The IASLC Lung Cancer Staging Project

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IASLC STAGING COMMITTEE ARTICLE
The IASLC Lung Cancer Staging Project
A Proposal for a New International Lymph Node Map in the
Forthcoming Seventh Edition of the TNM Classification for Lung Cancer
Valerie W. Rusch, MD,* Hisao Asamura, MD,† Hirokazu Watanabe, MD,‡ Dorothy J. Giroux, MS,§
Ramon Rami-Porta, MD,储 and Peter Goldstraw, MD,¶ on Behalf of the Members of the IASLC
Staging Committee
Abstract: The accurate assessment of lymph node involvement is an
important part of the management of lung cancer. Lymph node “maps”
have been used to describe the location of nodal metastases. However,
discrepancies in nomenclature among maps used by Asian and Western
countries hinder analyses of lung cancer treatment outcome. To achieve
uniformity and to promote future analyses of a planned prospective
international database, the International Association for the Study of
Lung Cancer proposes a new lymph node map which reconciles
differences among currently used maps, and provides precise anatomic
definitions for all lymph node stations. A method of grouping lymph
node stations together into “zones” is also proposed for the purposes of
future survival analyses.
Key Words: Lung cancer lymph node map, Lung cancer staging, Pulmonary and mediastinal lymph nodes, lymph node zones, TNM classification.
(J Thorac Oncol. 2009;4: 568 –577)
T
he accurate assessment of lymph node involvement is recognized as a pivotal component of the staging and treatment
of lung cancers. For approximately the past 40 years, lymph
node “maps” have been used to describe the clinical and pathologic extent of lymph node metastases in lung cancer patients by
labeling regions of intrathoracic nodes using a system of anatomic descriptors and numerical “levels.” Precise, universally
accepted nomenclature to describe lymph node involvement is
key to assessing treatment outcomes, comparing results across
institutions, designing and analyzing clinical trials, and selecting
therapy for individual patients. The first lymph node map,
*Thoracic Surgery Service, Memorial Sloan-Kettering Cancer Center, New
York City, New York; Divisions of †Thoracic Surgery, ‡Diagnostic
Radiology, National Cancer Center Hospital, Tokyo, Japan; §Cancer
Research and Biostatistics, Seattle, Washington; 储Thoracic Surgery Service, Hospital Mutua de Terrassa, Terrassa, Spain; and ¶Department of
Thoracic Surgery, Royal Brompton Hospital, London, United Kingdom.
Disclosure: Please see Acknowledgments Section.
Address for correspondence: Valerie W. Rusch, MD, Thoracic Service,
Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, C-868,
New York City, NY 10065. E-mail: ruschv@mskcc.org
Copyright © 2009 by the International Association for the Study of Lung
Cancer
ISSN: 1556-0864/09/0405-0568
568
developed by Naruke1,2 during the 1960s, was initially widely
used in North America, Europe, and Japan (Figure 1). However,
subsequent attempts to refine the anatomic descriptors of the
Naruke map led to the development of maps by the American
Thoracic Society (ATS)3 and to the so-called Mountain-Dresler
modification of the ATS map (MD-ATS).4 The MD-ATS map
(Figure 2) attempted to unify in a single system the features of
the Naruke lymph node classification and the schema developed
by the ATS and was reportedly adopted by the American Joint
Committee on Cancer (AJCC) and the Prognostic Factors TNM
Committee of the International Union Against Cancer (UICC) at
the 1996 annual meetings of these organizations.4 Subsequently,
the MD-ATS map was fully accepted across North America but
was only sporadically used in Europe. Indeed, further revisions
to the MD-ATS map were suggested by European surgeons.5
Following well-established national practice patterns, Japanese
surgeons and oncologists continued to use the Naruke map as
advocated by the Japan Lung Cancer Society.6
In 1998, the International Association for the Study
of Lung Cancer (IASLC) established its Lung Cancer
Staging Project which led to the development of an international lung cancer database. Analyses of that database
enabled the IASLC International Staging Committee to
propose revisions of the TNM staging system for lung
cancer which will be included in the 7th editions of the
UICC and AJCC staging manuals to be published in 2009.7
Analyses of the N descriptors in the IASLC international
database highlighted discrepancies in nomenclature between the Japanese (Naruke) and the MD-ATS lymph node
maps. Important differences in the descriptors for mediastinal lymph nodes included level 1 lymph nodes in the
Naruke map corresponding to levels 1 and 2 in the MDATS map, while levels 2, 3, 4R, and 4L in the Japanese
system corresponded to levels 4R and 4L in the MD-ATS
map. Perhaps the most significant discrepancy was that
level 7 subcarinal lymph nodes in the MD-ATS map
corresponded to levels 7 and 10 in the Naruke map. As a
result, some tumors staged as N2, stage IIIA according to
the MD-ATS map, were staged as N1, stage II by the
Naruke map. Within the context of a retrospective study,
this difference in nomenclature introduced an irreconcilable discrepancy in data analysis.8 As a consequence of the
Journal of Thoracic Oncology • Volume 4, Number 5, May 2009
Journal of Thoracic Oncology • Volume 4, Number 5, May 2009
The IASLC Lung Cancer Staging Project
FIGURE 1. The Naruke lymph node
map for the staging of lung cancers
as recommended by the Japan Lung
Cancer Society.6
difficulties encountered in analyses of N descriptors, members of the IASLC staging committee were charged to
develop a revised lymph node map that would reconcile
differences between the Japanese and MD-ATS maps and
provide more specific anatomic definitions for each of the
lymph node stations. This effort was considered critical to
the prospective international lung cancer data collection
planned by the IASLC starting in 2009 which will inform
revisions for the 8th editions of the UICC and AJCC
staging manuals 7 years hence. We now describe the
IASLC lymph node map which we anticipate will super-
sede all previous maps for the purposes of precision and
international uniformity in nomenclature.
METHODS
Two of the authors (V.R., H.A.) were assigned by the
IASLC Staging Committee to lead the effort in developing a revised
lymph node map that would reconcile the differences between the
Naruke and the MD-ATS maps and refine the definitions of the
anatomic boundaries of each of the lymph node stations.
Areas of discrepancy for the descriptors of each lymph
node station were identified and new, clarifying definitions for
Copyright © 2009 by the International Association for the Study of Lung Cancer
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Rusch et al.
FIGURE 2. The Mountain-Dresler modification of the lymph node map originally proposed by the American Thoracic Society.4
the anatomic borders established (Table 1). A collaborating
thoracic radiologist (H.W.) reviewed the definitions to insure
that they could be applied to clinical staging by computed
tomography (CT), and generated the CT scan illustrations that
corresponded to the IASLC lymph node map definitions. The
recommendations for the definitions of the lymph node stations and
for the illustration of the proposed IASLC map were reviewed by
the entire IASLC staging committee, an international multidisciplinary group including thoracic surgeons, medical and radiation
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oncologists, pulmonologists, epidemiologists, radiologists, pathologists, and data managers. In addition, one of the authors (H.A.)
presented the proposed lymph node map and anatomic definitions at
thoracic meetings in Japan for comments and approval.
RESULTS
The proposed IASLC lymph node map and the anatomic definitions for each of the lymph node stations are
Copyright © 2009 by the International Association for the Study of Lung Cancer
MD-ATS Map
Copyright © 2009 by the International Association for the Study of Lung Cancer
Located in the area superior to the carina. On the right side, located
medial to the azygos vein. On the left side, located in the area
surrounded by the medial wall of the aortic arch
#4 Tracheobronchial Lymph Nodes
IASLC Map
The lower paratracheal nodes on the right lie to the right of the midline of the
trachea between a horizontal line drawn tangential to the upper margin of the
aortic arch and a line extending across the right main bronchus at the upper
margin of the upper lobe bronchus, and contained within the mediastinal
pleural envelope; the lower paratracheal nodes on the left lie to the left of
the midline of the trachea between a horizontal line drawn tangential to the
upper margin of the aortic arch and a line extending across the left main
bronchus at the level of the upper margin of the left upper lobe bronchus,
medial to the ligamentum arteriosum and contained within the mediastinal
pleural envelope. Researchers may wish to designate the lower paratracheal
nodes as No. 4s (superior) and No. 4i (inferior) subsets for study purposes;
the No. 4s nodes may be defined by a horizontal line extending across the
trachea and drawn tangential to the cephalic border of the azygos vein; the
No. 4i nodes may be defined by the lower boundary of No. 4s and the lower
boundary of no.4, as described above
(Continued)
4R: includes right paratracheal nodes, and pretracheal nodes
extending to the left lateral border of trachea
Upper border: intersection of caudal margin of innominate vein with
the trachea
Lower border: lower border of azygos vein
4L: includes nodes to the left of the left lateral border of the trachea,
medial to the ligamentum arteriosum
Upper border: upper margin of the aortic arch
Lower border: upper rim of the left main pulmonary artery
#4 Lower Paratracheal Nodes
3a: Prevascular
On the right
Upper border: apex of chest
Lower border: level of carina
Anterior border: posterior aspect of sternum
Posterior border: anterior border of superior vena cava
On the left:
Upper border: apex of chest
Lower border: level of carina
Anterior border: posterior aspect of sternum
Posterior border: left carotid artery
3p: Retrotracheal
Upper border: apex of chest
Lower border: carina
#3 Prevascular and Retrotracheal Nodes
Nodes lying above a horizontal line drawn tangential to the upper margin of the 2R: Upper border: apex of the right lung and pleural space, and in
aortic arch and below the inferior boundary of No. 1 nodes
the midline, the upper border of the manubrium
Lower border: intersection of caudal margin of innominate vein with
the trachea
As for lymph node station 4R, 2R includes nodes extending to the
left lateral border of the trachea
2L: Upper border: apex of the left lung and pleural space, and in the
midline, the upper border of the manubrium
Lower border: superior border of the aortic arch
#2 Upper Paratracheal Nodes
Nodes lying above a horizontal line at the upper rim of the brachiocephalic (left Upper border: lower margin of cricoid cartilage
innominate) vein where it ascends to the left, crossing in front of the trachea Lower border: clavicles bilaterally and, in the midline, the upper
at its midline
border of the manubrium, 1R designates right-sided nodes, 1L,
left-sided nodes in this region
For lymph node station 1, the midline of the trachea serves as the
border between 1R and 1L
#1 Low Cervical, Supraclavicular, and Sternal Notch Nodes
Located in the area anterior to the trachea and inferior to the superior Prevascular and retrotracheal nodes may be designated 3A and 3P; midline
nodes are considered to be ipsilateral
mediastinal lymph nodes (#1). On the right side, the boundary
is limited to the posterior wall of the superior vena cava. On the
left side, the boundary is limited to the posterior wall of the
brachiocephalic vein
#3a Anterior mediastinal lymph nodes
On the right side, located in the area anterior to the superior vena
cava. On the left side, the boundary is limited to the line
connecting the left bracheocephalic vein and the ascending aorta
#3p Retrotracheal mediastinal lymph nodes/Posterior mediastinal
lymph nodes
Located in the retrotracheal or posterior area of the trachea
#3 Pretracheal Lymph Nodes
Located in the area between the superior mediastinal lymph nodes
(#1) and the tracheobronchial lymph nodes (#4). Paratracheal
lymph nodes with primary tumor can be defined as ipsilateral
lymph nodes; paratracheal lymph nodes without primary tumor
can be defined as contralateral lymph nodes
#2 Paratracheal Lymph Nodes
Located in the area of the upper 1/3 of the intrathoracic trachea.
Boundary level from the upper margin of the subclavian artery
or the apex to the crossing point of the upper margin of the left
brachiocephalic vein and the midline of the trachea
Japan Lung Cancer Society Map
TABLE 1. Comparison of the Naruke, MD-ATS and IASLC Lymph Node Maps with Respect to the Anatomical Definitions for Each Lymph Node Station
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#9 Pulmonary Ligament Nodes
Nodes lying adjacent to the wall of the esophagus and to the right or left of the
midline, excluding subcarinal nodes
#8 Paraesophageal Nodes (Below Carina)
Nodes lying caudal to the carina of the trachea, but not associated with the
lower lobe bronchi or arteries within the lung
#7 Subcarinal Nodes
Located between the lobar bronchi. On the right side, subclassified
into 2 groups:
#11s: Superior interlobar nodes: located at the bifurcation of the
upper and middle lobar bronchi
#11i: Inferior interlobar nodes: located at the bifurcation of the
middle and lower lobar bronchi
Located around the right and left main bronchi
Nodes lying between the lobar bronchi
#11 Interlobar Nodes
(Continued)
Between the origin of the lobar bronchi
a
#11s: between the upper lobe bronchus and bronchus intermedius
on the right
a
#11i: between the middle and lower lobe bronchi on the right
The proximal lobar nodes, distal to the mediastinal pleural reflection and the
Includes nodes immediately adjacent to the mainstem bronchus and
hilar vessels including the proximal portions of the pulmonary
nodes adjacent to the bronchus intermedius on the right; radiographically, the
hilar shadow may be created by enlargement of both hilar and interlobar
veins and main pulmonary artery
nodes
Upper border: the lower rim of the azygos vein on the right; upper
rim of the pulmonary artery on the left
Lower border: interlobar region bilaterally
#10 Hilar Nodes
Nodes lying within the pulmonary ligament
Upper border: the inferior pulmonary vein
Lower border: the diaphragm
Nodes lying adjacent to the wall of the esophagus and to the right or
left of the midline, excluding subcarinal nodes
Upper border: the upper border of the lower lobe bronchus on the
left; the lower border of the bronchus intermedius on the right
Lower border: the diaphragm
Upper border: the carina of the trachea
Lower border: the upper border of the lower lobe bronchus on the
left; the lower border of the bronchus intermedius on the right
Nodes lying anterior and lateral to the ascending aorta and the aortic arch or the Lymph nodes anterior and lateral to the ascending aorta and aortic
innominate artery, beneath a line tangential the upper margin of the aortic
arch
arch
Upper border: a line tangential to the upper border of the aortic arch
Lower border: the lower border of the aortic arch
#6 Paraaortic Nodes (Ascending Aorta or Phrenic)
IASLC Map
Subaortic lymph nodes lateral to the ligamentum arteriosum
Upper border: the lower border of the aortic arch
Lower border: upper rim of the left main pulmonary artery
#5 Subaortic (Aortopulmonary Window)
Subaortic nodes are lateral to the ligamentum arteriosum or the aorta or left
pulmonary artery and proximal to the first branch of the left pulmonary
artery and lie within the mediastinal pleural envelope
MD-ATS Map
Located in the area of the posterior and the lower edge of the inferior Nodes lying within the pulmonary ligament, including those in the posterior
pulmonary vein
wall, and lower part of the inferior pulmonary vein
Located below the subcarinal lymph nodes, and along the esophagus
Located in the area below the carina, where the trachea bifurcates to
the two main bronchi
Located along the ascending aorta, and in the area of the lateral wall
of the aortic arch. Posterior boundary limited to the site of the
vagal nerve
Located in the area adjacent to the ligamentum arteriosum (Botallo’s
ligament). The boundary extends from the aortic arch to the left
main pulmonary artery
#5 Subaortic Lymph Nodes/Botallo’s Lymph Nodes
Japan Lung Cancer Society Map
TABLE 1. (Continued)
Rusch et al.
Journal of Thoracic Oncology • Volume 4, Number 5, May 2009
Copyright © 2009 by the International Association for the Study of Lung Cancer
Adjacent to the subsegmental bronchi
Nodes around the subsegmental bronchi
Optional notations for subcategories of station.
MD-ATS, Mountain-Dresler modification of the ATS map; IASLC, International association for the study of lung cancer; ATS, American Thoracic Society.
a
Located along the subsegmental branches
Adjacent to the segmental bronchi
#14 Subsegmental Nodes
#13 Segmental Nodes
Nodes adjacent to the segmental bronchi
Located along the segmental branches
Adjacent to the lobar bronchi
#12 Lobar Nodes
Located in the area around the lobar branches, which are subclassified Nodes adjacent to the distal lobar bronchi
into three groups:
#12u: Upper lobar lymph nodes
#12m: Middle lobar lymph nodes
#12l: Lower lobar lymph nodes
Japan Lung Cancer Society Map
TABLE 1. (Continued)
MD-ATS Map
IASLC Map
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The IASLC Lung Cancer Staging Project
shown in Figure 3 and Table 1, respectively. There are
several notable changes relative to the Naruke and MD-ATS
maps. Concise and anatomically distinct descriptions are now
provided for all lymph node stations and especially for the
upper and lower borders of lymph node stations 1 through 10
where it is critical to avoid overlap in definitions. As a result,
the pleural reflection no longer serves as the border between
nodal stations 4 and 10, which are now defined by anatomic
landmarks that are more reliably identified on imaging studies
and at endoscopy and surgery. The supraclavicular and sternal notch lymph nodes which were not previously identified
as a lymph node station separate from the intrathoracic nodes
are now clearly described as level 1. The discrepancies
between levels 2 and 4 lymph nodes in the Naruke and
MD-ATS lymph node maps (noted above) have been resolved by providing more precise definitions. The arbitrary
division along the midline of the trachea created by the ATS
has been eliminated. Recognizing that lymphatic drainage in
the superior mediastinum predominantly occurs to the right
paratracheal area and extends past the midline of the trachea,
the boundary between the right- and left-sided levels 2 and 4
lymph nodes has been reset to the left lateral wall of the
trachea (Figures 3, 4). The arbitrary designation of level 3
lymph nodes as nodes overlying the midline of the trachea in
the Naruke map has been eliminated because these nodes are
not reliably distinguishable from levels 2 and 4 and are
generally removed en-bloc with level 4 during a mediastinal
component of systematic nodal dissection from the right. The
designation of prevascular (anterior mediastinal) and retrotracheal nodes as 3a and 3p has been retained and clarified.
The entire subcarinal group of lymph nodes, previously
labeled as level 7 in the MD-ATS map but divided into levels
7 and 10 in the Naruke map is now defined as level 7, again
with precise anatomic borders. Specific boundaries are also
provided for the frequently problematic separation between
levels 4 and 10 on the right, levels 5 and 10 on the left, and
levels 10 and 11 bilaterally. Exploratory analyses of overall
survival in relationship to various levels of lymph node
involvement previously grouped together certain lymph node
stations into “zones.”8 The zone concept is proposed for
future survival analyses, not for current standard nomenclature. It is hoped that this concept will prove of value to
oncologists and radiologists when dealing with large nodal
masses that transgress individual nodal stations.
Figures 4A–F illustrate how the anatomic definitions of
the lymph node stations are applied to clinical staging on CT
scans in the axial (Figures 4A–C), coronal (Figure 4D), and
sagittal (Figures 4E, F) views. The division between right and
left sided nodes at levels 2 and 4 is also shown (Figures 4A, B).
DISCUSSION
Scientific investigation into the patterns of lymphatic
drainage of the lung dates back to the early 1900s. However,
Rouvière9 is generally credited with the first comprehensive
study of the lymphatic drainage of the lung. In 1929, he described the lymph nodes draining each lobe of the lung as
determined by selective injection of the lymphatics in 200
human specimens. In his report, he noted that it was possible to
Copyright © 2009 by the International Association for the Study of Lung Cancer
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Rusch et al.
FIGURE 3. The International Association for the Study of Lung Cancer (IASLC) lymph node map, including the proposed
grouping of lymph node stations into “zones” for the purposes of prognostic analyses.
predict which lymph nodes would be involved based on the
location of the primary tumor. The illustrations of lobar lymphatic drainage included in this seminal article have been cor-
574
roborated by more recent studies and are still accurate today.
During the 1950s and 1960s additional studies expanded our
knowledge of the patterns of pulmonary and mediastinal lym-
Copyright © 2009 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 4, Number 5, May 2009
The IASLC Lung Cancer Staging Project
FIGURE 4. A–F: Illustrations of how the International Association for the Study of Lung Cancer (IASLC) lymph node map can
be applied to clinical staging by computed tomography scan in axial (A–C), coronal (D), and sagittal (E, F) views. The border
between the right and left paratracheal region is shown in A and B. Ao, aorta; AV, azygos vein; Br, bronchus; IA, innominate
artery; IV, innominate vein; LA, ligamentum arteriosum; LIV, left innominate vein; LSA, left subclavian artery; PA, pulmonary
artery; PV, pulmonary vein; RIV, right innominate vein; SVC, superior vena cava.
phatic drainage especially in patients with lung cancer.10,11 More
recently, Riquet defined the lymphatic drainage of lung segments including direct drainage to mediastinal lymph nodes by
injecting the subpleural lymphatics of 483 lung segments in 260
adult cadavers.12 Overall, these various studies indicated that
mediastinal lymph node metastases from right upper lobe tumors occur predominantly in the right paratracheal area, while
those from left upper lobe tumors occur most frequently in the
peri- and subaortic lymph nodes, and those from middle and
lower lobe tumors occur in the subcarinal, then the right paratracheal nodes. Direct drainage to the mediastinal lymph nodes
bypassing the hilar and interlobar nodes or so-called skip metastases, can be seen in up to 25% of lung segments injected
experimentally.12 Clinically, skip metastases have been reported
in 7 to 26% of resected lung cancer specimens and are most
frequent in upper lobe tumors and in adenocarcinomas.13,14
Studies of the patterns of lymphatic drainage of the lung
gradually led to an understanding of the importance of lymph
node staging in the management of lung cancers. Cahan is
credited with the first description of a systematic approach to
hilar and mediastinal lymph node dissection, initially in 1951 in
conjunction with pneumonectomy,15 and later, in 1960, in association with lobectomy.16 Shortly thereafter, Ishikawa introduced the dissection proposed by Cahan to Japan and based on
the results of patients undergoing pulmonary resection with hilar
and mediastinal lymph node dissection by Ishikawa and his
Copyright © 2009 by the International Association for the Study of Lung Cancer
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Rusch et al.
team, Naruke created his lymph node map in 1967. The Japan
Lung Cancer Society endorsed lymph node dissection and the
Naruke map as standard procedure for lung cancer resection in
1980.17,18 In North America during the 1960s, the group at
Memorial Sloan-Kettering Cancer Center (of which Cahan was
part) devised a lung cancer staging system and lymph node
nomenclature similar to the Naruke system.19 However, ultimately, MSKCC and other North American groups adopted the
Naruke map which was then accepted in 1976 by the AJC
(American Joint Committee for Cancer Staging and End Results
Reporting) for standard use in the staging of lung cancers. The
need to provide more precise anatomic definitions for intrathoracic lymph node stations in a way that would be useful for
radiologists, pathologists, and all clinicians involved in the care
of lung cancer patients led to the development of the ATS and
MD-ATS maps. The presence of these two mapping systems
was acknowledged starting in 1997 with the 4th edition of the
UICC TNM Atlas20 and the 5th and 6th editions of the AJCC
staging manuals.21 During this time, the Japan Lung Cancer
Society refined the anatomic definitions of the lymph node
stations in the Naruke map. Detailed descriptions as well as
anatomic and CT illustrations provided in the Japan Lung
Cancer Society monograph Classification of Lung Cancer established national standards of staging and pathologic classification for lung cancer with a degree of precision unparalleled
elsewhere in the world. Unfortunately, an English edition of this
monograph was not published until 2000.6 Therefore, although
clinicians, especially surgeons, were generally aware of discrepancies between the Japanese and MD-ATS map and knew that
such differences could affect analyses of treatment outcomes
because of their impact on staging, the extent of these discrepancies was not evident until recently. The difficulties in assessing the outcomes of treatment for patients staged accordingly to
different lymph node maps are emphasized by the complexities
and irreconcilable discrepancies encountered during analyses of
the N descriptors in the IASLC database.8 However, discrepancies in the labeling of lymph node stations occur even among
experienced Japanese and non-Japanese surgeons utilizing only
the Naruke map. In one study, a Japanese surgeon and a
European surgeon who were jointly present during pulmonary
resections performed on 41 patients designated in a manner
blinded to one another each lymph node station removed during
a systematic lymph node dissection. The total concordance rate
was only 68.5%. Of even greater concern was that in 34.1% of
patients, lymph nodes designated as N1 by one surgeon were
labeled as N2 by the other surgeon.22 Clearly, a single internationally accepted lymph node map is needed for future studies of
lung cancer treatment and revisions of the staging system. This
is especially important during the coming decades as an increasing number of developing countries with large lung cancer
patient populations that have not systematically used either one
lymph node map or the other in the past begin to contribute their
data to the prospective international IASLC database.
Analyses of outcome in relationship to the extent of lymph
node involvement have been used to propose changes to the lung
cancer staging system, to select patients for multimodality treatment and to stratify patients within clinical trials. The published
surgical literature is replete with such analyses, which are too
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numerous to list in their entirety here.13,23–33 Areas of continuing
controversy regarding the relationship between lymph nodes
metastases and overall survival include: intranodal versus extranodal disease23; single versus multiple (either N1 or N2)
lymph node station disease13,24,27–32; the specific sites of lymph
node metastases in relationship to the location of the primary
tumor24,28,31; the significance of skip metastases13; and the need
for systematic lymph node dissection versus a less extensive
lymph node sampling,25 especially for tumors less than 2 cm in
size.26 Analyses of the IASLC database suggested that left upper
lobe tumors with skip metastases in the AP zone (levels 5 and 6)
were associated with a more favorable prognosis than other N2
subsets. In addition, analyses of the potential impact of the
number of involved lymph node zones on survival found three
groups to have significantly different survival rates: patients who
had N1 single zone disease, those who had either multiple N1 or
single N2 zone metastases, and those who had multiple N2
lymph node zones involved. However, a firm recommendation
for changes in the N descriptors and stage groupings could not
be made because larger numbers of patients with precise lymph
node staging that can be analyzed across each T stage are
required to yield statistically valid results. Grouping together
patient groups according to lymph node “zones” was a
mechanism used in the analysis of the retrospective IASLC
database to reconcile the Naruke and the MD-ATS lymph
node maps which seemed justified on the basis of exploratory analyses.8 Prospective analyses in larger number of
uniformly staged patients are required to determine whether
grouping lymph node stations together into “zones,” as proposed here, is truly appropriate for analyses of survival. The
continuing controversies about the current N classifications
and the challenges encountered by the IASLC staging committee in analyzing an international database attest to the need
for an internationally accepted lymph node map that will
support an uniform approach to lymph node staging.34 It is
our hope that widespread implementation of the IASLC
lymph node map will provide the basis for future analyses to
resolve many of the controversies about N stage classification
that currently affect patient care and clinical trials.
ACKNOWLEDGMENTS
Eli Lilly and Company provided funding to support the
International Association for the Study of Lung Cancer
(IASLC) Staging Committee’s work to suggest revisions to the
6th edition of the TNM classification for Lung Cancer (staging) through a restricted grant. Lilly had no input into the
Committee’s suggestions for revisions to the staging system.
The project was also supported by the AJCC grant “Improving AJCC/UICC TNM Cancer Staging.”
We are grateful for the patient assistance of editor Melody
Owens. The authors thank Dr. Annie Frazier for her superb
contribution to the creation of the figures for this manuscript.
APPENDIX
IASLC International Staging Committee
P. Goldstraw (Chairperson), Royal Brompton Hospital,
Imperial College, London, UK; H. Asamura, National Cancer
Centre Hospital, Tokyo, Japan; D. Ball, Peter MacCallum
Copyright © 2009 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 4, Number 5, May 2009
Cancer Centre, East Melbourne, Australia; V. Bolejack, Cancer Research and Biostatistics, Seattle, Washington, USA; E.
Brambilla, Laboratoire de Pathologie Cellulaire, Grenoble
Cedex, France; P.A. Bunn, University of Colorado Health
Sciences, Denver, Colorado; D. Carney, Mater Misericordiae
Hospital, Dublin, Ireland; K. Chansky, Cancer Research and
Biostatistics, Seattle, Washington, USA; T. Le Chevalier
(resigned), Institute Gustave Roussy, Villejuif, France; J.
Crowley, Cancer Research and Biostatistics, Seattle, Washington, USA; R. Ginsberg (deceased), Memorial Sloan-Kettering Cancer Center, New York, USA; D. Giroux, Cancer
Research And Biostatistics, Seattle, Washington, USA; P.
Groome, Queen’s Cancer Research Institute, Kingston, Ontario, Canada; H.H. Hansen (retired), National University
Hospital, Copenhagen, Denmark; P. Van Houtte, Institute
Jules Bordet, Bruxelles, Belgium; J.-G. Im, Seoul National
University Hospital, Seoul, South Korea; J.R. Jett, Mayo
Clinic, Rochester, Minnesota, USA; H. Kato, (retired), Tokyo
Medical University, Tokyo, Japan; C. Kennedy, University of
Sydney, Sydney, Australia; M. Krasnik, Gentofte Hospital,
Copenhagen, Denmark; J. van Meerbeeck, University Hospital, Ghent, Belgium; T. Naruke (deceased), Saiseikai Central
Hospital, Tokyo, Japan; E.F. Patz, Duke University Medical
Center, Durham, North Carolina, USA; P.E. Postmus, Vrije
Universiteit Medical Center, Amsterdam, the Netherlands; R.
Rami-Porta, Hospital Mutua de Terrassa, Terrassa, Spain; V.
Rusch, Memorial Sloan-Kettering Cancer Center, New York,
USA; J.P. Sculier, Institute Jules Bordet, Bruxelles, Belgium; Z.
Shaikh, Royal Brompton Hospital, London, UK; F.A. Shepherd,
University of Toronto, Toronto, Ontario, Canada; Y. Shimosato
(retired), National Cancer Centre, Tokyo, Japan; L. Sobin,
Armed Forces Institute of Pathology, Washington DC; W.
Travis, Memorial Sloan-Kettering Cancer Center, New York, USA;
M. Tsuboi, Tokyo Medical University, Tokyo, Japan; R. Tsuchiya,
National Cancer Centre, Tokyo, Japan; E. Vallieres, Swedish Cancer Institute, Seattle, Washington, USA; J. Vansteenkiste, Leuven
Lung Cancer Group, Belgium; Yoh Watanabe (deceased), Kanazawa Medical University, Uchinada, Japan; and H.
Yokomise, Kagawa University, Kagawa, Japan.
REFERENCES
1. Naruke T. [The spread of lung cancer and its relevance to surgery.]
Nippon Kyobu Geka Gakkai Zasshi 1967;68:1607–1621.
2. Naruke T, Suemasu K, Ishikawa S. Lymph node mapping and curability
at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg 1978;76:833– 839.
3. Tisi GM, Friedman PJ, Peters RM, et al. Clinical staging of primary lung
cancer. Am Rev Respir Dis 1983;127:659 – 664.
4. Mountain CF, Dresler CM. Regional lymph node classification for lung
cancer staging. Chest 1997;111:1718 –1723.
5. Zielinski M, Rami-Porta R. Proposals for changes in the Mountain and Dresler
mediastinal and pulmonary lymph node map. J Thorac Oncol 2007;2:3–6.
6. The Japan Lung Cancer Society. Classification of Lung Cancer. Tokyo:
Kanehara & Co; 2000.
7. 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 –714.
8. Rusch VW, Crowley J, Giroux DJ, et al. The IASLC lung cancer staging
project: proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac
Oncol 2007;2:603– 612.
The IASLC Lung Cancer Staging Project
9. Rouvière H. Les vaisseaux lymphatiques des poumons et les ganglions
viscéraux intrathoraciques. Ann Anat Pathol 1929;6:113–158.
10. Nohl HC. An investigation into the lymphatic and vascular spread of
carcinoma of the bronchus. Thorax 1956;11:172–185.
11. Pennell TC, Bradshaw HH. Anatomical study of the peripheral pulmonary lymphatics. J Thorac Cardiovasc Surg 1966;52:629 – 634.
12. Riquet M, Hidden G, Debesse B. Direct lymphatic drainage of lung
segments to the mediastinal nodes. An anatomic study on 260 adults.
J Thorac Cardiovasc Surg 1989;97:623– 632.
13. Riquet M, Manac’h D, Saab M, Le Pimpec-Barthes F, Dujon A, Debesse
B. Factors determining survival in resected N2 lung cancer. Eur J Cardiothorac Surg 1995;9:300 –304.
14. Libshitz HI, McKenna RJ Jr, Mountain CF. Patterns of mediastinal
metastases in bronchogenic carcinoma. Chest 1986;90:229 –232.
15. Cahan WG, Watson WL, Pool JL. Radical pneumonectomy. J Thorac
Cardiovasc Surg 1951;22:449 – 473.
16. Cahan WG. Radical lobectomy. J Thorac Cardiovasc Surg 1960;39:
555–572.
17. Tsuchiya R. The complete hilar-mediastinal lymph node dissection. Ann
Ital Chir 1999;70:887.
18. Naruke T. Mediastinal lymph node dissection. In FG Pearson, J Deslauriers, RJ Ginsberg (Eds.), Thoracic Surgery, 1st Ed. New York:
Churchill-Livingston, 1995. Pp. 909 –917.
19. Martini N. Mediastinal lymph node dissection for lung cancer. The
memorial experience. Chest Surg Clin N Am 1995;5:189 –203.
20. Union Internationale Contre le Cancer. Lung and pleural tumours. In P
Hermanek, RVP Hutter, LH Sobin, et al. (Eds.), TNM Atlas, 4th Ed.
Berlin: Springer, 1997.Pp. 153–166.
21. American Joint Committee on Cancer. AJCC Cancer Staging Handbook.
New York: Springer-Verlag, 2002.
22. Watanabe S, Ladas G, Goldstraw P. Inter-observer variability in systematic nodal dissection: comparison of European and Japanese nodal
designation. Ann Thorac Surg 2002;73:245–249.
23. Martini N, Flehinger BJ, Zaman MB, Beattie EJ Jr. Results of resection
in non-oat cell carcinoma of the lung with mediastinal lymph node
metastases. Ann Surg 1983;198:386 –397.
24. Patterson GA, Piazza D, Pearson FG, et al. Significance of metastatic
disease in subaortic lymph nodes. Ann Thorac Surg 1987;43:155–159.
25. Izbicki JR, Thetter O, Habekost M, et al. Radical systematic mediastinal
lymphadenectomy in non-small cell lung cancer: a randomized controlled trial. Br J Surg 1994;81:229 –235.
26. Sugi K, Nawata K, Fujita N, et al. Systematic lymph node dissection for
clinically diagnosed peripheral non-small cell lung cancer less than 2 cm
in diameter. World J Surg 1998;22:290 –295.
27. Andre F, Grunewald D, Pignon J, et al. Survival of patients with resected
N2 non-small cell lung cancer: evidence for a subclassification and
implications. J Clin Oncol 2000;18:2981–2989.
28. Ichinose Y, Kato H, Koike T, et al. Completely resected stage IIIA
non-small cell lung cancer: the significance of primary tumor location
and N2 station. J Thorac Cardiovasc Surg 2001;122:803– 808.
29. Okada M, Sakamoto T, Yuki T, et al. Border between N1 and N2
stations in lung carcinoma: lessons from lymph node metastatic patterns
of lower lobe tumors. J Thorac Cardiovasc Surg 2005;129:825– 830.
30. Keller SM, Vangel MG, Wagner H, et al. Prolonged survival in patients
with resected non-small cell lung cancer and single-level N2 disease.
J Thorac Cardiovasc Surg 2004;128:130 –137.
31. Inoue M, Sawabata N, Takeda S, et al. Results of surgical intervention for
p-stage IIIA (N2) non-small cell lung cancer: acceptable prognosis predicted by complete resection in patients with single N2 disease with primary
tumor in the upper lobe. J Thorac Cardiovasc Surg 2004;127:1100 –1106.
32. Ohta Y, Shimizu Y, Minato H, et al. Results of initial operations in
non-small cell lung cancer patients with single-level N2 disease. Ann
Thorac Surg 2006;81:427– 433.
33. Sakao Y, Miyamoto H, Yamazaki A, et al. The spread of metastatic
lymph nodes to the mediastinum from left upper lobe cancer: results of
superior mediastinal nodal dissection through a median sternotomy. Eur
J Cardiothorac Surg 2006;30:543–547.
34. Groome PA, Bolejack V, Crowley JJ, et al. The IASLC lung cancer
staging project: validation of the proposals for revision of the T, N, and
M descriptors and consequent stage groupings in the forthcoming
(seventh) edition of the TNM classification of malignant tumours.
J Thorac Oncol 2007;2:694 –705.
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