Journal of Cancer Research and Therapeutics

EDITORIAL
Year
: 2020  |  Volume : 16  |  Issue : 2  |  Page : 199--202

Management of pulmonary multifocal ground-glass nodules: How many options do we have?


Baodong Liu1, Xin Ye2,  
1 Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
2 Department of Oncology, The First Affiliated Hospital of Shandong First Medical University, 16766 Jingshi Road, Jinan, Shandong Province 250014, China

Correspondence Address:
Xin Ye
Department of Oncology, The First Affiliated Hospital of Shandong First Medical University, 16766 Jingshi Road, Jinan, Shandong Province 250014
China




How to cite this article:
Liu B, Ye X. Management of pulmonary multifocal ground-glass nodules: How many options do we have?.J Can Res Ther 2020;16:199-202


How to cite this URL:
Liu B, Ye X. Management of pulmonary multifocal ground-glass nodules: How many options do we have?. J Can Res Ther [serial online] 2020 [cited 2020 Jul 5 ];16:199-202
Available from: http://www.cancerjournal.net/text.asp?2020/16/2/199/285184


Full Text



In 1996, the concept of pulmonary ground-glass nodule (GGN) or ground-glass opacity (GGO) nodule wasfirst proposed by the Fleischner Society.[1] Based on whether GGN contains the consolidation, it can be classified into pure GGN (pGGN) and part-solid nodule (PSN). pGGN and PSN are also known as the sub-solid nodule.[2],[3] The increasingly widespread use of high-resolution computed tomography (CT) and lung cancer screening program, incidentally detected pulmonary nodules are more common in routine diagnostic CT imaging (with an estimated frequency of detection >30% on CT[4]), many of which are pulmonary multifocal GGNs.

The NELSON study (3392 participants and 7258 nodules) showed that 1746 (51.5%) participants had one nodule, 800 (23.6%) had two nodules, 354 (10.4%) had three nodules, 191 (5.6%) had four nodules, and 301 (8.9%) had >4 nodules.[5] In other words, nearly half of the participants had multifocal pulmonary GGN. Moreover, 20%–30% of the resected GGN samples are accompanied with other multiple intrapulmonary small GGN focuses.[6] Pulmonary multifocal nodules were divided into four categories,[7] which are second primary lung cancer, separate tumor nodules, multifocal GGNs, and the diffuse pneumonic type. We are paying more attention on multifocal GGNs because multifocal GGNs have different imaging characteristics, the preferred treatment is different, and the treatment of each pulmonary nodule remains controversial.

The Italian Society of Thoracic Surgery has published the results of GGN-related investigations among 160 members:[8] About 50% of the interviewees supported percutaneous lung biopsy, especially >1 cm and persistent existence or PSN. After thefirst follow-up, it was agreed that persistent or ever-increasing PSN should be surgically removed, but there was disagreement over whether persistent pGGN would require surgical excision. For c-I stage GGN with consolidation <50%, the controversy over whether sublobectomy was superior to lobectomy, wedge resection, segmentectomy, and lymph node dissection still existed. For c-I stage GGN with consolidation >50%, sublobectomy was inferior to lobectomy and lymph node dissection should be performed at the same time. Nearly 96.2% of the interviewees believed that video-assisted thoracoscopic surgery (VATS) could be used for the treatment of pGGN, but 68% of the interviewees believed that VATS would be more suitable for those patients who can be positioned during the operation. Sixty-eight percent of the interviewees recommended follow-up imaging of pGGN <5 mm, but they had different opinions about the time duration and the time interval of follow-up CT scan.

In a questionnaire survey, about the treatment of pulmonary multifocal GGN, which was conducted among 221 cross-disciplinary members of the International Association for the Study of Lung Cancer:[9] 63% of the respondents recommended preoperative multifocal focus pathological examination and 66% of the respondents recommended gene test for evaluating the consistency between histology and gene; 63% of the respondents recommended surgical resection (in remaining respondents, 18% recommended not to perform operation, and 19% were unsure); 81% of surgeons were inclined to perform surgical resection, and this proportion was obviously higher than that of oncologists (54%), pulmonologists (66%) and radiation oncologists (45%); the main surgical techniques included lobectomy (for primary focus) and various types of combined segmentectomy (for secondary focus).

It can be seen that many options are available for the management of pulmonary multifocal GGNs, such as follow-up, surgery, thermal ablation, stereotactic body radiotherapy (SBRT), molecular-targeted drug, and chemotherapy.

Follow-up

It is important for physicians to distinguish between transient GGNs and persistent GGNs. Transient GGN is one that disappears during follow-up. Approximately 40%–50% of GGNs have been reported to disappear after 3–4 months follow-up.[10],[11],[12] If a GGN remains during the follow-up, the lesion is called a persistent GGN. It is generally believed that for GGN showing no change in size and shape during 3–4 month follow-up period, the possibility of lung cancer cannot be completely excluded. Persistent multifocal GGNs represent independent histopathologic diagnoses according to their sizes, as in a single GGN. Their management methods and prognoses are not different in terms of nodule number and size.[13],[14],[15]

In a follow-up study of 78 patients with pulmonary multifocal GGN conducted in Japan, 37% cases showed enlargements within a follow-up period (median follow-up time: 45.5 months) and most appeared within 36 months. Therefore, the recommended optimal observation time for pulmonary multifocal GGN patient is 36 months.[16] Some researches proved that after the resection of primary focus, patients' prognosis would not be affected no matter whether other focuses continuously grow, new focus is developed or the remaining focuses are not treated.[17],[18],[19],[20] If the secondary focus is pGGN and it is impossible to remove all focuses due to the limitation by cardiopulmonary functions, it is recommended to follow-up once every 6–12 months; if there is no change subsequently, follow-up once every 2 years.

Surgery

Deciding upon surgical intervention for multifocal GGNs is challenging. The determination of timing of GGN intervention is mainly dependent on the size of GGN, size of consolidation, and dynamic follow-up changes. In clinical practice, some 5–10 mm GGNs can be intervened actively: (1) peripheral GGN close to visceral pleura: locally resectable; (2) existence of high-risk factors: previous history of malignant tumor, family history, and long-term history of smoking; (3) sign of malignant tumor detected by imaging: lobulation sign, spicule sign, pleural indentation, and part solid; (4) increased metabolism detected by positron emission tomography/CT (PET-CT); and (5) patients' extreme anxiety about GGN cannot be alleviated. In following cases, 5–10 mm GGN should be treated with caution: (1) GGN in pulmonary parenchyma: not locally resectable; (2) pure GGN followed up dynamically; (3) part-solid GGN, but no sign of malignancy on image, nor metabolism or hypometabolism in PET-CT; and (4) advanced age and poor performance status.

Principles of operation: (1) Give the priority to the treatment of primary focus, and then, give consideration to secondary focus and (2) make every effort to remove the focus completely and preserve pulmonary function (e.g., sublobectomy) provided that patients' survival is not affected and the tumor-free principle is met.

According to the anatomical position, size, and quantity of GGN, consider sublobectomy and lobectomy; for bilateral lesions, consider one-stage resection. As demonstrated in some studies, for nodules predominantly composed of pure GGN, sublobectomy can achieve the prognosis that is similar to that of lobectomy; for GGN having a large proportion of consolidations, lobectomy is controversial. The preliminary results of the prospective randomized controlled clinical trial JCOG0802 have been published: segmentectomy showed that postoperative short-term effects are similar to that of lobectomy except slightly more blood loss, higher rate of chest tube reinsertion, and slightly higher alveolar pleural fistula incidence.

Stereotactic body radiotherapy

There have been few clinical researches on the treatment of multifocal GGNs with SBRT, and almost no such study can be found in SEER. Sinha et al.[21] and Matthiesen et al.[22] reported a small cohort of medically inoperable multiple primary lung cancer (MPLC) patients treated with SBRT, respectively. Their results showed excellent local control rates and clinically acceptable toxicity. Chang JY et al.[23] reported that 101 patients were treated with stereotactic ablative radiation therapy for early-stage MPLC. With a median follow-up time of 40 months, the 2-year and 4-year infield local control rates were 97.4% and 95.7%, respectively; the 2-year and 4-year overall survival (OS) rates were 73.2% and 47.5%, respectively. For patients who either underwent surgery or received SABR, the incidence of Grade 3 radiation pneumonitis was 3% (2 of 71 patients); however, this increased to 17% (5 of 30 patients) for those who received conventional radiotherapy. Certainly, there is a difference between MPLC and multifocal GGNs.

Eriguchi et al.[24] reported that 24 patients were treated with SBRT for operable early-stage non-small cell lung cancer with GGNs. With a median follow-up time of 40 months, cause-specific survival (CSS) and OS rates at 3 years were 100% and 100%, respectively. As for toxicities, the patient can tolerate it. No Grade 4 or 5 radiation pneumonitis occurred.

However, there were very few clinical studies on SBRT for treating GGN, especially on multifocal GGNs. The possible reasons are as follows: (1) it is very difficult to obtain the pathologic results of GGN; (2) AIS and MIA have lepidic growth, and target volume can hardly be determined; (3) multitarget radiation may be too toxic; and (4) due to the influence of radiation pneumonia, sometimes it is difficult to evaluate the local efficacy of GGN after SBRT.[25],[26]

Thermal ablation

Thermal ablation, as a precise minimally invasive technique, has been increasingly used to treat the early-stage lung cancer year by year.[27],[28],[29],[30],[31] The techniques include radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation, and laser ablation.

In recent years, there were several clinical studies focused on the outcomes and safety of RFA, MWA, and cryoablation in the treatment of GGO. Kodama et al.[32] reported that lung RFA was performed on 33 patients with 42 lung tumors with ≥50% GGO components. OS and CSS rates were 96.4% and 100% at 3 years, and 96.4% and 100% at 5 years, respectively. Iguchi et al.[33] reported that 16 patients with 17 lung cancer lesions showing GGO received a total of 20 percutaneous CT-guided RFA sessions. The median follow-up period of all the patients was 65.6 months. OS and disease-specific survival rates were 93.3% and 100% at 1 year, 93.3% and 100% at 5 years, respectively. These results suggested that lung RFA was safe and effective on treating lung cancer with GGO, bringing about promising survival rates. Yang et al.[34] reported that 51 patients with 51 lung adenocarcinoma lesions showing GGO received a total of 52 percutaneous CT-guided MWA sessions. The median follow-up period of all the patients was 27.2 months. The rates of 3 years local progression-free survival, CSS, and OS rates were 98%, 100%, and 96%, respectively. The technical success rate was 100%, without MWA procedure-related death. Pneumothorax was one of the most common complications for MWA. The incidence of pneumothorax was similar to that of previous report.[35] These results suggested that CT-guided percutaneous MWA was a feasible, safe, and effective therapeutic approach for treating GGO lung adenocarcinoma. Liu et al.[36] retrospectively analyzed the preliminary results of cryoablation of 19 GGNs in 14 patients, and all nodules were completely ablated within a 24-month median follow-up period. The technical success rate was 100%, without cryoablation procedure-related death.

Certainly, the above studies also have some limitations. The main limitations were its retrospective nature, single GGN (no multifocal GGNs), relatively short follow-up period of time after addressing GGO lesions, as well as the small sample size. Fortunately, a multicenter, prospective, large-sample clinical trial (NCT03490890) of MWA for pulmonary GGO is under way, so we can look forward to the results of this study. Furthermore, the above studies were not designed to compare the thermal ablation with other treatments such as surgery, SBRT. Can thermal ablation be used in the treatment of multifocal GGNs? The answer should be “yes”!

Molecular-targeted drug treatment

Although GGN has about 40% of mutations in estimated glomerular filtration rate or other genes,[37],[38] there have been no studies on molecular-targeted drug for treating GGN. Only a very few PSN patients who have lymph node metastasis and driver gene mutation need such type of drug treatment.

Chemotherapy

At present, no study has proved that chemotherapy is beneficial to patient after GGN resection. Only a very few PSN patients who have large focus or lymph node metastasis and do not have driver gene mutation need chemotherapy.[39]

To sum up, the troika for current treatment of pulmonary multifocal GGN includes surgery, SBRT, and thermal ablation. Surgical resection has very good effects. Sublobectomy is being accepted by more and more physicians, but the long-term follow-up results from prospective randomized controlled trial are needed. SBRT has certain limitations in the treatment of multifocal GGNs, and there are few relevant clinical studies. Thermal ablation, a new weapon in the treatment of GGN,[40] has shown its advantages. In the near future, we believe that thermal ablation will challenge surgery and will gradually replace the surgery in the treatment of GGN.

References

1Austin JH, Müller NL, Friedman PJ, Hansell DM, Naidich DP, Remy-Jardin M, et al. Glossary of terms for CT of the lungs: Recommendations of the nomenclature committee of the fleischner society. Radiology 1996;200:327-31.
2Baldwin DR, Callister ME; Guideline Development Group. The British Thoracic Society guidelines on the investigation and management of pulmonary nodules. Thorax 2015;70:794-98.
3MacMahon H, Naidich DP, Goo JM, Lee KS, Leung ANC, 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.
4Gould MK, Tang T, Liu IL, Lee J, Zheng C, Danforth KN, et al. Recent Trends in the identification of incidental pulmonary nodules. Am J Respir Crit Care Med 2015;192:1208-14.
5Heuvelmans MA, Walter JE, Peters RB, Bock GH, Yousaf-Khan U, Aalst CM, et al. Relationship between nodule count and lung cancer probability in baseline CT lung cancer screening: The NELSON study. Lung Cancer 2017;113:45-50.
6Lim HJ, Ahn S, Lee KS, Han J, Shim YM, Woo S. Persistent pure ground-glass opacity lung nodules≥10 mm in diameter at CT scan: Histopathologic comparisons and prognostic implications. Chest 2013;144:1291-99.
7Detterbeck FC, Bolejack V, Arenberg DA, Crowley J, Donington JS, Franklin WA. The IASLC lung cancer staging project: Background data and proposals for the classifcation of lung cancer with separate tumor nodules in the forthcoming eighth edition of the TNM classifcation for lung cancer. J Thorac Oncol 2016;11:681-92.
8Lococo F, Cusumano G, De Filippis AF, Curcurù G, Quercia R, Marulli G, et al. Current practices in the management of pulmonary ground-glass opacities: A survey of SICT members. Ann Thorac Surg 2018;106:1504-11.
9Leventakos K, Peikert T, Midthun DE, Molina JR, Blackmon S, Nichols FC, et al. Management of multifocal lung cancer: Results of a survey. J Thorac Oncol 2017;12:1398-402.
10Felix L, Serra-Tosio G, Lantuejoul S, Timsit JF, Moro-Sibilot D, Brambilla C, et al. CT characteristics of resolving ground-glass opacities in a lung cancer screening programme. Eur J Radiol 2011;77:410-6.
11Libby DM, Wu N, Lee IJ, Farooqi A, Smith JP, Pasmantier MW, et al. CT screening for lung cancer: The value of short-term CT follow-up. Chest 2006;129:1039-42.
12Oh JY, Kwon SY, Yoon HI, Lee SM, Yim JJ, Lee JH, et al. Clinical significance of a solitary ground-glass opacity (GGO) lesion of the lung detected by chest CT. Lung Cancer 2007;55:67-73.
13Kim TJ, Kim CH, Lee HY, Chung MJ, Shin SH, Lee KJ, et al. Management of incidental pulmonary nodules: Current strategies and future perspectives. Expert Rev Respir Med 2020;14:173-94.
14Suzuki K. Whack-a-mole strategy for multifocal ground glass opacities of the lung. J Thorac Dis 2017;9:S201-S207.
15Yu J, Zhu S, Ge Z, Shen B, Shen Y, Wang C, et al. Multislice spiral computed tomography in the differential diagnosis of ground-glass opacity. J Cancer Res Ther 2018;14:128-32.
16Sato Y, Fujimoto D, Morimoto T, Uehara K, Nagata K, Sakanoue I, et al. Natural history and clinical characteristics of multiple pulmonary nodules with ground glass opacity. Respirology 2017;22:1615-21.
17Shimada 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.
18Gu B, Burt BM, Merritt RE, Stephanie S, Nair V, Hoang CD. A dominant adenocarcinoma with multifocal ground glass lesions does not behave as advanced disease. Ann Thorac Surg 2013;96:411-8.
19Kim HK, Choi YS, Kim J, Shim YM, Lee KS, Kim K. Management of multiple pure ground-glass opacity lesions in patients with bronchioloalveolar carcinoma. J Thorac Oncol 2010;5:206-10.
20Hattori A, Matsunaga T, Takamochi K, Oh S, Suzuki K. Surgical management of multifocal ground-glass opacities of the lung: Correlation of clinicopathologic and radiologic findings. Thorac Cardiovasc Surg 2017;65:142-9.
21Sinha B, McGarry RC. Stereotactic body radiotherapy for bilateral primary lung cancers: The Indiana University experience. Int J Radiat Oncol Biol Phys 2006;66:1120-4.
22Matthiesen C, Thompson JS, De La Fuente Herman T, Ahmad S, Herman T. Use of stereotactic body radiation therapy for medically inoperable multiple primary lung cancer. J Med Imaging Radiat Oncol 2012;56:561-6.
23Chang JY, Liu YH, Zhu Z, Welsh JW, Gomez DR, Komaki R, et al. Stereotactic ablative radiotherapy: A potentially curable approach to early stage multiple primary lung cancer. Cancer 2013;119:3402-10.
24Eriguchi T, Takeda A, Sanuki N, Tsurugai Y, Aoki Y, Oku Y, et al. Stereotactic body radiotherapy for operable early-stage non-small cell lung cancer. Lung Cancer 2017;109:62-7.
25Kalman NS, Hugo GD, Kahn JM, Zhao SS, Jan N, Mahon RN, et al. Interobserver reliability in describing radiographic lung changes after stereotactic body radiation therapy. Adv Radiat Oncol 2018;3:655-61.
26Mattonen SA, Palma DA, Haasbeek CJ, Senan S, Ward AD. Early prediction of tumor recurrence based on CT texture changes after stereotactic ablative radiotherapy (SABR) for lung cancer. Med Phys 2014;41:033502.
27Dupuy DE, Fernando HC, Hillman S, Ng T, Tan AD, Sharma A, et al. Radiofrequency ablation of stage IA non-small cell lung cancer in medically inoperable patients: Results from the American College of Surgeons Oncology Group Z4033 (Alliance) trial. Cancer 2015;121:3491-8.
28Ye X, Fan W, Wang H, Wang J, Wang Z, Gu S, et al. Expert consensus workshop report: Guidelines for thermal ablation of primary and metastatic lung tumors (2018 edition). J Cancer Res Ther 2018;14:730-44.
29Uhlig J, Ludwig JM, Goldberg SB, Chiang A, Blasberg JD, Kim HS. Survival rates after thermal ablation versus stereotactic radiation therapy for stage 1 non-small cell lung cancer: A national cancer database study. Radiology 2018;289:862-70.
30Postmus PE, Kerr KM, Qudkerk M, Senan S, Waller DA, Vansteenkiste J, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28(Suppl 4):Iv121.
31Han X, Yang X, Huang G, Li C, Zhang L, Qiao Y, et al. Safety and clinical outcomes of computed tomography-guided percutaneous microwave ablation in patients aged 80years and older with early-stage non-small cell lung cancer: A multicenter retrospective study. Thorac Cancer 2019;10:2236-42.
32Kodama H, Yamakado K, Hasegawa T, Takao M, Taguchi O, Fukai I, et al. Radiofrequency ablation for ground-glass opacity-dominant lung adenocarcinoma. J Vasc Interv Radiol 2014;25:333-9.
33Iguchi T, Hiraki T, Gobara H, Fujiwara H, Matsui Y, Soh J, et al. Percutaneous radiofrequency ablation of lung cancer presenting as ground-glass opacity. Cardiovasc Intervent Radiol 2015;38:409-15.
34Yang X, Ye X, Lin Z, Jin Y, Zhang K, Dong Y, et al. Computed tomography-guided percutaneous microwave ablation for treatment of peripheral ground-glass opacity-Lung adenocarcinoma: A pilot study. J Cancer Res Ther 2018;14:764-71.
35Zheng A, Wang X, Yang X Wang WB, Huang GH, Gai YH. Major complications after lung microwave ablation: A singlecenter experience on 204 sessions. Ann Thorac Surg 2014; 98:243248.
36Liu S, Zhu X, Qin Z, Xu J, Zeng J, Chen J, et al. Computed tomography-guided percutaneous cryoablation for lung ground-glass opacity: A pilot study. J Cancer Res Ther 2019;15:370-4.
37Wang D, Yan N, Yang X, Ge Y, Xu D, Shao G, et al. Correlation between epidermal growth factor receptor mutation and histologic subtypes or characteristics of computed tomography findings in patients with resected pulmonary adenocarcinoma. J Cancer Res Ther 2018;14:240-4.
38Lu Q, Ma Y, An Z, Zhao T, Xu Z, Chen H. Epidermal growth factor receptor mutation accelerates radiographic progression in lung adenocarcinoma presented as a solitary ground-glass opacity. J Thorac Dis 2018;10:6030-9.
39Lu W, Cham MD, Qi L, Wang J, Tang W, Li X, et al. The impact of chemotherapy on persistent ground-glass nodules in patients with lung adenocarcinoma. J Thorac Dis 2017;9:4743-9.
40Hertzanu Y, Ye X. Computed tomography-guided percutaneous microwave ablation: A new weapon to treat ground-glass opacity-lung adenocarcinoma. J Cancer Res Ther 2019;15:265-6.