GGO nodules:

1. Focus on the solid component. This appears to correlate better with the more typical behavior of lung cancer, and the new stage classification will focus on the solid-appearing or invasive component of a cancer.

2. Be sure of what you see. There is a lot of variability in the assessment of small imaging changes. It is generally best to evaluate several scans over a period of time to be sure that a perceived change is real.

3. Is it a cancer that matters? The spectrum of lung cancer, especially of cancer that presents as a GGO nodule, includes very indolent cancers. The rate of growth must be balanced against comorbidities and competing risks when making management decisions.

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

References:

1. Pedersen JH, Saghir Z, Winkler Wille MM, et al. Ground-glass opacity lung nodules in the era of lung cancer CT screening: radiology, pathology, and clinical management. Oncology (Williston Park). 2016;30:266-74.

2. Son JY, Lee HY, Lee KS, et al. Quantitative CT analysis of pulmonary ground-glass opacity nodules for the distinction of invasive adenocarcinoma from pre-invasive or minimally invasive adenocarcinoma. PLoS One. 2014;9:e104066.

3. Lim HJ, Ahn S, Lee KS, et al. Persistent pure ground-glass opacity lung nodules ≥ 10 mm in diameter at CT scan: histopathologic comparisons and prognostic implications. Chest. 2013;144:1291-9.

4. Mimae T, Miyata Y, Tsutani Y, et al. What are the radiologic findings predictive of indolent lung adenocarcinoma? Jpn J Clin Oncol. 2015;45:367-72.

5. Detterbeck FC, Homer RJ. Approach to the ground-glass nodule. Clin Chest Med. 2011;32:799-810.

6. Thunnissen F, Beasley M, Borczuk AC, et al. Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study. Mod Pathol. 2012;25:1574-83.

7. Travis D, Asamura H, Bankier AA, et al. The IASLC Lung Cancer Staging Project: Proposals for coding T categories for adenocarcinoma in situ and minimally invasive adenocarcinoma, and for measurement of tumor size in part-solid tumors in the forthcoming eighth edition of the TNM Classification of Lung Cancer. J Thorac Oncol. 2016. [In press]

8. Detterbeck F, Gibson C. Turning gray: the natural history of lung cancer over time. J Thorac Oncol. 2008;3:781-92.

9. Kobayashi Y, Fukui T, Ito S, et al. How long should small lung lesions of ground-glass opacity be followed? J Thorac Oncol. 2013;8:309-14.

10. Yatabe Y, Borczuk AC, Powell CA. Do all lung adenocarcinomas follow a stepwise progression? Lung Cancer. 2011;74:7-11.

11. Kobayashi Y, Mitsudomi T, Sakao Y, Yatabe Y. Genetic features of pulmonary adenocarcinoma presenting with ground-glass nodules: the differences between nodules with and without growth. Ann Oncol. 2015;26:156-61.

12. Jennings SG, Winer-Muram HT, Tarver RD, Farber MO. Lung tumor growth: assessment with CT-comparison of diameter and cross-sectional area with volume measurements. Radiology. 2004;231:866-71.

13. Nietert PJ, Ravenel JG, Leue WM, et al. Imprecision in automated volume measurements of pulmonary nodules and its effect on the level of uncertainty in volume doubling time estimation. Chest. 2009;135:1580-7.

14. Revel M-P, Bissery A, Bienvenu M, et al. Are two-dimensional CT measurements of small noncalcified pulmonary nodules reliable? Radiology. 2004;231:453-8.

15. Oda S, Awai K, Murao K, et al. Computer-aided volumetry of pulmonary nodules exhibiting ground-glass opacity at MDCT. AJR Am J Roentgenol. 2010;194:398-406.

16. Kim H, Park CM, Woo S, et al. Pure and part-solid pulmonary ground-glass nodules: measurement variability of volume and mass in nodules with a solid portion less than or equal to 5 mm. Radiology. 2013;269:585-93.

17. Murakawa T, Konoeda C, Ito T, et al. The ground glass opacity component can be eliminated from the T-factor assessment of lung adenocarcinoma. Eur J Cardiothorac Surg. 2013;43:925-32.

18. Tsutani Y, Miyata Y, Mimae T, et al. The prognostic role of pathologic invasive component size, excluding lepidic growth, in stage I lung adenocarcinoma. J Thorac Cardiovasc Surg. 2013;146:580-5.

19. Tsutani Y, Miyata Y, Nakayama H, et al. Prognostic significance of using solid versus whole tumor size on high-resolution computed tomography for predicting pathologic malignant grade of tumors in clinical stage IA lung adenocarcinoma: a multicenter study. J Thorac Cardiovasc Surg. 2012;143:607-12.

20. Maeyashiki T, Suzuki K, Hattori A, et al. The size of consolidation on thin-section computed tomography is a better predictor of survival than the maximum tumour dimension in resectable lung cancer. Eur J Cardiothorac Surg. 2013;43:915-8.

21. Raz DJ, Glidden DV, Odisho A, Jablons DM. Clinical characteristics and survival of patients with surgically resected, incidentally detected lung cancer. J Thorac Oncol. 2007;2:125-30.

22. Kawachi R, Watanabe S, Asamura H. Clinicopathological characteristics of screen-detected lung cancers. J Thorac Oncol. 2009;4:615-9.