Lung Adenocarcinomas Manifesting as Radiological Part-Solid Nodules Define a Special Clinical Subtype

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ORIGINAL ARTICLE
Lung Adenocarcinomas Manifesting as Radiological
Part-Solid Nodules Define a Special Clinical
Subtype
Ting Ye, MD, PhD,a,b Lin Deng, MD,c Shengping Wang, MD, PhD,b,d
Jiaqing Xiang, MD, PhD,a,b Yawei Zhang, MD, PhD,a,b Hong Hu, MD,a,b
Yihua Sun, MD, PhD,a,b Yuan Li, MD, PhD,b,e Lei Shen, MD,b,e Li Xie, MD,f
Wenchao Gu, MD,g Yue Zhao, MD,a,b Fangqiu Fu, MD,a,b Weijun Peng, MD, PhD,b,d
Haiquan Chen, MD, PhDa,b,h,i,*
aDepartment of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, People’s Republic of China
bDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China
cDepartment of Radiology, Shanghai Proton and Heavy Ion Center, Shanghai, People’s Republic of China
dDepartment of Radiology, Shanghai Cancer Center, Fudan University, Shanghai, People’s Republic of China
eDepartment of Pathology, Shanghai Cancer Center, Fudan University, Shanghai, People’s Republic of China
fClinical Research Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
gDepartment of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi,
Japan
hSchool of Life Sciences, Fudan University, Shanghai, People’s Republic of China
iInstitutes of Biomedical Sciences, Fudan University, Shanghai, China
Received 3 August 2018; revised 10 December 2018; accepted 14 December 2018
Available online - 16 January 2019
*Corresponding author.
Dr. Ye, Dr. Deng, and Dr. Wang contributed equally to this work.
Disclosure: The authors declare no conflict of interest.
Address for correspondence: HaiquanChen,MD,PhD,270Dong’anRoad,
Shanghai, People’s Republic of China. E-mail: hqchen1@yahoo.com
ª 2019 International Association for the Study of Lung Cancer.
Published by Elsevier Inc. All rights reserved.
ISSN: 1556-0864
https://doi.org/10.1016/j.jtho.2018.12.030
ABSTRACT
Introduction: The clinicopathologic features and prog-
nostic predictors of radiological part-solid lung adenocar-
cinomas were unclear.
Methods: We retrospectively compared the clinicopatho-
logic features and survival times of part-solid tumors with
those of pure ground glass nodules (pGGNs) and pure solid
tumors treated with surgery at Fudan University Shanghai
Cancer Center and evaluated the prognostic implications of
consolidation-to-tumor ratio (CTR), solid component size,
and tumor size for part-solid lung adenocarcinomas.
Results: A total of 911 patients and 988 pulmonary nodules
(including 329 part-solid nodules [PSNs], 501 pGGNs, and
158 pure solid nodules) were analyzed. More female pa-
tients (p ¼ 0.015) and nonsmokers (p ¼ 0.003) were seen
with PSNs than with pure solid nodules. The prevalence of
lymphatic metastasis was lower in patients with PSNs
than in those with pure solid tumors (2.2% versus 27% [p
< 0.001]). The 5-year lung cancer–specific (LCS)
recurrence-free survival and LCS overall survival of patients
with PSNs were worse than those of patients with pGGNs
(p < 0.001 and p ¼ .042, respectively) but better than
those of patients with pure solid tumors ([p < 0.001 and
p < 0.0001, respectively]). CTR (OR ¼ 12.90; 95% confi-
dence interval [CI]: 1.85–90.04), solid component size
(OR ¼ 1.45; 95% CI: 1.28–1.64), and tumor size (OR ¼ 1.23;
95% CI: 1.15–1.31) could predict pathologic invasive
adenocarcinoma for patients with PSNs. None of them
could predict the prognosis. Patients receiving sublobar
resection had prognoses comparable to those of patients
receiving lobectomy (p ¼ .178 for 5-year LCS recurrence-
free survival and p ¼ .319 for 5-year LCS overall
survival). The prognostic differences between patients
with systemic lymph node dissection and those without
systemic lymph node dissection were statistically
insignificant.
Conclusions: Part-solid lung adenocarcinoma showed
clinicopathologic features different from those of pure solid
tumor. CTR, solid component size, and tumor size could not
predict the prognosis. Part-solid lung adenocarcinomas
define one special clinical subtype.
Journal of Thoracic Oncology Vol. 14 No. 4: 617-627
mailto:hqchen1@yahoo.com
https://doi.org/10.1016/j.jtho.2018.12.030
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618 Ye et al Journal of Thoracic Oncology Vol. 14 No. 4
� 2019 International Association for the Study of Lung
Cancer. Published by Elsevier Inc. All rights reserved.
Keywords: Part-solid nodule; Lung adenocarcinoma; Prog-
nosis; Solid component size; Tumor size
Introduction
With the wide application of thoracic computed to-
mography (CT) scans, an increase in the detection of
incidental pulmonary nodules, especially subsolid nod-
ules, is being encountered.1–4 According to guidelines
from the Fleischner Society in 2017, subsolid nodules
are categorized as either pure ground glass nodules
(pGGNs) having only a ground glass opacity (GGO)
component or part-solid nodules (PSNs) having both
GGO and solid components on thin-section CT (TS-CT).
Persistent PSNs with solid components 6 mm or larger
should be considered highly suspicious.5 There have
been some controversies regarding lung cancers mani-
festing as PSNs. In 2017, a systemic review indicated
that lung cancers manifesting as PSNs had different
surgical outcomes depending on the different percent-
ages of solid component in relation to the entire nodule
size and that both disease-free survival (DFS) and
overall survival (OS) were higher in patients with solid
component percentages lower than 80% than in patients
with solid component percentages of 80% or higher. The
authors suggested a clear definition of the upper limit of
the solid component of PSNs.6
In 2017, Matsunaga et al. divided part-solid lung
cancers into ground glass–predominant and
consolidation-predominant tumors, with a cutoff value
0.5 for the consolidation-to-tumor (CTR) ratio. They
found that PSNs with a CTR of 0.5 or higher had a higher
prevalence of lymphatic invasion and worse 5-year
recurrence-free survival (RFS) than those with a CTR
less than 0.5.7 However, they did not provide the data for
5-year OS in their article. Currently, our Japanese col-
leagues use CTR to classify PSNs and determine surgical
strategy in their clinical practice. Several Japanese Clin-
ical Oncology Group trials were designed depending on
the different CTR values.8–10 But application of CTR for
PSNs is not well accepted globally. In the eighth edition
of the TNM classification of lung cancer, the International
Association for the Study of Lung Cancer (IASLC) used
the size of the solid part to classify clinical T stage for
part-solid tumors (for cT1mi, 0 < solid part � 5 mm; for
cT1a, 6 � solid part � 10 mm; for cT1b,11 mm � solid
part � 20 mm; and for cT1c, 21 mm � solid part � 30
mm ).11 However, in 2016, Hattori et al. found that CTR
value, maximum tumor size, and solid component size
could not predict the OS in radiological part-solid lung
cancer.12 In 2017, they indicated that tumor size
significantly affected survival outcome only in pure solid
lung cancer, but neither maximum tumor size nor solid
component size could predict the long-term survival in
part-solid lung cancer when they evaluated the prog-
nostic impact of several clinicopathologic variables in the
clinical T classification based on solid component size
according to the eighth edition of the classification of
NSCLC.13 Therefore, how to clinically define and classify
the part-solid tumors requires further investigations.
Thus, in this study we compared the clinicopathologic
features and long-term survival of patients with radio-
logical PSNs with those of patients with pGGNs and pure
solid nodules in a large, homogeneous cohort of patients
undergoing an operation at a single institution. We
aimed to find the prognostic predictors to classify lung
adenocarcinomas manifesting as PSNs.
Material and Methods
Patient Cohort
We retrospectively reviewed the medical records of
patients with small pulmonary nodules who underwent
surgical resectionat Fudan University Shanghai Cancer
Center (FUSCC) between January 2008 and December
2014. The inclusion criteria were a pathologic diagnosis
of lung adenocarcinoma and clinical stage IA disease
(according to the TNM eighth edition). The exclusion
criteria were a having received a diagnosis of benign or
atypical adenoid hyperplasia lesion, having synchronous
subsolid and pure solid nodules, not having received a
TS-CT scan in our institution, or not having complete
radiological information. Analyses for lung cancer–
specific (LCS) recurrence and LCS survival were per-
formed on all eligible patients who underwent an oper-
ation. This study was approved by the institutional
review board of FUSCC. Informed consent was waived
because it was a retrospective study.
Radiological and Histologic Evaluation
Whole lung CT scans were performed with a helical
technique using a 64- or 40-slice multidetector scanner
(Siemens Somatom Sensation, Berlin, Germany). The
scanning parameters were as follows: pitch, 1.2; section
thickness and interval, 5.0 and 5.0 mm, respectively;
reconstruction section width and interval, 1.0 and 1.0 mm,
respectively; field of view, 375 mm; voltage, 120 kV; and
electric charge, 270 mAs. Two radiologists (L. D. and S. P.
W.) with more than 6 years of experience in chest radi-
ology and without any clinical information evaluated these
CT images on lung window settings (window width, 1600
HU; window level, –600 HU; and width and interval, 1.0
and 1.0 mm, respectively). The maximum diameter on the
single largest axial dimension was measured on a lung
window, and an edge-enhancing (sharp) filter was
April 2019 Lung Adenocarcinomas as Part-Solid Nodules 619
recorded for the size of solid component and whole nodule.
Subsolid and pure solid nodules were distinguished
depending on the presence of GGO. In the subsolid nodules,
pGGN was defined as a nodule without a solid component
and PSN was defined as a lung lesion with both a GGO and
solid component.5 CTR was defined as the ratio of the
maximum size of solid component to the maximum tumor
size on the TS-CT scan in the axial plane (for pGGNs, CTR¼
0; for part-solid tumors, 0 < CTR < 1; and for pure solid
tumors, CTR ¼ 1) (Fig. 1). When the solid part was irreg-
ular or multiple, multiple-plane reconstruction was used
and only the largest diameter was analyzed.
Interobserver and intraobserver agreements were
analyzed for the first 110 radiological measurements to
quantify the reproducibility and accuracy between the two
radiologists in this study. For differentiating between
subsolid and pure solid lung nodules, the interobserver
agreement (k) value was 0.703 (95% confidence interval
[CI]: 0.565–0.821) and the intraobserver agreement (k)
values were 0.867 (95% CI: 0.761–0.956) and 0.783 (95%
CI: 0.619–0.913). Each radiologist interpreted the first 110
lung nodules in two different sessions that were separated
by 4 weeks. They resolved differences of opinion through
discussion. In view of the favorable levels of interobserver
and intraobserver agreements, the two radiologists pre-
formed the rest of the radiological measurements
separately.
Postoperative pathologic diagnosis was made
according to the IASLC/American Thoracic Society/
European Respiratory Society classification as adeno-
carcinoma in situ, minimally invasive adenocarcinoma,
Figure 1. Definition of pure ground glass nodules (GGNs), part-
logical measurements for consolidation-to-tumor ratio (CTR), th
and invasive adenocarcinoma (IAD), which was further
divided into lepidic predominant, acinar predominant,
papillary predominant, micropapillary predominant,
solid predominant, and invasive mucinous adenocar-
cinoma. The predominant pattern was defined as the
pattern with the largest percentage (not necessarily
50% or higher).14
Follow-up Protocol
Patients were followed up every 3 months after the
operation for the first 2 years and underwent chest CT
scans and abdominal ultrasonography every 3 to 6
months. The follow-up frequency was changed to every 6
months for the third year and once per year for subse-
quent years. CT or magnetic resonance imaging scans of
the brain and bone scintigraphy were performed every 6
months for patients with IAD in the first 3 years. Posi-
tron emission tomography–CT scan was optional and
performed if necessary.
LCS-RFS was defined as time from initial resection to
date of first lung cancer–related recurrence. Diagnosis of
recurrence was confirmed by biopsy if possible, and
imaging (i.e., positron emission tomography–CT scan or
brain magnetic resonance imaging) was performed to
support the clinical diagnosis and the decision to initiate
treatment. In cases in which a new tumor developed in
the lung or pleura and a biopsy specimen was available,
the histologic profile was reviewed to determine
whether the new tumor was a metachronous primary
tumor, recurrence, or metastasis (especially for the pure
solid lesion). Genetic information, including common
soid nodules and pure solid nodules and description of radio-
e solid component size (red line), and tumor size (black line).
620 Ye et al Journal of Thoracic Oncology Vol. 14 No. 4
oncogenic mutations, was evaluated if necessary. The
date of recurrence was defined as the time of pathologic
or radiological confirmation. LCS-OS was defined as the
time from initial resection to death resulting from lung
cancer. Non-cancer–related deaths or deaths related to
other malignancies were censored at date of death.
Statistics
Baseline characteristics were reported as number
(percentage) for categorical variables. Categorical vari-
ables were compared by using the Pearson chi-square test
or Fisher exact test, when appropriate. Continuous vari-
ables were compared by using the paired t test. Estima-
tion of survival curves of LCS-RFS and LCS-OS were
generated by the Kaplan-Meier method; the log-rank test
was used to compare survival curves. Logistic regression
modeling was used as the method for identifying
risk factors for pathologic diagnosis of IAD. All p values
were two sided with a significance level of 0.05. All sta-
tistical analysis were performed by using SPSS software
(version 19.0, (IBM Corporation, Armonk, NY) and PRISM
software (version 7.0, GraphPad Software, La Jolla, CA).
Results
In all, 1212 patients with 1339 lung nodules under-
went surgical resection in FUSCC; benign disease was
diagnosed in 75 patients and 85 nodules, atypical
adenoid hyperplasia was diagnosed in 46 patients and
62 nodules, 17 patients had 38 synchronous subsolid
and pure solid nodules, and 163 patients did not a
receive TS-CT scan or have complete radiological infor-
mation. In total, 911 patients and 988 pulmonary nod-
ules were analyzed in this study.
This study included 329 PSNs, 501 pGGNs, and 158
pure solid nodules. Females accounted for 71.1% of
those seen for the 329 PSNs versus for 60.5% of those
seen for the 158 part-solid nodules (p ¼ 0.015). Also,
nonsmokers accounted for 83.5% of those seen for PSNs
versus for 75.2% of those seen for pure solid nodules
(versus [p ¼ .003]). Patients with PSNs were older than
those with pGGNs (58.89 ± 9.71 versus 53.64 ± 10.86 y
[p < 0.001]) but younger than those with pure solid
nodules (58.89 ± 9.71 versus 60.54 ± 10.52 y [p ¼
.102]). PSNs were more common in bilateral upper
lobes than pure solid nodules were (68.1% versus 49.9%
[p ¼ .009]). The mean tumor diameter of the PSNs
was larger than that of the pGGNs (20.51 ± 7.18 versus
10.22 ± 3.84 mm [p < 0.001]) but similar to that of pure
solid nodules (20.51 ± 7.18 versus 19.54 ± 5.58 mm
[p ¼ .066]). The percentage of IAD in patients with
PSNs was higher than that in patients with pGGNs
(83.0% versus 10.8% [p < 0.001]) but lower than that in
patients with pure solid nodules (83.0% versus 96.2%
[p < 0.001]). The percentage of lepidic predominant
adenocarcinomas was higher in patients with PSNs than
the percentage in patients with pure solid tumors
(38.8% versus 13.3% [p < 0.001]) whereas the per-
centage of solid/micropapillarypredominant adenocar-
cinomas was lower in patients with PSNs than the
percentage in patients with pure solid tumors (1.5%
versus 3.4% [p < 0.001]). Seven patients with PSNs
(2.2%) had lymphatic metastasis (N1/2), whereas 41
patients with pure solid nodules (27%) had lymphatic
metastasis (N1/2). No patients with pGGNs had
lymphatic metastasis. Detailed clinicopathologic charac-
teristics of patients are described in Table 1.
Among the 329 PSNs, there were 185 nodules with a
CTR less than 0.5 (0 ＜ CTR � 0.5) and 144 nodules with
CTR larger than 0.5 (0.5＜CTR＜1). The differences in
patient characteristics, including age, sex, and smoking
status, between the two groups were statistically insig-
nificant. The differences in mean tumor size, distribution
of nodules, and prevalence of IAD between the two
groups were statistically insignificant. There were two
cases with lymph node metastasis (1.2%) in patients
with PSNs with a CTR less than 0.5 (0 ＜CTR � 0.5),
whereas there were five cases with lymph node metas-
tasis (3.5%) in patients with PSNs with a CTR higher
than 0.5 (0.5＜CTR＜1) (Table 2).
The mean follow-up period was 42.22 plus or
minus 14.70 months. Of the 911 patients enrolled, five
(0.55%) were lost during follow-up period, 81
(8.89%) experienced recurrence, and 36 (3.9%) died.
The 5-year LCS-RFS rate was 88.30% (95% CI:
85.31%–90.71%). The 5-year LCS-OS rate was 94.87%
(95% CI: 92.39%–96.56%). For patients with PSNs,
the 5-year LCS-RFS rate was worse than that of pa-
tients with pGGNs (91.74% [95% CI: 87.15%–94.74%]
versus 99.43% [95% CI: 98.25%–99.82%]) (p <
0.001) but better than that of patients with pure solid
tumors (91.74% [95% CI: 87.15%–94.74%] versus
58.08% [95% CI: 49.33%–65.77%]) (p < 0.001).
Similarly, the 5-year LCS-OS rate of patients with PSNs
was worse than that of patients with pGGNs (98.13%
[95% CI: 95.52%–99.23%] versus 100% [p ¼ .042])
but better than that of patients with pure solid tumors
(98.13% [95% CI: 95.52%–99.23%] versus 80.27%
[95% CI: 72.27%–86.19%]) (p < 0.0001) (Fig. 2). In
this study, one patient with pGGNs, 20 patients with
PSNs, and 60 patients with pure solid nodules expe-
rienced tumor recurrence. The recurrence sites are
illustrated in Supplementary Table 1. No deaths
occurred among the patients with pGGNs, whereas six
patients with PSNs and 30 patients with pure solid
tumors died during the follow-up period.
There were no significant differences in 5-year LCS-
RFS or LCS-OS between PSNs with CTR less than 0.5 (0
April 2019 Lung Adenocarcinomas as Part-Solid Nodules 621
＜CTR � 0.5) or those with a CTR higher than 0.5 (0.5＜
CTR ＜1) (5-year LCS-RFS of p ¼ .062 and 5-year of LCS-
OS [p ¼ .556]). Also, there were no statistical differences
in the 5-year LCS-RFS or 5-year LCS-OS between patients
with PSNs with a CTR less than 0.8 (0＜CTR�0.8) and
patients with PSNs with a CTR higher than 0.8 (0.8 ＜
CTR＜1) (5-year LCS-RFS of p ¼ .410 and 5-year LCS-OS
of p ¼ .616, respectively) (Fig. 3).
In addition, there were no significant differences in 5-
year LCS-RFS or LCS-OS among patients with the
different categories of solid component sizes (0 < solid
component size� 10 mm, 10< solid component size� 20
mm, and 20 < solid component size � 30 mm ) (5-year
LCS-RFS of p ¼ 0.198 and 5-year LCS-OS of p ¼ 0.768)
(Fig. 4). When we defined CTR and solid component size as
continuous variables, neither of them could predict the 5-
year LCS-RFS or 5-year LCS-OS (Table 3).
Table 1. Baseline Clinicopathologic Characteristics of Objects
Characteristic
All
(N ¼ 988)
PSN
(n ¼ 3
Mean age, y (± SD) 56.49 ± 10.83 58.89 ±
Sex
Male 277 (30.4) 91 (28.
Female 634 (69.6) 224 (71
Smoking status
Smoker 153 (16.8) 52 (16.
Nonsmoker 758 (83.2) 263 (83
Tumor size, mm 15.14 ± 7.38 20.51 ±
Location
RUL 364 (36.8) 126 (38
RML 67 (6.8) 21 (6.4
RLL 181 (18.3) 48(14.6
LUL 266 (26.9) 98 (29.
LLL 110 (11.2) 36 (10.
Surgery
Wedge resection 456 (46.2) 72 (21.
Segmentectomy 97 (9.8) 33 (10.
Lobectomy 435 (44.0) 224 (68
Pathologic type
AIS/MIA 509 (51.5) 56 (17.
IAD 479 (48.5) 273 (83
Lepidic predominant 154 (32.6) 104 (38
Solid/micropapillary predominant 21 (4.5) 4 (1.5)
Acinar/papillary predominant 290 (61.4) 157 (58
Mucinous adenocarcinoma 7 (1.5) 3 (1.1)
Lepidic componentc 216 (45.1) 148 (55
Solid/micropapillary componentc 67 (14.0) 15 (5.6
Acinar/papillary componentc 356 (74.3) 197 (73
Mucinous componentc 10 (2.1) 3 (1.1)
Pathologic N status
N0 904 (94.9) 305 (97
N1/2 48 (5.1) 7 (2.2)
aOf 273 PSNs, 268 had the confirmed subtypes of IADs.
bOf 152 pure solid nodules, 150 had the confirmed subtypes of IADs.
cAny amount of subtypes present.
PSN, part-solid nodule; GGN, ground glass nodule; RUL, right upper lobe; RML, r
lobe; AIS, adenocarcinoma in situ; MIA, minimally invasive adenocarcinoma; IAD
Moreover, we compared the impact of clinical T
stage on the prognosis between patients with part-
solid lung adenocarcinoma and patients with pure
solid lung adenocarcinoma based on the eighth edi-
tion of the IASLC TNM classification of lung cancer.
We found that patients with part-solid tumors had
better 5-year LCS-RFS and LCS-OS than did patients
with pure solid tumors according to similar clinical
T stage (cT1b and cT1c). Tumor size could predict
the 5-year LCS-RFS and LCS-OS for patients with
pure solid tumors, but solid component size could
not predict the prognosis for patients with part-solid
tumors (see Fig. 4).
Furthermore, we evaluated risk factors related to
the postoperatively pathologic diagnosis of IAD for
patients with PSNs. When logistic regression analysis
was used, higher CTR value (OR ¼ 12.90, 95%
in This Study
29)
Pure GGN
(n ¼ 501)
Pure Solid Nodule
(n¼158) p Value
9.71 53.64 ± 10.86 60.54 ± 10.52 0.000
0.015
9) 124 (28.2) 62 (39.5)
.1) 315 (71.8) 95 (60.5)
0.003
5) 62 (14.1) 39 (24.8)
.5) 377 (85.9) 118 (75.2)
7.18 10.22 ± 3.84 19.54 ± 5.58 0.000
0.009
.3) 197 (39.3) 41 (25.9)
) 29 (5.8) 17 (10.7)
) 93 (18.6) 40 (25.3)
8) 130 (25.9) 38 (24)
9) 52 (10.4 ) 22 (14.1)
0.000
9) 370 (73.8) 14 (8.9)
0) 58 (11.6) 6 (3.8)
.1) 73 (14.6) 138 (87.3)
0.000
0) 447(89.2) 6(3.8)
.0)a 54 (10.8) 152 (96.2)b
.8) 30 (55.5) 20 (13.3) 0.000
1 (1.9) 16 (3.4) 0.000
.6) 22 (40.7) 111 (74.0) 0.000
1 (1.9) 3 (2.0) 0.753
.2) 36 (66.7) 32 (21.3) 0.000
) 1 (1.8) 51 (34) 0.000
.5) 31 (57.4) 128 (85.3) 0.005
1 (1.8) 6 (3.4) 0.052
0.000
.8) 488 (100) 111 (73)
0 (0) 41 (27)
ight middle lobe; RLL, right lower lobe; LUL, left upper lobe; LLL, left lower
, invasive adenocarcinoma.
622 Ye et al Journal of Thoracic Oncology Vol. 14 No. 4
CI: 1.85–90.04, p ¼ 0.010), larger solid component
size (OR ¼ 1.45, 95% CI: 1.28–1.64, p ¼ 0.000), and
larger tumor size (OR ¼ 1.23, 95% CI: 1.14–1.31, p ¼
0.000) remained independently associated with inva-
sive lung adenocarcinoma (see Supplementary
Table 2).
For the 329 part-solid lung adenocarcinomas, 224
lobectomies, 33 segmentectomies, and 72 wedge
resections were performed. Patients receiving
segmentectomy or wedge resection had a 5-year
LCS-RFS comparable to that of patients receiving
lobectomy. Also, 5-year LCS-OS was similar among
patients who underwent the three different opera-
tions (Supplementary Fig. 1). In addition, of the
patients with part-solid IAD, 16 did not undergo
systemic lymph node dissection (sLND) whereas 251
did undergo sLND. There was no recurrence or
death among the 16 patients. The differences in the
5-year LCS-RFS and 5-year LCS-OS between
patients with sLND and those without sLND were
statistically insignificant (p ¼ 0.231for 5-year LCS-
RFS and p ¼ .501 5-year LCS-OS ) (Supplementary
Fig. 2).
Table 2. Comparison of Clinicopathologic Features between P
Greater than 0.5 but Less than 1
Feature
All
(N ¼ 329)
0＜
(n
Age, y 58.89 ± 9.71 59.
Sex
Male 88 (27.9) 50 (
Female 227 (72.1) 123
Smoking status
Smoker 52 (16.5) 26 (
Nonsmoker 263 (83.5) 147
Tumor size, mm 20.52 ± 7.18 20.
Location
RUL 126 (38.3) 66 (
RML 21 (6.4) 10 (
RLL 48 (14.6) 31 (
LUL 98 (29.8) 56 (
LLL 36 (10.9) 22 (
Surgery
Wedge resection 72 (21.9) 47 (
Segmentectomy33 (10.0) 22 (
Lobectomy 224 (68.1) 116
Pathology
AIS/MIA 56 (17.0)a 37 (
IAD 273 (83.0) 148
Pathologic N status
N0 305 (97.8) 166
N1/2 7 (2.2) 2 (1
aIncluded 19 AISs and 37 MIAs.
bIncluded 12 AISs and 25 MIAs.
cIncluded 7 AISs and 12 MIAs.
PSN, part-solid nodule; CTR, consolidation-to-tumor ratio; RUL, right upper lobe
lower lobe; AIS, adenocarcinoma in situ; MIA, minimally invasive adenocarcinom
Discussion
One of the most important questions regarding lung
adenocarcinomas manifesting as PSNs is how to define
or classify them. In other words, according to the results
in this study, is it reasonable that part-solid lung ade-
nocarcinomas could be clinically regarded as one sub-
type when we are deciding on treatment strategies
because CTR value, solid component, and tumor size
could not predict the prognosis for them? Currently, size
of the solid component is applied to the category T stage
for part-solid lung cancers according to the eighth edi-
tion of the TNM classification of lung cancer because the
solid component is regarded as the invasive part.11 In
2018, Yamanashi et al.15 found that the prognoses of
part-solid and pure-solid tumors of clinical T1a-c
NSCLCs based on the eighth edition of the TNM classi-
fication of lung cancer after propensity score–matched
analysis were similar. As a result, they supported justi-
fication of the T component categories in the eighth
edition of the TNM classification for part-solid tumors.15
However, they did not evaluate the influences of
different solid component sizes on prognosis of part-
solid tumors. If the part-solid tumors with different
SNs with CTR Greater than Zero but Less than 0.5 and CTR
CTR�0.5
¼ 185)
0.5＜CTR＜1
(n ¼ 144) p Value
54 ± 9.49 58.05 ± 9.96 0.169
0.972
28.9) 38 (26.8)
(71.1) 104 (73.2)
0.566
15.0) 26 (18.3)
(85.0) 116 (81.7)
65 ± 7.00 20.35 ± 7.44 0.295
0.536
35.7) 60 (41.7)
5.4) 11 (7.6)
16.7) 17 (11.8)
30.3) 42 (29.2)
11.9) 14 (9.7)
0.059
25.4) 25 (17.4)
11.9) 11 (7.6)
(62.7) 108 (75.0)
0.164
20.0)b 19 (13.2)c
(80.0) 125 (86.8)
0.136
(98.8) 139 (96.5)
.2) 5 (3.5)
; RML, right middle lobe; RLL, right lower lobe; LUL, left upper lobe; LLL, left
a; IAD, invasive adenocarcinoma.
Figure 2. Comparisons of survival times between patients with part-solid nodules (PSNs) and patients with pure ground glass
nodules (pGGNs) and pure solid tumors.
April 2019 Lung Adenocarcinomas as Part-Solid Nodules 623
solid component sizes had similar prognoses, Yamanashi
et al.15 could not have reached their conclusions. More-
over, Hattori et al. suggested that the impact of tumor
Figure 3. Comparison of survival times between patients with
and 0.8. CTR, consolidation-to-tumor ratio.
size be applied exclusively to radiological pure solid lung
cancer and recommended that radiological part-solid
lung cancer be described as c-T1a.12 Similarly, our
part-solid nodules (PSNs) with different cutoff values of 0.5
Figure 4. Impact of clinical T stage on the prognosis between part-solid lung adenocarcinoma and pure solid lung adeno-
carcinoma based on the eighth edition of the International Associaton for the Study of Lung Cancer TNM classification of lung
cancer.
624 Ye et al Journal of Thoracic Oncology Vol. 14 No. 4
results indicated that tumor size and solid component
size might be valuable for selection of extent of surgery
(sublobar or lobar resection) because they could predict
the pathologic invasive adenocarcinoma for PSNs. How-
ever, they promised similar favorable prognoses despite
the different sizes or percentages of the “invasive” solid
component. Accordingly, it might be reasonable that
part-solid lung adenocarcinomas be regarded as one
special subtype when evaluating their long-term
survivals.
Presence of the feature GGO on a TS-CT scan always
suggests favorable surgical outcomes for early-stage
lung adenocarcinoma.16,17 In 2015, Cho et al. showed
that the 5-year OS rate was 98.6% for patients with
pure GGO adenocarcinoma versus 95.5% for patients
Table 3. Multivariate Analysis for Prognosis of Part-Solid Lung
Feature
5-y Recurrence-Free Surviva
HR (95% CI)
Age 0.99 (0.95–1.04)
Sex
Male 3.06 (1.04–8.94)
Female 1.0
Smoking status
Nonsmoker 0.414 (0.139–2.256)
Smoker 1.0
CTR valuea 0.004 (0.000–20.034)
Solid component size, mma 1.424 (0.97–2.093)
Tumor size, mma 0.828(0.657-1.043)
Pathology
IAD 26.09 (0.13-5238.47)
AIS/MIA 1.0
aCalculated as the continuous variable.
HR, hazard ratio; CI, confidence interval; CTR, consolidation-to-tumor ratio;
invasive adenocarcinoma.
with mixed GGO adenocarcinoma.16 In 2017, Hattori
et al. indicated that clinical stage IA radiological
invasive NSCLC with a GGO component had a 5-year OS
rate of 95.3%; in their study, GGO predominant tumor
had a 5-year OS rate of 95.3% and solid predominant
tumor had a 5-year OS rate of 96.8%.17 Similarly, for
patients with part-solid lung adenocarcinoma in this
study, the 5-year LCS-RFS rate was 91.74% (95% CI:
87.10%–94.74%) and the 5-year LCS-OS rate was
98.13% (95% CI: 95.52%–99.23%). The favorable
prognosis of part-solid tumors might be one reason
why radiological CTR and solid component size could
not be the prognostic predictors despite the fact that
larger CTR, larger solid component size, and larger
tumor size were independently associated with
Adenocarcinomas in This Study (Cox Regression Model)
l 5-y Overall Survival
p Value HR (95% CI) p Value
0.728 1.005 (0.919–1.099) 0.911
0.041 1.764 (0.185–16.817) 0.622
1.0
0.414 0.555 (0.029–10.513) 0.695
1.0
0.202 0.54 (0.004–71.36) 0.806
0.071 0.517 (0.000–6943123.23) 0.937
0.108 0.993(0.682-1.446) 0.972
0.962 25.72 (0.001-855626.85) 0.979
1.0
IAD, invasive adenocarcinoma; AIS, adenocarcinoma in situ; MIA, minimally
April 2019 Lung Adenocarcinomas as Part-Solid Nodules 625
postoperative IAD. Our findings seem to be inconsis-
tent with the results of several previous studies. In
2013, Matsuguma et al. indicated that proportion of
GGO was a significant prognostic factor for DFS along
with solid area diameter for clinical stage I NSCLC.18 In
2015, Saji et al. found that solid component size could
predict pathologic high-grade malignancy and prog-
nosis more precisely than whole tumor size for pri-
mary lung adenocarcinoma could.19 However, both of
these studies included pure solid and pGGNs as well.
Considering that solid tumors had an obviously worse
prognosis than part-solid tumors did, the conclusions
could be statistically different. Contrarily, the results
of the study by Hattori et al.12 and our study showed
that CTR value, maximum tumor size, and solid
component size could not predict OS when we focused
on analyzing radiological part-solid lung adenocarci-
noma. It could be postulated that part-solid IAD had
the much less invasive instinct than pure solid IAD did,
and though PSNs had numerous subgroups with
different percentages of solid components, the prog-
noses were similar and favorable.
Another question was whether sublobar resection
was enough for part-solid lung adenocarcinomas
considering the favorable prognosis. In 2014, Tsutani
et al. demonstrated that segmentectomy and wedge
resection could provide 3-year RFS comparable to that
provided by lobectomy for GGO predominant adenocar-
cinoma (96.1% and 98.7% versus 96.4% [p ¼ 0.44]) and
segmentectomy provided 3-year DFS similar to that
provided by lobectomy for solid predominant adeno-
carcinoma (84.8% versus 84.4% [p ¼ 0.69]).20,21 In
2015, Yoshida et al. evaluated wedge or segmental
resection for subsolid cT1N0M0 lung carcinoma with a
GGO ratio of 0.5 or higher, and they found no recurrence
with a median follow-up period of 88 months.22 In
addition, Cho et al. showed that patients with mixed GGO
adenocarcinoma receiving wedge resection had a 5-year
OS rate of 95.5%.16 Also, our results showed that pa-
tients with part-solid adenocarcinoma treated with
wedge resection or segmentectomy had 5-year LCS-RFS
and OS rates similar to those of patients receiving lo-
bectomy. This indicated that sublobar resection could be
enough forpart-solid lung adenocarcinomas when it is
appropriately selected.
Moreover, because the prevalence of lymph node
metastasis was very low for part-solid lung adenocarci-
noma, could sLND still be necessary? In 2015, when
evaluating 876 patients with clinical stage I NSCLCs,
Haruki et al. showed that there were no cases with hilar
and mediastinal nodal involvement in GGO predominant
tumors.23 In 2017, Floves et al. evaluated sLND for pure
solid and subsolid nodules detected by CT screening and
found that for 203 patients with a subsolid nodule (151
patients with sLND and 52 without sLND), the survival
rate was 100%. For the 404 patients with a pure solid
nodule (311 with and 93 without sLND), the rate was
87% versus 94%. They advocated that performing sLND
is not mandatory when screen-diagnosed NSCLC mani-
fests as a subsolid nodule.24 In this study, in which 16
patients did not receive sLND and 251 patients did
receive sLND, the 5-year LCS-RFS and 5-year OS values
were similar. As a result, we thought that it was not
obligatory to perform sLND for part-solid lung
adenocarcinoma.
Limitations of this study are that the sample size of
329 part-solid tumors analyzed might be small, though
a total of 988 lung nodules were included in this study.
In addition, the mean follow-up period of 42 months
was relatively short regarding the favorable prognosis
of part-solid tumor. Therefore, a larger number of
patients with a longer follow-up period might be
required to identify the prognostic implications of CTR
value, solid component size, and tumor size for 5-year
LCS-RFS and 5-year LCS-OS in the future. Moreover,
selection bias should be pointed out, especially when
analyzing the impact of sublobar resection on patients’
survival. We routinely select wedge and segmental
resections for patients with adenocarcinoma in situ or
minimally invasive adenocarcinoma according to
intraoperative pathologic diagnosis25 or for those with
insufficient cardiopulmonary function, whereas we
choose lobectomy for patients with invasive adeno-
carcinma. Therefore, the long-term survival of the
patients in the Japanese Clinical Oncology Group 0802
trial was expected.9 Strengths of this study were that
comprehensive radiological and histologic assess-
ments were performed and detailed analysis of post-
operative recurrence and death were documented. In
addition, we evaluated LCS recurrence and death in
this study. Considering the favorable prognosis of
part-solid adenocarcinomas, recurrence and death
related to other malignancies should be carefully
distinguished. Moreover, we first evaluated the CTR
value, solid component size, and tumor size as
continuous variables, whereas most of previous
studies evaluated the prognostic implications of these
three parameters as categorical variables.
In conclusion, lung adenocarcinomas manifesting
as PSNs had significantly different clinicopathologic
characteristics and rare prevalence of lymph node
metastases compared with pure solid lung adenocar-
cinomas. Considering that CTR value, solid component
size, and tumor size could not predict the favorable
prognosis, part-solid lung adenocarcinomas might be
clinically regarded as one special subtype when being
treated. Sublobar resection might be suitable for this
cohort when appropriately selected.
626 Ye et al Journal of Thoracic Oncology Vol. 14 No. 4
Acknowledgments
The authors thank Dr. Qiongjie Zhou, who is a visiting
scholar in Brigham and Women’s Hospital of Harvard
Medical School, for helpwith language revision. This study
was supported by the National Natural Science Founda-
tion of China (grant 81572253), Shanghai Shen Kang
Hospital Development Center City Hospital Emerging
Cutting-edge Technology Joint Research Project (grant
SHDC12017102) and Shanghai Municipal Health Com-
mission Key Discipline Project (2017ZZ02025).
Supplementary Data
Note: To access the supplementary material accompa-
nying this article, visit the online version of the Journal of
Thoracic Oncology at www.jto.org and at https://doi.
org/10.1016/j.jtho.2018.12.030.
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http://refhub.elsevier.com/S1556-0864(19)30021-8/sref25
http://refhub.elsevier.com/S1556-0864(19)30021-8/sref25http://refhub.elsevier.com/S1556-0864(19)30021-8/sref25
	Lung Adenocarcinomas Manifesting as Radiological Part-Solid Nodules Define a Special Clinical Subtype
	Introduction
	Material and Methods
	Patient Cohort
	Radiological and Histologic Evaluation
	Follow-up Protocol
	Statistics
	Results
	Discussion
	Acknowledgments
	Supplementary Data
	References