Solid Component and Tumor Size Correlate With

Prognosis of Stage IB Lung Adenocarcinoma

Songtao Xu, MD,* Junjie Xi, MD,* Wei Jiang, MD, Shaohua Lu, MD, and Qun Wang, MD
Departments of Thoracic Surgery and Pathology, Zhongshan Hospital, Fudan University, Xuhui District, Shanghai, China

gender (HR, 0.558; p [ 0.033), presence of the solid component (HR, 1.976; p [ 0.016), and presence of a micropapillary
component (HR, 2.371; p [ 0.018) were prognostic for
progression-free survival. Multivariable analysis revealed
that tumor size was an independent prognostic factor for
overall survival (HR, 2.083; 95% condence interval, 1.433
to 3.029; p < 0.001) and progression-free survival (HR, 2.036;
95% condence interval, 1.546 to 2.681; p < 0.001) and that
the presence of the solid component (HR, 2.045; 95% condence interval, 1.172 to 3.568; p [ 0.012) was an independent prognostic factor for progression-free survival.
Conclusions. Solid component and tumor size signicantly correlate with prognosis in stage IB pulmonary
adenocarcinoma.

subtype that is present, along with the percentages, is

supposed to be recorded in diagnostic reports.
Adjuvant chemotherapy is the standard therapy for stage
II to stage IIIA non-small cell lung cancer (NSCLC) [7], but
the role of adjuvant chemotherapy in stage IB NSCLC has
not been established [8]. Results of clinical trials [911] did
not support routine use of adjuvant chemotherapy for stage
IB patients; nevertheless, a subset of stage IB patients may
benet from adjuvant chemotherapy. Identifying prognostic factors of stage IB NSCLC will help nd candidates
who may benet from adjuvant chemotherapy.
The new IASLC/ATS/ERS classication can represent
the heterogeneity of pulmonary adenocarcinoma, and
some studies have validated the prognostic value of
the new classication for pulmonary adenocarcinomas
[1220]. Therefore, we hypothesized that the new classication may correlate with survival of stage IB pulmonary
adenocarcinoma as well. In this study, we focused on the
prognostic value of the new IASLC/ATS/ERS classication in patients with completely resected stage IB
pulmonary adenocarcinoma.

ung cancer is one of the leading causes of cancerrelated death worldwide [1], of which adenocarcinoma is the most frequent histologic type, with increasing
incidence trends during the past decades [2]. Histologic
and molecular heterogeneity of pulmonary adenocarcinoma has been recognized [3, 4]. Components, as well as
the percentage of each component, differ in pulmonary
adenocarcinomas. However, according to the 2004 World
Health Organization classication of pulmonary adenocarcinoma, more than 80% of invasive pulmonary
adenocarcinomas are classied as mixed type [5], which
could not present the histologic heterogeneity. In 2011 the
International Association for the Study of Lung Cancer,
the American Thoracic Society, and the European
Respiratory Society (IASLC/ATS/ERS) proposed a new
histologic classication of pulmonary adenocarcinoma [6]
with several important modications to the previous
World Health Organization classication:
First, the term bronchioloalveolar carcinoma is
discontinued.
Second, adenocarcinoma in situ and minimally invasive adenocarcinoma are introduced to the classication.
Third, the classication recommends performing
comprehensive histologic subtyping with semiquantitative
assessment in 5% increments, and each adenocarcinoma
Accepted for publication Oct 31, 2014.
*

Songtao Xu and Junjie Xi contributed equally to this work.

Address correspondence to Dr Wang, Zhongshan Hospital, 180 Fenglin Rd,

6th Flr, Bldg 10, Shanghai, China; e-mail: lu.shaohua@zs-hospital.sh.cn.

2015 by The Society of Thoracic Surgeons

Published by Elsevier

(Ann Thorac Surg 2015;99:9617)

2015 by The Society of Thoracic Surgeons

Patients and Methods

This study was conducted in accordance with the amended Declaration of Helsinki. The Zhongshan Hospital
Ethics Committee on Human Research approved the
protocol (approval number: B2014-042). Written informed
consent was obtained from all patients.
0003-4975/$36.00
http://dx.doi.org/10.1016/j.athoracsur.2014.10.079

GENERAL THORACIC

Background. Prognostic factors for stage IB lung cancer

remain controversial. The International Association for
the Study of Lung Cancer, American Thoracic Society,
and European Respiratory Society proposed a new classication for pulmonary adenocarcinoma. We investigated the prognostic value of this new classication in
resected stage IB pulmonary adenocarcinoma.
Methods. The study included 187 patients with stage
IB pulmonary adenocarcinoma. All pathologic slides
were reevaluated according to the new classication for
pulmonary adenocarcinoma, with each histologic
component recorded in 5% increments. Survival analyses
were performed to determine the prognostic factors for
stage IB pulmonary adenocarcinoma.
Results. Univariable analysis showed tumor size was
prognostic for overall survival (hazard ratio [HR], 2.083;
p < 0.001) and progression-free survival (HR, 1.991; p < 0.001);

GENERAL THORACIC

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PROGNOSTIC FACTORS FOR LUNG CANCER

We reviewed our thoracic surgical database and

screened patients with stage IB pulmonary adenocarcinoma from January 2005 to December 2009 at the
Zhongshan Hospital Division of Thoracic Surgery. All
patients received lobectomy and mediastinal lymph node
dissection. The study excluded patients undergoing neoadjuvant or adjuvant therapy. A total of 187 patients were
included.
Pathologic diagnoses were made according to the 2004
World Health Organization criteria for pulmonary
adenocarcinoma. Tumor stage was determined based on
the Seventh Edition of the TNM classication of the
American Joint Committee on Cancer and the International Union Against Cancer.
All patients underwent a routine preoperative workup
to preclude distant metastasis, including enhanced chest
computed tomography (CT) scan, enhanced upper
abdominal CT scan or abdominal ultrasonography,
beroptic bronchoscopy, enhanced cranial magnetic
resonance imaging, and bone scan. Mediastinoscopy was
performed for patients with suspected N2 lymph node
metastasis detected by CT scan.
The longest diameters of tumors were measured by
pathologists. All resected specimens were formalin-xed
and stained with hematoxylin and eosin. Pleural invasion was established using elastin stains in instances
where pleural invasion was difcult to diagnose. According to the new IASCL/ATS/ERS classication, all
slides were evaluated by 2 experienced pathologists, who
were blinded to clinical information. Controversial slides
were reevaluated by the 2 pathologists under a multiheaded microscope. Each histologic component (lepidic,
acinar, papillary, micropapillary, and solid) was recorded
in 5% increments. The predominant pattern was dened
as the pattern with the largest percentage.
Cumulative survival rates were calculated by the
Kaplan-Meier method, and survival curves were
compared using the log-rank test. Univariable and
multivariable analyses using the Cox proportional hazard
model were conducted to obtain the risk factors on overall
survival (OS) and progression-free survival (PFS). Multivariable analyses were conducted in a forward step-wise
manner for factors with a p value of less than 0.10. All
statistical tests were 2-sided, and statistical signicance
was dened as a p value of less than 0.05. Statistical
analysis was conducted using SPSS 20.0 software (IBM
Corp, Armonk, NY).

Results
Clinicopathologic Characteristics
The clinicopathologic characteristics of the 187 patients
(80 men, 107 women) are reported in Table 1. Patents
were an average age of 60.3 years (range, 34 to 82 years),
153 (81.8%) were nonsmokers, and 18 (9.6%) had history
of diabetes mellitus. The average tumor size was 3.2 cm
(range, 0.8 to 5.0 cm). The diameters of most of the tumors
(82 [43.9%]) were between 3 and 5 cm, followed by tumors
that were between 2 and 3 cm (65 [34.8%]) and those 2 cm

Ann Thorac Surg

2015;99:9617

or smaller (40 [21.4%]). Visceral pleural invasion was

present in 150 patients (80.2%). Lymphovascular invasion
was present in 13 patients (7.0%). Necrosis was present in
14 patients (7.5%).
According to the new IASLC/ATS/ERS classication,
all tumors were invasive adenocarcinoma, and the subtypes were lepidic-predominant in 2 (1.1%), acinarpredominant in 120 (64.2%), papillary-predominant in
31 (16.6%), micropapillary-predominant in 5 (2.7%), solidpredominant in 19 (10.2%), invasive mucinous adenocarcinoma in 9 (4.8%), and fetal in 1 (0.5%). The acinar
component was the most common (140 [74.9%]), followed
by papillary component (61 [32.6%]), solid component
(49 [26.2%]), lepidic component (21 [11.2%]), and micropapillary component (17 [9.1%]).

Survival Analysis
The follow-up period was a mean of 4.5 years (range, 1 to
8.6 years). The 5-year PFS rates and the 5-year OS rates
are summarized in Table 2. To investigate the effect of
each component on survival, we compared the survival
rates of patients with and without each component, as
reported in Table 3. The presence of the micropapillary
component and the solid component signicantly correlated with the PFS rate (p 0.015 and p 0.014, respectively; Figs 1 and 2).

Cox Regression
Univariable and multivariable analyses results are summarized in Tables 4 and 5. Gender, age, smoking status,
tumor size, visceral pleural invasion, lymphovascular
invasion, tumor necrosis, and presence of each component were included in the analysis. For OS, tumor size
and the presence of the solid component were included in
multivariable analysis, but only tumor size (hazard ratio
[HR], 2.083; 95% condence interval [CI], 1.433 to 3.029;
p < 0.001) was an independent prognostic factor for OS.
For PFS, gender, tumor size, presence of the micropapillary component and presence of the solid component were included in multivariable analysis, but only
tumor size (HR, 2.036; 95% CI, 1.546 to 2.681; p < 0.001)
and presence the solid component (HR, 2.045; 95% CI,
1.172 to 3.568; p 0.012) were identied as prognostic
factors.

Comment
Clinical trials have failed to demonstrate a survival
benet for adjuvant chemotherapy in stage IB NSCLC
patients, so consensus has not been reached on adjuvant
chemotherapy for stage IB NSCLC until now. The randomized controlled clinical trials JBR10 [21] and Cancer
and Leukemia Group B (CALGB) 9633 [22, 23] indicated
that postoperative adjuvant chemotherapy could prolong
patients survival time and increase survival rates in patients with stage IB NSCLCs, but recent updated data of
the two trials [9, 10] revealed that adjuvant chemotherapy
did not improve survival.
On the basis of the results mentioned above, routine
use of adjuvant chemotherapy for stage IB NSCLC was

Ann Thorac Surg

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XU ET AL
PROGNOSTIC FACTORS FOR LUNG CANCER

963

Table 1. Clinicopathological Characteristics of Patients

Patients
No. (%)

Variables

Gender

Male
Female
<70 years
70 years
Never
Current/former
Yes
No
2cm
>2cm and 3cm
>3cm and 5cm
Present
Absent
Present
Absent
Present
Absent
Lepidic-predominant
Acinar-predominant
Papillary-predomination
Micropapillary-predominant
Solid-predominant
Invasive mucinous adenocarcinoma
Fetal
Present
Absent
Present
Absent
Present
Absent
Present
Absent
Present
Absent

Age
Smoking status
History of diabetes
Tumor size

Visceral pleural invasion

Lymphovascular invasion
Necrosis
New IASLC/ATS/ERS classication

Lepidic component
Acinar component
Papillary component
Micropapillary component
Solid component

ATS American Thoracic Society;

ERS European Respiratory Society;

not recommended by American College of Chest Physicians [8]. However, the National Comprehensive Cancer
Network recommended adjuvant chemotherapy for highrisk stage IB NSCLC patients [24]. The risk factors were
poorly differentiated tumors, vascular invasion, wedge
resection, tumors larger than 4 cm, visceral pleural
involvement, and incomplete lymph node sampling [24].
It is possible that a subset of stage IB NSCLC patients can
benet from adjuvant chemotherapy, yet the subset remains unrecognized. To identify the patients who might
benet from adjuvant chemotherapy, we have to discern
poor prognostic factors, and then, clinical trials could be
designed to conrm which factors feature the subset.
IASLC/ATS/ERS proposed new classication for lung
adenocarcinoma in 2011 [6]. The prognostic value of the
new classication has been veried in a number of
studies [1220]. Some research [12, 1618] conrmed that

80
107
147
40
153
34
18
169
40
65
82
150
37
13
174
14
173
2
120
31
5
19
9
1
21
166
140
47
61
126
17
170
49
138

(42.8)
(57.2)
(78.6)
(21.4)
(81.8)
(18.2)
(9.6)
(90.4)
(21.4)
(34.8)
(43.9)
(80.2)
(19.8)
(7.0)
(93.0)
(7.5)
(92.5)
(1.1)
(64.2)
(16.6)
(2.7)
(10.2)
(4.8)
(0.5)
(11.2)
(88.8)
(74.9)
(25.1)
(32.6)
(67.4)
(9.1)
(90.9)
(26.2)
(73.8)

IASLC International Association for the Study of Lung Cancer.

the subtypes of adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic-predominant adenocarcinoma had 5-year survival rates approaching 100%.
Micropapillary-predominant and solid-predominant adenocarcinomas were indicated to have poor survival, and
papillary-predominant and acinar-predominant adenocarcinomas were supposed to have intermediate survival.
Hung and colleagues [19] and Yoshizawa and
colleagues [13] investigated the value of the new classication in stage I NSCLC. Hung and colleagues [19]
found that micropapillary-predominant and solidpredominant adenocarcinomas were associated with
recurrence and that solid-predominant adenocarcinoma
correlated with worse postrecurrence survival. Yoshizawa
and colleagues [13] discovered that solid-predominant,
micropapillary-predominant, invasive mucinous, and
colloid-predominant adenocarcinomas had lower 5-year

GENERAL THORACIC

Characteristics

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Table 2. Five-Year Survival Rates of Pathologic Subtypes

Subtype

Patients
(No.)

5-Year PFS
Rate
(%)

5-Year OS
Rate
(%)

2
120
31
5
19
9

100
71.2
69.7
0
57
88.9

100
84.5
80.2
0
78.9
100

GENERAL THORACIC

Lepidic-predominant
Acinar-predominant
Papillary-predominant
Micropapillary-predominant
Solid-predominant
Invasive mucinous
adenocarcinoma
OS overall survival;

PFS progression-free survival.

disease-free survival rates. We hypothesized that the new

classication might also correlate with survival in stage IB
lung adenocarcinoma and designed this study.
Solid-predominant adenocarcinoma and micropapillarypredominant adenocarcinoma have been reported to be a
poor prognostic factor [12, 1618]. Solis and colleagues [14]
proposed a model to predict survival of patients with pulmonary adenocarcinoma based on the new classication,
and the model suggested that the solid component was
related with an unfavorable prognosis. However, the relationship of the solid component and survival in stage IB
pulmonary adenocarcinoma has not yet been established.
Our study found that the solid component signicantly
correlated with recurrence.
As recommended by the new classication, each
component should be recorded in 5% increments.
Detailed records help distinguish metastasis from multiple primary cancers, and our results showed that records
of each component could provide prognostic information
as well. Clinical trials also need pathologic information to

Table 3. Five-Year Survival Rates Related With Each

Component

58

0.893

81.2

0.751

166
140

70.4
68

0.569

83.5
80.5

0.282

Absent
Present

47
61

71.2
69.9

0.945

91.1
81.2

0.893

Absent
Micropapillary Present
component
Absent
Solid
Present
component
Absent

126
17

68.1
37.8

0.015

84.1
80.8

0.397

170
49

71.6
58

0.014

83.4
75.5

0.064

138

72.6

Acinar
component
Papillary
component

nd candidates who might benet from adjuvant

chemotherapy. The presence of the solid component
should be considered in the process of grouping in prospective clinical trials involving stage IB lung adenocarcinoma, although this factor has never been taken into
account in the past. Therefore, this recommendation is
denitely benecial to patients.
Tumor size was recognized as another prognostic factor
for stage IB adenocarcinoma in this study. The CALGB
9633 [9] and JBR10 [10] clinical trials both indicated that
patients with tumors sized 4 cm or larger would benet
from adjuvant chemotherapy in stage IB NSCLC.
Nevertheless, as the TNM staging system has been
updated since 2009, tumors larger than 5 to 7 cm were
staged as T2b, and some former stage IB tumors were
restaged as stage IIa tumors in the latest TNM staging
system. We staged the tumors according to the latest
TNM staging system and still found that patients with

5-Year
5-Year
Patients PFS Rate p OS Rate p
(No.)
(%)
Value
(%)
Value

Component
Lepidic
component

Fig 1. Progression-free survival for patients with (dashed line) and

without (solid line) the micropapillary component (p 0.015).

Present

21

Absent
Present

OS overall survival;

85.7

PFS progression-free survival.

Fig 2. Progression-free survival for patients with (dashed line) and

without (solid line) the solid component (p 0.014).

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XU ET AL
PROGNOSTIC FACTORS FOR LUNG CANCER

965

Table 4. Univariable and Multivariable Survival Analysis for Overall Survival

Univariable Analysis
Variables

CI condence interval;

HR

95% CI

p Value

1
0.573
1.014

0.2761.192
0.9751.054

0.136
0.497

1
0.53

0.1601.751

0.298

1
0.307
2.083

0.0422.257
1.4333.029

0.246
<0.001

1
1.232

0.4703.229

0.672

1
2.42

0.8386.987

0.102

1
1.619

0.4905.351

0.430

1
0.825

0.2502.725

0.752

1
1.685

0.6434.417

0.289

1
1.054

0.4902.268

0.893

1
1.571

0.5464.515

0.402

1
2.003

0.9464.241

0.07

HR

95% CI

p Value

2.083

1.4333.029

<0.001

HR hazard ratio.

larger tumor size had worse survival. Further trials are

needed to validate the effect of adjuvant therapy for
tumors of larger size in stage IB NSCLC, and nding the
cutoff is crucial.
The micropapillary-predominant subtype was
introduced to the new classication of lung adenocarcinoma because several studies demonstrated that
the micropapillary component was a poor prognostic
factor [2527]. The micropapillary component signicantly correlated with recurrence in univariable analysis but was not signicantly prognostic in
multivariable analysis. The average size of tumors
with the micropapillary component was larger than
that of tumors without the micropapillary component
(3.9 cm vs 3.1 cm, p 0.005), so the micropapillary

component might be regarded as a confounding variable of tumor size in the outcome of multivariable
analysis. Furthermore, the micropapillary component
was present in only 17 tumors, so sample size was
another explanation for the result.
Results of some studies have supported the prognostic
signicance of the new pathology classication, but these
studies enrolled cases of two or more stages. Our study is
the rst to focus on stage IB lung adenocarcinoma.
Furthermore, sample size of this study was larger than
the sample size of stage IB lung adenocarcinoma in most
of other studies.
In conclusion, our research suggests that the solid
component and tumor size correlate with prognosis of
stage IB pulmonary adenocarcinoma.

GENERAL THORACIC

Gender
Male
Female
Age
Smoking status
No
Yes
History of diabetes
No
Yes
Tumor size
Pleural invasion
No
Yes
Lymphovascular invasion
No
Yes
Necrosis
No
Yes
Lepidic component
No
Yes
Acinar component
No
Yes
Papillary component
No
Yes
Micropapillary component
No
Yes
Solid component
No
Yes

Multivariable Analysis

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Table 5. Univariable and Multivariable Survival Analysis for Progression-Free Survival

Univariable Analysis

GENERAL THORACIC

Variables
Gender
Male
Female
Age
Smoking status
No
Yes
History of diabetes
No
Yes
Tumor size
Pleural invasion
No
Yes
Lymphovascular invasion
No
Yes
Necrosis
No
Yes
Lepidic component
No
Yes
Acinar component
No
Yes
Papillary component
No
Yes
Micropapillary component
No
Yes
Solid component
No
Yes
CI condence interval;

Multivariable Analysis

HR

95% CI

p Value

1
0.558
1.007

0.3260.954
0.9791.036

0.033
0.618

1
1.325

0.6972.517

0.39

1
0.955
1.991

0.3802.396
1.5232.604

0.921
<0.001

1
1.01

0.5201.958

0.978

1
1.613

0.6434.057

0.309

1
1.433

0.5713.599

0.443

1
1.085

0.4912.401

0.84

1
1.204

0.6342.287

0.571

1
1.02

0.5791.796

0.946

1
2.371

1.1584.854

0.018

1
1.976

1.1363.437

0.016

HR

95% CI

p Value

2.036

1.5462.681

<0.001

1
2.045

1.1723.568

0.012

HR hazard ratio.

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PROGNOSTIC FACTORS FOR LUNG CANCER