REVIEW ARTICLE Year : 2022  |  Volume : 55  |  Issue : 3  |  Page : 75-80

Management of pulmonary ground glass opacity: A review of current clinical practice guidelines

Tsai Ping-Chung1, Han-Shui Hsu2
1 Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
2 Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital; School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan

Date of Submission06-May-2022Date of Decision12-May-2022Date of Acceptance16-May-2022Date of Web Publication28-Jun-2022

Correspondence Address:
Han-Shui Hsu
Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei
Taiwan

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/fjs.fjs_107_22

The wide application of computed tomography (CT) and lung cancer screening has increased the incidence of ground-glass opacities (GGOs). For those malignant potential of pulmonary lesions, several guidelines are conducted for radiologists or clinicians while encountering newly formed or persisted GGOs on CT scan. Active surveillance scanning instead of upfront surgical resection was mostly suggested as an initial decision of choice for small pulmonary lesions, except developing solid components or new growth. Standard surgical treatment has been lobectomy in the past decades for early-stage lung cancer, the feasibility of limited pulmonary resection based on radiologic features had investigated also recently. Several pivotal trials have been conducted using consolidation-to-tumor ratio, advocating the hypothesized advantages of preserving pulmonary function with equivalent oncologic outcome to lobectomy. After initial surgery for a main tumor, observation alone without further therapy is suggested for those residual GGOs which are not resected. Even though there might be no inferiority in postoperative survival outcomes, the evaluation made by experienced multidisciplinary team during follow-up is necessary. This paper is a review of the recent managements and guidelines for GGOs.

Keywords: Current guidelines, early lung cancer, ground glass opacity

How to cite this article:
Ping-Chung T, Hsu HS. Management of pulmonary ground glass opacity: A review of current clinical practice guidelines. Formos J Surg 2022;55:75-80
How to cite this URL:
Ping-Chung T, Hsu HS. Management of pulmonary ground glass opacity: A review of current clinical practice guidelines. Formos J Surg [serial online] 2022 [cited 2022 Jun 29];55:75-80. Available from: https://www.e-fjs.org/text.asp?2022/55/3/75/348326   Introduction 

The National Lung Screening Trial[1] has for long struggled to decrease the mortality from lung cancer with the aid of the low-dose computed tomography (LDCT), and to compare it with the screening aided by chest radiography. However, with the increasing utilization of CT in screening, larger numbers of ground-glass opacities (GGOs) were also identified,[2] possibly as a potential adverse effect of lung cancer overdiagnosis.

Over the years, a variety of studies have investigated the impact of surgical outcome or surveillance of GGOs, including size, solid content, and progression of the GGOs, which may affect the natural history of these lesions.[3],[4],[5] Current guidelines[6],[7],[8],[9],[10] stress the value of assessing the probability of malignancy, to weigh the benefits and harms of different management strategies by utility of CT imaging, and the importance of eliciting patient preferences. They have focused on the natural history of GGOs based on CT change.

Surgical resection for this disease is the standard of care as aggressive approach to obtain curative intent while highly suspicion of malignancy. The optimal resection mode applying to early lung cancer is still under debate, limited or anatomic resection. In this review, we focused on the current GGO management guidelines and overview of further considerations as surgeons.

  Radiologic Features and Definition of Ground-Glass Opacities 

So far, the Fleischner Society defines GGO appearance as homogeneous hazy increased opacity of lung area without obscuration of bronchial and vascular margins,[11] distinguishing them from solid tumor of lung cancer. For differentiation of malignant rate, Henschke et al.[12] divide the detected GGOs into part-solid (with GGO and solid components) and nonsolid (upcoming pure GGO, without solid component). Nevertheless, predominance of GGO has been widely recognized as a better prognostic predictor to correlate with less invasive pathological findings.[13] With the rapid advances in determining radiological features and consistency, recent emphasis shifts onto the solid proportion of GGO. To establish effective radiological criteria to diagnose noninvasive peripheral lung adenocarcinoma based on CT findings, the Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group (JCOG) started a cohort study (JCOG0201)[14] in 2002. The criteria mostly used is consolidation-to-tumor ratio (CTR), defined as the ratio of solid portion size to total size in the lung window.[15] Another parameter less used is the tumor disappearance ratio, defined as the difference between 1 and the ratio of solid portion size in the mediastinal window to total tumor size in the lung.[16] To examine the feasibility of limited pulmonary resection for early-stage lung cancer, such as function-preserving and curative surgery, several pivotal trials[14],[17],[18],[19],[20] have been conducted using CTR criteria. However, the optimal timing of decision for surgical pulmonary resection should base on several guidelines.

  Follow-Up Suggestion of Ground-Glass Opacities 

Fleischner society guidelines

The advances in diagnostic technology, especially thin-slice computed tomography (CT), have increased the detection of small lung lesions and GGOs. Therefore, several guidelines [Table 1] are developed for radiologists or clinicians to recognize at the first glance over GGOs on CT scan.[6],[7],[8],[9],[10] The Fleischner Society 2017 guidelines[6] categorize pulmonary nodules into solid and subsolid lung nodules, and recommended that patients with subsolid nodules containing GGO component smaller than 6 mm in diameter do not require routine follow-up. For pure GGOs ≥6 mm in diameter, active surveillance scanning is recommended in 6–12 months and then every 2 years thereafter until 5 years. Multiple pure GGOs ≤6 mm are usually benign requiring no follow-up strategy except for selected patients. For subsolid GGOs ≥6 mm with a solid component <6 mm in diameter, follow-up is recommended at 3–6 months intervals for a minimum of 5 years. Although subsolid GGOs have a high likelihood of malignancy, transient infections are among the possible causes and could be resolved after a short period. Surgical resection or biopsy is highly suggested in case with development and growth of solid components, in surveillance group of pulmonary nodules ≥6 mm in diameter.

American College of Chest Physicians practice guidelines

The recommendations from the American College of Chest Physicians (ACCP) practice guidelines, 3rd Edition,[7] emphasize the value of using imaging tests to weigh the benefits and harms of different management strategies. Individuals with pure GGO ≤5 mm in diameter need no further evaluations, but annual surveillance with CT scan for at least 3 years is necessary if GGO is larger than 5 mm. Similar to Fleischner Society guidelines, ACCP guidelines recommend prompt consideration for resection of growing or developing solid component. In patients with subsolid GGOs (>50% GGO component) measuring >8 mm in diameter or pure GGOs >10 mm, repeat chest CT in 3 months should be applied. Further evaluation with positron emission tomography, nonsurgical biopsy, or surgical resection might be considered if the lesions persisted. Once the subsolid GGOs >15 mm appear, prompt evaluation, either noninvasive or invasive procedures, should proceed directly.

The American Association for Thoracic Surgery lung cancer screening guidelines

The American Association for Thoracic Surgery (AATS) lung cancer screening guidelines categorize subsolid GGOs and pure GGOs into the same group as the counter of solid lung nodules.[8] For GGOs sized between 5 and 10 mm on LDCT, a repeat LDCT should be performed in 6 months, followed by annual LDCT scans up to the age of 79 years if the appearance of image remains stable. However, a suspicious change in size or appearance should lead to a referral to a lung cancer specialist or surgical excision. For GGOs >10 mm showing no regression in 3–6 months on repeat LDCT scan, the choices of biopsy, surgical resection, or repeat CT in 6–12 months should be considered.

British Thoracic Society guidelines

Similar to the AATS guidelines, the British Thoracic Society guidelines categorize subsolid GGOs and pure GGOs into universal surveillance algorithm.[9] There is no need for repeat CT follow-up while GGOs are sized <5 mm or remain stable over 4 years. Otherwise, repeat thin section chest CT is recommended to perform in 3 months, and resection/nonsurgical treatment is favored over observation alone when growth or altered morphology such as enlargement/development of new solid component was found. If stable GGOs are noticed on repeat CT performed in 3 months, multiple factors such as patient choice, age, comorbidities, and risk of surgery should be taken into account, according to the Brock model.[21]

National Comprehensive Cancer Network guidelines

The National Comprehensive Cancer Network (NCCN) guidelines[10] as recommended from a multidisciplinary expert panel are world-widely used or referenced. The NCCN guidelines define a positive initial screening scan only for pure GGOs ≥20 mm in diameter, which require a short-term CT scan in 6 months. For subsolid GGOs containing both ground-glass and solid components, positive initial screening scan is defined as measuring ≥6 mm in mean diameter. The recommendation for a tumor sized ≥6 mm but with solid component <8 mm is close surveillance and rigorous evaluation. Further, the likelihood of malignancy is mentioned in the NCCN flowchart as the solid component ≥8 mm requiring tissue sampling. Furthermore, the assessment would change to a suspicious malignancy if increasing size or a new or growing solid component was found on interval CT scans. The NCCN guidelines emphasize multidisciplinary approach for decision making, which cannot be replaced by the use of risk calculators.

  Surgical Strategy 

Standard surgical treatment for early-stage lung cancer in the past decades has been lobectomy whenever possible. Yet more and more investigations have reported limited resection as having an equivalent cure rate to lobectomy, but with the theoretically hypothesized advantages of preserving pulmonary function. In 1982, the North American Lung Cancer Study Group[22] initiated a prospective, randomized trial comparing limited resection and lobectomy. This trial failed to demonstrate the equivalence of wedge or segmental resection to lobectomy for patients with lung cancer deemed to have a peripheral NSCLC T1N0 tumor. If pulmonary nodules are detected by screening to grow in number and present in different disease spectrum, lobectomy may not be suitable for lung cancer manifesting as GGO.

The first multi-institutional prospective study on defining radiological early lung cancer in Japan (JCOG0201),[14] enrolling 811 patients from 31 institutions, supported that lung cancer with a CTR <0.5 and a wide GGO could be regarded as early lung cancer. The exploratory analysis further identified that tumor ≤2.0 cm in size and with CTR ≤0.25 could be predicted as pathologically noninvasive cancer. Despite the findings of better pathologic report with a CTR ≤0.25 in tumor ≤2.0 cm than with a CTR ≤0.5 in tumor sized ≤3.0 cm, both of these radiologic criteria could achieve 5-year overall survival to approximate 97% as an excellent prognosis in JCOG0201 population.[23]

Based on the conception of the JCOG0201 trial, another Phase III study (JCOG0804/WJOG4507 L)[18] investigated the optimal mode of surgery for peripheral GGO dominant lung cancer with size ≤2 cm and CTR ≤0.25. Patients subjected to sublobar resection (mainly wedge resection) could achieve sufficient local control and 99.7% of 5-year relapse-free survival rate. For tumors ≤2 cm with CTR >0.25, a Phase III randomized trial of lobectomy versus segmentectomy JCOG0802/WJOG4607 L was started in 2008.[17] The protocol was revised 4 years after enrollment to change the eligibility criteria from CTR >0.25 to >0.5 based on the results of the previous JCOG study (JCOG0201). 1106 patients were enrolled from 68 institutions in 2014, and the outcomes showed no difference in almost all parameters of complications, except a higher chance of air leak for segmentectomy.[24] Superior pulmonary function preservation and noninferiority in overall survival were still pending in JCOG0802/WJOG4607 L trial. Therefore, a nonrandomized confirmatory trial (JCOG 1211)[19] of segmentectomy for clinical T1N0 lung cancer for tumors sized ≤3 cm and CTR ≤0.5 based on thin-section CT was conducted. Totally 390 patients from 42 Japanese institutions were accrued in 2015. The primary endpoint was a 5-year relapse-free survival in all the patients who underwent segmentectomy, with surgical margin estimated >2 cm.

Beside East Asia, CALGB/Alliance 140503 was a multicentre, Phase III trial recruiting patients from 69 academic and community-based institutions in Australia, Canada, and the USA. This trial purposed to demonstrate the state of noninferiority of lobar resection to sublobar resection, focusing on peripheral non-small cell lung cancers ≤2 cm in size. So far, this post hoc analysis showed no difference between lobar and sublobar resection in perioperative mortality and morbidity.[20] Even though the results of ongoing trials [Table 2] are expected, the issue of defining sublobar resection as a standard care is still controversial before any subgroup of patients could actually benefit from limited resection.

Table 2: Randomized control trials based on ground-glass opacities features

Click here to view

  Presurgical Resection Tissue Proof 

To identify how to optimize management of GGOs in lung cancer screening, the NCCN guidelines recommend biopsy or surgical excision for patients highly suspicious of lung cancer.[10] Tissue diagnosis for lung cancer via biopsies to confirm the pathological diagnosis is crucial for following an adequate treatment strategy. Nonsurgical biopsy such as CT-guided needle biopsy and trans-bronchoscopic biopsy could be obtained with increasing availability of chest imaging techniques. Overall, both techniques deserve well diagnostic performance. CT-guided biopsy generally provides better diagnostic yield and accuracy but higher procedural risk as pneumothorax and bleeding.[25] The accuracy of trans-bronchoscopic biopsy decreased as the distance from the hilum to lesion increased. Further, based on limited specimens, percutaneous lung biopsy could only provide additional information about the invasiveness of the subtypes even according to CTR percentage.[26] On the other hand, noninvasive adenocarcinoma is the predominant pathologic type of the most GGO predominant or radiographically determined noninvasive lung cancers. It should be judged carefully in the evaluation of subpleural lesion under percutaneous biopsies because of the potential risk for significantly higher incidence of local recurrence with pleural dissemination.[27],[28]

Beside preoperative tissue diagnosis, the decision to perform limited resection versus anatomical resection has also to be made by clinicians. Intraoperative frozen section is a practical option because former pathologists usually leave a large amount of tissue available for evaluation. Frozen section can provide information on the presence of aggressive histologic patterns, but is difficult to predict the predominant pattern.[29] Surgeons may consider using this information when making their decision regarding the extent of surgical resection to perform.

  Multiple Primary Lung Cancer and Residual Ground-Glass Opacities 

The development of novel technologies has made rapid advances in the diagnosis and management of multiple primary lung cancer. While surgery remains the primary treatment, the extent of surgery should be evaluated by an experienced multidisciplinary team.[30] The residual GGOs that are not resected with the main tumor in the initial surgery may experience growth or new development of GGOs, although the postoperative survival outcomes remained unaffected in Shimada et al.'s study.[31] Since most of the residual GGOs made no change or grew slowly during the follow-up period, observation alone without further adjuvant therapy should be advocated.[32] By relying on the surveillance CT reports, physicians should consider surgical therapy for residual GGOs if indicated and appropriately staged while progressed.

  Conclusion 

Worldwide application of lung screening has undoubtedly turned previously invisible GGOs into a crucial part of lung morbidity. Most evidence of optimal treatment strategy for GGO-featured lung adenocarcinoma come from Asia, but recommendations for GGO management come mostly from the West. Especially in East Asia, surgeons or clinicians tend to be slightly more aggressive in offering surgery. Considering the feasibility of limited resection for early lung cancer with GGO components, the debate will probably continue for a long while.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 

  References 
1.National Lung Screening Trial Research Team; Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409.  
    2.Zhang Y, Fu F, Chen H. Management of ground-glass opacities in the lung cancer spectrum. Ann Thorac Surg 2020;110:1796-804.  
    3.Tsai PC, Hsu PK, Yeh YC, Chen CK, Chang YY, Huang CS, et al. Active surveillance or early resection for ground-glass nodules that need preoperative localization. J Surg Oncol 2021;123:322-31.  
    4.Yankelevitz DF, Yip R, Smith JP, Liang M, Liu Y, Xu DM, et al. CT screening for lung cancer: Nonsolid nodules in baseline and annual repeat rounds. Radiology 2015;277:555-64.  
    5.Fukui M, Suzuki K, Matsunaga T, Oh S, Takamochi K. Surgical intervention for ground glass dominant lesions: Observation or outright resection? Jpn J Clin Oncol 2017;47:749-54.  
    6.MacMahon H, Naidich DP, Goo JM, Lee KS, Leung AN, Mayo JR, et al. Guidelines for management of incidental pulmonary nodules detected on CT images: From the Fleischner Society 2017. Radiology 2017;284:228-43.  
    7.Gould MK, Donington J, Lynch WR, Mazzone PJ, Midthun DE, Naidich DP, et al. Evaluation of individuals with pulmonary nodules: When is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143 Suppl 5:S93-120.  
    8.Jacobson FL, Austin JH, Field JK, Jett JR, Keshavjee S, MacMahon H, et al. Development of The American Association for Thoracic Surgery guidelines for low-dose computed tomography scans to screen for lung cancer in North America: Recommendations of The American Association for Thoracic Surgery Task Force for Lung Cancer Screening and Surveillance. J Thorac Cardiovasc Surg 2012;144:25-32.  
    9.Callister ME, Baldwin DR, Akram AR, Barnard S, Cane P, Draffan J, et al. British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax 2015;70 Suppl 2:i1-54.  
    10.Wood DE, Kazerooni EA, Baum SL, Eapen GA, Ettinger DS, Hou L, et al. Lung cancer screening, version 3.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2018;16:412-41.  
    11.Hansell DM, Bankier AA, MacMahon H, McLoud TC, Müller NL, Remy J. Fleischner Society: Glossary of terms for thoracic imaging. Radiology 2008;246:697-722.  
    12.Henschke CI, Yankelevitz DF, Mirtcheva R, McGuinness G, McCauley D, Miettinen OS, et al. CT screening for lung cancer: Frequency and significance of part-solid and nonsolid nodules. AJR Am J Roentgenol 2002;178:1053-7.  
    13.Ohde Y, Nagai K, Yoshida J, Nishimura M, Takahashi K, Suzuki K, et al. The proportion of consolidation to ground-glass opacity on high resolution CT is a good predictor for distinguishing the population of non-invasive peripheral adenocarcinoma. Lung Cancer 2003;42:303-10.  
    14.Suzuki K, Koike T, Asakawa T, Kusumoto M, Asamura H, Nagai K, et al. A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201). J Thorac Oncol 2011;6:751-6.  
    15.Hattori A, Matsunaga T, Hayashi T, Takamochi K, Oh S, Suzuki K. Prognostic impact of the findings on thin-section computed tomography in patients with subcentimeter non-small cell lung cancer. J Thorac Oncol 2017;12:954-62.  
    16.Kim H, Goo JM, Kim YT, Park CM. Consolidation-to-tumor ratio and tumor disappearance ratio are not independent prognostic factors for the patients with resected lung adenocarcinomas. Lung Cancer 2019;137:123-8.  
    17.Nakamura K, Saji H, Nakajima R, Okada M, Asamura H, Shibata T, et al. A phase III randomized trial of lobectomy versus limited resection for small-sized peripheral non-small cell lung cancer (JCOG0802/WJOG4607L). Jpn J Clin Oncol 2010;40:271-4.  
    18.Suzuki K, Watanabe S, Wakabayashi M, Moriya Y, Yoshino I, Tsuboi M, et al. A nonrandomized confirmatory phase III study of sublobar surgical resection for peripheral ground glass opacity dominant lung cancer defined with thoracic thin-section computed tomography (JCOG0804/WJOG4507L). J Clin Oncol 2017;35 Suppl 15:8561.  
    19.Aokage K, Saji H, Suzuki K, Mizutani T, Katayama H, Shibata T, et al. A non-randomized confirmatory trial of segmentectomy for clinical T1N0 lung cancer with dominant ground glass opacity based on thin-section computed tomography (JCOG1211). Gen Thorac Cardiovasc Surg 2017;65:267-72.  
    20.Altorki NK, Wang X, Wigle D, Gu L, Darling G, Ashrafi AS, et al. Perioperative mortality and morbidity after sublobar versus lobar resection for early-stage non-small-cell lung cancer: Post-hoc analysis of an international, randomised, phase 3 trial (CALGB/Alliance 140503). Lancet Respir Med 2018;6:915-24.  
    21.McWilliams A, Tammemagi MC, Mayo JR, Roberts H, Liu G, Soghrati K, et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med 2013;369:910-9.  
    22.Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 1995;60:615-22.  
    23.Asamura H, Hishida T, Suzuki K, Koike T, Nakamura K, Kusumoto M, et al. Radiographically determined noninvasive adenocarcinoma of the lung: Survival outcomes of Japan Clinical Oncology Group 0201. J Thorac Cardiovasc Surg 2013;146:24-30.  
    24.Suzuki K, Saji H, Aokage K, Watanabe SI, Okada M, Mizusawa J, et al. Comparison of pulmonary segmentectomy and lobectomy: Safety results of a randomized trial. J Thorac Cardiovasc Surg 2019;158:895-907.  
    25.Zhan P, Zhu QQ, Miu YY, Liu YF, Wang XX, Zhou ZJ, et al. Comparison between endobronchial ultrasound-guided transbronchial biopsy and CT-guided transthoracic lung biopsy for the diagnosis of peripheral lung cancer: A systematic review and meta-analysis. Transl Lung Cancer Res 2017;6:23-34.  
    26.Tsai PC, Yeh YC, Hsu PK, Chen CK, Chou TY, Wu YC. CT-guided core biopsy for peripheral sub-solid pulmonary nodules to predict predominant histological and aggressive subtypes of lung adenocarcinoma. Ann Surg Oncol 2020;27:4405-12.  
    27.Huang CS, Hsu PK, Chen CK, Yeh YC, Chen HS, Wu MH, et al. Preoperative biopsy and tumor recurrence of stage I adenocarcinoma of the lung. Surg Today 2020;50:673-84.  
    28.Tomiyama N, Yasuhara Y, Nakajima Y, Adachi S, Arai Y, Kusumoto M, et al. CT-guided needle biopsy of lung lesions: A survey of severe complication based on 9783 biopsies in Japan. Eur J Radiol 2006;59:60-4.  
    29.Yeh YC, Nitadori JI, Kadota K, Yoshizawa A, Rekhtman N, Moreira AL, et al. Using frozen section to identify histological patterns in stage I lung adenocarcinoma of ≤3 cm: Accuracy and interobserver agreement. Histopathology 2015;66:922-38.  
    30.Chiang CL, Tsai PC, Yeh YC, Wu YH, Hsu HS, Chen YM. Recent advances in the diagnosis and management of multiple primary lung cancer. Cancers (Basel) 2022;14:242.  
    31.Shimada Y, Saji H, Otani K, Maehara S, Maeda J, Yoshida K, et al. Survival of a surgical series of lung cancer patients with synchronous multiple ground-glass opacities, and the management of their residual lesions. Lung Cancer 2015;88:174-80.  
    32.Stiles BM, Schulster M, Nasar A, Paul S, Lee PC, Port JL, et al. Characteristics and outcomes of secondary nodules identified on initial computed tomography scan for patients undergoing resection for primary non-small cell lung cancer. J Thorac Cardiovasc Surg 2015;149:19-24.  
    

 
 

  [Table 1], [Table 2]