COMMENTARY
Anatomy, Biology and Concepts, Pertaining to Lung
Cancer Stage Classification
Frank C. Detterbeck, MD,*† Lynn T. Tanoue, MD,*‡ and Daniel J. Boffa, MD*†
Abstract: The proposed lung cancer stage classification system
remains grounded in anatomic characteristics, although the large
patient database contributing to this revision has dramatically expanded our body of knowledge. Predictably this has led to increased
complexity due to the identification of an increasing number of
subpopulations of patients. Patterns of clinical presentation characterizing these subgroups may provide clues about the propensity of
tumors within a subgroup toward a particular pattern of biologic
behavior. This article explores concepts regarding tumor biology
that can be applied to the anatomically based new staging system.
Key Words: Lung cancer, Anatomy, Biology, Concepts, Stage.
(J Thorac Oncol. 2009;4: 437–443)
A
stage classification system provides a common nomenclature about patients with a particular type of cancer. A
common language facilitates communication among different
centers, allowing observations from different sources to be
combined and thereby enhance our collective knowledge. As
knowledge is gained, further details of a staging system can
be defined, and thus the system requires periodic revision and
refinement. In lung cancer, a major effort led by the International Association for the Study of Lung Cancer (IASLC)
Staging Committee was undertaken to inform a revision of
the Union Internationale Contre le Cancer and American
Joint Committee on Cancer staging system,1–5 involving an
unprecedented extent of data collection and scientific analysis.1–5 This has prompted us to reflect on the goals of a staging
system, the limitations of our current understanding of the
biology of lung cancer, and how underlying concepts can
help or hinder our ability to make new observations.
Inherent in the development of the nomenclature of a
staging system is the ability to define homogeneous patient
cohorts. This raises the question of how homogeneity is
*Thoracic Oncology Program, Yale Cancer Center; †Division of Thoracic
Surgery Department of Surgery, Yale University; and ‡Division of
Pulmonary and Critical Care Medicine, Department of Medicine, Yale
University, New Haven, Connecticut.
Disclosure: The authors declare no conflicts of interest.
Address for correspondence: Frank C. Detterbeck, MD, Division of Thoracic
Surgery, Yale University School of Medicine, 330 Cedar St., BB 205,
New Haven, CT 06520-8062. E-mail: frank.detterbeck@ yale.edu
Copyright © 2009 by the International Association for the Study of Lung
Cancer
ISSN: 1556-0864/09/0404-0437
Journal of Thoracic Oncology • Volume 4, Number 4, April 2009
defined. While many measures can be considered, the one
most commonly used is prognosis. Indeed, this is the primary
end point used in the analysis and staging recommendations
of the IASLC staging committee.2,6,7 Another common expectation of a staging system is to define patient cohorts for
which the same treatment approach is appropriate.
However, it must be recognized that prognosis and
treatment approaches are not static. There is an incessant
quest to define treatments that lead to better outcomes. Moreover, prognosis is continually changing due to progress in
aspects other than treatment. Advances in imaging affect the
prognosis of stage groups through the resultant stage migration.8,9 Changing methods of detection (e.g., computed tomography screening) also affect prognosis by altering the
spectrum of disease that is encountered.10
Therefore, grouping patients by prognosis alone carries
the risk that some patients will be grouped together because
they happen to have the same prognosis at the current time,
even though they are inherently different. For example,
within stage IIIa the IASLC staging revision groups together
patients with N2 involvement, those with a T4N0M0 tumor
and those with additional nodules of cancer in a different
ipsilateral lobe.2 As we explore new treatment approaches,
we may find that the optimal treatment and resultant prognosis for subpopulations of patients within a stage group or even
a T,N, and M descriptor group may be divergent.
The ideal stage classification system would reflect the
biology of the tumor, because patients grouped by tumor
biologic characteristics will probably continue to share many
similarities even as treatment approaches, staging procedures
and outcomes change. This suggests that classification by
molecular biologic characteristics may be more useful than
by anatomic characteristics. However, our current ability to
predict tumor biology is rudimentary, and we have a poor
understanding of which biologic characteristics of a tumor are
really the key factors.11–13 There was no choice for the
IASLC staging committee but to describe patient cohorts
using anatomic characteristics. Nevertheless, as we look to
the future we should use whatever means we currently have
available to define biologic behavior. This article proposes a
categorization of lung cancer by patterns of clinical presentation, which are postulated to reflect biologic behavior. This
approach has the advantage that it can be used with the
currently available anatomic descriptors as defined by the
proposed IASLC stage classification system, which are summarized in Tables 1 and 2.
437
Journal of Thoracic Oncology • Volume 4, Number 4, April 2009
Detterbeck et al.
TABLE 1. Definitions for T,N,M Descriptors in the IASLC Staging Classificationa
TNM
T (Primary Tumor)
T0
T1
T1a
T1b
T2
T2a
T2b
T3
T4
N (regional lymph nodes)
N0
N1
N2
N3
M (distant metastasis)
M0
M1a
M1b
Special situations:
TX, NX, MX
Tis
T1e
Subgroupb
Descriptions
No primary tumor
Tumor ⱕ3 cmc, surrounded by lung or visceral pleura, not more proximal than the lobar bronchus
Tumor ⱕ2 cmc
Tumor ⬎2 but ⱕ3 cmc
Tumor ⬎3 but ⱕ7 cmc or tumor with any of the followingd:
Invades visceral pleura, involves main bronchus ⱖ2 cm distal to the carina, atelectasis/obstructive
pneumonia extending to hilum but not involving the entire lung
Tumor ⬎3 but ⱕ5 cmc
Tumor ⬎5 but ⱕ7 cmc
Tumor ⬎7 cmc
or directly invading chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium,
or tumor in the main bronchus ⬍2 cm distal to the carinae,
or atelectasis/obstructive pneumonitis of entire lung,
or separate tumor nodule(s) in the same lobe
Tumor of any size with invasion of: heart, great vessels, tracheae, recurrent laryngeal nerve, esophagus,
vertebral body, or carinae;
or separate tumor nodule(s) in a different ipsilateral lobe
T1a
T1b
T2a
T2b
T3⬎7
T3Inv
T3Centr
T3Centr
T3Satell
T4Inv
T4Ipsi Nod
No regional node metastasis
Metastasis in ipsilateral peribronchial and/or perihilar lymph nodes and intrapulmonary nodes, including
involvement by direct extension
Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or
supraclavicular lymph node(s)
No distant metastasis
Separate tumor nodule(s) in a contralateral lobe;
or tumor with pleural nodules or malignant pleural disseminationf
Distant metastasis
M1aContr Nod
M1aPl Dissem
M1b
T, N, or M status not able to be assessed
Focus of in situ cancer
Superficial spreading tumor of any size but confined to the wall of the trachea or mainstem bronchus
Tis
T1SS
a
Reflects the IASLC staging Committee’s recommendations and not necessarily the UICC 7th Edition Staging System.
These subgroup labels are not defined in the IASLC publications, but are added here to facilitate a clear discussion. Goldstraw et al., J Thorac Oncol 2007;2:706 –714;
Rami-Porta et al., J Thorac Oncol 2007;2:593– 602; Postmus et al., J Thorac Oncol 2007;2:686 – 693; Rusch et al., J Thorac Oncol 2007;2:603– 612.
c
In greatest dimension.
d
T2 tumors with these features are classified as T2a if ⱕ5 cm.
e
The uncommon superficial spreading tumor in central airways is classified as T1.
f
Pleural effusions are excluded that are cytologically negative, nonbloody, transdative, and clinically judged not to be due to cancer.
IASLC, International Association for the Study of Lung Cancer; TNM, tumor, node, metastasis.
b
Proposed Categories of Biologic Behavior
Because our understanding is limited, an attempt at
characterization of tumors according to biologic behavior
is inherently speculative. We postulate that there are four
types of biologic behavior: tumors with a primary propensity for direct local invasion, those with a propensity for
spread to regional lymph nodes, those with a propensity to
develop additional foci of cancer within the lung(s), and
those with a propensity for systemic dissemination (Table
3). These categories fit commonly observed patterns of
clinical presentation, e.g., patients presenting with large
tumors and no metastases, others with small tumors and
metastatic deposits in nodes and/or distant sites, and patients with multiple foci of cancer within the lung paren-
438
chyma in the absence of any extrapulmonary involvement.
In Table 4 the new IASLC stage groups and tumor, node,
metastasis descriptors are depicted aligned according to
these clinical patterns.
Categorization according to patterns of clinical presentation may be an important concept that allows us to recognize
differences among patients within a stage grouping and similarities among patients in different groups. In Table 4, the patterns
of presentation (and the presumed patterns of biologic behavior)
are aligned vertically, while the stage groupings are aligned
horizontally. This underscores that some stage groups combine
patients with very different clinical presentations, and that there
are similarities between subgroups of patients that belong to
different stage groups.
Copyright © 2009 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 4, Number 4, April 2009
TABLE 2. Stage Groups in the IASLC Staging Classificationa
Stage group
T
N
M
I
Ia
Ib
T1a,b
T2a
N0
N0
M0
M0
IIa
T1a,b
T2a
T2b
N1
N1
N0
M0
M0
M0
T2b
T3
N1
N0
M0
M0
T1–3
T3
T4
N2
N1
N0,1
M0
M0
M0
T4
T1–4
N2
N3
M0
M0
TAny
NAny
M1a,b
II
IIb
III
IIIa
IIIb
IV
a
Reflects the IASLC staging Committee’s recommendations and not necessarily the
UICC 7th edition staging system.
IASLC, International Association for the Study of Lung Cancer; TNM, tumor,
node, metastasis.
TABLE 3. Proposed Patterns of Biologic Behavior of Lung
Cancer
Tumors marked by:
Propensity for local growth/invasion
Propensity for lymph node involvement
Propensity for multifocal disease in lung parenchyma
Propensity for systemic dissemination
Attempting to predict biologic behavior is fraught with
more uncertainty than identifying clinical patterns of presentation. It seems reasonable, however, to use characteristics observed in individual tumors at presentation to estimate the future
behavior. In very early tumors, there may be insufficient growth
or development to form the basis for a prediction. In tumors
presenting somewhat later in their development we think that the
predominant pattern observed at presentation may well predict
future behavior. Anatomic descriptors remain the most studied
aspects of lung cancers, and are the only characteristics for
which data exists in a large number of patients. Furthermore, the
proposed categorization shown in Table 4 has the advantage that
it is readily applicable around the world (without genomic
analysis). Therefore it seems that this might be a useful tool to
investigate how well we are able to predict biologic behavior.
There is ample clinical experience indicating that some
tumors primarily grow and invade locally, and seem to have
a diminished propensity for nodal or systemic dissemination.
Many reports substantiate that patients with local invasion of
additional structures exhibit good survival after resection,
particularly when a complete resection is accomplished. The
Anatomy, Biology and Concepts
good outcome with local therapy alone corroborates the
postulated decreased propensity for dissemination. A common example are tumors invading the chest wall (consistent
50 – 60% 5 years survival for T3N0M0 tumors after R0
resection).14 Good survival has been reported after complete
resection of T4invN0M0 tumors invading the vertebral column15–17 or carina.18 –21 However, much of the data is difficult
to interpret because of inclusion of patients with nodal involvement and incomplete resections. In the extensive database of the IASLC staging project, the good survival of
patients with locally invasive or large tumors without significant nodal involvement was clearly documented. In summary, although there may be difficulties in the ability to
deliver effective local therapy to tumors marked by local
invasion, there is data to support the postulated decreased
propensity for nodal or systemic metastases in this subgroup.
Patients with tumors involving lymph nodes seem to
have a higher propensity for both regional and systemic
recurrence. Treatment increasingly involves both more aggressive local therapy as well as more aggressive systemic
therapy. This includes adjuvant chemotherapy after completely resected stage II(N1) and IIIa(N2) tumors, exploration
of the role of surgery in addition to chemotherapy and
radiotherapy in stage IIIa(N2), and the use of high dose
three-dimensional conformal radiotherapy together with chemotherapy for stage III(N2,3) tumors.22
The category that is the most obviously distinct, yet
also the hardest to accurately define, are the patients with
additional nodules of tumor in the lungs. It has long been
recognized that a satellite focus of cancer in the same lobe
carries a good prognosis, only slightly different than that of
the same tumor without a satellite.23–32 Similarly, multiple
studies have suggested relatively good outcomes for patients
with an additional focus of tumor in an ipsilateral different
lobe, clearly better than for patients with other forms of
distant spread.23,25–30,32,33 Frequently such patients have multiple additional malignant foci in the lungs.27,28,33,34 An extreme example of this process may be those patients with what
is termed a “pneumonic type” of adenocarcinoma, meaning
diffuse involvement of a portion of the lung parenchyma.35–37 A
mechanism for how such “spread” occurs is not readily apparent, but the clinical observations do not seem to fit the concepts
of either lymphatic or hematogenous dissemination. It appears
that a better concept for the behavior of these tumors is not
“spread” from one area to another, but the development of
multifocal disease. This may be due to “field cancerization”, or
it may be a yet obscure change in the host microenvironment
that sets the stage for this pattern of tumor development. These
tumors appear to have a lower propensity for nodal involvement
or distant dissemination.29,33,37– 40
Data regarding the proportions of patients entered into
the IASLC database (Table 5) shows that the majority of
patients fall into the category defined by the extent of nodal
involvement (57%). A smaller group is characterized by the
extent of the primary tumor (28%). The patients whose stage
is characterized by the presence of additional nodules of
tumor account for only a small proportion (2.5%). Although
a population-based registry is needed to define the true
Copyright © 2009 by the International Association for the Study of Lung Cancer
439
Journal of Thoracic Oncology • Volume 4, Number 4, April 2009
Detterbeck et al.
TABLE 4. IASLC Stage Grouping Aligned by Patterns of Biologic Behaviora
Local Growth
and Invasion
Nodal
Involvement
Multifocal Disease
(Additional Nodules)
Systemic Dissemination
Stage Group
T
N
T
N
T
N
M
Ia
—
—
T1a,b
N0
—
—
M0
Ib
—
—
T2a
N0
—
—
M0
.....................................................................................................................................................................................................................................................
II a
T2b> 5
—
—
N0
—
—
—
—
M0
—
—
T1a,b
T2a
N1
N1
—
—
—
—
M0
M0
.....................................................................................................................................................................................................................................................
II b
III a
T2b> 5
N1
—
—
—
—
M0
T3binv,> 7
—
N0
—
—
—
—
—
—
—
N0
M0
M0
T3binv,> 7
T4inv
—
—
—
N1
N0,1
—
—
—
—
—
T1–3Any
—
—
—
—
N2
—
—
—
—
—
N1
N0,1
M0
M0
M0
M0
M0
T4inv
—
—
N2
—
—
—
T1–4Any
—
—
N3
—
—
—
N2
M0
M0
M0
—
—
—
—
—
—
—
—
—
—
—
T3
Satell
—
—
—
T3
T4
Satell
Ipsi Nod
.....................................................................................................................................................................................................................................................
III b
IV
—
—
T4
Ipsi Nod
M1acContr Nod
—
—
—
—
—
—
M1ac PlDissem
M1bc
a
Reflects the IASLC staging Committee’s recommendations and not necessarily the UICC 7th Edition Staging System.
T3Cent is included whenever T3inv is denoted; it is not separately recorded in order to simplify the table.
c
Any T, Any N.
b
incidence of these categories of patients, the IASLC database
provides a rough estimate of the proportions. This rough
estimate points out that the impression of complexity in the
IASLC staging system is created primarily by relatively small
subsets of patients.
DISCUSSION
A critical examination of accepted clinical concepts is
important because so much of how we approach patients, and
even how we conduct research, is driven by preconceived
beliefs (often in the absence of data). Viewing the IASLC
stage subgroups from the perspective of patterns of clinical
presentation has several potential benefits. There is reason to
think that these patterns of clinical presentation may well
correlate with biologic behavior of the tumor. This categorization may have implications for the relevance of local and
systemic therapies as well as of specific pretreatment staging
procedures. It may turn out that a particular treatment
strategy that addresses a pattern of biologic behavior may
be useful for many patients within a vertical category
outlined in Table 4, even though the patients fall within
different stage groups. We should consider these concepts
as we analyze the results of new treatments so that we do
not overlook an observation because we are focused only
on horizontal stage groups as a whole.
440
What exactly is meant by “biologic behavior” of a
tumor? From a clinical standpoint, the relevant issues are the
rapidity of growth of the tumor and the pattern of spread into
adjacent organs or distant sites. By definition, a cancer has the
ability to grow in an unlimited fashion, to invade other
normal tissues, and/or to metastasize and grow in sites distant
from the primary tumor. It is the aggressiveness of the tumor
and the pattern of dissemination that have the greatest influence on prognosis and on the general approach to treatment.
On a cellular level, biologic behavior includes the genetic,
regulatory and metabolic factors that determine cellular
growth. It also includes the interactions between tumor cells,
the local tissue microenvironment and the host in general.
We have by necessity focused on the macroscopic
aspects of tumor biology rather than cell signaling or genomic
aspects. Clearly major advances are being made into understanding cellular mechanisms of tumor growth.41– 43 At
present, however, these insights are limited to small groups of
patients. More importantly, characterization of tumors by
cellular biologic features requires sophisticated laboratory
analysis, and thus from a practical standpoint is not easy to
incorporate in clinical practice. Furthermore, cellular biologic
features are not currently readily grafted onto the lung cancer
staging system, which remains grounded in anatomic features. This is not meant to imply that molecular biologic
Copyright © 2009 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 4, Number 4, April 2009
Anatomy, Biology and Concepts
TABLE 5. Relative Proportion of IASLC Stage Grouping by Patterns of Biologic Behaviora
Relative Proportion (% of all patients)b
Stage Group
TNM Classification
Tumor Extent
Nodal Involvement
Ia
T1a,b N0 M0
15
Ib
T2a N0 M0
13
II a
T2b 5 N0 M0
T1a,b N1 M0
T2a N1 M0
Multifocal (Add’l Nodules)
Systemic Dissemination
.....................................................................................................................................................................................................................................................
4
2
4
.....................................................................................................................................................................................................................................................
II b
T2b
5 N1 M0
T3cinv,> 7 N0 M0
T3Satell N0 M0
III a
c
inv,> 7 N1 M0
T4inv N0,1 M0
T1–3Any N2 M0
T3Satell N1 M0
T4Ipsi Nod N0,1 M0
T3
2
13
0.6
6
2
20
0.3
0.4
.....................................................................................................................................................................................................................................................
III b
T4Inv N2 M0
1d
3e
T1–4Any N3 M0
T4Ipsi Nod N2M0
0.3
f
IV
M1a
0.9
Contr Nod
M1af Pl Dissem
M1bf
Total (%)
3
10
28
a
57
2.5
13
th
Reflects the IASLC staging Committee’s recommendations and not necessarily the UICC 7 Edition Staging System.
Proportion of patients in IASLC database as defined by “best stage” (pathologic, if available, otherwise clinical).2 Values are a percentage, rounded to the nearest integer (or
nearest 10th when less than 1). This incidence of patients within the IASLC database does not necessarily represent the true incidence of each stage group, because the data came
from a variety of source types, and exclusion criteria may have disproportionately excluded more patients in certain subgroups (e.g. incomplete data may be more common among
M1 patients).
c
T3Cent is included whenever T3inv is denoted; it is not separately recorded in order to simplify the table.
d
Including T4N3M0.
e
Excluding T4N3M0.
f
Any T, Any N.
b
characterization is less important; in fact it may become
the dominant factor at some point in the future. It is simply
less broadly applicable across the world and less readily
applicable to the lung cancer stage classification system at
this time.
Adding biologic categorization to the anatomic grouping
of the staging system may be most helpful in patients in the stage
III group. These patients comprise a large percentage of patients
with NSCLC and a group whose optimal care has been particularly difficult to define, perhaps because stage III includes a
variety of T and N subgroups. The clinical pattern of presentation may help guide the selection of appropriate treatment. For
example, an extensive surgical resection may be curative for a
T4InvN0M0 tumor but less beneficial in patients with a T13N2M0 tumor. Conversely systemic treatment with a new targeted agent may be of benefit in patients with a T1-3N2M0
tumor but not for those with a T4InvN0M0 tumor. A limited
(sublobar) resection may be of value for a T4Ipsi NodN0M0
tumor but not a T1N2M0 tumor.
There is reason to consider a propensity for nodal
involvement separately from a propensity for distant metas-
tases. Although increasing nodal stage is clearly associated
with an increased incidence of distant metastases, dissemination via the lymphatic system is no longer considered the
mechanism for the development of distant metastases. Clinical experience certainly documents many patients who develop distant metastases after an apparent curative resection,
but never have any evidence of nodal involvement. Multiple
studies have shown that tumor cells are commonly present in
the bone marrow or peripheral blood, even in patients with
early stage lung cancer, when assessed by sensitive assays.44 – 49 Moreover, the ability to detect these cells does not
correlate with the nodal stage, although it is significantly
associated with a higher distant recurrence rate.44 – 48 The
development of metastases is determined by a complex interplay of characteristics of the tumor cell population, the
host microenvironment and the interactions between them.50
It is best to consider a propensity for nodal involvement and
for systemic metastases separately, although both factors may
be at play in many patients.
The proposed categorization within the IASLC stage
groupings seems logical when dealing with tumors at the ex-
Copyright © 2009 by the International Association for the Study of Lung Cancer
441
Journal of Thoracic Oncology • Volume 4, Number 4, April 2009
Detterbeck et al.
tremes (e.g., a T1N3M0 or a T4InvN0M0 tumor), but it is less
obvious how some other subgroups should be viewed. For
example, should a T4InvN2M0 (stage IIIb) tumor be categorized
predominantly by the invasive nature of the primary tumor or by
a propensity for lymphatic involvement? In this example there
may be a difference between direct extension of the primary
tumor into a node versus spread to noncontiguous nodes via
lymphatic channels. The same reasoning may be applicable to
T2b⬎5N1M0, T3InvN1M0 and T4InvN1M0 tumors: i.e., there
may be a difference between direct lymph node invasion and
involvement of noncontiguous nodes.
Another group of patients in whom the clinical presentation does not lend itself easily to speculation about the
biologic behavior are those patients with multifocal disease as
well as node involvement. For T3SatellN1M0 or T4IpsiN1M0
tumors it is easier to accept the multifocal characteristic as
being the most distinctive feature. However, patients with a
T4IpsiN2M0 tumor may be much more likely to actually have
multiple metastases, with the additional parenchymal nodule
being the only “distant” site that was apparent at presentation.23,24 In other words, such patients may, in fact, turn out
to fit better with patients with a propensity for nodal and
for systemic spread, similar to the T1-3AnyN2M0 or
TAnyNAnyM1b patients. Reclassifying such patients in this
manner, however, is in conflict with the IASLC staging
committee’s findings and recommendations. Furthermore,
only a minority of patients with additional pulmonary foci of
cancer present with N2 nodal involvement.2,29 Therefore, it
seems most appropriate to view the T4IpsiN2M0 patients
among other patients with multifocal disease and as a subgroup of stage IIIb, consistent with the IASLC staging committee’s recommendations, at least until significant data is
generated that supports a different view.
Whether pleural dissemination should be viewed as a
form of direct invasion, of multiple nodules or of distant
dissemination is also unclear. It may be that there are different types of patients with pleural involvement (e.g., those
with otherwise limited disease and no effusion but with
several visceral pleural nodules, and those with a malignant
pleural effusion, who often have large tumors with significant
nodal involvement). The fact that patients with pleural dissemination but no nodal metastases have exhibited good
survival after resection (25–30% 5 year survival) corroborates this speculation.3,51 However, most patients with pleural
dissemination have extensive tumors, multiple metastases,
and poor survival. Therefore, we think it is best to consider
these patients as having a form of distant metastatic spread, at
least until we can develop a valid way to subclassify them.
Other methods of defining the biologic behavior of a
lung cancer do not appear to be close to being ready for
clinical application. There have been many reports that
positron emission tomography (PET) intensity correlates with
prognosis, suggesting that PET intensity may be a marker for
the metabolic rate of a tumor as well as the propensity to
metastasize.52 However, these studies have generally not
accounted for other prognostic factors such as tumor size or
stage. The only carefully controlled, prospective study found
that PET intensity offers no significant independent prognostic
442
information, and that size and stage are the dominant factors.11
Much attention has also been given to characterization of genetic
changes in tumor cells.53,54 However, most of the studies have
had significant methodological flaws, and clinical application
appears elusive.55 Furthermore, different studies have identified
different genes as predictive of the same outcome with only rare
overlap.56 In general, the prognostic prediction based on genetic
characterization does not outperform conventional clinical and
pathologic factors at this time.12,56 The IASLC staging committee also considered this issue, and concluded that molecular
characterization of tumors was insufficiently studied to be included in the current staging revision.
We believe that using patterns of clinical presentation
as a potential tool to predict the behavior of a tumor is a
reasonable avenue to explore. Clearly research is needed to
determine whether the speculation of a propensity to a particular type of progression is borne out. Because the ability to
define biologically similar cohorts using anatomic characteristics will be imperfect, it is likely that the categorization
proposed will not predict patterns of behavior in all subgroups. Nevertheless, we believe that the concept of incorporating patterns of biologic behavior is worthy of exploration. We hope the proposed categorization will stimulate a
productive debate, and that clinical investigation may bring
about deeper insights into tumor biology that prove useful in
the management of patients with lung cancer.
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