Does an incomplete interlobar fissure influence survival or recurrence in resected non-small-cell lung cancer?

Lung Cancer 25 (1999) 33 – 38 www.elsevier.nl/locate/lungcan

Does an incomplete interlobar fissure influence survival or recurrence in resected non-small-cell lung cancer? Mitsuhiro Kamiyoshihara a,b,*, Osamu Kawashima a, Syuji Sakata a, Toshikazu Hirai a, Susumu Ishikawa b, Yasuo Morishita b b

a Department of Surgery, National Sanatorium Nishi-Gunma Hospital, Shibukawa, Gunma, Japan Second Department of Surgery, Gunma Uni6ersity School of Medicine, 3 -39 -15 Showa-machi, Maebashi, Gunma 371 -8511, Japan

Received 5 February 1999; received in revised form 14 April 1999; accepted 15 April 1999

Abstract Objecti6e: There have been various reports on prognostic factors in non-small-cell lung cancer (NSCLC) under a complete resection, but an incomplete interlobar fissure has not been discussed yet. We attempted to clarify whether this influences survival or recurrence. Patients and methods: From 1981 to 1994, 239 patients (43%) who had a single lobectomy with mediastinal lymph node dissection were pathologically diagnosed as stage IA/IB or IIA/IIB (excluding T3N0M0). These patients were divided in two groups: patients with a complete interlobar fissure group (group L); and patients with an incomplete one (group NL). Postoperative survivals and cancer-free periods were retrospectively assessed. Patients’ characteristics had no statistical difference between groups L and NL by N category. Results: The 5-year survival was 77.0% in group L-N0, 79.3% in group NL-N0, 48.7% in group L-N1, and 66.2% in group NL-N1. No statistical difference was found between groups L-N0 and NL-N0, L-N1 and NL-N1, L-T1N0 and NL-T1N0, L-T1N1 and NL-T1N1, L-T2N0 and NL-T2N0, and L-T2N1 and NL-T2N1. The 5-year-relapse-free survival was 81.2% in group L-N0, 85.4% in group NL-N0, 69.4% in group L-N1, and 72.2% in group NL-N1. No statistical difference was found between groups L-N0 and NL-N0, L-N1 and NL-N1, L-T1N0 and NL-T1N0, L-T1N1 and NL-T1N1, L-T2N0 and NL-T2N0, and L-T2N1 and NL-T2N1. There was no statistical difference in recurrent sites between groups L-N0 and NL-N0, and L-N1 and NL-N1. Conclusion: We conclude that the incomplete interlobar fissure does not influence the prognosis of resected stage I or II NSCLC (excluding T3N0M0). © 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Non-small-cell lung cancer; Incomplete interlobar fissure; Survival; Recurrence

* Corresponding author. Tel./fax: + 81-27-220-8245. E-mail address: [email protected] (M. Kamiyoshihara) 0169-5002/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 9 9 ) 0 0 0 4 7 - 1

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1. Introduction There have been many reports on the prognosis of non-small-cell lung cancer (NSCLC) in patients who underwent a complete resection. These papers have adverted to various prognostic factors such as lymphatic vessels [1,2], tumor size [1,3], histologic type [3], grade of differentiation [1], pleural involvement [1], and angiogenesis factor [4]. However, an incomplete interlobar fissure as a prognostic factor of NSCLC has never been discussed on American Joint Committee on Cancer (AJCC) [5] and International Union Against Cancer (UICC) [6]. Additionally, the new staging system about the TNM classification of malignant tumors [7] also does not refers to it. According to the Japan Lung Cancer Society [8], when a primary tumor invades another lobe through an incomplete lobar fissure, the T factor is regarded

as T1. We attempted to clarify whether the incomplete interlobar fissure influence survival or relapse-free survival in stages I or II (excluding T3N0M0) NSCLC.

2. Patients and methods From 1981 to 1994, 558 patients with primary lung cancer underwent surgical treatment at National Sanatorium Nishi-Gunma Hospital. Of them, 239 patients (43%) who underwent a single lobectomy with mediastinal lymph node dissection had curative (complete) resections, and were pathologically diagnosed as stage IA/IB or IIA/ IIB (excluding T3N0M0). The histologic diagnosis of tumors was based on the criteria of the World Health Organization [9]. Patients’ characteristics by group N or NL are given in Table 1. No

Table 1 Patients’ characteristicsa Group L-N0 (%) (n= Group NL-N0 (%) 131) (n= 53) Age (year) Mean Range

Group L-N1 (%) (n =34)

Group NL-N1 (%) (n = 21)

63 910 34–80

63 9 9 31–77

N.S.

64 9 9 40–78

64.9 99 44–78

N.S.

Gender Male Female Location RUL RML RLL LUL LLL

72(55) 59(45)

24(45) 29(55)

N.S.

23(68) 11(32)

11(52) 10(48)

N.S.

34(26) 7(5) 51(39) 19(15) 20(15)

20(38) 2(4) 9(17) 13(25) 9(17)

N.S.

10(29) 0(0) 7(21) 13(38) 4(12)

8(38) 0(0) 2(10) 7(33) 4(19)

N.S.

Histology Ad Sq Large

93(71) 36(27) 2(2)

37(70) 15(28) 1(2)

N.S.

22(65) 10(29) 2(6)

17(81) 3(14) 1(5)

N.S.

T-factor T1 T2

85(65) 46(35)

37(70) 16(30)

N.S.

16(47) 18(53)

13(62) 8(38)

N.S.

Diameter Mean

3.0 91.3

2.79 1.1

N.S.

3.8 9 1.8

3.2 91.1

N.S.

a

Ad, adenocarcinoma; Group L, complete interlobar fissure group; Group NL, incomplete interlobat fissure group; Large, large cell carcinoma; LLL, left lower lobe; LUL, left upper lobe; RLL, right lower lobe; RML, right middle lobe; RUL, right upper lobe; Sq, squamous cell carcinoma.

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statistical difference was found in age, gender, smoking habit, primary site, histologic type and pathological T factor between groups N and NL. These patients were classified into two groups depending on whether an interlobar fissure was complete or incomplete in the primary lobe. Postoperative survivals and cancer-free periods were retrospectively assessed in patients with a complete or an incomplete interlobar fissure. A follow-up examination was, generally, done every 6 months for the first 2 years and yearly after that, including a physical examination, a complete blood count, blood chemistry, and chest radiography. In addition, all patients routinely received screening examinations by computed tomography or radionuclide bone scanning once or twice a year after operation. Recurrent disease was confirmed by biopsy whenever clinically feasible. When a biopsy was not feasible, radiographic evidence (roentgenography, computed tomography, or radionuclide scan) was accepted for the diagnosis of recurrence. The final date of evaluation in this study was December 31, 1997. The follow-up duration ranged from 3 to 16 years. Surgical-pathologic staging was assigned according to the UICC [7]. The lymph node classification scheme recommended by the AJCC [5] and adapted from Naruke et al. [10] was used to designate N1 and N2 disease. The proposal of Craig and Walker [11] was adopted as a method of classifying pulmonary fissures. They proposed a fissural classification based on both the degree of completeness of the fissures and the location of the pulmonary artery at the base of the oblique fissure. Completeness of a fissure was graded in four stages: grade 1, complete fissure with entirely separate lobes; grade 2, complete visceral cleft but parenchymal fusion at the base of the fissure; grade 3, visceral cleft evident for part of the fissure; and grade 4, complete fusion of the lobes with no evident fissural line. In the present study, we defined a complete interlobar fissure as grades 1 and 2, and an incomplete interlobar fissure as grades 3 and 4. None of patients died within 30 days after surgery. Death from the cause other than primary cancer was treated as a censored case. All statistical analyses were conducted using Statview™

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Fig. 1. Survival curves between groups L and NL.

(Abacus Concepts, Inc., Berkeley). A survival rate was calculated with the Kaplan–Meier method, and a statistical significance was evaluated using the x 2-test, the t-test and the Cox–Mantel test with a P value of less than 0.05 being defined as statistically significant. Zero time was the date of surgical treatment. No one was lost during the follow-up period and we regarded the outcome as ‘death’, in so far as possible, through personal knowledge, physician’s reports, autopsy or death certificates.

3. Results

3.1. Sur6i6al The 5-year survival (5YS) and the mean survival time (MST) were: 77.0% and 143 months, respectively, in group L-N0; 79.3% and 139 months, respectively, in group NL-N0; 48.7% and 97 months, respectively, in group L-N1; and 66.2% and 98 months, respectively, in group NLN1. No statistical difference was found between groups L-N0 and NL-N0 (P= 0.6), or groups L-N1 and NL-N1 (P= 0.5), shown in Fig. 1. Additionally, we divided each group into two subgroups by T factor. In T1 category, 5YS and MST were: 84.7% and 149 months, respectively, in group L-T1N0; 84.2% and 168 months, respectively, in group NL-T1N0; 65.8% and 117 months, respectively, in group L-T1N1; and 52.1% and 93 months, respectively, in group NLT1N1 (Fig. 2(a)). In T2 category, 5YS and MST were: 67.7% and 118 months, respectively, in group L-T2N0; 84.7% and 162 months, respec-

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tively, in group NL-T2N0; 30.2% and 46 months, respectively, in group L-T2N1; and 85.7% and 110 months, respectively, in group NL-T2N1 (Fig. 2(b)). No statistical difference was found between groups L-T1N0 and NL-T1N0 (P = 0.7), groups L-T1N1 and NL-T1N1 (P =0.61), groups LT2N0 and NL-T2N0 (P =0.34), and groups LT2N1 and NL-T2N1 (P =0.07), given in Fig. 2(a, b).

3.2. Relapse-free sur6i6al

Fig. 3. Relapse-free survival between groups L and NL.

The 5-year-relapse-free survival (5YRFS) and the mean cancer-free period (MCFP) were: 81.2% and 167 months, respectively in group L-N0; 85.4% and 164 months, respectively, in group NL-N0; 69.4% and 123 months, respectively, in group L-N1; and 72.2% and 131 months, respectively, in group NL-N1. No statistical difference was found between groups L-N0 and NL-N0 (P = 0.47), or groups L-N1 and NL-N1 (P = 0.57), shown in Fig. 3. Additionally, we divided each group into two subgroups by T factor. In T1 category, 5YRFS

and MCFP were: 88.2% and 176 months, respectively, in group L-T1N0; 88% and 162 months, respectively, in group NL-T1N0; 67% and 117 months, respectively, in group L-T1N1; and 67.4% and 144 months, respectively, in group NL-T1N1 (Fig. 4(a)). In T2 category, 5YRFS and MCFP were: 67.4% and 144 months, respectively, in group L-T2N0; 79.4% and 155 months, respectively, in group NL-T2N0; 72% and 59 months, respectively in group L-T2N1; and 85.7% and 146 months, respectively, in group NL-T2N1 (Fig. 4(b)). No statistical difference was found between groups L-T1N0 and NL-T1N0 (P= 0.81), groups

Fig. 2. Survival curves between groups L and NL in T1 factor (a), and in T2 factor (b).

Fig. 4. Relapse-free survival between groups L and NL in T1 factor (a), and in T2 factor (b).

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Table 2 Recurrent site Group L-N0 (%) Ipsilateral side Lung Lymph node Pleura, pericardium Contralateral distant Lung Brain Bone Liver Adrenal gland Total

8 (28) 2 (7) 1 (3) 8 3 6 0 1 29

(28) (10) (21) (0) (3)

Group NL-N0 (%)

3 (33) 1 (11) 1 (11) 2 0 1 1 0 9

(22) (0) (11) (11) (0)

L-T1N1 and NL-T1N1 (P =0.98), groups LT2N0 and NL-T2N0 (P =0.55), or groups LT2N1 and NL-T2N1 (P =0.43), given in Fig. 4(a, b).

3.3. Recurrent site (Table 2) Recurrent sites in groups L-N0, NL-N0, L-N1, and NL-N1 are shown in Table 2. No statistical difference was found between groups L-N0 and NL-N0, and groups L-N1 and NL-N1.

4. Discussion The outcome of NSCLC in patients undergoing a complete resection is largely influenced by the presence of regional lymph node metastases. In fact, stage I-IIIA cancer according to the new International Staging System of Lung Cancer is based mainly on the level of lymph node involvement [12]. Meanwhile, in spite of a complete surgical resection for localized stage I NSCLC, cancer recurrence occurs in a third of patients [13 – 15]. Several physicians have studied various prognostic factors of stage I NSCLC [4,1 – 3]. However, they have never adverted to an incomplete interlobar fissure as a prognostic factor. However, the main problem about this study is that it is retrospective. Unfortunately, the presence or absence of an incomplete fissure cannot be determined in preoperative examination (e.g.

N.S.

Group L-N1 (%)

Group NL-N1 (%)

2 (22) 1 (11) 0 (0)

1 (20) 0 (0) 0 (0)

3 1 2 0 0 9

2 1 1 0 0 5

(33) (11) (22) (0) (0)

N.S.

(40) (20) (20) (0) (0)

chest roentgenography, chest tomography and computed tomography). One of the purposes of the TNM staging is to have prognostic variables that can be identified preoperatively so that the stage can be determined before treatment. We cannot suggest a method to look at the integrity of fissure based on preoperative examinations. Therefore, this study might have only a meaning as one of the prognostic factor of the patients with pulmonary resection. The lung has mainly two lymph flow systems. One is the lymph flow system along the bronchus, and the pulmonary artery and vein. Another is the lymph flow system on the visceral pleura. Both the lymph flow systems converge at the hilar lymph nodes [16]. Accordingly, there might be a direct invasion of tumor cells or lymphatics flow in N0 patients, and dissemination of tumor cells on visceral pleura in N1 via an incomplete interlobar fissure. This study adverted to only patients with T1 or T2, N0 or N1, and M0, because we excluded the influence of a direct invasion via organs around the lung. Although systematical lymph node dissection for primary lung cancer has been discussed, it has been common knowledge that a lobectomy is a radical surgical treatment for primary lung cancer [17,18]. McCormack [19] reported that a lobectomy should be performed in all cases unless pulmonary function precludes excision of this volume of lung tissue. In resections of less than a lobectomy for a primary tumor, the recurrence

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rate is high and usually precludes a salvage lobectomy. If the visceral pleura of each lobe in a complete interlobar fissure blocks off the invasion, the dissemination or the direct lymphatic flow of tumor cells to other lobes, it will be possible that an incomplete interlobar fissure influences survival or relapse-free survival after surgical resection. Regarding survival, this study showed that, however, no statistical difference was found between patients with the complete or incomplete interlobar fissure group by T- (T1 or T2) and N-factor (N0 or N1). Additionally, regarding relapse-free survival, no statistical difference was also found between patients with the complete or incomplete interlobar fissure group by T- and N-factor. For Fig. 2(b), the difference in 5-year survival for the L-T2N1 and NL-T2N1 groups is substantial although not statistically significant because of the small numbers of patients. If there is larger group of these patients, this might be statistically significant.

5. Conclusion We conclude that the incomplete interlobar fissure does not influence the prognosis of resected stage I or II NSCLC (excluding T3N0M0).

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