[ Evidence-Based Medicine ]

Evaluation of Pulmonary Nodules

Clinical Practice Consensus Guidelines for Asia
Chunxue Bai, MD, PhD, FCCP; Chang-Min Choi, MD, PhD; Chung Ming Chu, MD, FCCP; Devanand Anantham, MBBS;
James Chung-man Ho, MD, FCCP; Ali Zamir Khan, MD, PhD; Jang-Ming Lee, MD, PhD; Shi Yue Li, MD, PhD;
Sawang Saenghirunvattana, MD, PhD; and Anthony Yim, MD, PhD

BACKGROUND: American College of Chest Physicians (CHEST) clinical practice guidelines

on the evaluation of pulmonary nodules may have low adoption among clinicians in
Asian countries. Unique patient characteristics of Asian patients affect the diagnostic
evaluation of pulmonary nodules. The objective of these clinical practice guidelines was to
adapt those of CHEST to provide consensus-based recommendations relevant to practi-
tioners in Asia.
METHODS: A modified ADAPTE process was used by a multidisciplinary group of pulmo-
nologists and thoracic surgeons in Asia. An initial panel meeting analyzed all CHEST
recommendations to achieve consensus on recommendations and identify areas that required
further investigation before consensus could be achieved. Revised recommendations were
circulated to panel members for iterative review and redrafting to develop the final guidelines.
RESULTS: Evaluation of pulmonary nodules in Asia broadly follows those of the CHEST
guidelines with important caveats. Practitioners should be aware of the risk of lung cancer
caused by high levels of indoor and outdoor air pollution, as well as the high incidence of
adenocarcinoma in female nonsmokers. Furthermore, the high prevalence of granulomatous
disease and other infectious causes of pulmonary nodules need to be considered. Therefore,
diagnostic risk calculators developed in non-Asian patients may not be applicable. Overall,
longer surveillance of nodules than those recommended by CHEST should be considered.
CONCLUSIONS: TB in Asia favors lesser reliance on PET scanning and greater use of
nonsurgical biopsy over surgical diagnosis or surveillance. Practitioners in Asia are
encouraged to use these adapted consensus guidelines to facilitate consistent evaluation of
pulmonary nodules. CHEST 2016; 150(4):877-893

KEY WORDS: Asia; diagnosis; lung neoplasms; peripheral pulmonary nodules; solitary pulmonary
nodules

FOR EDITORIAL COMMENT SEE PAGE 763

ABBREVIATIONS: CHEST = American College of Chest Physicians;
ENB = electromagnetic navigation bronchoscopy; TTNA = trans-
thoracic needle aspiration; TTNB = transthoracic needle biopsy
AFFILIATIONS: From Pulmonary Medicine Department (Dr Bai),
Zhongshan Hospital, Fudan University, Shanghai Respiratory Research
Institute, Shanghai, China; Department of Pulmonary and Critical Care
Medicine (Dr Choi), Asan Medical Center, College of Medicine, Uni-
versity of Ulsan, Seoul, South Korea; Respiratory Medicine (Dr Chu),
United Christian Hospital, Kwun Tong, Hong Kong SAR, China; Res-
piratory Medicine and Critical Care Medicine (Dr Anantham),
Singapore General Hospital, Singapore; Respiratory Medicine (Dr
Chung-man Ho), University of Hong Kong, Queen Mary Hospital,
Pokfulam, Hong Kong SAR, China; Minimally Invasive and Robotic
Thoracic Surgery (Dr Khan), Medanta The Medicity, Gurgaon, India;
Thoracic Surgery (Dr Lee), National Taiwan University Hospital, Taipei,
Taiwan; Respiratory Medicine (Dr Li), The First Affiliated Hospital of
Guangzhou Medical University, Guangzhou, China; Respiratory Medi-
cine (Dr Saenghirunvattana), Bangkok Hospital Medical Center,
Bangkok Hospital Group, Bangkok, Thailand; and the Minimally
Invasive Thoracic Surgery Centre (Dr Yim), Hong Kong SAR, China.

journal.publications.chestnet.org 877
Summary of Recommendations
1.1. In an individual with an indeterminate nodule
that is visible on chest radiography, review prior
imaging tests.
1.2. In an individual with an indeterminate nodule
that has been stable for at least 2 years, annual low-
dose CT screening beyond 2 years for high-risk
patients for early detection of lung cancer should be
individualized.
1.3. In an individual with an indeterminate nodule
identified by chest radiography, perform low-dose
chest CT (preferably with thin sections through the
nodule) to characterize the nodule and assess the
likelihood of malignancy.
2.1. Individuals with solid, indeterminate nodules
> 8 mm should be referred to a center for management
by a multidisciplinary team. Diagnostic capabilities
of the center should include CT/PET scans, tests for
benign diseases (eg, TB), and biopsy (surgical or
minimally invasive).
2.2. In an individual with a solid, indeterminate
nodule > 8 mm in diameter, estimate the probability
of malignancy using clinical judgement. If possible,
make a quantitative assessment using a validated
model with appropriate regional caveats.
2.3. In an individual with a solid, indeterminate
nodule > 8 mm in diameter, perform surveillance
with serial low-dose CT scans in the following
circumstances:

The clinical probability of malignancy is deemed
low (< 5%)

Biopsy is non-diagnostic and the lesion is not
hypermetabolic as assessed by PET
DISCLAIMER: American College of Chest Physician guidelines are
intended for general information only, are not medical advice, and do
not replace professional medical care and physician advice, which al-
ways should be sought for any medical condition. The complete
disclaimer for this guideline can be accessed at http://www.chestnet.
org/Guidelines-and-Resources/Guidelines-and-Consensus-Statements/
CHEST-Guidelines.
FUNDING/SUPPORT: Medical writing assistance was provided by Mark
Snape, MB BS, and Serina Stretton, PhD, CMPP, of ProScribe–Envi-
sion Pharma Group and was funded by Covidien. ProScribe’s services
complied with international guidelines for Good Publication Practice
(GPP3).
CORRESPONDENCE TO: Chunxue Bai, MD, PhD, FCCP, Pulmonary
Medicine Department, Zhongshan Hospital, Fudan University,
Shanghai Respiratory Research Institute, No. 180 Fenglin Rd,
Shanghai, 200032 China; e-mail: bai.chunxue@zs-hospital.sh.cn
Copyright Ó 2016 American College of Chest Physicians. Published by
Elsevier Inc. All rights reserved.
DOI: http://dx.doi.org/10.1016/j.chest.2016.02.650
878 Evidence-Based Medicine

A fully informed patient prefers this nonaggres-
sive management approach, despite the potential
risk of disease progression.
2.4. In an individual with a solid, indeterminate
nodule > 8 mm in diameter who undergoes
surveillance, serial CT scans using thin sections and
non-contrast, low-dose techniques should be
performed at 3 to 6 months, 9 to 12 months, 18 to 24
months, and, depending on clinical judgement and
patient preference, annually thereafter.
2.5. In an individual with a solid, indeterminate
nodule > 8 mm in diameter with moderate (5-60%)
probability of malignancy, consider functional
imaging, preferably with PET, to characterize the
nodule before surgical resection or continued
radiological surveillance. Consider caveats to PET
screening.
2.6. In an individual with a solid, indeterminate
nodule > 8 mm in diameter with high (> 60%)
probability of malignancy, functional imaging has a
greater role in preoperative staging than in
characterizing the nodule.
2.7. In an individual with a solid, indeterminate
nodule that measures > 8 mm in diameter, the expert
panel suggests nonsurgical biopsy in the following
circumstances:

The clinical (pretest) probability of malignancy is
moderate (5-60%)

When the clinical (pretest) probability and the
findings on imaging are discordant

A benign diagnosis such as TB requiring specific
medical treatment is suspected

A fully informed patient desires proof of a ma-
lignant diagnosis before surgery, especially when
the risk of surgical complications is high.
2.8. In an individual with a solid, indeterminate
nodule that measures > 8 mm in diameter, surgical
biopsy (and possibly resection) in a patient with
suitable surgical risk is suggested in the following
circumstances:

The clinical probability of malignancy is high
(> 60%)

There is clear evidence of growth on serial imag-
ing suggestive of malignancy

The nodule is intensely hypermetabolic as assessed
by PET

Nonsurgical biopsy is suspicious for malignancy

A fully informed patient prefers undergoing a
definitive diagnostic procedure.
[ 150#4 CHEST OCTOBER 2016 ]
2.9. In an individual with a solid, indeterminate
nodule > 8 mm in diameter who chooses surgical
biopsy, the expert panel recommends minimally
invasive surgery where appropriate.
2.10. In an individual with a solid, indeterminate
nodule > 8 mm in diameter, clinicians should elicit
preferences for management, and consider family
input where appropriate before offering
management options.
3.1. In an individual with a solid nodule £ 8 mm in
diameter and low risk for lung cancer, perform low-
dose CT surveillance according to the size of the
nodule:

Nodules measuring £ 4 mm in diameter: consider
ongoing annual CT depending on clinical judge-
ment and patient preference

Nodules measuring > 4 mm to £ 6 mm: re-evaluate
by low-dose CT annually if stable depending on
clinical judgement and patient preference

Nodules measuring > 6 mm to £ 8 mm: re-evaluate
by low-dose CT at 6 to 12 months, 18 to 24
months, and then annually if stable depending on
clinical judgement and patient preference.
3.2. In an individual with a solid nodule that
measures £ 8 mm in diameter who has moderate to
high risk for lung cancer, perform low-dose CT
surveillance according to the size of the nodule:

Nodules measuring £ 4 mm in diameter: re-evaluate
by low-dose CT at 12 months and then consider
annual CT surveillance depending on clinical
judgement and patient preference

Nodules measuring > 4 mm to £ 6 mm: re-evaluate
by low-dose CT between 6 and 12 months and
then again between 18 and 24 months if un-
changed, and then annually if stable depending on
clinical judgement and patient preference

Nodules measuring > 6 mm to £ 8 mm: re-evaluate
by low-dose CT at 3 months, 6 months, 12
months, and then annually if stable depending on
clinical judgement and patient preference.
4.1. In an individual with a nonsolid (pure ground
glass) nodule measuring £ 5 mm in diameter,
consider ongoing annual CT surveillance depending
on clinical judgement and patient preference.
4.2. In an individual with a nonsolid (pure ground
glass) nodule measuring > 5 mm in diameter, re-
evaluate by annual CT surveillance for at least 3
journal.publications.chestnet.org
years, and then consider ongoing annual CT
surveillance depending on clinical judgement and
patient preference.
5.1. In an individual with a partsolid nodule
measuring £ 8 mm in diameter, the expert panel
suggests low-dose CT surveillance at approximately
3, 12, and 24 months, with consideration given
to ongoing annual low-dose CT surveillance
depending on clinical judgement and patient
preference. Consideration should also be given
to empiric antimicrobial therapy if there are
symptoms or signs of bacterial infection at the
time of detection.
5.2. In an individual with a partsolid nodule
measuring > 8 mm in diameter, repeat CT at 3
months and consider empiric antimicrobial therapy
if deemed clinically appropriate at the time of
detection. Perform further evaluation with
nonsurgical biopsy and/or surgical resection for
nodules that persist beyond 3 months, with the
additional option of PET scanning for staging of
disease before surgical intervention.
6.1. In an individual with a dominant nodule and
one or more additional small nodules, the expert
panel suggests that each nodule be evaluated
individually, curative treatment not be denied, and
histopathological confirmation of metastasis be
considered where appropriate.
7.1. When considering nonsurgical biopsy, base the
choice of technique on factors related to the patient
and nodule as well as resources:

Consider use of TTNA or TTNB for nodules close
to the chest wall or deeper lesions especially if
fissures do not need to be traversed and there is no
surrounding emphysema

Consider use of bronchoscopy techniques for
nodules closer to a patient bronchus and with a
visible bronchus sign or for individuals at high
risk of pneumothorax

Consider use of advanced bronchoscopic tech-
niques, if available, over traditional bronchoscopy
especially for smaller nodules, and over TTNA or
TTNB if there is surrounding emphysema.
Pulmonary nodules are predominantly peripheral
solitary or multiple small (# 3 cm in diameter),
focal radiographic opacities that may signal an early
malignancy.1,2 Therefore, the task of clinicians is to
879
accurately characterize pulmonary nodules, especially Male Female
in relation to their likelihood of malignancy. Based China 70.4 36.3
on the estimation of the probability of malignancy,
clinicians can develop an appropriate management India 11.0 3.1
plan, which typically involves either surveillance or
Japan 38.8 12.9
definitive diagnosis and treatment. By definition,
peripheral pulmonary nodules are not visible Korea 58.5 33.4
endobronchially and are completely surrounded by
lung parenchyma without associated atelectasis, Singapore 35.7 15.5
effusion, or enlarged lymph nodes.
Taiwan 59.6 35.6
Clinical practice guidelines on the evaluation of
pulmonary nodules have been published by the Thailand 30.7 12.6
American College of Chest Physicians (CHEST).1
However, implementation of these clinical practice 75 50 0 50
guidelines is often very low among clinicians in Asian Age-Standardized Incidence of Lung Cancer
(per 100,000)
countries, even when awareness of those guidelines is
high.3,4 CHEST has recommended that clinical practice Figure 1 – Incidence of lung cancer reported in several Asian countries
and regions.
guidelines should be adapted to the local setting by
critical review of recommendations against the
background of local strengths and challenges.5
generally several times higher (China, 70; India, 171;
Local adaptation of guidelines is critical for helping
Thailand, 119 cases per 100,000 population per year),
to ensure that recommendations are relevant and
although rates are lower in a few high-income Asian
more likely to be implemented. This multidisciplinary
countries (eg, Japan).
group is committed to following up on the CHEST
recommendation to adapt the guidelines to Asia. The existence of local guidelines on the evaluation of
pulmonary nodules varies widely throughout different
In Asia, the incidence of lung cancer is high and rising
countries in Asia. Local guidelines currently exist in
in many countries, particularly in response to the
China, Korea, and Japan. However, no national
maturation of the smoking epidemic (Fig 1).6-9 There
clinical guidelines have been formulated in Singapore,
are many unique characteristics of Asian patients
India, or Thailand, where institutional standards are used
related to ethnicity, genetics, risk profile, prevalence
instead. An informal survey of clinicians in the Asian
of benign diseases that require treatment, prevalence
region has highlighted several points of difference between
of malignancy, access to diagnostic services, and
practices recommended by the current CHEST guidelines
cultural understanding of disease. TB is highly prevalent,
and those often carried out in clinical practice.
which often means that even the presence of apparently
benign lung nodules requires a definitive diagnosis The primary aim of these clinical practice guidelines was
because of both individual treatment and public to provide consensus-based expert recommendations
health implications. Incidence rates of TB in most adapted from the current CHEST guidelines that are
countries in western Europe, Canada, and the United broadly relevant to countries in Asia. Evidence that
States are < 10 cases per 100,000 population per year.10 forms the basis for such adaptation of the CHEST
In contrast, incidence rates in Asian countries are guidelines is presented.

Methods Participants and Evidence Collection

The development of these adapted clinical practice guidelines
was based on a modified ADAPTE process that “provides a
systematic approach to adapting guidelines produced in one
setting to use in a different cultural and organisational context.”11
The key steps of the adaptation phase consisted of: a search
for, and screening of, existing guidelines; assessment of these
guidelines; a decision and selection phase; and drafting of a
guideline report.
A panel of experts was assembled consisting of pulmonologists and
thoracic surgeons from various countries and regions in Asia. Panel
members were individually asked to collect data and evidence regarding
local practices. Current CHEST guidelines on the evaluation of
pulmonary nodules were reviewed before and during the panel meeting.1
Consensus Generation
An initial panel meeting was held on August 23, 2014, in Hong Kong
and facilitated by one of the panel members (C. B.). The panel critically

880 Evidence-Based Medicine [ 150#4 CHEST OCTOBER 2016 ]

analyzed all recommendations from the CHEST guidelines in two separate
groups. The panel as a whole then discussed each recommendation and
achieved broad consensus on most recommendations based on expert
clinical opinion. Several recommendations regarded as more contentious
and difficult to reach consensus on were identified for further investigation
of existing evidence. An initial draft of the revised guidelines was
developed based on the consensus and on region-specific evidence, and
the draft version was circulated to panel members for review. An iterative
process of review and redrafting of guidelines was undertaken to develop
the final recommendations.

Recommendations made to the original CHEST recommendations or

The main aims of the initial diagnostic approach
taken toward a pulmonary nodule are to establish a
definitive diagnosis where possible and to avoid invasive
procedures in patients with benign disease that does not
require treatment. Pulmonary nodules, whether benign
or malignant, can be broadly classified radiologically on
CT scans as solid or subsolid nodules. In solid nodules,
the likelihood of malignancy is influenced by the age of
the patient, smoking history, size of the nodule, presence
of spiculated edges, hemoptysis, absence of calcification,
history of malignancy, history of TB and other benign
lung disease, and uptake on PET scans (Table 1).12
Subsolid nodules are further classified as either
nonsolid (pure ground-glass appearance) or part-solid
(containing a solid component but > 50% ground-glass
appearance). Subsolid nodules can be associated with
either inflammatory causes or various forms of
peripheral adenocarcinoma, including premalignant
atypical adenomatous hyperplasia, carcinoma in situ,
and mixed subtype adenocarcinoma.13 Subsolid nodules,
especially pure ground-glass opacities, often have an
indolent course and although malignancy has been
linked to size, there is less association with smoking
history, especially for pure ground-glass nodules.14
The following specific recommendations are intended
to be broadly relevant to populations in Asia and
represent adapted CHEST recommendations. Additional
remarks either relate to the justification for changes
provide additional guidance.
Individuals With an Indeterminate Nodule (Fig 2)
All newly identified pulmonary nodules are
indeterminate until a definitive diagnosis is made.
Benign etiology is suggested by radiologic features such
as diffuse, central, laminated, and popcorn patterns of
calcification.1 Systematic radiography screening has
been common in many Asian countries (eg, for TB and
malignancy) and has led to a large number of incidental
pulmonary nodules being detected.15
1.1. In an individual with an indeterminate nodule
that is visible on chest radiography, review prior
imaging tests.
This recommendation from CHEST is applicable in
Asian countries, although the expert panel noted that
the transition to digital radiography has made prior
radiograph films difficult to assess or compare with
digital images. Radiology images are compared to assess
stability of nodule size.
1.2. In an individual with an indeterminate nodule
that has been stable for at least 2 years, annual
low-dose CT screening beyond 2 years for high-risk
patients for early detection of lung cancer should be
individualized.

TABLE 1 ] Radiographic Characteristics of Pulmonary Nodules on CT Scans Suggestive of Malignancy

Parameter Characteristics Associated With Malignant Nodules
Growth rate Doubling time 20-400 d (< 100 d for most solid nodules); growth rate may be slower with ground-glass
and subsolid nodules (> 200 d); very rapid doubling suggests an infectious or inflammatory cause
Location Upper lobe is a more common site for malignant nodules, although the diagnostic significance of this
finding is reduced in Asia due to the high prevalence of TB
Margins Lobulated or speculated margins are strongly associated with malignancy; notches are commonly seen
in adenocarcinomas with overt invasion
Cavitation Malignant lesions are associated with irregular, thicker walls > 15 mm thick
Size Probability of malignancy increases with size (nodules > 2 cm are more likely to be malignant, although
smaller size does not exclude malignancy)
Calcification Punctate and eccentric (evidence of necrosis within nodule) calcification may occur with malignancy
Other features Vascular convergence, dilated bronchus leading into the nodule

journal.publications.chestnet.org 881
 Indeterminate nodule on
chest radiography
Review prior imaging
tests (1.1)
Yes
Nodule is stable?
No
Perform high-resolution
chest CT scan (1.3)
Solid or subsolid
malignant
features?
Subsolid
See Figure 5
Figure 2 – Algorithm for initial characterization of a solitary pulmonary nodule. Note: This algorithm was developed primarily from CHEST guidelines,
and the original authors reserve all the copyright. Numbers in parentheses refer to recommendations in text.
There is little evidence to support a longer duration of
surveillance for patients with solid nodules once 2 years
of stability have been documented. However, patients at
high risk for lung cancer should be offered annual
screening with low-dose CT surveillance according to
national guidelines and local standards of care.
1.3. In an individual with an indeterminate nodule
identified by chest radiography, perform low-dose
chest CT (preferably with thin sections through the
nodule) to characterize the nodule and assess the
likelihood of malignancy (Table 1).
Compared with chest radiography, CT scans provide
additional information about the location, shape,
margins, and attenuation characteristics of pulmonary
nodules.1 The expert panel emphasized that obtaining
thin (# 1 mm) sections through the nodule increased
the ability to radiologically characterize the nodule.
Analysis of tumor volume may be of assistance for
detecting tumor growth.
Individual With a Solid, Indeterminate Nodule
> 8 mm in Diameter (Fig 3)
2.1. Individuals with solid, indeterminate nodules
> 8 mm should be referred to a center for management
882 Evidence-Based Medicine
Discuss annual low-dose CT
surveillance with patient
based on clinical judgment
and patient preference (1.2)
Nodule > 8 mm
Figure 3
in diameter
solid
Nodule ≤ 8 mm
Figure 4
in diameter
by a multidisciplinary team. Diagnostic capabilities
of the center should include CT/PET scans, tests for
benign diseases (eg, TB), and biopsy (surgical or
minimally invasive).
The expert panel developed this new recommendation
to accommodate the large variation in practice
conditions and resources available in many Asian
countries. In addition, the expert panel recommends the
involvement of a multidisciplinary team consisting of
physicians, surgeons, radiologists, and pathologists to
develop an individualized patient plan.
2.2. In an individual with a solid, indeterminate
nodule > 8 mm in diameter, estimate the probability
of malignancy using clinical judgement. If possible,
make a quantitative assessment using a validated
model with appropriate regional caveats.
In Asian countries, initial (“pretest”) estimates of the
likelihood of malignancy are often made by using clinical
judgment. Clinicians who wish to estimate the probability
of malignancy by using quantitative models should be
aware that these models may not have been validated in
Asian populations. Indeed, the CHEST guidelines
recommend that the choice of a quantitative model may
[ 150#4 CHEST OCTOBER 2016 ]
 Solid nodule > 8 mm in diameter

Refer to center with appropriate

diagnostic equipment and expertise (2.1)

Determine clinical (pretest)

probability of malignancy (2.2)

Low (< 5%) Moderate (5-60%) High (> 60%)

Negative or mild PET scan

Serial CT surveillance
hypermetabolic?
No (2.3, 2.4)
(2.5)

Intense
Yes
Surgical biopsy Nonsurgical biopsy
Clear growth?
(2.8) Suspicious (2.7)
Positive
Positive
Surgical resection

Figure 3 – Algorithm for evaluation of a solid solitary pulmonary nodule > 8 mm in diameter in patients with an acceptable surgical risk profile.
Numbers in parentheses refer to recommendations in text.

be guided by the target population, ease of use, and the
extent of validation.1 The expert panel recommends that
regardless of whether clinical judgment or a calculation
model is used, clinicians must decide if the clinical
probability suggests further imaging studies, biopsy, and/
or resection are needed.
(ie, low probability of malignancy), an accurate diagnosis
may sometimes be necessary rather than surveillance.
Examples of relevant scenarios include: (1) TB or other
infections requiring specific treatment, and (2) patients
who use high-dose immunosuppression (eg, transplant)
may need a more aggressive approach.

2.3. In an individual with a solid, indeterminate
nodule > 8 mm in diameter, perform surveillance
with serial low-dose CT scans in the following
circumstances:

The clinical probability of malignancy is deemed
low (< 5%)

Biopsy is non-diagnostic and the lesion is not
hypermetabolic as assessed by PET

A fully informed patient prefers this nonaggres-
sive management approach, despite the potential
risk of disease progression.
The threshold for what is considered “low probability”
may depend on the geographical and cultural context
of individuals. Generally, the probability of malignancy of
pulmonary nodules is higher in Asian populations than in
Western populations. For seemingly benign nodules
2.4. In an individual with a solid, indeterminate
nodule > 8 mm in diameter who undergoes
surveillance, serial CT scans using thin sections and
non-contrast, low-dose techniques should be
performed at 3 to 6 months, 9 to 12 months, 18 to
24 months, and, depending on clinical judgement and
patient preference, annually thereafter.
In Asia, the high prevalence of risk factors for lung cancer
and anecdotal reports of the emergence of malignancy in
otherwise stable nodules after many years suggest that
consideration should be given to extended (3 years and
beyond) annual surveillance based on clinical judgment
and patient preference.4,16,17 However, the expert panel
acknowledged the lack of evidence for this approach
and the potential risk of ongoing ionizing radiation.
Surveillance may cease in nodules that show progressive
shrinkage or disappearance.

journal.publications.chestnet.org 883
2.5. In an individual with a solid, indeterminate
nodule > 8 mm in diameter with moderate (5-60%)
probability of malignancy, consider functional
imaging, preferably with PET, to characterize the
nodule before surgical resection or continued
radiological surveillance. Consider caveats to PET
screening.
In some Asian countries, availability and cost of PET
scanning may be an issue. Cost-effective use of PET
surveillance is for nodules that have indeterminate CT
scan features when the clinical probability of malignancy
is relatively low (ie, discordance between the clinical and
radiologic features).1 False-positive and false-negative
results may also be an issue with PET scanning because
of infections (eg, TB, fungal and parasitic disease) and
slow-growing tumors (eg, adenocarcinoma in situ),
respectively. For these reasons, PET scans may not
always be a highly discriminative tool in Asian countries,
and biopsy for other possible causes may also be
required.
2.6. In an individual with a solid, indeterminate
nodule > 8 mm in diameter with high (> 60%)
probability of malignancy, functional imaging has a
greater role in preoperative staging than in
characterizing the nodule.
When there is a high probability of malignancy, PET
scans are useful for disease staging to rule out previously
undetected metastases before surgical intervention.1
2.7. In an individual with a solid, indeterminate
nodule that measures > 8 mm in diameter, the expert
panel suggests nonsurgical biopsy in the following
circumstances:

The clinical (pretest) probability of malignancy is
moderate (5-60%)

When the clinical (pretest) probability and the
findings on imaging are discordant

A benign diagnosis such as TB requiring specific
medical treatment is suspected

A fully informed patient desires proof of a
malignant diagnosis before surgery, especially
when the risk of surgical complications is high.
In Asia, there is variation in practices related to surgical
versus nonsurgical biopsy depending on the availability of
local expertise. Techniques for minimally invasive biopsy
include CT scan-guided transthoracic needle biopsy
(TTNB), transbronchial lung biopsy under fluoroscopic
guidance, radial probe endobronchial ultrasound (with or
884 Evidence-Based Medicine
without guide sheath), electromagnetic navigation
bronchoscopy (ENB), and virtual bronchoscopy
navigation.1 The type of biopsy performed should be
selected based on radiologic characteristics (size, location,
and relation to airways), potential risk of complications,
and expertise of practitioners. For nodules difficult to
access with bronchoscopy or TTNB, consider surgical
diagnosis for nodules with moderate probability of
malignancy if the rates of positive diagnosis with
nonsurgical biopsy are low in routine clinical practice. In
areas where TB is endemic, use of nonsurgical biopsy may
be useful for minimizing unnecessary thoracotomy.18,19
However, the expert panel noted that an infectious or
inflammatory etiology as the only pathology may be
incorrect during the initial diagnosis.20-22 Accordingly,
implement careful surveillance during therapy and, if the
patient fails to respond to treatment, the possibility of a
second diagnosis should be considered.
2.8. In an individual with a solid, indeterminate
nodule that measures > 8 mm in diameter, surgical
biopsy (and possibly resection) in a patient with
suitable surgical risk is suggested in the following
circumstances:

The clinical probability of malignancy is high
(> 60%)

There is clear evidence of growth on serial imag-
ing suggestive of malignancy

The nodule is intensely hypermetabolic as assessed
by PET

Nonsurgical biopsy is suspicious for malignancy

A fully informed patient prefers undergoing a
definitive diagnostic procedure.
Surgical biopsy is different from surgical resection
that aims to curatively remove all the malignancy
(eg, anatomical lobar resection). Generally, surgical
resection and surgical biopsy are simultaneous,
providing the gold standard for evaluation and
treatment of a lung nodule.1 A frozen section biopsy
can be performed intraoperatively and, if confirmed
malignant, curative lung resection will then be
performed. In Asia, the high incidence of benign causes
of pulmonary nodules such as TB reduces the
confidence with which malignant growth can be
predicted on serial imaging alone.23 However, surgical
resection is still considered the gold standard for the
diagnosis of pulmonary nodules where malignancy is
suspected.1 Clinicians should be mindful of patient
preferences and assess both fitness and suitability prior
to recommending surgery. Minimally invasive surgery
[ 150#4 CHEST OCTOBER 2016 ]
such as video-assisted thoracoscopic surgery is
recommended to reduce morbidity.
2.9. In an individual with a solid, indeterminate
nodule > 8 mm in diameter who chooses surgical
biopsy, the expert panel recommends minimally
invasive surgery where appropriate.
2.10. In an individual with a solid, indeterminate
nodule > 8 mm in diameter, clinicians should elicit
preferences for management, and consider family
input where appropriate before offering
management options.
In many Asian countries, the roles of patients, family
members, and clinicians in decision-making may differ
from those in Western countries. Clinicians should
consider the cultural norms regarding decision-making
in their country or region. However, patient preference
on the decision-making process should be elicited. In
addition, the expert panel noted that, in many Asian
countries, there is commonly an expectation that
clinicians will present more than one alternative in rank
order from most to least preferred to guide patient
decision-making. Multidisciplinary team input can assist
in developing the recommended management options.
Individual With a Solid Nodule # 8 mm in Diameter
(Fig 4)
3.1. In an individual with a solid nodule £ 8 mm
in diameter and low risk for lung cancer, perform
Solid nodule ≤ 8 mm in diameter
Determine clinical (pretest)
probability of malignancy
Low (< 5%) (3.1)
Characterize nodule size
≤ 4 mm > 4 to ≤ 6 mm > 6 to ≤ 8 mm
Patient CT scan at CT scan at 6-12
discussion 12 mo and 18-24 mo
Annual CT surveillance after discussion with patient based on clinical judgment/patient preference
Figure 4 – Algorithm for evaluation of a solid solitary pulmonary nodule # 8 mm in diameter. Numbers in parentheses refer to recommendations in text.
journal.publications.chestnet.org
low-dose CT surveillance according to the size of the
nodule:

Nodules measuring £ 4 mm in diameter: consider
ongoing annual CT depending on clinical judge-
ment and patient preference

Nodules measuring > 4 mm to £ 6 mm: re-evaluate
by low-dose CT annually if stable depending on
clinical judgement and patient preference

Nodules measuring > 6 mm to £ 8 mm: re-
evaluate by low-dose CT at 6 to 12 months, 18 to
24 months, and then annually if stable depending
on clinical judgement and patient preference.
No data are available to properly support modifications to
the CHEST recommendations. However, solid nodules
# 8 mm in diameter have a low, but not negligible,
probability of malignancy.24 In addition, environmental
risk factors may make the dichotomy between high and
low risk not applicable in many parts of Asia.25,26 As a
result, the expert panel suggested more frequent and
longer term CT surveillance (3 years and beyond
depending on clinical judgment and patient preference)
for small nodules than recommended by the CHEST
with an algorithm that is similar to the “high-risk”
group. This approach is aimed at detecting changes
such as an increase in size or to confirm that the nodule
is stable. One recent study from Thailand also observed
a very high prevalence of TB in nodules # 8 mm but
especially in smaller nodules (4.5-11 mm).27 This
Moderate to high (> 5%) (3.2)
Characterize nodule size
≤ 4 mm > 4 to ≤ 6 mm > 6 to ≤ 8 mm
CT scan at 6-12 CT scan at 3, 6,
12 months
and 18-24 mo and 12 mo
885
finding highlights the need for careful consideration
of nonmalignant causes in the Asian region. Follow-up
CT scans should be conducted at the lowest effective
dose possible. Clinicians are reminded of the major
limitation of PET scans in characterizing nodules
# 8 mm in diameter due to the low mass of
metabolically active cells.2
3.2. In an individual with a solid nodule that
measures £ 8 mm in diameter who has moderate to
high risk for lung cancer, perform low-dose CT
surveillance according to the size of the nodule:

Nodules measuring £ 4 mm in diameter: re-
evaluate by low-dose CT at 12 months and then
consider annual CT surveillance depending on
clinical judgement and patient preference

Nodules measuring > 4 mm to £ 6 mm: re-
evaluate by low-dose CT between 6 and 12 months
and then again between 18 and 24 months if
unchanged, and then annually if stable depending
on clinical judgement and patient preference

Nodules measuring > 6 mm to £ 8 mm: re-
evaluate by low-dose CT at 3 months, 6 months,
12 months, and then annually if stable depending
on clinical judgement and patient preference.
Compared with the CHEST guidelines, the expert
panel suggested long-term CT surveillance (3 years
and beyond) of small nodules in Asian individuals
with a higher risk profile. Although the expert panel
acknowledged that there are no data to explicitly support
this approach, the recommendation is based on the
natural history of slowly growing early-stage
adenocarcinoma.
Individual With a Nonsolid (Pure Ground-Glass)
Nodule (Fig 5)
Nonsolid (pure ground-glass) nodules represent
areas of increased lung attenuation that allow normal
parenchymal tissue such as blood vessels to be
visible. Atypical adenomatous hyperplasia is a
premalignant condition with ground-glass features
that may lie dormant for many years before
becoming malignant.13
4.1. In an individual with a nonsolid (pure ground
glass) nodule measuring £ 5 mm in diameter,
consider ongoing annual CT surveillance depending
on clinical judgement and patient preference.
The expert panel noted that ground-glass nodules still
have an appreciable potential for premalignant and
886 Evidence-Based Medicine
malignant changes, which justifies an active surveillance
approach. Furthermore, ground-glass nodules that are
benign will generally disappear over time, again
justifying the surveillance approach.
4.2. In an individual with a nonsolid (pure ground
glass) nodule measuring > 5 mm in diameter, re-
evaluate by annual CT surveillance for at least 3
years, and then consider ongoing annual CT
surveillance depending on clinical judgement and
patient preference.
The expert panel broadly agreed with the suggested
approach for nonsolid nodules in Asian countries but
acknowledged that there is not strong enough evidence
at present for long-term surveillance. However, based on
the indolent nature of early-stage adenocarcinoma,
consideration should be given to long-term surveillance
(ie, beyond 3 years).
Individual With a Part-Solid Nodule (Fig 5)
Part-solid nodules have a solid component but also have
a > 50% ground-glass appearance.1,2 When more solid
components are visible on a CT scan, there is a greater
propensity for invasive features.2
5.1. In an individual with a part-solid nodule
measuring £ 8 mm in diameter, the expert panel
suggests low-dose CT surveillance at approximately
3, 12, and 24 months, with consideration given to
ongoing annual low-dose CT surveillance depending
on clinical judgement and patient preference.
Consideration should also be given to empiric
antimicrobial therapy if there are symptoms or signs
of bacterial infection at the time of detection.
Although empirical antimicrobial therapy is potentially
harmful, the expert panel noted that use of empiric
antimicrobial therapy can be considered if the patient is at
low clinical risk for an alternative diagnosis such as TB.28
5.2. In an individual with a part-solid nodule
measuring > 8 mm in diameter, repeat CT at
3 months and consider empiric antimicrobial
therapy if deemed clinically appropriate at the time
of detection. Perform further evaluation with
nonsurgical biopsy and/or surgical resection for
nodules that persist beyond 3 months, with the
additional option of PET scanning for staging of
disease before surgical intervention.
[ 150#4 CHEST OCTOBER 2016 ]
 Subsolid nodule

Determine if nonsolid (pure

ground glass) or part-solid (> 50%
ground glass) and diameter

Nonsolid Part-solid

≤ 5 mm (4.1) > 5 mm (4.2) ≤ 8 mm (5.1) > 8 mm (5.2)

Discuss role of Annual CT CT surveillance at 3, Repeat CT scan at 3 mo

continued surveillance surveillance for at 12, and 24 mo and consider
with patient least 3 y and then annually antimicrobial therapy

Consider ongoing annual CT surveillance after discussion with patient Nonsurgical ± surgical
biopsy (consider PET
scanning for staging
before biopsy)

Figure 5 – Algorithm for evaluation of a subsolid solitary pulmonary nodule. Numbers in parentheses refer to recommendations in text.

The expert panel noted that, in the appropriate clinical
context, allowing an additional 3 months for a repeat CT
evaluation for a larger nodule (> 8 mm) with part-solid
characteristics may unnecessarily delay definitive
diagnosis.29 In such cases, immediate intervention is
suggested. The choice of nonsurgical biopsy or surgical
resection should be made based on the availability of
relevant expertise at each center, fitness for surgery, and
patient preferences. If available, PET scanning is an
option for the staging of disease.
Individual With One or More Nodules
Individuals may have one or more additional nodules
detected on CT scanning. Additional nodules should be
considered individually in terms of their likelihood of
malignancy. Preoperative PET scanning may help
guide further evaluation, although nodules # 8 mm
in diameter are difficult to characterize by using PET
scans. Newer technologies, such as ENB, may enable
biopsy and histopathologic assessment of multiple
smaller peripheral lesions during the same procedure.
6.1. In an individual with a dominant nodule and
one or more additional small nodules, the expert
panel suggests that each nodule be evaluated
individually, curative treatment not be denied, and
histopathological confirmation of metastasis be
considered where appropriate.
Interventional Pulmonology and Future Directions
Procedures to definitively diagnose and manage
pulmonary nodules have expanded with the
emergence and refinement of various technologies.
Available procedures can be broadly classified
as radiologic, cytologic, traditional, or advanced
bronchoscopic techniques, and surgical or
nonsurgical (eg, bronchoscopy-guided) biopsy
procedures. Each procedure type is associated with
different benefits, risks, and diagnostic yields
(Table 2). Increasingly, procedures are being
combined to improve diagnostic accuracy compared
with single techniques and potentially to mitigate
against risks.
Decisions regarding the choice of technique(s) that
maximize diagnostic yield and minimize complications
should consider factors related to the patient and
pulmonary nodule (eg, location, size), expense, and
the availability of local expertise.
Radiologic surveillance via serial CT scanning is
appropriate in several situations (see Recommendations
1.2, 2.3, 2.4, 3.1, 3.2, 4.1, 4.2, and 5.1).
Cytologic procedures include sputum cytology and
cytologic samples gained via nonsurgical biopsy such
as transthoracic needle aspiration (TTNA) cytology.
Sputum cytology is completely noninvasive but has

journal.publications.chestnet.org 887
888 Evidence-Based Medicine

TABLE 2 ] Overview of Currently Available Diagnostic Techniques for Pulmonary Nodules

Procedure Description
Radiologic
Serial CT scans Surveillance by repeat CT scan to
(“radiologic detect malignant growth
surveillance”)
Cytologic
Sputum cytology Examines sputum to determine
presence of abnormal cells or
tumor markers
CT-guided TTNA Thin-walled, flexible aspiration
needle is passed under CT
guidance to obtain adequate
sample for cytologic assessment
(via percutaneous/transthoracic
route)
Nonsurgical biopsy
Transthoracic needle Cutting or automated core-biopsy
biopsy needle is passed under CT/
fluoroscopic guidance to obtain
tissue for histologic examination
[
Benefits

Noninvasive

Allows detection of nonma-
lignant causes and other
pathology

Noninvasive

Low cost

Relatively low cost

High diagnostic yield in
appropriately selected cases

High diagnostic yield

Provides tissue for molecular
testing
Risks/Disadvantages

Variable diagnostic yield

Radiologic exposure

Delay in diagnosis and
treatment

Limited diagnostic yield,
especially for peripheral
lesions

Relatively high rate of phys-
ical complications, especially
pneumothorax

Nondiagnostic result does not
exclude malignancy

Nondefinitive management if
malignancy present

High rate of physical compli-
cations, especially pneumo-
thorax and hemorrhage

Nondiagnostic result does not
exclude malignancy

Nondefinitive management if
Diagnostic Yield (Sensitivity)

Highly variable (between and
within observers for
measuring size differences)1

Sensitivity 49% overall for
peripheral lesions30

Higher yield with specific
tumor markers (CEA, CA125,
and CA15-3)31

High (sensitivity
> 80% overall)30

Higher with larger nodules
(> 3 cm) and with immediate
cytologic assessment30

Sensitivity > 90%30

Lower diagnostic yield with
smaller nodules (< 1.5 cm)30

malignancy present
150#4 CHEST OCTOBER 2016

Nonsurgical biopsy using

conventional
bronchoscopy
With fluoroscopic Flexible bronchoscope
Relatively low complication
Limited diagnostic yield with
Sensitivity 34% for nodules
guidance þ TBB rate peripheral nodules # 2 cm (63% for nodules

Can establish benign
Physical complications > 2 cm)32
diagnosis
Nondefinitive management if
cancer diagnosed

(Continued)
]
journal.publications.chestnet.org
TABLE 2 ] (Continued)
Procedure Description
Nonsurgical biopsy using
advanced
bronchoscopic
technologies
EBUS Generates 360-degree ultrasound
image of lung parenchyma in a
disposable guide sheath that can
also allow biopsy or placement of
surgical markers
ENB Employs magnetic field and sensor
to determine location with a CT-
generated 3-D image; various
tools (TBB, cytology needle
brush, TBNA, forceps biopsy) are
available to biopsy one or
multiple lesions within the same
procedure
VNB Creates computer-simulated
roadmap to region of interest
from CT scans
Surgical biopsy
Surgical resection Wedge resection under VAT is
strongly preferred; other
techniques include thoracotomy
and mediastinoscopy
3-D ¼ three-dimensional; CA125 ¼ cancer antigen 125; CA15-3 ¼ carbohydrate antigen 15-3; CEA ¼ carcinoembryonic antigen; EBUS ¼ endobronchial ultrasound; ENB ¼ electromagnetic navigational bronchoscopy;
PPL ¼ peripheral pulmonary lesion; ROSE ¼ rapid on-site cytopathologic evaluation; TBB ¼ transbronchial biopsy; TBNA ¼ transbronchial needle aspiration; TTNA ¼ transthoracic needle aspiration; VAT ¼ video-
assisted thoracoscopy; VNB ¼ virtual navigational bronchoscopy.
889
Benefits

Improved targeting of nod-
ules compared with tradi-
tional bronchoscopy

Navigation methods may be
combined with biopsy tech-
niques (eg, TBB, TBNA,
lavage) or with each other to
increase diagnostic yield

Low complication rate

High diagnostic yield

Provides definitive manage-
ment of nodule
Risks/Disadvantages

Relatively high cost of acqui-
sition or disposable items (eg,
sheaths)

Nondiagnostic result does not
exclude malignancy

Nondefinitive management if
malignancy present

Physical complications

Short-term deterioration of
lung function

Possibility of unnecessary
surgery in benign disease that
does not require treatment
Diagnostic Yield (Sensitivity)

EBUS: Overall sensitivity
58.3%-80% (with TBB)

Sensitivity 54.5% for
nodules < 2 cm with TBB
(66% for nodules > 2 cm
with TBB)

ENB: Pooled/weighted
diagnostic yield
65%-67% (multiple studies
involving various sampling
methods)

Diagnostic yield 75.6% for
nodules # 2 cm and
89.6% for nodules > 2 cm
(with CT-PET and ROSE)

VNB: Weighted diagnostic
yield 72% excluding PPL
(biopsy via TBB in most
included studies)

High (approaches 100%)

Localization of small, deep
nodules may be problematic

Yield may be improved by
radio guidance, hook and
wire, methylene blue,
percutaneous microcoils,
ultrasound, and fluoroscopy
limited diagnostic yield for peripheral lesions (overall
sensitivity, 49%).30,31
Other recommendations in these guidelines provide
broad guidance on the use of nonsurgical (see
Recommendations 2.7 and 5.2) (Fig 3) versus surgical
biopsy (see Recommendations 2.8 and 5.2) (Fig 3).
Nonsurgical biopsy options include conventional
techniques such as TTNB and traditional bronchoscopy
combined with transbronchial biopsy (under
fluoroscopic guidance) or one of the newer advanced
bronchoscopic techniques.
7.1. When considering nonsurgical biopsy, base the
choice of technique on factors related to the patient
and nodule as well as resources:

Consider use of TTNA or TTNB for nodules close
to the chest wall or deeper lesions especially if
fissures do not need to be traversed and there is no
surrounding emphysema

Consider use of bronchoscopy techniques for
nodules closer to a patient bronchus and with a
visible bronchus sign or for individuals at high
risk of pneumothorax

Consider use of advanced bronchoscopic tech-
niques, if available, over traditional bronchoscopy
especially for smaller nodules, and over TTNA or
TTNB if there is surrounding emphysema.
TTNB provides high diagnostic yield with sensitivity
$ 90% for peripheral nodules except for nodules
< 1.5 cm.1,28,32 Sensitivity is affected by nodule size,
needle size, the number of needle passes, and the
presence of on-site cytopathologic examination.1
However, complications with TTNB, particularly
pneumothorax, may not be tolerated in patients with
underlying pulmonary disease. The incidence of
pneumothorax with TTNB reported over the last
decade has been reported to be between 9% and 54%,33
whereas one large cross-sectional analysis of 15,865
adults reported a 15% risk of any pneumothorax.34
When surgical biopsy is considered appropriate,
thoracoscopic wedge resection is generally preferable.1
However, nodules that are small (< 1 cm), deep, or
subsolid in attenuation may be difficult to locate by
digital palpation. Diagnostic yield may be improved
by various techniques, including use of radio guidance,
methylene blue, and ultrasound (Table 2). In addition
to allowing biopsy of lesions, ENB may be used during
the same procedure to localize lesions with dye marking
890 Evidence-Based Medicine
to facilitate their immediate surgical removal.35,36 For
the treatment of resectable non-small cell lung cancer,
lobectomy and systematic sampling of mediastinal
lymph nodes should be conducted.1 For small peripheral
lesions (< 2 cm), sublobar resection including
segmentectomy or wedge resection with mediastinal
lymph node sampling or dissection may be another
treatment option. However, this option awaits
validation from the results of a previous randomized
clinical trial.37
Apart from use of procedures, early detection of
pulmonary nodules and timely intervention may be
facilitated by telemedicine interventions, which include
video, telephone, and Internet links among health-care
professionals.38 Teleradiology, as a specific application
of telemedicine technologies, has the potential to
improve access to health-care services and expertise
in remote areas, although data protection to preserve
patient confidentiality must not be compromised.
Hospitals with Internet-based medical technology
capabilities should consider applying teleradiology to
assist in early diagnosis of lung nodules if necessary.
Teleradiology has its own networking, information
mining, and monitoring capabilities. These capabilities
can be applied not only for lung nodule management
and facilitating information collection and storage but
can also help facilitate remote expert multidisciplinary
consultation and follow-up tracking.39
In this text, we developed clinical practice consensus
guidelines for Asia in evaluating pulmonary nodules
based on CHEST guidelines and the specific conditions
in Asia. The suggested adoption of a standardized size
threshold is reasonable but not based on current
evidence.
Discussion
These clinical practice guidelines were developed in
response to the need for local guidance on the evaluation
of pulmonary nodules, especially given the increasing
incidence and unique characteristics of lung cancer in
many Asian countries. Recommendations based on
the CHEST guidelines on the evaluation of pulmonary
nodules were adapted by a panel of experts in
pulmonary medicine and thoracic surgery from different
Asian countries. Some of the considerations (eg, higher
prevalence of granulomatous disease) apply equally
well to some settings outside of Asia. However, the
present consensus emphasizes that the high prevalence
of TB in Asia favors lesser reliance on PET scanning
[ 150#4 CHEST OCTOBER 2016 ]
and greater use of nonsurgical biopsy over surgical
diagnosis (at high probabilities) or surveillance (at low
probabilities).
The incidence of lung cancer in many Asian countries
has risen in response to multiple risk factors, including
cigarette smoking, air pollution, and use of coal and
biomass fuels.40-43 The smoking epidemic in many
Asian countries, in contrast to the situation in many
Western countries, has only just peaked or is still rising
and continues to represent a key risk factor for lung
cancer.44,45 In China, smoking rates among men were
estimated at 52.9% in 2010.46 In Korea, smoking has
been shown to increase the risk of lung cancer by a
factor of 4.2.47 Accordingly, Korea has developed
guidelines for the screening of lung cancer among
heavy smokers, aged 50 to 74 years, which includes
guidance on the evaluation of nodules detected during
screening.15 Several populations in Asia, especially
Chinese and Korean men, have higher lung cancer
incidence rates than those noted in Asian subjects
residing in Western countries such as the United
States.44 This finding may reflect both higher smoking
rates and the presence of other risk factors.
Air pollution is considered the largest environmental
cause of death worldwide, with mutagenic effects on
DNA leading to an increased risk of several cancers,
including lung cancer.41,48 Air pollution is common
and severe in many Asian countries, particularly in
large cities in China and India.4,25 Occupational
exposure to asbestos or other carcinogens can increase
the risk for lung cancer.4 In addition to outdoor air
pollution, widespread use of household coal and
biomass fuels for heating and cooking leads to
indoor air pollution, which has been associated with
respiratory tract infections, chronic respiratory diseases,
or lung cancer,48-50 especially among those with a
history of chronic lung disease such as TB and
COPD.42
In many Asian countries, women who have never
smoked also seem to have an increased risk of
developing lung cancer compared with women living
in Western countries.51 Adenocarcinoma is the most
common form of lung cancer in Asia, particularly in
women, and this finding may reflect both genetic
differences and other risk factors.52 In support of a
genetic role, a recent genome-wide association analysis
in never-smoking Asian women from mainland China,
South Korea, Japan, Singapore, Taiwan, and Hong Kong
journal.publications.chestnet.org
identified three new susceptibility loci and confirmed
associations for other loci.53 Women also seem to be
more susceptible to developing lung cancer than men,
which may relate to functional genetic differences
between the sexes.4 Risk factors that have been
noted among women in Asia include the widespread
use of coal and biomass fuels, passive smoking, cooking
smoke, and second-hand smoke.26,48,54-56
In broad terms, the diagnosis and management of
pulmonary nodules in most Asian countries are not
substantially different from those performed in Western
countries. However, evaluation of pulmonary nodules is
likely to be affected by differences between Asian and
Western countries, between different countries in Asia,
and between different regions within countries. These
differences primarily relate to the greater prevalence in
Asia of: (1) lung cancer risk factors as discussed earlier,
(2) granulomatous and infectious disease that can
confound the diagnosis, and (3) genetic predisposition
to lung cancer. Moreover, access to diagnostic
equipment, religious and cultural beliefs, and the role
of family in decision-making may also influence the
evaluation of pulmonary nodules. The expert panel
acknowledges that guidelines on the evaluation of
pulmonary nodules already exist in several Asian
countries. The adapted recommendations reported
here are not designed to replace these local guidelines
but are meant to supplement them with an overview
applicable to Asia. One of the key differences between
the CHEST recommendations and those suggested here
is the consideration to increase the duration of CT
surveillance to 3 years and beyond. The panel
acknowledged there is insufficient published evidence
supporting this practice and that it is based on the
greater levels of overall risk in many countries in Asia.
The panel experts also acknowledged that the risks of
repetitive exposure to ionizing radiation may not be
trivial. Another important difference between the
CHEST recommendations and those suggested by the
panel relates to the use of quantitative measures for
assessing the initial, pretest probability of malignancy.
The populations used to validate the models for
assessing pretest probability of malignancy (eg, the
Mayo Clinic model suggested by CHEST6,24) may
be inaccurate when applied to populations in Asia for
several key reasons. These reasons include high rates
of granulomatous and other infectious diseases, severe
air pollution, and lung cancer among nonsmokers.
The expert panel agreed there is a need to develop a
891
locally validated prediction model in different Asian
countries. At present, efforts are currently underway
in China to update the Mayo Clinic prediction model
using local data.
There are several key limitations of these adapted
clinical practice guidelines. Most importantly, there is
a lack of published evidence to support the suggested
changes to the CHEST recommendations. The panel
agreed on the importance of updating these
recommendations based on new evidence as it emerges
and on feedback from end users. In this regard, the
process of adapting recommendations highlights
deficiencies in the available evidence and suggests
areas for future research. Secondly, the wide variations
both between countries and regions within individual
countries make it difficult to provide recommendations
that are universally applicable to the whole of Asia.
Therefore, clinicians are urged to apply the
recommendations as appropriate to their practice,
taking into consideration available resources, expertise,
and other constraints. It should be noted that a different
recommendation may have been made if a patient,
caregiver or primary care physician had been included
on the panel.
Conclusions
These clinical practice guidelines used a consensus-
based approach to adapt the current CHEST
recommendations on the evaluation of pulmonary
nodules to be relevant to clinical practice in Asia.
Most of the CHEST recommendations are broadly
applicable to Asia, with some modification required,
mainly to address the increased risk of lung cancer in
the region, especially in nonsmokers, as well as the
different prevalence of infectious lung disease. In
addition, the panel recommended standardization
of all future guidelines using a 4-mm threshold (as
opposed to 4 mm for solid nodules and 5 mm for
nonsolid nodules) for ease of implementation.
Acknowledgments
Author contributions: All authors participated in the drafting, critical
revision, and approval of the final version of the manuscript. The
consensus was developed primarily from CHEST guidelines, and the
original authors reserve all the copyright.
Financial/nonfinancial disclosures: The authors have reported to
CHEST the following: D. A. has received accommodation and travel
expenses from the sponsor. None declared (C. B., C.-M.C., C. M. C.,
J. C. H., A. Z. K., J.-M. L., S. Y. L., S. S., A. Y.).
Role of sponsors: Covidien was involved in organizing the consensus
meeting. However, the guidelines reflect the expert opinion of the
authors.
892 Evidence-Based Medicine
References
1. Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals
with pulmonary nodules: when is it lung cancer? Diagnosis and
management of lung cancer, 3rd ed: American College of Chest
Physicians evidence-based clinical practice guidelines. Chest.
2013;143(suppl 5):e93S-e120S.
2. Patel VK, Naik SK, Naidich DP, et al. A practical algorithmic
approach to the diagnosis and management of solitary pulmonary
nodules: part 1: radiologic characteristics and imaging modalities.
Chest. 2013;143(3):825-839.
3. Kim YK, Lee SH, Seo JH, Kim JH, Kim SD, Kim GK. A
comprehensive model of factors affecting adoption of clinical practice
guidelines in Korea. J Korean Med Sci. 2010;25(11):1568-1573.
4. She J, Yang P, Hong Q, Bai C. Lung cancer in China: challenges and
interventions. Chest. 2013;143(4):1117-1126.
5. Detterbeck FC, Lewis SZ, Diekemper R, Addrizzo-Harris D,
Alberts WM. Executive summary: diagnosis and management of
lung cancer, 3rd ed: American College of Chest Physicians evidence-
based clinical practice guidelines. Chest. 2013;143(suppl 5):7S-37S.
6. Herder GJ, van Tinteren H, Golding RP, et al. Clinical prediction
model to characterize pulmonary nodules: validation and added
value of 18F-fluorodeoxyglucose positron emission tomography.
Chest. 2005;128(4):2490-2496.
7. GLOBOCAN 2012: estimated cancer incidence, mortality in
prevalence worldwide in 2012. International Agency for Research
on Cancer (IARC) website. http://globocan.iarc.fr/Default.aspx.
Accessed May 1, 2014.
8. Incidence and mortality rates for the top 10 cancer in Taiwan, 2011.
Taiwan Cancer Registry website. http://tcr.cph.ntu.edu.tw/main.
php?Page¼N2. Accessed May 1, 2014.
9. National Center for Cancer Registry. Chinese Cancer Registry
Annual Report (2012).
10. Global tuberculosis report 2014. World Health Organization website.
http://www.who.int/tb/publications/global_report/en/. Accessed
October 14, 2014.
11. The ADAPTE Collaboration. The ADAPTE process: resource toolkit
for guideline adaptation. Version 2.0. Guidelines International
Network website. http://www.g-i-n.net. 2009.
12. Ha DM, Mazzone PJ. Pulmonary nodules. Cleveland Clinic
website. http://www.clevelandclinicmeded.com/medicalpubs/
diseasemanagement/hematology-oncology/pulmonary-nodules/.
Accessed May 1, 2014.
13. Godoy MC, Naidich DP. Subsolid pulmonary nodules and the
spectrum of peripheral adenocarcinomas of the lung: recommended
interim guidelines for assessment and management. Radiology.
2009;253(3):606-622.
14. Detterbeck FC, Homer RJ. Approach to the ground-glass nodule.
Clin Chest Med. 2011;32(4):799-810.
15. Lee HJ, Kim JH, Kim YK, Park CM, Yi CA, Jeong YJ. Korean Society
of Thoracic Radiology guideline for lung cancer screening with
low-dose CT. J Korean Soc Radiol. 2012;67(5):349-365.
16. Soo RA, Loh M, Mok TS, et al. Ethnic differences in survival
outcome in patients with advanced stage non-small cell lung cancer:
results of a meta-analysis of randomized controlled trials. J Thorac
Oncol. 2011;6(6):1030-1038.
17. Zhou W, Christiani DC. East meets West: ethnic differences in
epidemiology and clinical behaviors of lung cancer between East
Asians and Caucasians. Chin J Cancer. 2011;30(5):287-292.
18. Lai RS, Lee SS, Ting YM, Wang HC, Lin CC, Lu JY. Diagnostic value
of transbronchial lung biopsy under fluoroscopic guidance in
solitary pulmonary nodule in an endemic area of tuberculosis. Respir
Med. 1996;90(90):139-143.
19. Gu Y, Hao X, Shen Y, et al. Electromagnetic navigation bronchoscopy
in the diagnosis of sputum-negative pulmonary tuberculosis: 3-case-
report and literature review. Chinese Journal of Antituberculosis.
2014;36(12):1084-1088.
20. Bae J, Gwack J, Park SK, Shin HR, Chang SH, Yoo KY. Cigarette
smoking, alcohol consumption, tuberculosis and risk of lung cancer:
[ 150#4 CHEST OCTOBER 2016 ]
 the Korean multi-center cancer cohort study [article in Korean].
J Prev Med Public Health. 2007;40(4):321-328.
21. Hara H, Soejima R, Matsushima T. A study of the coexistence of
pulmonary tuberculosis and bronchogenic carcinoma: results of a
questionnaire in Chugoku and Shikoku areas [article in Japanese].
Kekkaku. 1990;65(11):711-717.
22. Yu YH, Liao CC, Hsu WH, et al. Increased lung cancer risk among
patients with pulmonary tuberculosis: a population cohort study.
J Thorac Oncol. 2011;6(1):32-37.
23. Global tuberculosis report, 2013. World Health Organization
website. http://apps.who.int/iris/bitstream/10665/91355/1/978
9241564656_eng.pdf.
24. Swensen SJ, Silverstein MD, Ilstrup DM, Schleck CD, Edell ES. The
probability of malignancy in solitary pulmonary nodules.
Application to small radiologically indeterminate nodules. Arch
Intern Med. 1997;157(8):849-855.
25. Badami MG. Transport and urban air pollution in India. Environ
Manage. 2005;36(2):195-204.
26. Zhang JJ, Smith KR. Household air pollution from coal and biomass
fuels in China: measurements, health impacts, and interventions.
Environ Health Perspect. 2007;115(6):848-855.
27. Saenghirunvattana S, Kurimoto N, Suwanakijboriharn C, et al.
Etiology of size based pulmonary nodules in Asia. Poster presented
at: American Thoracic Society (ATS); May 15-20, 2015; Denver, CO.
28. Yuan Z, Ledesma KR, Singh R, et al. Quantitative assessment of
combination antimicrobial therapy against multidrug-resistant bacteria
in a murine pneumonia model. J Infect Dis. 2010;201(6):889-897.
29. Shen GH, Tsao TC, Kao SJ, et al. Does empirical treatment of
community-acquired pneumonia with fluoroquinolones delay
tuberculosis treatment and result in fluoroquinolone resistance in
Mycobacterium tuberculosis? Controversies and solutions. Int J
Antimicrob Agents. 2012;39(3):201-205.
30. Schreiber G, McCrory DC. Performance characteristics of different
modalities for diagnosis of suspected lung cancer: summary of
published evidence. Chest. 2003;123(suppl 1):115S-128S.
31. Bekci TT, Senol T, Maden E. The efficacy of serum
carcinoembryonic antigen (CEA), cancer antigen 125 (CA125),
carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 15-3
(CA15-3), alpha-fetoprotein (AFP) and human chorionic
gonadotropin (hCG) levels in determining the malignancy of solitary
pulmonary nodules. J Int Med Res. 2009;37(2):438-445.
32. Rivera MP, Mehta AC; American College of Chest Physicians. Initial
diagnosis of lung cancer: ACCP evidence-based clinical practice
guidelines (2nd edition). Chest. 2007;132(suppl 3):131S-148S.
33. Boskovic T, Stanic J, Pena-Karan S, et al. Pneumothorax after
transthoracic needle biopsy of lung lesions under CT guidance.
J Thorac Dis. 2014;6(suppl 1):S99-S107.
34. Wiener RS, Schwartz LM, Woloshin S, Welch HG. Population-based
risk for complications after transthoracic needle lung biopsy of a
pulmonary nodule: an analysis of discharge records. Ann Intern
Med. 2011;155(11):137-144.
35. Bolton WD, Howe H III, Stephenson JE. The utility of
electromagnetic navigational bronchoscopy as a localization tool for
robotic resection of small pulmonary nodules. Ann Thorac Surg.
2014;98(2):471-475; discussion 475-476.
36. Krimsky WS, Minnich DJ, Cattaneo SM, et al. Thoracoscopic
detection of occult indeterminate pulmonary nodules using
bronchoscopic pleural dye marking. J Community Hosp Intern Med
Perspect. 2014;4(1):4.
37. Blasberg JD, Pass HI, Donington JS. Sublobar resection: a movement
from the Lung Cancer Study Group. J Thorac Oncol. 2010;5(10):
1583-1593.
journal.publications.chestnet.org
38. Cai BQ, Cai SX, Chen RC, et al. Expert consensus on acute
exacerbation of chronic obstructive pulmonary disease in the
People’s Republic of China. Int J Chron Obstruct Pulmon Dis. 2014;9:
381-395.
39. Bai C. Teleradiology in differential diagnosis of pulmonary nodules
in three and two-act. International Journal of Respiration (Chinese
Language). 2014;16:1201-1202.
40. Loomis D, Huang W, Chen G. The International Agency for
Research on Cancer (IARC) evaluation of the carcinogenicity of
outdoor air pollution: focus on China. Chin J Cancer. 2014;33(4):
189-196.
41. Wong IC, Ng YK, Lui VW. Cancers of the lung, head and neck
on the rise: perspectives on the genotoxicity of air pollution. Chin
J Cancer. 2014;33(10):476-480.
42. Hosgood HD, Chapman RS, He X, et al. History of lung disease
and risk of lung cancer in a population with high household fuel
combustion exposures in rural China. Lung Cancer. 2013;81:343-346.
43. Wang L, Zhang H, Ruan Y, et al. Tuberculosis prevalence in China,
1990-2010; a longitudinal analysis of national survey data. Lancet.
2014;383(9934):2057-2064.
44. Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of
cancer incidence and mortality rates and trends. Cancer Epidemiol
Biomarkers Prev. 2010;19(8):1893-1907.
45. Huxley R, Jamrozik K, Lam TH, et al. Impact of smoking and
smoking cessation on lung cancer mortality in the Asia-Pacific
region. Am J Epidemiol. 2007;165(11):1280-1286.
46. Li Q, Hsia J, Yang G. Prevalence of smoking in China in 2010.
N Engl J Med. 2011;364(25):2469-2470.
47. Bae JM, Lee MS, Shin MH, Kim DH, Li ZM, Ahn YO. Cigarette
smoking and risk of lung cancer in Korean men: the Seoul Male
Cancer Cohort Study. J Korean Med Sci. 2007;22(3):508-512.
48. Gordon SB, Bruce NG, Grigg J, et al. Respiratory risks from
household air pollution in low and middle income countries. Lancet
Respir Med. 2014;2(10):823-860.
49. Prasad R, Singh A, Garg R, Giridhar GB. Biomass fuel exposure and
respiratory diseases in India. Biosci Trends. 2012;6(5):219-228.
50. Sapkota A, Gajalakshmi V, Jetly DH, et al. Indoor air pollution from
solid fuels and risk of hypopharyngeal/laryngeal and lung cancers:
a multicentric case-control study from India. Int J Epidemiol.
2008;37(2):321-328.
51. Thun MJ, Hannan LM, Adams-Campbell LL, et al. Lung cancer
occurrence in never-smokers: an analysis of 13 cohorts and 22
cancer registry studies. PLoS Med. 2008;5:e185.
52. Wu YL, Zhou Q. Lung cancer management in the Asia-Pacific
region: what’s the difference compared with the United States and
Europe? Results of the Second Asia Pacific Lung Cancer Conference.
J Thorac Oncol. 2007;2(6):574-576.
53. Lan Q, Hsiung CA, Matsuo K, et al. Genome-wide association
analysis identifies new lung cancer susceptibility loci in never-
smoking women in Asia. Nat Genet. 2012;44(12):1330-1335.
54. Wang DM, Chen BJ, Li WM, Li Jiang CW. Risk factors on lung
cancer: a meta-analysis [in Chinese]. Chin J Evid-Based Med.
2010;10(12):1446-1449.
55. Seow A, Poh WT, Teh M, et al. Fumes from meat cooking and lung
cancer risk in Chinese women. Cancer Epidemiol Biomarkers Prev.
2000;9(11):1215-1221.
56. Saenghirunvattana S, Tesavibul C, Saenghirunvattana R,
Castillon CL, Sutthisri K, Suwangool P. Higher incidence of
lung cancer in female passive smokers. Bangk Med J. 2013;5:
13-17.
893