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Clinical Upstaging of Non-Small Cell Lung CancerThat Extends Across the Fissure: Implications forNon-Small Cell Lung Cancer StagingVijay Joshi, MRCS, James McShane, BS, Richard Page, FRCS (CTh),Martyn Carr, FRCS (CTh), Neeraj Mediratta, FRCS (CTh), FRCS,Michael Shackcloth, FRCS (CTh), FRCS, and Michael Poullis, FRCS (CTh)

Liverpool Heart and Chest Hospital, Liverpool, England

Background. Little data exist as to the long-term out-come of non-small cell lung cancer that extends acrossthe fissure into the adjacent lobe that requires either abilobectomy or a lobectomy and wedge resection.

Methods. Lobectomy survival data was benchmarkedwith the International Association for the Study of LungCancer (IALSC) dataset. Matched analysis of a prospec-tive thoracic surgery database of 1,020 patients who hadundergone lobectomy during a 6-year period was ana-lyzed to elucidate the effect on long–term survival oftumors that extend across the interlobar fissure.

Results. Benchmarking revealed our data are not sig-nificantly different from the IALSC dataset, allowingsurvival recommendations to be drawn. Histopathologicstaging of matched patients was IA, 11.7%; IB, 51.1%; IIA,

1.7%; IIB, 21.1%; IIIA, 10.0%; IIIB, 2.8%; and IV, 1.7%.

pital, Thomas Dr, Liverpool, England L14 3PE; e-mail: mike.poullis@lhch.nhs.uk.

© 2011 by The Society of Thoracic SurgeonsPublished by Elsevier Inc

Stage I tumors crossing the interlobar fissure had areduction in survival that is significant (10% to 15%) after5 years (p � 0.037). The 5-year survival for stage I tumorsextending across a lung fissure was 50%. This places the5-year survival between stage I and II (60% and 40%,respectively). There was no difference in survival fortumors stage IIA and above with regard to importance ofinterlobar extension. The number of patients was toosmall to detect a significant difference between bilobec-tomy versus lobectomy and wedge.

Conclusions. Non-small cell lung cancer that extendsacross the fissure into an adjacent lobe requiring abilobectomy or a lobectomy and wedge resection has a5-year survival between stages I and II.

(Ann Thorac Surg 2011;91:350–4)

© 2011 by The Society of Thoracic Surgeons

The previous TNM classification system for the stagingof non-small cell lung cancer (NSCLC) lung cancer

classifies a tumor invading the visceral pleura as a T2tumor [1]. There has been no adjustment in this classifi-cation after the development by the International Asso-ciation for the Study of Lung Cancer (IALSC) of theseventh edition of the TNM staging system [2–4]. Tumorsextending across a lung fissure and invading adjacentlobes have not been taken into consideration. Visceralpleural invasion is thought to be a poor predictor ofoutcome in patients with NSCLC [5], hence patientsbeing currently classified as T2 instead of T1.

Previous work by Okada and colleagues [6] suggeststhat interlobar pleural extension should be classified asT3; however, Miura and coworkers [7] concluded thatinterlobar pleural extension makes no difference to sur-vival and should be classified as stage T2. Both studieswere confounded by inclusion of patients undergoingpneumonectomy.

In this study we sought to compare the long-termsurvival at a single center with regard to 5-year outcomesof NSCLC that extends across the fissure into the adja-

Accepted for publication Sept 29, 2010.

Address correspondence to Dr Poullis, Liverpool Heart and Chest Hos-

cent lobe and requires either a bilobectomy or a lobec-tomy and wedge resection, compared with a tumorconfined to a single lobe.

Patients and Methods

The ethics committee of Liverpool Heart and ChestHospital approved the protocol of the current study.

Data were collected prospectively on all patients un-dergoing lung resection for NSCLC between 2001 and2007. Patients undergoing pneumonectomy were ex-cluded. A total of 1,020 patients underwent a lobectomy.Patients with small cell lung cancer or benign lesionswere excluded. We identified 180 patients from this totalas having lesions that crossed a lung fissure and ex-tended between two adjacent lobes. These patients un-derwent either a bilobectomy or a lobectomy and wedgeresection as primary treatment for their cancer. All stag-ing was based on pathologic specimens. Histopathologicstages were matched with 420 patients who underwentlobectomy for a tumor confined to a single lobe (3:1matching). No other significant differences existed be-tween the matched groups (overall patient characteristicsafter matching are listed in Table 1).

Survival data were obtained using the National Stra-

tegic Tracing Service for all patients, and a Kaplan-Meier

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analysis was performed. Mean follow-up was 2.98 years.Differences in categorical variables were evaluated using�2 tests, whereas the Wilcoxon test was used for contin-

ous variables.Preoperative workup consisted of routine biochemistry

nd hematology, pulmonary function tests with or with-ut pulmonary diffusing capacity for carbon monoxidend ventilation–perfusion scan, thoracic computed to-ography, and fiberoptic bronchoscopy by means of a

igid telescope. Mediastinoscopy or mediastinotomy waserformed for any lymph node greater than 1 cm in thehort axis, and for any suspicious lymph nodes on com-uted tomography scanning. Mediastinal lymph nodetaging through nodal sampling or dissection, dependingn surgeon preference, was undertaken in all cases.Bone scans were carried out on suspicious radiologic or

linical grounds. Positron emission tomography was notsed owing to the period of study.

BenchmarkingThe results for all NSCLC surgical resections (n � 1,450)

Table 1. Patient Characteristics for Study Populationa

Characteristic Confined to a Single Lobe (n

Females (%) 188 (45.6)Age at operation (y) 69 (61–75)COPD (%) 99 (24)% FEV1 76.5 (63.5–89.9)

EV1/FVC ratio 68.5 (60.8–75.2)Smoking history

Current smoker (%) 131 (31.8)Ex-smoker (%) 261 (63.4)Non-smoker (%) 20 (4.9)

Pack years 40.0 (20.0–52.8)Excess alcohol (%) 21 (5.0)PVD (%) 61 (14.8)Diabetes (%) 37 (9.0)Hypertension (%) 147 (35.7)Renal dysfunction (%) 10 (2.4)TIA/CVA (%) 34 (8.3)Histology

Adenocarcinoma (%) 202 (49.0)Squamous cell ca (%) 173 (42.0)Other (%) 37 (9.0)

StagingIA 49 (11.7)IB 214 (51.0)IIA 7 (1.7)IIB 73 (21.2)IIIA 42 (10.0)IIIB 12 (2.9)IV 7 (1.7)

a Categorical variables given as number (percentage), continuous variabl15%).

OPD � chronic obstructive pulmonary disease; CVA � cerebrovasorced vital capacity; PVD � peripheral vascular disease; TIA � t

rom our center were compared with those from the

urrent IALSC series stage for stage to ensure our centerelivered results comparable to internationally acceptedgures [2].

Statistical AnalysisAll analysis performed using SAS for Windows, version8.1 (SAS Institute, Cary, NC).

Results

BenchmarkingFive-year survival for NSCLC for stages I to IV was foundto be not significantly different from the IALSC publishedsurvival curves used to recommend the TNM classifica-tion system (Fig 1).

There was no significant difference between patientswho had tumors confined to a single lobe, or those withtumors spreading across the fissure with regard to meanage, sex, chronic obstructive pulmonary disease, percent-age predicted forced expiratory volume in 1 second, the

20) Crossing the Fissure (n � 180) p Value

42 (43.3) 0.6869 (62–74) 0.8832 (33) 0.07

78.1 (65.0–90.1) 0.7067.8 (61.1–75.0) 0.92

0.6237 (38.1)56 (57.7)4 (4.1)

40.0 (25.0–50.0) 0.657 (3.9) 0.55

16 (16.5) 0.686 (6.2) 0.37

33 (34.0) 0.761 (1.0) 0.39

10 (10.3) 0.520.17

39 (40.2)45 (46.4)13 (13.4)

0.9921 (11.7)92 (51.1)3 (1.7)

38 (21.1)18 (10.0)5 (2.8)3 (1.7)

edian (interquartile range); missing data for some variables in 91 cases

accident; FEV1 � forced expiratory volume in 1 second; FVC �nt ischemic attack.

� 4

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forced vital capacity, smoking history, pack years, excessalcohol, peripheral vascular disease, diabetes, hyperten-sion, renal dysfunction, cerebrovascular disease, andhistology type (Table 1).

Histopathologic staging of matched patients was asfollows: IA, 11.7%; IB, 51.1%; IIA, 1.7%; IIB, 21.1%; IIIA,10.0%; IIIB, 2.8% and IV, 1.7%.

Stage IStage I tumors crossing the interlobar fissure had anidentifiable reduction in survival that is significant (10%to 15%) after 5 years (log rank test � 0.037; Fig 2).

The 5-year survival for stage I tumors extending acrossa lung fissure was approximately 50%. This places the5-year survival rates for these types of tumors betweenstage I and II tumors not crossing a lung fissure (60% and40%, respectively).

Fig 1. Benchmarking of our stage I to III resected non-small cell car-cinoma of the lung 5-year survival figures. (No significant differencecompared with International Association for the Study of Lung Can-cer stage survival curves, n � 1,450). Error bars signify 95% confi-dence intervals.

Fig 2. Survival curves of non-small cell carcinoma for stage 1 and II

crossing and not crossing an interlobar fissure.

Stage IIThere was no difference in survival identified in ourstudy for tumors stage IIA and above with regard to theimportance of interlobar extension (Fig 2).

Bilobectomy Versus Lobectomy and WedgeThe number of patients in each group was too small, 42not crossing the fissure and 18 crossing the fissure, todetect a significant difference (Fig 3).

Comment

Revisions in the international lung cancer staging havenot addressed tumors invading interlobar pleura intoadjacent lobes [2]. In this study we compared the out-come of patients with NSCLC that invade into an adja-cent lobe that requires either a bilobectomy or a lobec-tomy and wedge resection to remove it, compared withstage-matched patients who required an isolatedlobectomy.

Previous work on interlobar spread of lung cancer thatis treated surgically has resulted in highly variable con-clusions. Okada and colleagues [6] suggest that interlo-bar pleural extension should be classified as T3; however,Miura and associates [7] concluded that interlobar pleu-ral extension makes no difference to survival and shouldbe classified as stage T2. Both of these studies, however,included patients undergoing pneumonectomy, which isassociated with a higher operative mortality and moreproximal and extensive tumor characteristics, a fact com-mented on by Demir and coworkers [8]. Further confu-sion exists with univariate analysis by T stage. Previousstudies have all been too small to have separate analysisof N0, N1, and N2 for each T stage, making analysispotentially erroneous. Stage T2 lesions can be classifiedas stage IB, IIB, IIIA, IIIB, or IV depending on lymph nodeand metastatic status. Similarly, stage T3 lesions can beclassified as stage IIB, IIIA, IIIB, or IV depending on

Fig 3. Survival curves of non-small cell carcinoma for patients un-dergoing bilobectomy or lobectomy and wedge versus isolated lobec-tomy for stage I non-small cell lung cancer.

lymph node and metastatic status, hence our use of stage

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analysis, which forms the basis of current IALSC lungcancer guidelines. In addition we excluded patients un-dergoing pneumonectomy.

Our data suggest that there is a clearly identifiablereduction in survival for stage I tumors extending acrossa lung fissure when compared with stage I tumorsconfined to a single lobe. The study by Demir andassociates [8] demonstrated that the 5-year survival fortumors extending across lung fissures (for any stage) wassimilar to that of T3 tumors. This suggests a similaritybetween these tumors and stage IIB and IIIA tumorsconfined to a single lobe in terms of overall 5-yearsurvival. Our results suggest something different. Wefound that the survival rate for stage I tumors extendingacross a lung fissure was approaching, but not equal to,stage II tumors confined to a single lobe.

Standardization and benchmarking is important whenmaking recommendations based on survival to an inter-national audience [9]. We benchmarked our 5-year lobec-tomy survival figures, for stages I through IV, with thosepublished by the IALSC [3] to confirm that our staging,

atient characteristics, and operative factors were com-arable with those guiding the next edition of the TNMlassification system.

Statistical power is important when drawing conclu-ions from studies [10]. Excluding patients who under-ent pneumonectomy, Demir and colleagues [8] in-

cluded 20, Okada and associates [6] 22, and Miura andcoworkers [7] 14 patients, making a total of 56. Weincluded 180 patients, but even this is too small a samplesize to make statistically valid conclusions with regard tothe relative significance of tumor histology, lobectomyand wedge versus bilobectomy effect, sex, age, or pre-dicted postoperative pulmonary function tests.

Previous studies looking at the prognosis of NSCLCinvading into an adjacent lobe revealed survival out-comes closer to those of T3 tumors [8]. Their conclusionssuggested that it is more appropriate for these tumors tobe upstaged as 5-year survival for these patients wasmuch worse than tumors confined to a single lobe.However, the vast majority of patients in this studyreceived a pneumonectomy as their primary form oftreatment, which is associated with a higher mortalitywhen compared with bilobectomy.

In summary we believe that stage I NSCLC invadingthrough the fissure has a 5-year survival between stage Iand stage II.

Implications of StudyCurrent flux in adjuvant therapy for NSCLC means thattherapy is critically dependent on stage, be it IA, IB, IIA,or IIB [11]. Stage migration from I to II may mean patientswith interlobar extension of tumor may benefit fromadjuvant chemotherapy. We realize that we present no

data to confirm or refute this hypothesis.

LimitationsThe completeness of the interlobar fissure was not re-corded intraoperatively or in the histopathology reports.Tumor size is a known important prognostic indictor ofsurvival as the most recent IASLC recommendationspropose. Unfortunately the tumors were sized for stag-ing, but the actual size was not recorded in our database.Cause of death during follow-up was unknown. Ourstudy was too small to allow bilobectomy versus lobec-tomy and wedge resection subset analysis.

Future WorkLarger numbers are needed to evaluate the effects offemale sex, histologic type, size of tumor, and presentingcomplaint(s) with regard to whether tumors extendingacross the fissure have a significant effect on long-termsurvival in some or all stages of lung cancer.

References

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