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CHEST Supplement

journal.publications.chestnet.org CHEST / 143 / 5 / MAY 2013 SUPPLEMENT e191S

DIAGNOSIS AND MANAGEMENT OF LUNG CANCER, 3RD ED: ACCP GUIDELINES

Stage classification is an essential part of the approachto patients with cancer, and there are many things

we would like to get from a stage classification. Theprimary purpose of the classification is to consistently

describe the anatomic extent of disease, thus providinga common, consistent language. The anatomic extentof the tumor has a major impact on which treatment

we choose and what the outcome will be. However, itis important to recognize that the stage classificationdoes not by itself completely define the prognosis(which depends on multiple factors, eg, comorbidi-ties, performance status, treatment given) or serve asa treatment algorithm (which is driven by data from

clinical trials and treatment selection criteria). Effortsto develop a comprehensive prognostic index systemare under way.

Stage classification is founded on the TNM system,

which dates back to 1944. Furthermore, the methodof staging is classified as clinical stage (denoted by theprefix c) and pathologic stage (denoted by the prefix p).Clinical stage is determined using all informationavailable prior to any treatment, and pathologic stageis determined after a resection. The extent of clin-ical staging can vary from a clinical evaluation alone(history and physical examination) to extensive imaging(CT and PET scans) or invasive staging techniques.It must be emphasized that a surgical staging proce-dure (eg, mediastinoscopy) is still part of clinical stag-ing because surgical resection as a treatment has not

taken place.

The current Lung Cancer Stage Classification system is the seventh edition, which took effect inJanuary 2010. This article reviews the definitions for the TNM descriptors and the stage groupingin this system. CHEST 2013; 143(5)(Suppl):e191Se210S

Abbreviations: AAH5atypical adenomatous hyperplasia; ACCP5American College of Chest Physicians; AJCC5American Joint Committee on Cancer; BAC5bronchioloalveolar carcinoma; GGO5ground glass opacity; IASLC5Inter-national Association for the Study of Lung Cancer; ITC5isolated tumor cell; UICC5Union Internationale Contre leCancer

The Stage Classification of Lung Cancer

Diagnosis and Management of Lung Cancer,3rd ed: American College of Chest Physicians

Evidence-Based Clinical Practice Guidelines

Frank C. Detterbeck, MD, FCCP; Pieter E. Postmus, MD, PhD, FCCP;and Lynn T. Tanoue, MD, FCCP

Manuscript received September 24, 2012; revision acceptedNovember 30, 2012.

Affiliations: From the Yale University School of Medicine

(Dr Detterbeck), New Haven, CT; Department of Pulmonary Dis-eases (Dr Postmus), VU University Medical Center, Amsterdam,The Netherlands; and Section of Pulmonary and Critical Care Med-icine (Dr Tanoue), Yale School of Medicine, New Haven, CT.Funding/Sponsors:The overall process for the development ofthese guidelines, including matters pertaining to funding and con-flicts of interest, are described in the methodology article. 1Thedevelopment of this guideline was supported primarily by theAmerican College of Chest Physicians. The lung cancer guidelinesconference was supported in part by a grant from the Lung Can-cer Research Foundation. The publication and dissemination ofthe guidelines was supported in part by a 2009 independent edu-cational grant from Boehringer Ingelheim Pharmaceuticals, Inc.COI grids reflecting the conflicts of interest that were current asof the date of the conference and voting are posted in the onlinesupplementary materials.

Disclaimer:American College of Chest Physicians guidelines areintended for general information only, are not medical advice, anddo not replace professional medical care and physician advice,

which always should be sought for any medical condition. Thecomplete disclaimer for this guideline can be accessed at http://dx.doi.org/10.1378/chest.1435S1 .Correspondence to: Frank C. Detterbeck, MD, FCCP, YaleSchool of Medicine, 330 Cedar St, PO Box 208062, New Haven,CT 06520-8062; e-mail: [email protected] 2013 American College of Chest Physicians. Reproductionof this article is prohibited without written permission from theAmerican College of Chest Physicians. See online for more details.DOI: 10.1378/chest.12-2354

wnloaded From: http://journal.publications.chestnet.org/ by Rafael Durand on 05/31/2013
http://journal.publications.chestnet.org/http://dx.doi.org/10.1378/chest.1435S1http://dx.doi.org/10.1378/chest.1435S1mailto:[email protected]://journal.publications.chestnet.org/http://dx.doi.org/10.1378/chest.1435S1http://dx.doi.org/10.1378/chest.1435S1mailto:[email protected]


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e192S The Stage Classification of Lung Cancer Diagnosis

central location) and were, therefore, placed withinthis group.

The size of a tumor is defined as the greatest dimen-sion, but how this is determined is not addressed byAJCC, UICC, or IASLC. The ACCP panel suggeststhat for consistency, this measurement be done onan axial CT image using lung windows during inspira-tion whenever possible (c stage); for p stage, we sug-

gest the greatest dimension (in any direction) of thespecimen fixed after inflation or of the unfixed spec-imen (fixation causes about 20% shrinkage).15Furtherissues arise with semisolid or ground glass opac-ities (GGOs), which have not been addressed by theAJCC or UICC. One can measure the solid or theground glass component with either mediastinal orlung windows on a CT image. Emerging data sug-gest that the size of the solid (invasive) componentis of greater prognostic value than the ground glass(lepidic) component.16-22The ACCP panel suggestsrecording the size of both the GGO and the solid

component on lung windows (or the percent solidby area) for c stage and both the entire tumor (includ-ing lepidic portions) and the invasive component forp stage.14This suggestion is consistent with a recentUICC supplement handbook.5

2.2 Invasion

There were insufficient numbers of patients forwhom reliable data were available to investigate thevalidity of other traditional T2, T3, or T4 descriptors(visceral pleural invasion, central location within a

lobar or mainstem bronchus, partial or complete atel-ectasis, direct invasion of particular structures, etc).These traditional definitions were retained even thoughthey could not be confirmed because there were nodata to suggest that they are not valid.

Invasion beyond the elastic layer of the pleura isdefined as T2, including invasion into an adjacentlobe. Elastin stains should be used whenever there isambiguity.23T3 includes invasion into the parietalor mediastinal pleura or the parietal pericardium.T4 includes invasion of the visceral (inner) pericar-dial surface and the intrapericardial pulmonary artery

and pulmonary veins. Involvement of either the intra-pericardial or extrapericardial vena cava or aortais considered T4. We suggest that involvement ofthe azygous vein be classified as T3 because it isnot counted among the great vessels (but this is notaddressed by IASLC, AJCC, or UICC).

A Pancoast tumor is classified as T4 if there isunequivocal involvement of C8 or higher nerve roots,cords of the brachial plexus, subclavian vessels, verte-bral bodies, lamina, or spinal canal. The tumor is clas-sified as T3 if it involves only thoracic nerve roots(eg, T1 or T2 nerve roots).

The Union Internationale Contre le Cancer (UICC)and the American Joint Committee on Cancer (AJCC)are the official bodies that define, review periodically,and refine the stage classification systems. The cur-rent seventh edition of the lung cancer staging sys-tem was based on a major initiative undertaken bythe International Association for the Study of LungCancer (IASLC). This 12-year project increased the

patient base from 5,319 (collected over several decadespredominantly at one institution) to .100,000 (fromaround the world, all cases diagnosed between 1990and 2000).

In validating where to make a distinction betweenone stage descriptor or group and another, the IASLCrequired that consistent differences in prognosis hadto be seen in data sets from different continents, data-base types, clinical and pathologic staging, and his-tologic subtypes.2Furthermore, external validationagainst large databases was done. The statistical anal-

ysis was quite sophisticated; in all, the current classi-

fication is a quantum leap forward that is unequalledby any other cancer site. However, although the data-base was large and involved many institutions from20 countries, the distribution of cases was not uni-form. Certain patient subgroups came predominantlyfrom one region or one type of database and weretreated in many different ways, and the IASLC data-base did not report treatment-specific outcomes.

1.0Methods

This article addresses the official Lung Cancer Stage Classi-

fication system. Therefore, the primary sources of informationwere the AJCC and UICC staging manuals.3-5These sources weresupplemented by the publications of the IASLC InternationalStaging Committee, which provided the basis for the AJCC/UICCclassification,2,6-12as well as American College of Chest Physicians(ACCP) publications that reviewed and discussed details of theclassification.13,14

2.0T Descriptor

2.1 Size

A detailed analysis of tumor size by the IASLC

staging committee confirmed that 3 cm was signifi-cant as a cut point; thus, the definition of T1 vs T2

was retained. In addition, significant cut points wereidentified at 2, 5, and 7 cm. Therefore, subgroups weredefined for T1 (T1a and T1b) and T2 (T2a and T2b)as shown in Figure 1. The survival differences betweeneach size subgroup were highly statistically signifi-cant in pathologically staged patients; among clini-cally staged patients, the trends were consistent butnot always significant (probably because of a morelimited data set). Tumors.7 cm led to survival thattracked with other definitions of T3 (ie, invasion,



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survival than those with pathologic multizone N2involvement (5-year survival, 34% vs 20%; P,.001).In fact, the survival curves of patients with pathologicmultizone N1 and single-zone N2 involvement werealmost superimposed.8However, the prognostic impactof the number of pathologic nodal zones involvedcould not be validated within T-stage categories andby geographical region, type of databases, or clinical

staging because the number of patients in the subsetswas too small.8Therefore, the IASLC staging com-mittee decided against subdivision of N categories.The prognostic impact of nodal involvement by directextension of a primary tumor also could not be vali-dated through the IASLC database because of insuf-ficient sample sizes but was retained because it isconsistent with general UICC and AJCC rules.

3.1 Node Map

The IASLC node map is shown in Figures 3 and 4.Important features include better definition of thesubcarinal zone as extending down to the level oforigin of the left lower lobe and right middle lobebronchus.24The border between left- and right-sideparatracheal nodes is the left lateral border of the tra-chea (not the midline). The 4R nodal area extendsfrom the lower border of the left innominate vein tothe lower border of the azygous vein; the 4L nodalregion extends from the level of the top of the aorticarch to the upper border of the left-side pulmonaryartery medial to the ligamentum. The level 2 regionsextend from the border of level 4 to the upper borderof the manubrium in the midline. The supraclavicu-lar nodes extend from the lower border of the clavi-cles to the lower border of the cricoid. Further detailsand definitions of all the node stations can be foundin Rusch et al.24

3.2 Criteria for Pathologic N Assessment

The following comments apply to nodal staging atthe time of resection. Issues regarding clinical (pre-treatment) staging are discussed in section 7.0 of thisarticle, Type of Stage Classification.

A general AJCC/UICC recommendation is that at

least six lymph nodes/stations be sampled for patho-logic node staging. The IASLC manual recommendsthat three mediastinal (including level 7) and threeN1 nodes/stations be sampled. Whether the numberis supposed to apply to node stations or individualnodes is undefined. Moreover, the pathologist cannotdistinguish six nodal fragments from six separatenodes (unless the surgeon is meticulous in how nodesand fragments are labeled and submitted). However,the IASLC staging committee encourages systematicintraoperative node assessment as recommended byclinical guidelines.25,26

Extrathoracic node involvement is designated as M1b(eg, a positive axillary node).

Further analyses were done to explore whetherparticular node stations within an N category hadany particular impact. No such relationship could beidentified (Fig 2).8 Specifically, there was no differ-ence in survival among patients with involvement ofonly peripheral N1 nodes or hilar N1 nodes, and no

difference based on which N2 nodal stations wereinvolved. This was true globally as well as within geo-graphic regions. Survival among patients with pN2right upper lobe tumors with and without N1 involve-ment (skip metastases) was not different, althoughthere was a slight difference among such patients

with a left upper lobe tumor.8The IASLC staging committee developed a new

node map24to overcome ambiguities arising from dis-crepancies between previous node maps in use in dif-ferent geographic regions. Furthermore, the committeedefined several nodal zones as follows: a supraclavic-

ular zone (station 1), an upper zone (stations 2-4), anaortopulmonary zone (stations 5 and 6), a subcari-nal zone (station 7), a lower zone (stations 8 and 9),a hilar zone (stations 10 and 11), and a peripheral zone(stations 12-14). There were no differences in prog-nosis among involvement of different nodal zones

within the N1 or N2 category. Specifically, there wasno difference between patients with a left upper lobetumor and involvement of nodes only in station 5 and6 and patients with a tumor in a different lobe andinvolvement of another single N2 nodal zone.8

The number of involved nodal zones appeared to

have a prognostic impact. Patients with pathologicsingle-zone N1 involvement had better survival thanthose with pathologic multizone N1 involvement (5-yearsurvival, 48% vs 35%; P,.09). Similarly, patients

with pathologic single-zone N2 involvement had better

Figure2. [Section 3.0] Median survival (mo) of patients in theInternational Association for the Study of Lung Cancer database withsingle lymph node zone involvement.8NS5not significant.



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Furthermore, the definition of number of nodes/sta-tions needed for pathologic staging by IASLC andAJCC is confusing. If all nodes are negative, the tumoris defined as pN0, regardless of the number sam-pled, yet if some are positive, it is implied that onlycN status be used if fewer than six nodes/stations

were sampled. To avoid this awkward inconsistency,the ACCP panel endorses the suggestion14that when-

ever fewer than six nodes/stations are sampled atresection, the tumor is classified as pN0, pN1, or pN2

with the uncertainty descriptor [eg, pN0(un)], as isdescribed in section 8.0 of this article, AdditionalDescriptors. This descriptor has been suggested byIASLC for further testing relative to the complete-ness of resection (R) classification; however, extrapo-lation to address an inconsistency in the formal rules

Figure3. [Section 3.1] The International Association for the Study of Lung Cancer lymph node map,including the proposed grouping of lymph node stations into zones for the purposes of prognostic anal-

yses. Ao5aorta; Eso5esophagus; L5left side; mPA5main pulmonary artery; R5right side; SVC5superior vena cava; T5trachea. Reproduced with permission from Rusch et al.24

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regarding the definition of pN status seems reason-able to the panel.

Biopsy of only one sentinel node is consideredadequate and is denoted as pN0(sn) if findings arenegative and pN1-3(sn) if positive, reflecting the level

of the sentinel node. However, sentinel node iden-tification in lung cancer is variable and not widelypracticed.27-29

4.0 M Descriptor

The new stage classification system no longer rec-ognizes the term MXbecause clinical staging infor-mation is always available. A history and physicalexamination are critical parts of clinical staging andoften are very reliable without further imaging orbiopsy.

The presence of distant metastases is classified asM1b.9Slightly worse survival was seen in patients

with multiple vs a solitary distant metastasis (mediansurvival, 5 months vs 6 months; 1 year survival, 20%

vs 23%; P50,006).9No differences were noted by

the site of a solitary distant metastasis except slightlyshorter survival for a solitary brain metastasis. How-ever, the data set was too limited for adequate valida-tion, and further subdivision of the M1b category wasnot undertaken.9

Pleural (or pericardial) involvement (either mul-tiple implants or a malignant effusion) is classified asM1a because of slightly better survival than for dis-tant metastatic sites and worse survival than for othercategories of T4.9These prognostic differences werehighly statistically significant and held up to inter-nal validation (across database types and geographic

Figure4. [Section 3.1] A-F, Illustrations of how the International Association for the Study of Lung Cancerlymph node map can be applied to clinical staging by CT scan in axial (A-C), coronal (D), and sagittal(E, F) views. A and B, The border between the right- and left-side paratracheal region is shown. Az5azy-gous vein; InV5innominate vein; LLLB5left lower lobe bronchus; Lt5left; MB5mainstem bron-chus; PA5pulmonary artery; Rt5right; SCA5subclavian artery; SPV5superior pulmonary vein. SeeFigure 2 legend for expansion of other abbreviations. Reproduced with permission from Rusch et al.24



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regions) as well as external validation (ie, the Surveil-lance Epidemiology and End Results [SEER] database).9The IASLC, AJCC, and UICC manuals are confus-ing about whether M1a applies to only the ipsilateralpleura or also to the contralateral pleura14; the ACCPpanel suggests that it apply to both.

5.0Stage Grouping

The IASLC staging committee defined stage group-ings (Figs 5, 6). Despite the recognition of many newsubdivisions of the T and M descriptors, the stagegrouping has no new subdivisions. However, the def-inition of the stage groups has become more com-plex because of the additional T and M descriptorsubgroups. An online tool to manage the complexityand to assist in on-the-spot definition of a tumorsstage is available at http://staginglungcancer.org.30Illustrations of the TNM categories and subcate-gories included within each stage group are shown

in Figures 7 to 9.

6.0 Additional Tumor Nodules andMultiple Primary Lung Cancers

The classification of patients with additional tumornodules has created confusion largely related to a lackof appreciation of distinctly different categories ofsuch nodules. Applying a classification system intendedfor one category to a different group has the potentialto lead to suboptimal treatment and outcomes.

The first category involves patients with a newlyfound lung cancer who have another (small) noduledetected by imaging. The majority (about 75%) ofadditional pulmonary nodules seen on CT imaging inpatients with potentially operable cI to cIIIa primarylung cancer are benign (see Evaluation of Individuals

With Pulmonary Nodules: When Is It Lung Can-cer? by Gould et al31 in the ACCP Lung CancerGuidelines).32-35An expert panel (ie, a multidisciplinarytumor board that includes chest radiology, thoracicsurgery, and pulmonary medicine) usually can arriveat a strong consensus about most of these lesions.36Although firm data are lacking, experience suggeststhat the judgment is seldom wrong when such aninformed review deems an additional nodule to most

likely be benign.36A second category involves patients with an advanced

primary cancer (most often also with nodal involve-ment) who have several pulmonary nodules or a singlepulmonary nodule and other sites that appear typ-ical for distant metastases. Again, the judgment ofa tumor board that the additional nodules in such apresentation represent metastatic disease is rarelycalled into question by the subsequent course of thedisease (although specific data documenting thisare lacking).

6.1 Second Primary Lung Cancers

Occasionally, patients with a typical clinical presen-tation of a lung cancer (ie, a solid, spiculated mass ina patient with lung cancer risk factors) also exhibit asecond lesion with such a typical appearance (eithersynchronously or metachronously). In fact, the inci-dence of a second primary lung cancer has been con-sistently found to be approximately 1.5% to 2% perpatient per year.37-47Traditionally, this group has beendefined by a clinical team guided by criteria devel-oped empirically by Martini and Melamed48in 1975

Figure 5. [Section 5.0] Stage groups according to TNMdescriptor and subgroups. Reproduced with permission fromDetterbeck et al.13

Figure6. [Section 5.0] TNM elements included in stage groups.Adapted with permission from Detterbeck et al.13

*Percentage of patients in IASLC database according to best stage(rounded to nearest integer).10

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and more recently refined by the ACCP using indi-rect data (Fig 10).34,49The majority of tumors clas-sified in this way have been of the same histologictype,37,41,42,50-61which is logical because the etiology ofboth cancers is likely the same (ie, genetic predispo-sition, environmental exposures). Furthermore, similarsurvival results have consistently been found whetherthe histologic type is the same or different,51-55,58,60-66suggesting that the traditional definition of secondprimary lung cancers based on clinical features (asopposed to one based only on different histology) isgenerally correct.

The IASLC staging committee puts the responsi-bility of identifying second primary lung cancerssquarely on the pathologist.6However, defining sec-ond primary lung cancers primarily by histologic fea-tures is problematic for several reasons. First, thisdeviates from the definition that has been in use,thereby defining patients differently moving forwardthan what was done in the IASLC database. Second,this creates tremendous pressure to use genetic andmorphologic characteristics that are not yet standard-ized or validated. Finally, pathologic assessment hasprimarily involved resected specimens, yet clinical

Figure7. [Section 5.0] Graphic illustration of stages 0, I, and II. Reproduced with permission fromDetterbeck et al.13



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management necessitates a preoperative definition. Theapplicability of postoperative data to limited biopsyspecimens is poorly defined.

Differentiation of adenocarcinomas (in resectedspecimens) by the percentage of morphologic pat-terns (eg, acinar, papillary) has been proposed.16,19,22,66-70Definition of second primary lung cancers by geneticcharacteristics has produced conflicting results sofar.71-77How valid these measures are in differenti-ating a second primary lung cancer from a metastasisrequires further study, and whether these techniquescan be applied to small biopsy specimens is unclear.

The AJCC, UICC, and IASLC rules are confusingwith regard to stage classification. The IASLC statedthat multiple synchronous primary tumors shouldbe staged separately.6However, the next sentencestates, The highest T category and stage of diseaseshould be assigned and the multiplicity of the num-ber of tumors should be indicated in parenthesis,e.g. T2(m) or T2(5).6It seems contradictory that sepa-rate staging can be achieved by combining all tumorsunder one TNM designation. The AJCC specified thatthis multiple tumor classification T(m) applies to tumorsof the same histology,4but the IASLC implied that

Figure8. [Section 5.0] Graphic illustration of stages IIIA and IIIB. Reproduced with permission fromDetterbeck et al.13

the T(m) NM classification be used even with differ-ent histologic types.6The UICC 2010 manual did notcomment on this,3but the 2012 supplement manualstated, A tumor in the same organ with a differenthistologic type is counted as a new tumor.5Finally,the AJCC manual stated that in simultaneous bilat-eral cancers in paired organs, the tumors are classifiedseparately as independent tumors in different organs,4

with essentially the same wording used by UICC andIASLC.3,6Whether this means a TNM designation foreach one or for both together is not explained. Fur-thermore, there is confusion about whether the lungs

are considered together as one organ or two pairedorgans (unclear in AJCC but clearly listed as a pairedsingle organ by UICC).3,4

Therefore, the ACCP panel endorses the sugges-tion that second primary lung cancers be defined byan experienced multidisciplinary team,14 using collec-tive judgment and considering all information (includingthe imaging, risk factors, suspicion of distant dissem-ination, and the pathologists confidence given theavailable specimens). A careful evaluation for distantand mediastinal metastases is strongly recommended(see the articles Methods for Staging Non-small Cell



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Lung Cancer by Silvestri et al78and Treatment ofSmall Cell Lung Cancer by Jett et al79in the ACCPLung Cancer Guidelines). A regional dedicated tho-racic oncology team should be consulted if not avail-able locally.

In addition, with the hope that this will reduce con-fusion, the ACCP panel recommends that when twolung cancers with a typical appearance (solid, spicu-lated, or lobulated) are deemed to be synchronousprimary cancers, they be classified with a TNM descrip-tor for each tumor. The combined T(m) classificationshould be reserved for multifocal tumors (usuallymore than two) that typically have a GGO appear-ance (as discussed in section 6.3).

6.2 Additional Pulmonary Tumor Nodules

The IASLC database contains cases of lung cancer

with additional pulmonary tumor nodules of cancer,accounting for a small portion (2.5%) of the database.Second primary lung cancers and metastatic disease(M1) were specifically excluded from this category;however, there is no information regarding how thecontributing centers defined such additional nodulecases beyond this.

Because of similar relative survival differences,these nodules were classified within the T3, T4, andM1a descriptor cohorts if they were located in thesame lobe, an ipsilaterally different lobe, or the con-tralateral lung, respectively (ie, T3Satell, T4Ipsi Nod, and

M1aContr Nod in Fig 1). Because of conflicting defini-tions in the IASLC and AJCC manuals, it is unclear

whether the additional tumor nodule designation ismeant to apply only to lesions that can be recog-nized grossly or also to lesions detected solely by thepathologist.4-6

It has been suggested that the IASLC stage classi-fication of additional pulmonary tumor nodules T(m)be used for patients with a dominant classic lung can-cer (ie, solid, spiculated) who have an additional nod-ule with similar radiographic and histologic features.14The ACCP panel endorses this definition and suggests

Figure9. [Section 5.0] Graphic illustration of stage IV. Repro-duced with permission from Detterbeck et al.13

Figure10. [Section 6.1] Definition of multiple primary lungcancers.



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that the additional nodule classification also applies tolesions that are not clinically apparent. It is not clearthat this definition matches the cases included in theIASLC database. The database may have includedsome multifocal, predominantly GGO lesions becausethis cohort included mostly cases from Asia2(wheresuch tumors appear to becoming more common),80,81although the fact that the IASLC database includes

only cases from 1990 to 2000 probably diminishesthis effect because the detection of GGO lesionsappears to have been less common during this period.

It is important to note that the IASLC databasedoes not clearly define the prognosis of patients withadditional nodules that are encountered clinically today.First, the definitions used in the IASLC database forthis cohort are unclear. Second, the prognosis variessignificantly among geographic regions and types ofdatabases. Finally, treatment was not accounted forin the analysis yet varied markedly (96% and 88% ofT3Satelland T4Ipsi Nod, respectively, were managed sur-

gically vs 2% of M1aContr Nod).2,7,9In fact, patients withadditional tumor nodules who underwent resectionexhibited good 5-year survival (45% for T3SatellN0 M0R0, 48% for pT4Ipsi NodN0 M0 R0).7

6.3 Multiple (Multifocal) Lung Cancers

Multifocal disease is well recognized for bronchi-oloalveolar carcinoma (BAC)82-84; however, becausethe term BACwas used in different ways, its use hasbeen abandoned.19Although the term BAChas beenretired, patients are still seen with multiple foci of such

tumors. The spectrum of lesions that were includedunder the rubric of BAC included newly defined his-tologic entities (ie, adenocarcinoma in situ, mini-mally invasive adenocarcinoma, lepidic predominantadenocarcinoma)19; the nature and relationship of theselesions to one another is not yet well understood.19,21,83-90These factors have led to confusion about how toclassify multifocal disease, which is exacerbated by

wording in the stage classification manuals that canbe interpreted in different ways. Such multifocaltumors (ie, what would formerly have been calledmultifocal BAC) currently are variably classified as

multiple distant metastases, synchronous second pri-mary cancers, and additional nodules. A more uni-form classification is needed, or the data collected

will be uninterpretable.The ACCP panel endorses the suggestion that the

T(m) designation be used for patients with multifocallung cancer, meaning patients with several GGOlesions that are malignant or contain numerous smallfoci.14The AJCC and UICC rules suggest that mul-tiple simultaneous tumors be classified by the highestT stage of one focus with the number of tumors inparentheses.3,4For example, a patient with four GGO

lesions all measuring,2 cm would be classified ashaving T1a(4) disease. In this classification category,the N and M designations apply to all the multi-ple tumor foci. The T(m) designation should only beapplied to lesions that are either proven or stronglysuspected to be malignant, that is, not atypical adeno-matous hyperplasia (AAH) lesions. This appears tobe consistent with the intent of the T(m) designation

according to the IASLC manual, which specificallymentions the common occurrence of multiple fociof BAC tumors.

The ACCP panel defines multifocal lung cancers asmultiple GGO lesions, which may, however, developa solid component.62,83,87,91,92 There may be a fewor many lesions.92We include patients with such amalignant GGO lesion (either suspected or proven)and other small GGO lesions that are likely AAHbecause data suggest that AAH is a precursor to suchtumors.21,83-89,93,94 Including such patients also sat-isfies the need for a clinically applicable definition.

At the other end of the spectrum are patients with aninfiltrative pattern of disease confined to a partic-ular area (segment or lobe) or appearing diffusely inthe lung parenchyma (also called pneumonic typeof adenocarcinoma).62,95,96These lesions should alsobe included among multifocal cancers.

Multifocal cancers appear to have a decreased propen-sity for nodal or systemic spread and an increased pro-pensity to develop additional pulmonary foci.62,83,87,91,97This feature seems to fit with what was intended bythe T(m) nomenclature, which designates multipletumors in the T descriptor but maintains a composite

N and M designation that applies to all the multipletumors in aggregate. Further study of this form oflung cancer is needed. Nevertheless, adoption of aclassification nomenclature, even if imperfect, willfacilitate such research by more precisely identifyinga specific and homogeneous population.

7.0 Type of Stage Classification

The main stage classification types are clinical andpathologic (Fig 11). According to the AJCC manual,4

clinical stage (pretreatment classification) encom-passes any information obtainedbefore initiationof definitive treatment, incorporating symptoms and

Figure11. [Section 7.0] Types of staging assessments.



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physical examination; imaging; endoscopy; biopsy;and surgical staging procedures, including explora-tion. The pathologic stage (postsurgical classification)includes information from the clinical stage supple-mented by information obtainedthrough completionof definitive surgery.4Other stage classification types(Fig 11) include restaging after induction treatment(designated yc or yp), staging when recurrence develops

(designated by r), or staging at autopsy (designatedby a). Although pathologic stage is more accurate,clinical stage is what is available when treatmentdecisions are made.

Complexity arises because the AJCC allows clin-ical and pathologic classification to be applied to indi-

vidual T, N, and M descriptors and allows use ofindividual pT and pN descriptors outside the settingof (intended) surgical resection.4This creates confu-sion because procedures explicitly classified as clin-ical staging nevertheless yield results that can definea pT or pN descriptor, and the overall classification

can be a mixture of clinical or pathologic individual T,N, and M descriptors. Note that the UICC and IASLCdo not recognize this individual p designation out-side the setting of a surgical resection (or attemptedresection).

Definition of pT status outside the setting ofattempted resection requires biopsy specimen proofof invasion to confirm the highest T category. Practi-cally speaking, such a clinical determination of pT israre but might include biopsy specimen proof of cari-nal involvement (or potentially an excisional wedgeresection specimen that defines the largest tumor

dimension yet was not intended as a therapeutic pro-cedure). The designation of pM can be used whenthere is biopsy specimen proof of a distant (or pleu-ral/pericardial) metastasis; however, a pM0 designa-tion does not exist, even if a biopsy is done (only cM0).

AJCC definition of pN outside the setting ofattempted resection is particularly problematic.98,99This requires one of the following: (1) biopsy spec-imen proof of N3; (2) all nodes with negative biopsyspecimen findings, regardless of number sampled(presumably at least 1); (3) any microscopic evalu-ation of nodes if pT status is defined; or (4) a sentinel

node biopsy specimen and definition of pT status.Thus, although endobronchial ultrasound or medi-astinoscopy explicitly comprise clinical staging, theresult can be viewed as defining a pN status.

Complex rules govern assignment of an overall clin-ical or pathologic designation to a mixture of indi-

vidual descriptors (eg, cT1pN3cM1, pT2cN0cM1,cT2cN0pM1). In the absence of resection, the overallclassification is pathologic if (1) an M1 biopsy spec-imen finding is positive (ie, cTcNpM1), (2) an N3biopsy specimen finding (the highest N category) ispositive (ie, cTpN3cM0), or (3) the T stage is con-

firmed by biopsy specimen and nodal involvementat any level is confirmed (ie, pT1-4pN1-3cM0). All othercombinations of cT, pT, cN, pN, and cM define an over-all clinical stage. The definition is awkward in a non-resectional setting because pN0 is unacceptable fordefining overall pathologic stage (eg, pT1-4pN1-3cM0is classified as pathologic, whereas pT1-4pN0cM0is clinical). Presumably, these rules pertain only to

patients with unresected lesions; otherwise, clinicalstaging would apply to all with N0, even if resected,including a complete lymphadenectomy.

The AJCC staging rules are ambiguous and appearto allow for several approaches. The approach thatavoids the confusion and ambiguity arising from theothers is to restrict pathologic staging to the postresec-tion stage (or rarely an aborted resection with exten-sive biopsy specimens). Pretreatment staging remainsclinical; if such staging involves biopsy specimens,the UICC rules allow for the use of cT, cN, or cMalong with a certainty factor classification (eg, cN2C3)

rather than pT or pN. The C designation is describedin the next section and summarized in Figure 12.This approach is suggested by the ACCP panel.

8.0Additional Descriptors

8.1 Certainty Factor

The UICC has defined an optional C factor (Fig 12)to denote the extent of investigation performed toestablish the stage designation (ie, clinical evaluation,imaging and needle aspiration, surgical staging, resec-tion). This factor can be applied to the entire stageor to individual T, N, and M descriptors. This factorcarries the misleading name of certainty, implyingthat certainty is related primarily to the specific tech-nique, whereas in reality, the clinical setting is mostimportant (eg, a normal mediastinum on PET scanhas a false-negative rate of ,5% for peripheral cItumors vs about 25% for central tumors).100,101Fur-thermore, the thoroughness of staging procedures var-ies greatly.102

8.2 Completeness of Resection

The completeness of resection (radicality) is moreclearly defined in the new system (Fig 12). A positivemargin includes nodal margins and positive pleuralor pericardial fluid cytology. According to sugges-tive individual studies, several new classifications

will be tested, including pleural or pericardial lavagecytology, highest mediastinal node involvement, ornodal classification based on a limited assessment.Additional descriptors have been developed for thedepth of visceral pleural invasion, chest wall invasion,lymphatic and vascular invasion, and the number ofnodal zones involved.14



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tion and should be coded as N0 (or M0), regard-less of node level harboring the ITCs [eg, pN0(i1),pN0(mol1)]. The prognostic value of ITCs has been

inconsistent.104-109

9.0Applicability to DifferentLung Cancer Types

The seventh edition of the Lung Cancer StageClassification is applicable to all major types of pri-mary lung cancer. The system was developed basedon non-small cell lung cancer; however, validationstudies in patients with small cell lung cancer11andcarcinoid tumors12have demonstrated that the defi-nitions are also of value in these cohorts. Therefore,

8.3 Minimal Disease

Sophisticated immunohistochemical and genetictechniques permit detection of very small tumor

deposits (Fig 12). A micrometastasis as defined bythe UICC and AJCC3,4 is 0.2 to 2 mm in size andusually is detected by routine hematoxylin and eosinstaining; typically, mitoses and invasion are seen.103Such micrometastases in nodes or distant sites arecounted as positive and denoted by the symbol (mi)[eg cN1(mi), pN2(mi)]. However, the prognostic impact

was not evaluated in the IASLC staging analysis.Isolated tumor cells (ITCs) are small clumps of

tumor cells (,0.2 mm), typically without mitoses orvascular or lymphatic invasion. ITCs within nodes (ordistant sites) are not counted in the stage classifica-

Figure12. [Sections 7.0, 8.0] Additional descriptors.

The classification can also be applied to distant metastatic sites (M0). Nonmorphologic techniques include DNA or RNA analysis or flow cytometry.CXR5chest radiograph; ITC5isolated tumor cell.aIn greatest dimension.



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the stage classification should be applied to patientswith these tumors as well.

10.0 Discussion

The purpose of the stage classification system isto provide a nomenclature to describe the anatomicextent of disease. In the past, the descriptors andgroupings have been based largely on what seemedto be logical; in the current seventh edition, this isbased on extensive statistical analysis. The basis fordeciding that a particular cut point or definition was a

good criterion to distinguish one group from anotherwas a difference in prognosis between the groupsthat was consistent in multiple subset analyses (geo-

Figure13. [Section 10.0] Median survival (mo) of the clinicalT descriptor cohort (cN0, cM0) in the International Association forthe Study of Lung Cancer database according to the geographicregion and database type. Aus5Australia; Clin5clinical.2

Figure14. [Section 10.0] Median survival (mo) of the clinical Ndescriptor cohort (cTAny, cM0) in the International Associationfor the Study of Lung Cancer database according to the geo-graphic region and database type. See Figure 13 legend for expan-sion of abbreviations.2

Figure 15. [Section 10.0] Treatment given (as percentage of

total) in NCDB (2004-2007) to patients with non-small cell lungcancer (n522,044) whose stage grouping shifted from the desig-nation in the sixth to the seventh edition of the Lung Cancer StageClassification system. Ch5chemotherapy; ChRT5chemoradio-therapy; ChRT-S5chemoradiotherapy then surgery; Ch-S5che-motherapy then surgery; NCDB5National Cancer Database; NoTmt5no treatment; RT5radiotherapy; S5surgery alone; S-Ch5surgery then chemotherapy; S-ChRT5surgery then chemoradio-therapy; S-RT5surgery then radiotherapy. See Figure 4 legendfor expansion of other abbreviations. Reproduced with permis-sion from Boffa et al.110

graphic, histologic, database type, time period, clinicalor pathologic) as well as in external validation (ie, Sur-

veillance Epidemiology and End Results database).Thus, prognosis was used as a tool in the analysis,and differences in prognosis were the end points ofanalysis.

How do we use the staging nomenclature? A clin-ical need is to select the optimal treatment of patients,

and the anatomic extent of disease is certainly a majorfactor in the treatment selection. However, we cannotexpect the stage classification to serve as a treatmentalgorithm. First, many other factors affect the treat-ment selection, including functional status, comor-bidities, histology, and personal factors. Second, thecriterion used to separate or group patients was not

whether current guidelines recommended treatmentthat was the same or different. Finally, progress indefining optimal treatment should be continuous andinformed by the results of clinical trials. Stage classi-fication is relatively static, updated every 7 or 8 years

when a new edition is produced. Thus, the stageclassification is useful in describing one factor relatedto choosing a treatment strategy and in assessing

whether the results of a clinical trial may be applicableto a particular patient, but it does not by itself definea treatment approach.

Another clinical need is to define prognosis. Again,the anatomic extent of disease is an important factorthat contributes to prognosis. However, there are



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many other prognostic factors, including those relatedto the tumor, patient, treatment, and clinical and socialsetting. There is a need for a prognostication tool thattakes these factors into account, and it is often sug-gested that the stage classification be modified to includeother factors (eg, shifting stage grouping up or downdepending on patient age or other factors). However,prognostication is extremely complex, and such an

approach is overly simplistic. For example, certainfactors may be highly significant if a particular treat-ment is given but have little relevance in other set-tings. Therefore, acknowledging only a few prognosticfactors and adjusting the TNM stage would be insuf-ficient to define prognosis yet could tremendously

complicate use of the TNM system; it is best to sepa-rate prognostication from anatomic disease descrip-tion and allow time for development of a sophisticatedprognostication tool.

We need to be careful in applying prognostic datafrom the IASLC database. It is true that this databaseis the largest available and defines prognosis for patients

with a certain anatomic extent of disease from around

the world, but there were marked differences in pro-gnosis in different geographic regions and by data-base type (Figs 13, 14), and which region or databasetype was better varied between T and N categories. Itis not clear why prognosis varied so much; no consis-tent factor has been identified, although many have

Figure16. [Section 11.0] ACCP suggestions to avoid ambiguities in the IASLC, UICC, and AJCC stage classification systems.

ACCP5American College of Chest Physicians; AJCC5American Joint Committee on Cancer; GGO5ground glass opacity; IASLC5InternationalAssociation for the Study of Lung Cancer; UICC5Union Internationale Contre le Cancer.aExplicitly defined by AJCC or UICC, listed here nevertheless because of common lack of awareness of this.bImplied by AJCC or UICC.



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been suggested (eg, genetic variation, such as thefrequency of epidermal growth factor receptor muta-tions or differences in the proportion of nonsmokersin different regions). Furthermore, the treatmentgiven was not accounted for or validated in the IASLCdatabase. A comparison of what treatment was givenin the US National Cancer Database (which does have

validated treatment data) for those cohorts whose

stage grouping changed from the sixth to the seventhedition shows marked variation (Fig 15). Therefore,

we must acknowledge that the IASLC database doesnot precisely define the prognosis for a particularpatient, and we certainly cannot assume that it hasdefined the prognosis for a particular treatmentapproach.

We must be particularly careful in the use of prog-nosis to guide decisions about treatment. The fact thatsurvival is poor does not necessarily imply that it is

worth adding further therapy (eg, adjuvant chemo-therapy); what we really need is data demonstrating

that additional treatment actually improves survival.At the same time, we should not rule out a particularapproach just because (our perception of) prognosisis poor. In the IASLC database, patients with pleuralinvolvement or with ipsilaterally different lobe nod-ules who underwent resection actually had good sur-

vival (5-year survival, 31% if pTAnyN0 M1aPl DissemR0and 48% for pT4Ipsi NodN0 M0 R0).7The patients whounderwent resection, of course, represent a selectedsubgroup. However, these observations illustrate howthe interplay among clinical and pathologic staging,treatment approach, and patient selection can influ-

ence our perception of similar outcomes.Although the stage groupings are a reasonable way

to group patients and are based on a sound statisticalanalysis, this does not prove that the tumor biology ishomogeneous. For example, the survival curves ofpatients with T4Invand T4Ipsi Nodtumors do not neces-sarily track together, suggesting that there may bebiologic differences. Certainly, there are groups thathave a similar prognosis but markedly different clin-ical characteristics (eg, stage IIIA includes patients

with N2 disease [T1-3 N2 M0], those with extensivelocal invasion only [T4InvN0 M0], and those with ip-

silateral additional tumor nodules [T4Ipsi NodN0 M0]).We must view stage classification as a useful tool thatmay well change over time as our understanding andtreatment outcomes evolve.

11.0Conclusion

There is no question that the IASLC staging classi-fication is a major advance. The size of the database,the broad international spectrum, the careful anddetailed analysis, and the internal and external val-idation are tremendous achievements and relatively

unique among types of cancer. Inevitably, it is alsomore complex, and with more refined data comes agreater ability to discern granular details. As with anycomplex system, rules that seem clear in one contextcan seem awkward or conflicting in another. This arti-cle reviews the fundamental definitions as well assuggested approaches that minimize the conflicts inthose cases where ambiguous rules create confu-

sion (Fig 16). A thorough understanding of the stageclassification is essential because it is fundamentalto our ability to converse clearly about patients withcancer.

Acknowledgments

Author contributions:Dr Detterbeck had full access to all ofthe data in the study and takes responsibility for the integrity ofthe data and the accuracy of the data analysis.Dr Detterbeck: contributed to the conceptual approach, reviewof staging manuals, and writing of the manuscript.Dr Postmus:contributed to the review and revisions of the manu-

script.Dr Tanoue:contributed to the review and revisions of the manu-script.Financial/nonfinancial disclosures: The authors have reportedto CHESTthe following conflicts of interest: Dr Detterbeck is amember of the International Association for the Study of LungCancer International Staging Committee and a speaker in an edu-cational program regarding lung cancer stage classification; bothactivities are funded by Lilly Oncology (Lilly USA, LLC). He hasparticipated on a scientific advisory panel for Oncimmune (USA)LLC; an external grant administration board for Pfizer, Inc; a mul-ticenter study of a device for Medela; and formerly a multicenterstudy of a device for DeepBreeze. Compensation for these activ-ities is paid directly to Yale University. Drs Postmus and Tanouehave reported that no potential conflicts of interest exist with anycompanies/organizations whose products or services may be dis-

cussed in this article.Role of Sponsors: The American College of Chest Physicians

was solely responsible for the development of these guidelines.The remaining supporters played no role in the developmentprocess. External supporting organizations cannot recommendpanelists or topics, nor are they allowed prepublication access tothe manuscripts and recommendations. Further details on theConflict of Interest Policy are available online at http://chestnet.org.Endorsements:This guideline is endorsed by the EuropeanSociety of Thoracic Surgeons, Oncology Nursing Society, AmericanAssociation for Bronchology and Interventional Pulmonology, andthe Society of Thoracic Surgeons.Other contributions: The authors thank Ramon Rami-Porta,MD, for his thoughtful critique during the development of thisarticle and review of the final manuscript.

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