Hotta et al. Journal of Cardiothoracic Surgery
https://doi.org/10.1186/s13019-020-01196-x(2020) 15:149

RESEARCH ARTICLE

Open AccessComparative postoperative outcomes of
GGN-dominant vs single lesion lungadenocarcinomas
Takamasa Hotta1, Yukari Tsubata1* , Akari Tanino1, Mika Nakao1, Yoshihiro Amano1, Megumi Hamaguchi1,
Shunichi Hamaguchi1, Koji Kishimoto2 and Takeshi Isobe1

Abstract
Background: Multiple synchronous ground glass nodules (GGNs) are known to be malignant, however, they tend
to progress slowly. Multiple synchronous lesions in the same patient which show different characteristics must betreated individually.
Methods: This was a retrospective review of 34 lung adenocarcinoma patients with multiple synchronous GGNs in
an Asian population. One hundred twenty-seven single lung adenocarcinoma patients were included forcomparison purposes. The follow-up period was 5 years for all patients.
Results: The 5-year overall survival (OS) patients with multiple lesions did not differ from that of the patients withsingle lesions to a statistically significant extent (Single: 81.8% vs. Multiple: 88.2%, P = 0.3602). Dominant tumors(DTs) with a ground glass component and consolidation were divided into three categories based on the
consolidation-to-tumor ratio on radiological imaging. No significant differences were observed among the three DT
categories. Twenty-four patients had unresected GGNs, while a progression of the unresected GGN occurred in 10of these cases. The OS and disease-free survival (DFS) curves of patients with and without GGN progression did not
differ to a statistically significant extent (OS: 80% vs. 92.9%, P = 0.3870; DFS: 80% vs. 100%, P = 0.0977).
Conclusions: The outcomes were best predicted by the stage of the DT. After surgery patients require a carefulfollow-up because unresected GGNs may show progression. At the same time, the increase in residual lesions andthe appearance of new GGNs were not related to OS. The management of such patients should be determinedaccording to the DT with the worst prognosis.
Keywords: Multiple primary lung cancers, Adenocarcinoma, Ground glass opacity, Ground glass nodule,
Surgical treatment* Correspondence: ytsubata@med.shimane-u.ac.jp
1
Division of Medical Oncology & Respiratory Medicine, Department ofInternal Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane
693-8501, Japan
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which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
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Hotta et al. Journal of Cardiothoracic Surgery(2020) 15:149

Introduction
Low-dose computed tomography (CT) screening has led
to a relative reduction in mortality from lung cancer [1],and an increase in the incidental diagnosis of small
pulmonary ground glass nodules (GGNs) [2–5]. New
guidance on the management of GGN is required andhas been proposed [6, 7]. However, no standard algorithms have been established for multiple GGNs detectedby screening. Thus, there is a lack of clinical evidence on
their natural history, diagnosis and treatment.
A number of studies have suggested that multiple GGNs
have independent characteristics [8, 9]. Next-generation
sequencing has shown that some multiple synchronous
lesions show different mutation profiles in the same patient,while others share identical gene mutations [10]. These results suggest that the dominant tumor (DT) and synchronous GGNs are genetically independent tumors. Evidence isemerging that—given the independent characteristics ofeach of the multiple GGNs in a patient—the managementof multiple GGNs should be determined based on the DT
that carries the worst prognosis [11, 12]. Follow-up of theremaining lesions after the surgical treatment of the DT
has been reported [13, 14]. However, there no reports havecompared the outcomes of patients with multiple GGNs to
those of patients with single lesions. Furthermore, in cases

Page 2 of 9

of synchronous GGNs, the postoperative outcomes werecompared according to the progression of DT in order toinvestigate whether priority should be given to the DT
when deciding the treatment strategy.

Patients and methods
We retrospectively studied patients who were referred forsurgery at Shimane University Hospital, from January 2009
to December 2013. Two hundred seven patients met thefollowing criteria: [1] adenocarcinoma, and [2] pN0. Preoperative CT scans were reviewed to identify synchronous
GGNs. Thirty-nine patients had one or more lesions otherthan the DT. The DT was defined as the lung lesion of thelargest diameter or the lesion that showed the most radiological invasiveness (margin of the nodule, pleural indentation, presence of a solid component).
DTs with a ground glass component and consolidation
were divided into three categories based on the
consolidation-to-tumor (C/T) ratio on radiological imaging:pure GGN (C/T ratio = 0), part solid (C/T ratio > 0 to < 1)
and solid tumor (C/T ratio = 1). The following cases were
excluded from analysis: [1] cases involving recurrent lungcancer or in which the outcome was unknown, [2] stablelung cancer cases for which CT data had not been obtainedfor 5 years after surgery (Fig. 1). Radiological interpretation

Fig. 1 A flow diagram of the present study. GGNs; ground glass nodules, SCC; squamous cell carcinoma, AAH; atypical adenomatous hyperplasia,
OS; overall survival, DFS; Disease-free survivalHotta et al. Journal of Cardiothoracic Surgery(2020) 15:149

and date of recurrence were taken from the medical records as judged by two radiologists.
Lung cancers were staged in accordance with theseventh edition of the TNM Classification for Lung andPleural Tumors. Echocardiography, spirometry, and lower
limb echo in patients with a high d-dimer level were performed as preoperative tests. The preoperative CT-guided
hookwire localization for pulmonary nodules, particularly
for GGNs, was used. The operations typically removed theDT along with any accessible ipsilateral GGNs. Lobectomy
with complete systematic lymph node dissection was thestandard surgical treatment. Limited resection was applied
for patients with severe complications and for the elderly,
especially those presenting with pure GGNs. Lung adenocarcinomas were described pathologically as adenocarcinoma in situ, minimally invasive adenocarcinoma, invasive
adenocarcinoma or variants of invasive adenocarcinoma.
Slides were reviewed by a pathologist to confirm the presence of a lepidic component.
All patients were regularly evaluated by CT every 3months for the first 2 years after surgery and every 6months thereafter. Tegafur-uracil was selected as adjuvant treatment for T1b patients. Cisplatin-based adjuvant chemotherapy was selected for patients with stage
II disease. Non-dominant GGNs that were followed weregenerally treated by either surgical resection or stereotactic radiotherapy (SRT), when they grew size with any
solid component.
The patient and tumor characteristics were analyzed
to identify factors associated with overall survival (OS),disease-free survival (DFS), and progression of GGN. OS
was calculated from the date of surgery until either
death from any cause or the date of last follow-up, witha minimum of 5 years of study inclusion. DFS was
defined as survival without extrapulmonary metastasis,
locoregional or distant recurrence, or GGN progression
requiring intervention. GGN progression was defined as
growth of a GGN, development of a new solid component in a pure GGN, or enlargement of a solid component in a part-solid GGN with stable total diameter.
Considering the error due to CT slice thickness, growth
was defined as an increase of ≥5 mm.

Statistical analyses

Statistical analyses were performed using the GraphPad
Prism 7 software program (GraphPad Software, La Jolla,
CA, USA). Qualitative variables were reported thefrequency and percentage, while quantitative variables
were reported as the mean and standard deviation. Comparisons between two groups were performed using theunpaired t-test for normally distributed data. Categoricalvariables were compared using Fisher exact test. OS and
DFS were calculated from the date of surgery and estimatedPage 3 of 9

using a Kaplan-Meier analysis. P values of < 0.05 were considered to indicate statistical significance.

Results
Patient characteristics

DFS and OS analyses were performed in 159 patients(multiple GGNs [n = 34] vs Single lesion [n = 125]).
Dominant tumors were divided into three categories(Pure GGN, Part solid and Solid). Patients with multiple GGNs were divided into pure [n = 5], partly
solid [n = 20] and solid [n = 9). Patients with a single
lesion were divided into pure [n = 17], partly solid[n = 40] and solid [n = 68) (Fig. 1). The patient andsurgical characteristics are summarized in Table 1.
There were 159 patients (multiple GGN [n = 34], pure
GGN [n = 17], part solid [n = 40] and solid [n = 68]). Fiveyears of follow-up was completed in all cases. All patientswere Asians and underwent video-assisted thoracoscopic
resections. Combined resection of multiple lesions was
performed for 23% of the patients in the multiple GGNgroup. Twenty percent of the patients underwent wedge
resection alone. Fatal complications occurred in 2 patientsin the solid group due to pulmonary embolism and a pulmonary artery rupture. Histologically, no invasive cancer
was found in the Pure GGN group. Chemotherapy was
performed according to the DT tumor size (pStage). There
were three patients with pStage IIa disease in the multiple
GGN group who did not receive chemotherapy.
Postoperative outcomes

Table 2 lists the results of postoperative surveillance.
There were 17 cases of postoperative recurrence(multiple [n = 2], part solid [n = 3], and solid [n = 12]).
Eleven of them were positive for epidermal growth
factor receptor (EGFR) mutations. The OS decreased
as the C/T ratio increased (pure GGN, 94.1%; partsolid, 90%; solid, 75%; Table 2).
Kaplan-Meier analyses (Fig. 2a) were performed tocompare the patients with multiple lesions to those withsingle lesions; their survival did not differ to a statistically significant extent (single, 82.4% vs. multiple, 88.2%;
P = 0.3602). There when the outcomes were comparedaccording to the DT classifications (Pure GGN, 94.1%
vs. multiple GGN [pure], 100%; part solid, 90% vs. multiple GGN [part], 90%; solid, 75% vs. multiple GGN[solid]: 77.8%; Fig. 2b–d). The DFS was similar to the
OS (Fig. 3).
Characteristics of the DT and non-dominant GGNs in themultiple GGN group

Characteristics of the DT and the non-dominant GGN
are summarized in Table 3. As for non-dominant GGN,
there were 2 cases with very large numbers of nodules(46 and 18) in the part solid group; these cases wereHotta et al. Journal of Cardiothoracic Surgery(2020) 15:149

Page 4 of 9

Table 1 Patient characteristics

Age, (years)

Multiple(n = 34)

SinglePure GGN (n = 17)

Part Solid (n = 40)

Solid (n = 68)

73.7 ± 7.9

65.0 ± 11.2

71.3 ± 13.0

71.6 ± 9.4

Gender, (male/female), n

18/16

8/9

22/18

31/37

Previous cancer history, (Yes), n3 (9)4 (24)

11 (28)13 (19)Open Thoractomy

0

0

0

0

Video-assisted thoracoscopy

34 (100)

17 (100)

40 (100)

68 (100)

7 (20)

10 (59)5 (12)

4 (6)Surgical procedure, nOperation

Resection type
Wedge resection
Segmentectomy

0

0

3 (8)

1 (1)

Lobectomy

19 (37)7 (41)

32 (80)62 (92)

Combination

8 (23)

0

0

1 (1)

0

0

0

2 (3)

Adenocarcinoma in situ

15 (44)15 (88)9 (22)1 (1)Minimally-invasive adenocarcinoma

1 (3)2 (12)3 (8)0Invasive adenocarcinoma

17 (50)026 (65)59 (87)

Variants of invasive adenocarcinoma

1 (3)

0

2 (5)

8 (12)

Fatal complications
Histology, nChemotherapy, nNone

27 (79)17 (100)

31 (78)32 (47)UFT

6 (18)

0

9 (22)

31 (46)

Cisplatin based chemotherapy

1 (3)

0

0

5 (7)

23.7 ± 13.9

10.9 ± 4.6

19.4 ± 7.9

28.8 ± 20.1

pStage Ia, n

24 (70)17 (100)

35 (87)40 (59)

Stage Ib, n

6 (18)0

4 (10)

23 (34)

Stage IIa, n

4 (12)

0

1 (3)

4 (6)

pStage IIb, n

0

0

0

1 (1)

Dominant Tumor Size (mm)Values are means ± standard deviations or number, number (percentage). GGN ground glass nodule, UFT tegafur-uracil

Table 2 The results of postoperative surveillance
Multiple

SinglePure GGN (n = 5)

Part Solid (n = 20)

Solid (n = 9)

Pure GGN (n = 17)

Part Solid (n = 40)

Solid (n = 68)

0

1 (5)

1 (11)0

3 (8)

12 (18)EGFR (+)

0

1 (100)1 (100)0

1 (33)

7 (62)EGFR (−)

0

0

0

0

1 (33)

2 (15)

Unknown

0

0

0

0

1 (33)

3 (23)00

0

1 (33)

0

Recurrent patients, nMutation sutatus, nHistology, nAdenocarcinoma in situ0

1 (100)1 (100)2 (67)

12 (100)

5-year overall survival, %Invasive adenocarcinoma

100

90

77.8

94.1

90

75

5-year disease-free survival, %

100

95

87.5

100

92.2

80.2

Values are the number (percentage) or percentage
GGN ground glass nodule, EGFR epidermal growth factor receptor

Hotta et al. Journal of Cardiothoracic Surgery(2020) 15:149

Page 5 of 9

Fig. 2 The Kaplan-Meier analysis of the survival of patients with multiple and single lesions. a Single: 81.8% vs. Multiple: 88.2%. When classified foreach DT and compared (b) pure GGN, 94.1% vs. multiple GGN (pure), 100%; c part solid, 90% vs. multiple GGN (part), 90%; d Solid, 74.3% vs.
multiple GGN (solid), 77.8%. GGNs; ground glass nodules, OS: overall survival

excluded as outliers. Radiographically, the mean diameters of the DTs were as follows: Pure GGN, 8.6 ± 4.6mm; part solid, 21.7 ± 11.6 mm; and solid, 36.8 ± 11.2
mm. The mean diameters of the largest non-dominant
GGN at presentation were as follows: pure GGN, 8.1 ±1.8 mm; part solid, 8.2 ± 5.2 mm; and solid, 17.5 ± 11.7
mm. The numbers of with non-dominant GGNs were as
follows: pure GGN (range, 1–2), n = 8; part solid (range,
1–7), n = 38; and solid (range, 1–5), n = 17. Four pure
GGNs (50%), 19 part solid GGNs (50%) and 9 solid
GGNs (53%) were identified in the contralateral lung to
the DT. Some of the lesions in the lung lobe thatdiffered from the DT could not be resected. Twenty-six
patients had unresected GGNs. Two patients were excluded due to an extremely large numbers of unresected
GGNs (n = 46 and 18). Finally, 24 patients were included in the unresected GGNs analysis. In 10 ofthese patients, disease progression was observed in
the unresected GGNs (Fig. 4). In 2 cases, additional

surgery or SRT was performed to treat the unresected
GGN. Most unresected GGNs were pure GGN andnone had a C/T ratio of > 0.5.
Characteristics of the patients with GGN progression

The characteristics of the patients with or without progression of GGN are summarized in Table 4. The mean
size of the unresected GGNs in the any GGN progression group was predominantly larger than that in theother group (mean size, 10.3 ± 5.2 mm vs. 6.5 ± 4.3 mm,
respectively P = 0.0004). The OS curve of the cases withand without GGN progression did not differ to a statistically significant extent (80% vs. 92.9%, P = 0.3870).
The transition of the size of the 38 unresected GGNs
on CT is shown in Fig. 5a. Twelve GGNs fulfilled thegrowth condition. Among them, 10 GGNs showed achange in size changed within 3 years. It took four years
for all lesions change in size. The tumors of the GGNs
that changed in size were significantly larger than no

Hotta et al. Journal of Cardiothoracic Surgery(2020) 15:149

Page 6 of 9

Fig. 3 Disease-free survival curves of patients with multiple and single lesions. a) single vs. multiple, b pure GGN vs. multiple GGN (pure), c partsolid vs. multiple GGN (part), d solid vs. multiple GGN (solid). GGNs; ground glass nodules, DFS; disease free survival

growth tumors (mean size 11.7 ± 5.8 mm vs. 6.9 ± 3.8mm, P = 0.0003) (Fig. 5b).

Discussion
In this study, we compared multifocal GGNs and single
lesions. The number of GGNs had no impact on the OS.
As in the case of single lesions, the OS changed according to the pStage. The increase in residual lesions andthe appearance of new GGNs were not associated with
the OS.
Several studies have reported similar results, showing that prolonged survival was generally achieved byanatomic resection of the DT and wedge resection of
the accessible GGNs [11, 14–16]. As for OS and DFS,
our results were similar to those of several previous
studies. The novelty of this study was that it directlycompared the outcomes of patients with multiple
GGNs to those of patients with single lesions. The
DTs were divided into three categories based on the
C/T ratio, and the OS and DFS graphs for multiple

and single lesions overlapped. In patients with multiple GGNs, management should be determined basedon the DT with the worst prognosis.
Regarding unresected GGNs, previous studies haveshown that many lesions remained unchanged, butthat a certain proportion increase in size. No relationship was found between the prognosis and progression of the unresected GGN in this study, whichis in line with previous reports [15, 16]. In order toreduce wasteful follow-up, we think that is necessary
to screen patients and lesions that are likely to increase in size. In this study, we found that the larger
unresected GGN tended to increase in size. As far as
the lesion was concerned, we found that lesions thatwere larger in size were more likely to grow. In previous reports, the size of the DT and the proportionof the solid component were also associated with anincreased risk of lesion growth [15, 16]. When possible, resecting larger-sized lesions with the DT may
be the most efficient approach.

Hotta et al. Journal of Cardiothoracic Surgery(2020) 15:149

Page 7 of 9

Table 3 Characteristics of patients with multiple GGNs
Multiple (N = 34)
Pure GGNPart Solid

Solid

Patients, n

5

20

9

Dominant Tumor Size (mm)8.6 ± 4.6

21.7 ± 11.6

36.8 ± 11.2

Largest GGN size (mm)8.1 ± 1.8

8.2 ± 5.2

17.5 ± 11.7

Number, n (range per patient)

8 (1–2)38 (1–7)

17 (1–5)

Same lobe, n

2 (25)

7 (18)

6 (35)

Different lobe, n

2 (25)

12 (32)2 (12)

Contralateral lung, n

4 (50)

19 (50)9 (53)

5

22

11

Patients, n

3

14

7

Patients with unresected GGN that grew, n

0

7

3

Nondominant GGN

Location per GGN
Ipsilateral lung

Unresected GGN, nPatients with intervention for unresected GGN, n

0

2

0

Stereotactic radiotherapy, n

0

1

0

Surgical resection, n

0

1

0

C/T ratio= 0, n5 (100)19 (86)

11 (100)

0 < C/T ratio < 0.5, n0

3 (14)

0

Values are the mean ± standard deviation, number, number (percentage) or number (range per patient)
GGNs ground glass nodules

Fig. 4 A flow diagram of the patients with unresected GGN. GGNs; ground glass nodules

(2020) 15:149

Page 8 of 9

Table 4 Characteristics of patients with GGN progression

Regarding the follow-up period, GGNs may take 3–4
years to begin to increase in size [17–19]. The same
period was considered to be necessary in this study.
Patients should be followed up for the same period.
Adenocarcinoma with EGFR mutation is reported to
be associated with a higher incidence of GGN incomparison to adenocarcinoma with wild-type EGFR[20]. Many of the recurrent cases in this study had
EGFR mutations. Even in early-stage lung cancer, if
patients have GGN lesions, the EGFR gene mutation
status should be investigated during follow-up. However, it is worth noting that there are many reports ofcases in which genetic analyses revealed differences
between the DT and synchronous GGNs [10].
The present study was associated with some limitations, including the biases associated with the lack ofrandomization, as well as the relatively small sample
size and limited statistical power. We were unable toanalyze the effect of the mutation status. The strengthof this study was that it compared the outcomes ofpatients with multiple GGNs to those of patients witha single lesion. There were no differences between
the groups with regard to the methods of treatment
and follow-up, and it is was considered to be appropriate as a comparative group.

Hotta et al. Journal of Cardiothoracic Surgery

Unresected GGN (+)
Progression

No progression

N = 10N = 14Age, (years)

72.9 ± 8.1

72.9 ± 9.1

P=0.9656

Gender, (male/female), n

5/5

5/9

0.6785

Dominant Tumor Size (mm)28.4 ± 12.7

20.9 ± 14.5

0.1580

Smoking status (Pack-year)

19.4 ± 21.9

8.3 ± 13.7

Dominant Tumor Histology, nAdenocarcinoma in situ

3 (30)

9 (64)

Invasive adenocarcinoma

7 (70)

5 (36)

Unresected GGN, n0.32800.213820

18

Mean GGN size (mm)10.3 ± 5,2

6.5 ± 4.3

0.0004Largest GGN size (mm)12.4 ± 6.4

7.2 ± 4.6

0.0681

80

92.9

0.387

Survival
5-year overall survival, %Values are the mean ± standard deviation, number, number (percentage)or percentage
GGN ground glass nodule

Fig. 5 a The transition in the size of 38 unresected GGNs on CT. b Comparison of the tumor diameter before surgery between lesions with andwithout growth. The preoperative tumor size of GGNs was significantly larger in comparison to tumors that did not grow in size (mean size,
11.7 ± 5.8 mm vs. 6.9 ± 3.8 mm, P = 0.0003). GGNs; ground glass nodules

Hotta et al. Journal of Cardiothoracic Surgery(2020) 15:149

Conclusions
The postoperative outcome of lung adenocarcinoma
with synchronous GGN was good.
The outcomes were best predicted by the stage of theDT. After surgery, patients require careful follow-up because unresected GGNs grow in size. At the same time, it
is also true that many patients may not require follow-up.

Page 9 of 9

7.

8.

9.

10.
Abbreviations
CT: Computed tomography; GGNs: Ground glass nodules; DT: Dominant
tumor; OS: Overall survival; DFS: Disease-free survival; C/T: Consolidation-totumor; SRT: Stereotactic radiotherapy; EGFR: Epidermal growth factor
receptor

11.

12.

Acknowledgements
Not applicable.
13.
Authors’ contributions
Conception and design: TH, YT. Information Acquisition: TH, AT, MN, YA, MH,
SH, KK. Drafting of Manuscript: TH, YT, MN, YA, MH, SH, KK, TI. Critical Review:
YT, TI. The authors read and approved the final manuscript.

14.

15.
Funding
No funding was obtained for this manuscript.
16.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study conforms to the ethical guidelines in a priori approval by the local
Ethical Committee of the Shimane University. Our research was approved by
the Shimane University Research Ethics committee (approval number: 3672,
approval date: April 23, 2019).

17.
18.

19.
20.

Consent for publication
This manuscript has not been published or presented elsewhere in part or inentirety and is not under consideration by another journal. All the authors
have approved the manuscript and agree with submission to your esteemedjournal.
Competing interests
The authors have no competing interests to disclose.
Author details
1
Division of Medical Oncology & Respiratory Medicine, Department ofInternal Medicine, Shimane University, 89-1 Enya-cho, Izumo, Shimane
693-8501, Japan. 2Division of Thoracic Surgery, Shimane University, 89-1
Enya-cho, Izumo, Shimane 693-8501, Japan.
Received: 7 May 2020 Accepted: 15 June 2020

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