Japanese Journal of Clinical Oncology, 2015, 45(4) 367–372
doi: 10.1093/jjco/hyv005
Advance Access Publication Date: 27 January 2015
Original Article
Original Article
What are the radiologic findings predictive
of indolent lung adenocarcinoma?
Takahiro Mimae1, Yoshihiro Miyata1, Yasuhiro Tsutani1, Takeshi Mimura1,
Haruhiko Nakayama2, Sakae Okumura3, Masahiro Yoshimura4, and
Morihito Okada1,*
1
Department of Surgical Oncology, Hiroshima University, Hiroshima, 2Department of Thoracic Surgery, Kanagawa
Cancer Center, Yokohama, 3Department of Thoracic Surgery, Cancer Institute Hospital, Tokyo, and 4Department of
Thoracic Surgery, Hyogo Cancer Center, Akashi, Japan
*For reprints and all correspondence: Morihito Okada, Department of Surgical Oncology, Hiroshima University, 1-2-3 Kasumi,
Minami-ku, Hiroshima 734-8551, Japan. E-mail: [email protected]
Received 20 September 2014; Accepted 6 January 2015
Abstract
Objective: Small pulmonary nodules are often followed up. This study aimed to establish radiographic criteria with which to accurately and reproducibly predict indolent cancers including adenocarcinoma in situ.
Methods: We examined correlations between pre-operative factors and surgical outcomes, including pathological findings and prognosis among 609 patients with clinical Stage IA lung adenocarcinoma that had been completely resected at multiple institutions. Indolent cancers were defined as
tumors without lymphatic, blood vessel, pleural invasion or lymph node involvement (LY0V0PL0N0)
regardless of stromal invasion.
Results: Pathological assessments of specimens of 35 of 85 (41%) pure ground glass opacity tumors
including 3 (23%) of 13 pure ground glass opacity tumors ≤1 cm, revealed partially invasive components. Receiver operating characteristic curves for LY0V0PL0N0 revealed solid tumor size ≤6 mm on
high-resolution computed tomography or maximum standardized uptake values ≤0.6 on 2-[18F]
fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography as radiographic indolent tumor criteria for predicting indolent tumors. Among 216 (35.5%) of 609 patients who met
these criteria, none developed recurrence over a median follow-up of 41.6 months.
Conclusions: Pure ground glass opacity lesions on high-resolution computed tomography could
pathologically include invasive components and would not correspond to adenocarcinoma in situ.
Solid tumor size on high-resolution computed tomography and maximum standardized uptake values on positron emission tomography/computed tomography can predict indolent LY0V0PL0N0
lung tumors that can be followed up.
Key words: lung adenocarcinoma, indolent, solid tumor, SUVmax, follow-up
Introduction
Small solitary pulmonary nodules on computed tomography (CT) are
often simply followed up in clinical practice if malignancy is not proven because such lesions are less likely to be malignant (1–4). In addition, the prognosis of patients is expected to be good after small
nodules are completely resected even if they are malignant (5). The
American College of Chest Physicians guidelines for lung nodules
applies a follow-up algorithm for pulmonary nodules that are
≤8 mm (4). These guidelines are applied not only to pure- or partly
solid, but also to pure ground glass opacity (GGO) tumors. However,
© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
367
368
Radiologic indolent lung adenocarcinoma criteria
the malignant behavior of pure GGO and pure- or semi-solid 8 mm
lesions significantly differs (6,7). Thus, criteria for following up pulmonary solitary nodules should be defined according to both solid
tumor size excluding a GGO component on high-resolution computed
tomography (HRCT) and maximum standard uptake values (SUVmax)
on 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/
computed tomography (FDG-PET/CT) because these parameters indicate the malignant potential of lung adenocarcinoma more accurately
than whole tumor size (6–10).
Adenocarcinoma in situ (AIS) and invasive adenocarcinoma without lymphatic, blood vessel and pleural invasion and lymph node involvement (LY0V0PL0N0) are considered to be pre-lesions of invasive
adenocarcinoma with lymphatic, blood vessel or pleural invasion, or
lymph node involvement (11–13). Among lung adenocarcinomas
≤3 cm, those that show LY0V0PL0N0 including AIS are assumed to
be indolent because the prognosis of patients with such adenocarcinomas is excellent (8,9,13–16). Accordingly, radiographic criteria that
indicate indolent LY0V0PL0N0 adenocarcinoma including AIS have
potential for follow-up. However, such criteria have not been fully defined although one study has suggested pre-operative GGO ratios on
HRCT that indicate LY0V0PL0N0 (17).
Here, we aimed to define the pre-operative radiographic findings
that indicate AIS. We also examined the pre-operative radiographic
findings, including solid tumor size and SUVmax that could predict
indolent LY0V0PL0N0 lung adenocarcinoma. The results of this
study will facilitate decisions regarding whether small pulmonary nodules should be followed up or surgically treated.
Patients and methods
Patient population
This study included 609 consecutive patients with complete pathological data who underwent surgically curative R0 resection of clinical Stage
IA lung adenocarcinoma at Hiroshima University Hospital (Hiroshima,
Japan), Kanagawa Cancer Center (Yokohama, Japan), Cancer Institute
Hospital (Tokyo, Japan) and Hyogo Cancer Center (Akashi, Japan) between April 2007 and December 2010. The Institutional Review Boards
of the participating institutions approved this retrospective review of a
prospective database and waived the requirement for informed consent
from individual patients. All patients were staged according to the TNM
Classification of Malignant Tumors, seventh edition (18). Endobronchial ultrasonography or mediastinoscopy was not routinely performed. Swelling of the mediastinal or hilar lymph nodes was not
evident on HRCT, and FDG-PET revealed no accumulation of FDG
in those lymph nodes. Sublobar resection was allowed when a peripheral T1aN0M0 tumor was completely removed and surgical margins
were appropriate. Wedge resection without lymph node assessment
was allowed for GGO tumors, which a prospective study regarded as
node-negative and non-invasive (17). Segmentectomy with hilar and
mediastinal lymph node dissection was allowed for GGO-mixed tumors. If any lymph node involvement was detected on intraoperative
frozen sections, the procedure was converted to standard lobectomy.
All other patients underwent standard lobectomy. The inclusion criteria
included pre-operative staging determined by HRCT and FDG-PET/CT
and curative surgery without induction therapy. Patients with incompletely resected tumors (R1 or R2) and those with multiple tumors or
previous lung surgery were excluded.
Pathological studies
Specimens were fixed with 10% formalin, embedded in paraffin and
then consecutive 4 µm sections were histologically diagnosed by
microscopy based on the latest edition of the WHO classification.
The histological type of adenocarcinoma and presence of lymphatic
involvement were determined in hematoxylin–eosin (H–E)-stained tissues. If the type could not be determined by H–E staining alone, then
lymphatic and blood vessel invasion was assessed by immunohistochemistry for D2–40 and Elastica-van Gieson (EVG) staining and
pleural invasion was evaluated by staining elastic tissue fibers with
EVG as necessary. Indolent cancers were defined as LY0V0PL0N0
regardless of an invasive component. Pathologists from each institution histologically assessed all specimens.
HRCT imaging
Chest images were acquired using 16-row multidetector CT. We
defined solid tumor size as the maximum dimension of the solid component of the lung windows, excluding GGO (10), which we defined
as a hazy increase in lung attenuation that did not obscure underlying
vascular markings and the solid component was defined as having
residual high density. Radiologists from each institution reviewed all
CT images and determined tumor sizes.
FDG-PET/CT imaging
Patients were instructed to fast for at least 4 h before intravenous injection of 74–370 MBq of FDG and then to relax for at least 1 h before
FDG-PET/CT scanning. For imaging, Biograph Sensation 16 (Siemens
Healthcare, Erlangen, Germany), Aquiduo (Toshiba Medical Systems
Corporation, Tochigi, Japan) or Discovery ST (GE Healthcare, Little
Chalfont, UK) integrated three-dimensional PET/CT scanners were
used. Low-dose non-enhanced CT images of 2–4 mm section thickness were taken from the head to the pelvis of each patient. An anthropomorphic body phantom (NEMA NU2–2001; Data Spectrum Corp,
Hillsborough, NC, USA) was used to minimize variations in standardized uptake values among the institutions (8,19). The original SUVmax values were determined by radiologists from each institution for
the purposes of this study. On FDG-PET/CT images, all lymph nodes
in the thorax with FDG uptake no greater than the normal background activity of the mediastinal blood pool the SUVmax of which
was <1.5, regardless of size, were considered cN0. A lymph node
where the SUVmax was 1.5 or more was considered ‘suspicious for
malignancy’. However, even lymph nodes with high FDG uptake,
when they showed higher attenuation than mediastinal structures
(great vessels) or benign calcification (central, nodular, diffuse or
popcorn-like), were also considered benign (20).
Follow-up evaluation
All patients who underwent lung resections were followed up from the
day after surgery. Post-operative follow-up comprised a physical
examination and chest radiography every 3 months and chest and
abdominal CT examinations every 6 months for the first 2 years.
Thereafter, patients underwent a physical examination and chest radiography every 6 months and annual chest CT.
Statistical analyses
Continuous and categorical variables were analyzed using the Mann–
Whitney U-test and the χ 2 test or Fisher’s exact test. Receiver operating
characteristics (ROC) curves of solid tumor size and SUVmax for predicting lymphatic, blood vessel, pleural invasion or lymph node metastasis were generated to determine a cutoff value that was not
associated with pathological invasion. The threshold of the ROC
curves was defined as sensitivity plateaus. Overall survival (OS) and
Jpn J Clin Oncol, 2015, Vol. 45, No. 4
recurrence-free interval (RFI) curves were calculated using the
Kaplan–Meier method and the two groups were compared using univariate log-rank analyses. All data were statistically analyzed using
EZR (Saitama Medical Center, Jichi Medical University), which is a
graphical user interface for R (The R Foundation for Statistical
Computing, version 2.13.0). More precisely, it is a modified version
of R commander (version 1.6-3) designed to add statistical functions
frequently used in biostatistics. P ≤ 0.05 was deemed to indicate statistical significance.
369
GGO is usually considered from a pathological viewpoint to be AIS.
Therefore, we examined the whole tumor size and SUVmax of pure
GGO lesions to predict AIS. Thirty-five (41.2%) of 85 patients with
pure GGO tumors had non-AIS (Table 2). The whole tumor sizes in
3 (23.1%) of 13 patients with whole pure GGO lesions ≤10 mm
were 7, 9 and 10 mm and all had invasive component. Moreover,
some lesions were pathologically invasive adenocarcinoma even
when their SUVmax was equal to that of the background lung
(Table 3). These findings indicated that predicting AIS is difficult
based on whole tumor size and SUVmax even among pure GGO
tumors.
Results
Prediction of AIS
Radiographic indolent tumor criteria
Lobectomy, segmentectomy and wedge resection were performed in
375, 97 and 137 patients, respectively. Table 1 summarizes the clinicopathological findings and recurrence status of patients with AIS and
clinical Stage IA adenocarcinoma including the invasive component.
The patients with AIS were younger than those with invasive adenocarcinoma. Invasive adenocarcinoma appeared as larger whole and
solid tumors on HRCT and had a higher SUVmax on FDG-PET
than AIS. No recurrence was detected in any patient with AIS. Pure
We assessed pre-operative radiographic criteria based on pre-operative
solid tumor size and SUVmax and propose, ‘radiographic indolent
tumor criteria’ with which to accurately and reproducibly predict
LY0V0PL0N0 lung adenocarcinoma including AIS and minimally invasive adenocarcinoma. The ROC curves showed that all tumors
whose radiographic findings show a solid tumor size ≤6 mm on
HRCT or an SUVmax ≤0.6 on FDG-PET/CT had LY0V0PL0N0 status (Fig. 1 and Table 4). Therefore, these parameters were regarded as
radiographic indolent tumor criteria. Radiographic findings of nodules met these criteria in 216 (35.5%) patients with significantly
lower carcinoembryonic antigen levels, smaller whole or solid tumors
and a lower SUVmax compared with those for whom radiographic
findings of nodules did not meet the criteria (Table 4).
The 5-year OS rates of patients whose radiographic findings of nodules met and did not meet the criteria for radiographic indolent tumors were 96.5% [95% confidence interval (CI): 92.0–98.5%] and
85.1% (95% CI: 79.6–89.2%; P = 0.0019), whereas the 5-year RFI
rates were 100 and 83.7% (95% CI: 81.6–85.7%; P < 0.001;
Fig. 2A and B). Patients with nodules that met the radiographic indolent criteria had no recurrence, whereas 10 of 441 patients with
LY0V0PL0N0 tumors had recurrence (median follow-up, 41.6
months).
Table 1. Clinicopathological findings and recurrence status in
patients with clinical Stage IA adenocarcinomas according to
presence of invasive components
Variable
Adenocarcinoma
in situ (n = 96)
Age (year)
Mean
63.9 ± 10.8
Range
31–89
Gender
Male
37 (39%)
CEA (ng/ml)
Mean
2.4 ± 1.5
Range
0–8.4
Whole tumor size (cm)a
Mean
1.6 ± 0.5
Range
0.7–3
Solid tumor size (cm)a
Mean
0.3 ± 0.5
Range
0–2.7
SUVmax
Mean
1.0 ± 0.9
Range
0–4.0
Lymphatic invasion
Positive
0 (0%)
Blood vessel invasion
Positive
0 (0%)
Pleural invasion
Positive
0 (0%)
Lymph node metastasis
Positive
0 (0%)
Recurrence
Positive
0 (0%)
Invasive
adenocarcinoma
(n = 513)
P
66.1 ± 9.4
33–87
0.038
231 (45%)
0.26
3.7 ± 6.6
0.5–113.8
0.056
2.0 ± 0.6
0.6–3
<0.001
1.3 ± 0.8
0–3
<0.001
3.8 ± 2.4
0–16.9
<0.001
89 (17%)
<0.001
104 (20%)
<0.001
65 (13%)
<0.001
41 (8%)
0.001
58 (11%)
<0.001
Data are shown as counts and ratios (%) or means ± standard deviation, as
appropriate. Invasive adenocarcinomas include pure invasive tumors and
invasive tumors including a lepidic component.
CEA, carcinoembryonic antigen; SUVmax, maximum standardized uptake
values.
a
Determined by high-resolution computed tomography.
Discussion
Our proposed criteria for radiographic indolent tumors can predict
LY0V0PL0N0 lung adenocarcinoma including AIS if pulmonary nodules are malignant. The criteria comprised a solid tumor size ≤6 mm
or an SUVmax ≤ 0.6. Patients with lung adenocarcinoma whose preoperative radiographic findings met the criteria had an excellent
prognosis after complete resection. In addition, most nodules that preoperatively met the proposed criteria were expected to be benign (4).
Therefore, the proposed criteria are useful for following up pulmonary
nodules. The criteria cannot prohibit surgical intervention for diagnosis and treatment. If surgical intervention is considered, sublobar
resection including wedge resection for peripheral nodules and segmentectomy for central nodules without lymph node dissection
would be sufficient (5,16,17,21). However, the present findings indicate that surgical resection should be recommended for diagnosis and
treatment when the radiographic findings of pulmonary nodules exceed the criteria. Moreover, evaluating pulmonary nodules using the
criteria excluding the GGO component can provide insight to help
solve the clinical dilemma regarding whether or not to follow-up
GGO-predominant pulmonary nodules including pure GGO that
are ≥1 cm.
Pre-operative findings on HRCT or FDG-PET could not absolutely
predict AIS. Although pure GGO lesions are often regarded as AIS,
370
Radiologic indolent lung adenocarcinoma criteria
Table 2. Patients with clinical Stage IA adenocarcinoma and pure GGO according to whole tumor size
Variable
Adenocarcinoma in situ
Invasive adenocarcinoma
All (n = 85)
50 (59%)
35 (41%)
Whole tumor size (mm)
0–10 (n = 13)
11–15 (n = 33)
16–20 (n = 23)
21–25 (n = 11)
26–30 (n = 5)
10 (77%)
3 (23%)
21 (64%)
12 (36%)
11 (48%)
12 (52%)
6 (55%)
5 (45%)
2 (40%)
3 (60%)
Data are presented as counts and ratios (%) as appropriate. Invasive adenocarcinomas include pure invasive tumors and invasive tumors including a lepidic
component.
GGO, ground glass opacity.
Table 3. Patients with clinical Stage IA adenocarcinoma and pure GGO according to SUVmax
Variable
Adenocarcinoma in situ
Invasive adenocarcinoma
All (n = 85)
50 (59%)
35 (41%)
SUVmax
0–0.5 (n = 28)
0.6–1.0 (n = 39)
1.1–1.5 (n = 15)
1.6–2.0 (n = 2)
2.1–2.5 (n = 1)
16 (57%)
12 (43%)
26 (67%)
13 (33%)
6 (40%)
9 (60%)
1 (50%)
1 (50%)
1 (100%)
0 (0%)
Data are shown as counts and ratios (%) as appropriate. Invasive adenocarcinomas include pure invasive tumors and invasive tumors including a lepidic
component.
Figure 1. Receiver operating characteristics curves of solid tumor size and maximum standardized uptake values (SUVmax) for predicting no lymphatic, blood vessel
or pleural invasion or lymph node metastasis. (A) Optimal cutoff of solid tumor size for clinical Stage IA adenocarcinoma is 6 mm (n = 609; area under the curve
[AUC], 0.83; 95% confidence interval [CI], 0.79–0.86; P < 0.001). (B) Optimal SUVmax cutoff for clinical Stage IA adenocarcinoma is 0.6 (n = 609; AUC, 0.87; 95% CI,
0.84–0.90; P < 0.001).
some pure GGO lesions ≤10 mm had a partly pathological invasive
component. Because invasive adenocarcinomas including lepidic and
papillary components that have morphologically alveolar cavities
(5,13), the HRCT findings of such tumors might be pure GGO. Conversely, non-invasive AIS, such as Noguchi’s Type B adenocarcinoma,
show alveolar collapse, which is detectable as a consolidation component on HRCT (5,13). Hence, AIS is difficult to predict based on
HRCT findings. However, the grade of malignancy of pure GGO tumors was low and such tumors did not recur after complete resection
in the present study. More follow-up data, particularly within the
context of a larger-scale randomized prospective study, are needed
to elucidate the real prognosis of patients with pure GGO.
The proposed radiographic criteria can be applied to solid predominant tumors. Pure solid tumors >6 mm in diameter with a low
SUVmax can be followed up. The background lung SUVmax could
be considered as ≤0.6. Therefore, lung nodules with SUVmax values
exceeding the pulmonary background might have malignant and invasive potential. That is, pulmonary nodules with a similar SUVmax to
the background value have little malignant aggressiveness even if they
are predominantly solid. However, PET/CT might be too costly for
evaluating indolent GGO tumors. If LY0V0PL0N0 criteria were
adopted, all patients with lung lesions would require assessment by
HRCT and PET/CT and the latter modality is usually used to check
the status of local lesion or distant metastasis in patients with advanced lung cancer. Many institutions throughout the world might
have difficulty justifying the use of PET/CT to assess all patients
with clinical Stage IA tumors. In addition, lung lesions with the histological features of adenocarcinoma often show a halo pattern on CT,
whereas some lung lesions show a scatter pattern. Such features impose barriers to measuring solid tumor size and the SUVmax of
such lesions in the clinical setting. Therefore, the LY0V0PL0N0
criteria are difficult to apply to lesions with the scatter pattern.
Jpn J Clin Oncol, 2015, Vol. 45, No. 4
Table 4. Clinicopathological findings and recurrence status in
patients with clinical Stage IA adenocarcinomas according to
radiographic indolent tumor criteria
Variable
Age (year)
Mean
Range
Gender
Male
CEA (ng/ml)
Mean
Range
Whole tumor size (cm)a
Mean
Range
Solid tumor size (cm)a
Mean
Range
SUVmax
Mean
Range
Histology
Adenocarcinoma in situ
Invasive adenocarcinoma
Lymphatic invasion
Positive
Blood vessel invasion
Positive
Pleural invasion
Positive
Lymph node metastasis
Positive
Recurrence
Positive
Radiographic indolent tumor criteria
Met (n = 216)
Unmet (n = 393)
P
64.7 ± 9.5
31–89
66.3 ± 9.7
33–87
0.041
82 (38%)
186 (47%)
0.027
2.4 ± 2.3
0.5–24.3
3.9 ± 7.0
0–113.8
0.011
1.7 ± 0.6
0.6–3
2.1 ± 0.5
0.8–3
<0.001
0.2 ± 0.3
0–1.4
1.7 ± 0.6
0.6–3
<0.001
0.9 ± 1.0
0–9.8
3.1 ± 2.3
0–16.9
<0.001
78 (36%)
138 (64%)
18 (5%)
375 (95%)
<0.001
0 (0%)
89 (23%)
<0.001
0 (0%)
104 (26%)
<0.001
0 (0%)
65 (17%)
<0.001
0 (0%)
41 (10%)
<0.001
0 (0%)
58 (15%)
<0.001
Data are shown as counts and ratios (%) or means ± standard deviation, as
appropriate. Invasive adenocarcinomas include pure invasive tumors and
invasive tumors including a lepidic component.
a
Determined by high-resolution computed tomography.
371
Other novel modalities or evaluation methods are needed to assess the
malignant aggressiveness of lung lesions with scatter patterns.
Ten among the 441 patients who had LY0V0PL0N0 tumors in this
cohort recurred, whereas none of the pulmonary nodules that met the
proposed criteria recurred. Hence, the pre-operative radiographic indolent tumor criteria might predict true LY0V0PL0N0 lung adenocarcinomas compared with pathological assessments that can overlook
lymphatic, blood vessel and pleural invasion, as well as lymph node
metastasis because only some sections of surgical specimens are evaluated. Therefore, we suppose that some tumors with pathological
LY0V0PL0N0 status will in fact be positive for lymphatic, blood vessel, or pleural invasion or lymph node metastasis. Thus, that some
LY0V0PL0N0 tumors recurred is reasonable.
We examined only patients with cancers that were completely and
surgically resected. Not all lesions that appeared as solitary pulmonary
nodules on HRCT were assessed and thus pulmonary nodules that
were not surgically resected were not qualitatively evaluated. However, considering the difficulty of histopathologically evaluating nodules that are not surgically resected, the lack of data about
non-resected small pulmonary nodules is a limitation of this type of
study design. Other limitations of this study included the nonrandomized, retrospective nature and potential variations in radiographic interpretations. On the other hand, the median follow-up of
41.6 months in the present study might have been too short to evaluate
the prognosis of patients with lung lesions including a GGO component, because this type of tumor relapses very slowly. Further followup is required to accurately evaluate prognosis and whether patients
with pre-operative findings that meet radiographic indolent tumor
criteria could be cured by complete resection.
Conclusions
In summary, we propose new ‘radiographic indolent tumor criteria’.
Pulmonary nodules whose solid tumor size was ≤6 mm or SUVmax
was ≤0.6 were indolent tumors even if they were malignant and the
prognosis of patients with such lesions was excellent. The results of
this multi-institutional study require valuation in a larger-scale cohort.
Nevertheless, patients with pulmonary nodules that are not
Figure 2. Kaplan–Meier survival curves of patients with clinical Stage IA tumors that met or did not meet radiographic indolent tumor criteria. Overall survival (A) and
recurrence-free interval (B) curves significantly differ between the two groups (P = 0.0019 and P < 0.001, respectively; log-rank test). Thick and thin lines, patients who
met and did not meet radiographic indolent tumor criteria, respectively.
372
Radiologic indolent lung adenocarcinoma criteria
pathologically proven to be malignant could be followed up when the
radiographic findings of nodules meet the proposed criteria. Surgical
resection for diagnosis and therapy is recommended when the preoperative findings of nodules exceed the radiographic indolent
tumor criteria. Prediction of AIS with no life-threatening potential
based on pre-operative HRCT and FDG-PET findings is difficult.
9.
10.
Funding
This study was supported by the Japan Society for the Promotion of
Science Kakenhi (26861122 to T.M. and 24390329 to M.O.).
Conflict of interest statement
11.
12.
None declared.
References
13.
1. Kobayashi Y, Fukui T, Ito S, et al. How long should small lung lesions of
ground-glass opacity be followed? J Thorac Oncol 2013;8:309–14.
2. Lim HJ, Ahn S, Lee KS, et al. Persistent pure ground-glass opacity lung nodules ≥10 mm in diameter at CT: histopathologic comparisons and prognostic implications. Chest 2013;144:1291–9.
3. Naidich DP, Bankier AA, MacMahon H, et al. Recommendations for the
management of subsolid pulmonary nodules detected at CT: a statement
from the Fleischner Society. Radiology 2013;266:304–17.
4. Gould MK, Fletcher J, Iannettoni MD, et al. Evaluation of patients with
pulmonary nodules: when is it lung cancer? ACCP evidence-based clinical
practice guidelines (2nd edition). Chest 2007;132(Suppl 3):108S–30S.
5. Travis WD, Brambilla E, Noguchi M, et al. International association for the
study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma.
J Thorac Oncol 2011;6:244–85.
6. Tsutani Y, Miyata Y, Nakayama H, et al. Prognostic significance of using
solid versus whole tumor size on high-resolution computed tomography
for predicting pathologic malignant grade of tumors in clinical stage IA
lung adenocarcinoma: a multicenter study. J Thorac Cardiovasc Surg
2012;143:607–12.
7. Tsutani Y, Miyata Y, Yamanaka T, et al. Solid tumors versus mixed tumors
with a ground-glass opacity component in patients with clinical stage IA
lung adenocarcinoma: prognostic comparison using high-resolution computed tomography findings. J Thorac Cardiovasc Surg 2013;146:17–23.
8. Nakayama H, Okumura S, Daisaki H, et al. Value of integrated positron
emission tomography revised using a phantom study to evaluate malig-
14.
15.
16.
17.
18.
19.
20.
21.
nancy grade of lung adenocarcinoma: a multicenter study. Cancer
2010;116:3170–7.
Okada M, Nakayama H, Okumura S, et al. Multicenter analysis of highresolution computed tomography and positron emission tomography/computed tomography findings to choose therapeutic strategies for clinical stage
IA lung adenocarcinoma. J Thorac Cardiovasc Surg 2011;141:1384–91.
Tsutani Y, Miyata Y, Nakayama H, et al. Prediction of pathologic
node-negative clinical stage IA lung adenocarcinoma for optimal
candidates undergoing sublobar resection. J Thorac Cardiovasc Surg
2012;144:1365–71.
Aviel-Ronen S, Coe BP, Lau SK, et al. Genomic markers for malignant progression in pulmonary adenocarcinoma with bronchioloalveolar features.
Proc Natl Acad Sci USA 2008;105:10155–60.
Mimae T, Okada M, Hagiyama M, et al. Upregulation of notch2 and six1
is associated with progression of early-stage lung adenocarcinoma and
a more aggressive phenotype at advanced stages. Clin Cancer Res
2012;18:945–55.
Noguchi M, Morikawa A, Kawasaki M, et al. Small adenocarcinoma of the
lung. Histologic characteristics and prognosis. Cancer 1995;75:2844–52.
Sakurai H, Dobashi Y, Mizutani E, et al. Bronchioloalveolar carcinoma of
the lung 3 centimeters or less in diameter: a prognostic assessment. Ann
Thorac Surg 2004;78:1728–33.
Vazquez M, Carter D, Brambilla E, et al. Solitary and multiple resected
adenocarcinomas after CT screening for lung cancer: histopathologic features and their prognostic implications. Lung Cancer 2009;64:148–54.
Yamato Y, Tsuchida M, Watanabe T, et al. Early results of a prospective
study of limited resection for bronchioloalveolar adenocarcinoma of the
lung. Ann Thorac Surg 2001;71:971–4.
Suzuki K, Koike T, Asakawa T, 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.
Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging
Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours.
J Thorac Oncol 2007;2:706–14.
Delbeke D, Coleman RE, Guiberteau MJ, et al. Procedure guideline for
tumor imaging with 18F-FDG PET/CT 1.0. J Nucl Med 2006;47:885–95.
Li L, Ren S, Zhang Y, et al. Risk factors for predicting the occult nodal metastasis in T1-2N0M0 NSCLC patients staged by PET/CT: potential value
in the clinic. Lung Cancer 2013;81:213–7.
Watanabe S, Watanabe T, Arai K, Kasai T, Haratake J, Urayama H. Results
of wedge resection for focal bronchioloalveolar carcinoma showing pure
ground-glass attenuation on computed tomography. Ann Thorac Surg
2002;73:1071–5.