4 in.) 1.9 cm; still a safe length for bronchial resection margin?

Lung Cancer 30 (2000) 161 – 168 www.elsevier.nl/locate/lungcan

Changing patterns of lung cancer; (3/4 in.) 1.9 cm; still a safe length for bronchial resection margin? Murat Kara a,*, Serpil Dizbay Sak b, Diclehan Orhan b, Sinasi Yavuzer a a

Department of Thoracic Surgery, Ankara Uni6ersity School of Medicine, Ibn-i Sina Hospital, 06100 Sihhiye, Ankara, Turkey b Department of Pathology, Ankara Uni6ersity Faculty of Medicine, 06100 Sihhiye, Ankara, Turkey Received 13 September 1999; received in revised form 13 March 2000; accepted 22 March 2000

Abstract Background: Surgical resection is the best treatment modality in non-small cell lung cancer (NSCLC). As a guideline, it is suggested that at least a bronchial resection margin of 1.9 cm from the macroscopic tumor might provide a tumor-free margin in lung cancer. In some recent reports, there is great emphasis on the changing histopathological patterns of lung cancer, but no concern for the proximal extension of lung cancer. The aim of this study was to determine the validity of this guideline in the current time. Methods: Surgically resected specimens of NSCLC cases (n=70) were examined. The bronchial tree including tumor was dissected and beginning from the edge of the visible tumor, the bronchus were cut into serials in its transverse plane, 5 mm apart from each other. Cut sections were examined for proximal extension of tumor at different levels. Results: Microscopic proximal extension was observed in 24.2% (n =17/70) of all the cases. Peribronchial extension (n= 9/17) (52.9%) was more predominant compared with bronchial extension (n= 8/17) (47.0%). Squamous cell carcinoma (n=11/38) (28.9%) showed proximal extension more than adenocarcinoma (n=5/23) (21.7%). Adenocarcinoma showed more peribronchial extension (n= 4/5) (80.0%) whereas squamous cell carcinoma (n =7/11) (63.6%) showed more bronchial extension. The farthest extension was 3.0 cm for adenocarcinoma and 2.0 cm for squamous cell carcinoma. Excluding tumor positi6e specimens beyond 1.5 cm le6el to the bronchial resection margin, all tumors accounted for 96% of the whole series. Conclusions: Microscopic proximal extension of lung cancer occurs in 24.2% of NSCLC cases. Squamous cell carcinoma extends more proximally compared with adenocarcinoma in ratio whereas adenocarcinoma extends more in length. A bronchial resection of 1.5 cm in length from the macroscopic tumor will pro6ide clear margins in 93% of NSCLC cases. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Lung cancer; Bronchial resection margin; Histopathology; Proximal extension



Poster presented at the 100th Annual Congress of Japan Surgical Society, Tokyo, Japan, 12–14 April 2000. * Corresponding author. Present address: Guvenlik caddesi, Esenlik sokak 7/10, 06540 Asagıayrancı, Ankara, Turkey. Tel.: + 90-312-467-0054; fax: + 90-312-287-2390. E-mail address: [email protected] (M. Kara).

1. Introduction Provided that complete clearance of the primary tumor, in addition to extensive regional and mediastinal lymph node dissection, curative resection of lung cancer still remains the best treatment

0169-5002/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 0 0 ) 0 0 1 4 0 - 9

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fornon-smallcelllungcarcinoma.Curativeresection can be achieved with negative resection margins. In some earlier studies it is suggested to leave at least 1.9 cm of apparently normal bronchus from the macroscopic tumor to have a tumor-free bronchial resection margin (BRM) [1,2]. To date, many surgeons considered this suggestion as a guideline for a clear BRM. In spite of, the impression of apparently normal bronchial resection lines, thoracic surgeons are sometimes faced with microscopic residual tumor at the resection margins particularly bronchial margin. Recently, many papers about changing histopathological patterns of lung cancer were reported. It is stated that adenocarcinoma (AC) replaced squamous cell carcinoma (SCC) as the most frequent histologic subtype for all sexes and races [3]. Increasing incidence of peripheral lung cancers particularly bronchioloalveolar carcinoma (BAC) [4] and the decrease in the centrally originating tumors were also noted by various authors [5]. These recent findings attracted interest to reconsider the safe BRM in bronchial carcinoma. This report details our results in 70 lung carcinoma specimens which were investigated histopathologically for proximal extension of the tumor along the bronchial wall to determine the safe distance from the macroscopic tumor as the most reliable BRM. 2. Materials and methods

2.1. Patients and specimens The material for this survey was obtained from 70 specimens of NSCLC cases surgically resected

in Ibn-i Sina Hospital of Ankara University between September 1994 and July 1996. Two pathologists independently in the pathology department of the same university undertook histopathological examination. Post-mortem materials were not included in this survey. There were 69 males and one female patient with a median age of 56.1 years (range 35–76). All the patients were evaluated with either rigid or flexible bronchoscope. Preoperatively, 40 (57.1%) patients were diagnosed to have lung cancer. Lower lobectomy (n= 9) (26.4%) in the right hemithorax and upper lobectomy with lingular resection (n= 13) (36.1%) in the left hemithorax accounted for the majority of operations on each side (Table 1). Frozen section examination was undertaken in 31.4% (n = 22) of all the cases and this fragment of the bronchus had always been evaluated with the gross material together. Cases of bronchial wedge resections were excluded from this study, whereas sleeve resection specimens (n= 12) (17.1%) were also examined to investigate the distal bronchial extension. In total, 16 (22.8%) specimens were sampled both to each side of the tumor.Theseconsistedofsixlowersleevelobectomy, three upper bilobectomy, two upper sleeve lobectomy, one upper sleeve bilobec-tomy, one tracheal sleeve pneumonectomy, one pneumonectomy on the right and two lower sleeve lobectomy on the left side. Centrally located tumors, which had concomitant peribronchial extension and destruction of the bronchial tree were not dissected. These tumors were extracted en-bloc with BRM in six (85%) specimens. If the tumor was very close to the

Table 1 Analysis of resection types (n=70) Right lung Upper lobectomy Upperapicoposterior segmentectomy Upper-middle lobectomy Lower lobectomy Pneumonectomy Upper sleeve lobectomy Upper-middle sleeve lobectomy Lower sleeve lobectomy Tracheal sleeve pneumonectomy Totals

Left lung 6 1 3 9 5 2 1 6 1 34

Upper lobectomy+lingular resection Upperapicoposterior segmentectomy Lower lobectomy Pneumonectomy Lower sleeve lobectomy

13 1 9 11 2

36

M. Kara et al. / Lung Cancer 30 (2000) 161–168

163

sampling. Significantly, if the tumor extension was endobronchial, otherwise the most proximal edge of the tumor bulk if it was peribronchial, the most proximal part of the tumor extending out of the bronchus then apparently normal bronchus were considered to be the reference point (0 cm level) (Fig. 2(a) and (b). If both the extension patterns existed in the same specimen, the most prominent extension pattern, much closer to the BRM was determined as the reference level. Beginning from the reference point, several ring-shaped, trans-

Fig. 1. Bronchial tree dissection with the tumor in a left pneumonectomy specimen showing peribronchial tumor in the lingular bronchus.

the BRM and several samplings seemed to be impossible then only one cut section (0.6 cm) was obtained in one (1.4%) specimen. Since the entire bronchial tree was likely to be destroyed after a dissection, we preferred to obtain the cut sections not in the standard fashion but with the most convenient distances from the tumor as 0, 0.7, or 0, 0.3, 0.6 etc. in five (7.1%) specimens.

2.2. Technique All the specimens were received fresh and immersed into the isotonic saline solution temporarily. We had the samples of the bronchus after either blunt or sharp dissection of the bronchial tree including the tumor (Fig. 1). Cut sections of bronchus were obtained horizontally, in the transverse plane in relation to the bronchus after measuring and putting marks on the bronchus at different levels. The most predominant features of tumor extension were of importance at the time of

Fig. 2. (a) Diagram of an endobronchially extending tumor and the method used to obtain the cut serials in the transverse plane of the bronchus. (b) Diagram of a peribronchially extending tumor and the same sampling method. A represents 0 cm level between the macroscopic tumor and apparently normal bronchus which is called as reference point. B, C and D (BRM) represents 0.5, 1.0 and 1.5 cm levels, respectively.

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verse and circumferential cut sections were obtained. Cut sections which were 5 mm apart from each other contained the whole bronchial wall. The cut sections differed from one to nine (average five) in number for each specimen. Cut sections were kept in 10% formaldehyde solution for 24–48 h. Cut sections with routine samples were stained with hematoxylin-eosin (HE) and examined under light microscope. Immunohistochemical staining was undertaken if the tumor was found to contain different cell types.

3. Results

Fig. 3. Peribronchial extension of the tumor (arrow) and bronchial cartilage (thin arrow) (HE × 200).

Fig. 4. Endobronchial extension of the tumor (arrow) and the bronchial mucosa (thin arrow) (HE ×40).

The cut sections of 36 (51.4%) specimens were free of tumor at all levels. The cut sections were tumor positive in 34 (48.5%) specimens at different levels. Regarding to the tumor positive farthest level, tumor tissue existed at 0 cm in 17(50%), 0.5 cm in 6 (17.6%), 0.6 cm in 1 (2.9%), 1.0 cm in 5 (14.7%), 1.5 cm in 2 (5.8%), 2.0 cm in 2 (5.8%) and 3.0 cm in 1 (2.9%) cases. Out of tumor positive specimens, 17 (25%) showed the tumor at 0 cm level. In the remainder, proximal extension was observed as peribronchial extension in 9 (52.9%) (Fig. 3) and as bronchial extension in 8 (47.0%) (Fig. 4) specimens including submucosal lymphatic extension (Table 2). The histopathological analysis of all the tumors was as follows; SCC 38 (54.2%), AC 15 (21.4%), BAC 8 (11.4%), adenosquamous carcinoma (ASC) 6 (8.5%), large cell carcinoma (LCC) 3 (4.2%). In cut sections tumor positi6e specimens, SCC accounted for the majority (n= 25) (73.5%) (Table 3). Proximal extension occurred in 11 (64.7%) SCC, 5 (29.4%) AC and 1 (5.8%) ASC specimens. SCC (28.9%) (11/38) showed proximal extension more than AC (21.7%) (5/23). Of SCC specimens, 7 (63.6%) showed bronchial extension and 4 (36.3%) showed peribronchial extension. The same patterns were 1 (20%) and 4 (80%) in AC, respectively. The farthest extension was 3.0 cm for AC and 2.0 cm for SCC (Table 4). Sleeve resections consisted of 10 (29.4%) of cut sections tumor positive specimens. Of these, right lower sleeve lobectomy 5 (14.7%) was the most common resection type. Proximal extension was

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Table 2 Analysis of extension pattern and tumor positive farthest levela (n =34) Extension pattern

0.0

0.5

0.6

1.0

1.5

2.0

2.5

Bronchial Submucosal Peribronchial Totals

10 – 7 17

2 1 3 6

– – 1 1

2 – 3 5

1 1 – 2

1 – 1 2

– – – –

a

3.0 – – 1 1

Microscopically found tumor positive cut section level in cm.

Table 3 Analysis of cell type and tumor positive farthest levela (n= 34) Histology

0.0

0.5

0.6

1.0

1.5

2.0

2.5

Squamous cell carcinoma Adenocarcinoma Bronchioloalveolar carcinoma Adenosquamous carcinoma Totals

14 1 1 1 17

5 – 1 – 6

– – – 1 1

4 1 – – 5

1 1 – – 2

1 1 – – 2

– – – – –

a

3.0 – 1 – – 1

Microscopically found tumor positive cut section level in cm.

Table 4 Analysis of cases which showed proximal extension (n = 17)a Case

Age (years)

Sex

Bronchial localization of the tumor

Operation

Pattern of extension

Histology

Farthest tumor (+) cut sectionb

1 2 3

51 56 59

M M M

RLSL LUL+LR LP

B PB B

SCC SCC SCC

0.5 0.5 1.0

4

51

M

LLL

SMC

SCC

0.5

5

54

M

RUML

PB

AC

2.0

6 7 8

66 48 63

M M M

LUL+LR RUSL RUML

PB PB PB

SCC ASC BAC

1.0 0.6 0.5

9 10 11 12

43 49 63 46

M M F M

LLSL RTSP RLSL RUL

B PB PB B

SCC SCC AC AC

0.5 0.5 3.0 1.5

13 14 15 1.0 16 17

37 55 56 60 69

M M M M M

Right lower lobe basal Left upper lobe anterior Left lower lobe posterobasal Left lower lobe posterobasal Right upper lobe posterior Left upper lobe anterior Right upper lobe Right upper lobe anterior Left lower lobe apical Intermediate bronchus Right lower lobe apical Right upper lobe posterior Left lower lobe basal Intermediate bronchus Left upperlobe apicopos Right upper lobe Right lower lobe apical

LP RP terior RUMSL RLSL

PB SMC LUL+LR B B

AC SCC PB SCC SCC

1.0 1.5 SCC 1.0 2.0

a RLSL, right lower sleeve lobectomy; LUL+LR, left upper lobectomy+lingular resection; LP, left pneumonectomy; LLL, left lower lobectomy; RUML, right upper-middle lobectomy; RUSL, right upper sleeve lobectomy; LLSL, left lower sleeve lobectomy; RTSP, right tracheal sleeve pneumonectomy; RUL, right upper lobectomy; RP, right pneumonectomy; RUMSL, right upper-middle sleeve lobectomy; B, bronchial; SMC, submucosal; PB, peribronchial; SCC, squamous cell carcinoma; AC, adenocarcinoma; ASC, adenosquamous carcinoma; BAC, bronchioloalveolar carcinoma. b Microscopically found tumor positive cut section level in cm.

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4. Discussion

Fig. 5. Submucosal lymphatic extension at 1.5 cm level in a right pneumonectomy specimen (arrow) (HE × 100).

58.3% (n= 7/12) for sleeve resections. The farthest level was 3 cm in a right lower sleeve lobectomy specimen. Of the 16 specimens, which were also evaluated for distal tumor extension, there was no evidence of tumor in the distally obtained cut sections but epithelial changes including dysplasia in 2 (2.8%) and metaplasia in 1 (1.4%) specimens. Submucosal lymphatic extension was found in two (2.8%) specimens. Histopathological diagnosis was SCC in both the specimens. Right pneumonectomy specimen showed submucosal lymphatic extension at all the (0, 0.5, 1.0 and 1.5 cm of BRM) levels (Fig. 5). Left lower lobectomy specimen showed the same pattern up to 0.5 cm level but was tumor-free at 1.0 and 1.5 cm of BRM (Table 4). Metaplasia was found in two (2.8%) specimens. Of these one had SCC and the other had ASC. The former one, which was a right upper sleeve lobectomy specimen, showed either metaplasia or dysplasia at 0 cm proximal section. The latter which was a right lower sleeve lobectomy specimen showed both microscopic tumor at 0 cm and metaplasia also at 0.5 cm far from the main BRM which consisted of middle lobe BRM. Reinvasion or so-called secondary invasion was found in five (7.1%) specimens. Of these, three were AC and two SCC. Tumor cells were confined to the outer fibrous coat in all the specimens. Papillary or polypoid extension was found in eight (11.4%) specimens. All were SCC except one of a LCC. The farthest extension for this feature was 3.5 cm in the right tracheal sleeve pneumonectomy specimen.

Although it can be predicted that patients with residual tumor at BRM will have a poor prognosis, some authors reported favorable results of longterm survival [6–11]. Tumor cells at BRM [11] or the length of the resected bronchus [9] does not affect the survival time whereas recurrence in the bronchial stump [12] is related to the distance between the tumor and BRM. Also post-operative morbidity, mortality rates are likely to be high in patients with remaining tumor in the BRM [8,9]. Moreover, completeness of resection is acknowledged as the most important goal of any surgical treatment. Habein et al. reported that recurrence of BRM was related to the carcinomatous epithelial changes [13]. Griess et al. were the first workers on the bronchial extension of lung cancer. They pointed out that the bronchus should be severed at least 1.5 cm proximally from the gross tumor in SCC but for AC more than 2 cm would be a safe distance [1]. Most recently, Cotton stated that at least 3/4 in. (1.9 cm) of apparently normal bronchus should be severed to eliminate the risk of residual tumor in the BRM [2]. Several authors found out tumor positivity at BRM ranging from 1.6 to 14% [6– 9,11–16]. The latter reports only included the analysis of BRM but the safe resection length of bronchial stump was not outlined. The proximal direct extension of lung cancer was found out as 43 and 12% in Griess and Cotton’s series, respectively. We found the same ratio as 48.5%. We obtained 0 cm cut sections to assess the naked eye evaluation of the junctional area. Just considering the probable misevaluation at the junctional area, we just ignored 17 cases, which consisted of 0 cm tumor positive specimens. Our final ratio appeared as 24.2% for proximal extension of lung cancer. Peribronchial spread is the most common extension pattern in lung cancer. Our results were consistent with the other reports [1,2,11,15]. We found the farthest level for bronchial extension as 2.0 and 3.0 cm for peribronchial extension. Cotton reported the same figures as 2.0, 3.8 cm and Griess as 2.0 and 1.5 cm, respectively. Soorae and Stevenson reported that both figures were more

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than 2.5 cm. Referring to these findings, it might be reasonable to preclude that approximately 2.0 cm is a safe resection length for lung cancer. Whereas the results, in this series suggest that a margin of at least 1 and 1.5 cm provides tumorfree resection margins in 86 and 93% of all the cases, respectively. Therefore, extensive removal of bronchial tree is unnecessary because a margin of 1.0 – 1.5 cm will constitute adequate clearance. Our results were definitely in line with the criteria of Soorae and Stevenson for inadequate bronchial stump [9]. SCC extends more than AC in ratio and the extension type is mainly bronchial. Contrarily, AC extends further than SCC in length and the extension type is peribronchial [1]. Our results were compatible with these findings. Initially, we preferred to obtain cut sections because it is for sure that when the resected lung is kept in formaldehyde for fixation, some extent of shrinkage which gives the bronchus an irregular shape and causes distortion of BRM may occur [6,13]. Conversely from the previous methods [1,2,13] we obtained the cut sections in the transverse plane. Regardless of the number of longitudinally obtained cut sections, the possibility of undiagnosed tumor tissue will be existing at any plane along the bronchus. This newly established method allowed us to ignore the parabronchial spread as did Cotton in the final results of his study. That was why Cotton found out that the direct extension ratio was as low as 12%. We concentrated on outer fibrous coat involvement of the bronchus as peribronchial extension. In our study, extension of the tumor was classified into three types; (1) bronchial extension; (2) submucosal lymphatic extension and (3) peribronchial extension along the outer fibrous coat. Proximal extension appeared as 58.3% for sleeve resections. If the tumor exists either close to lobar bronchus or simply invading, should sleeve lobectomy be employed at any time to preserve lung tissue. It is stated that it would be wise to maintain the bronchial tissue section not less than 1 cm from the edge of visible carcinoma [17]. When it is technically not feasible to maintain the adequate length of bronchus from the visible carcinoma,

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frozen section diagnosis should be undertaken [18]. Submucosal lymphatic extension varies from 0.3 to 8.0% [1,2,9,11,15]. In the present series, the same ratio was 2.8%. The farthest extension differs from 1.5 to more than 2.5 cm [1,2,9]. We found the same figure as 1.5 cm in a right pneumonectomy specimen. The incidence of submucosal lymphatic extension is very low compared with direct extension and should not be a limitation for resection even for tumors close to carina [2]. We noticed metaplasia in two (3%) specimens and the farthest extension was 0.5 cm. Cotton reported the same figure as 31%. Ignoring the 17 specimens which had metaplasia in the immediate proximity of the tumor, his final results appear as 14%. The farthest extension in his series was 1/2 in. (1.27 cm). Similarly, Habein et al. reported that the same figure as 55% [13]. The low incidence of metaplasia in the present series can be attributed to the method used by us. In conclusion, it is essential to have tumor-free resection margins for a curative resection. Proximal extension occurs in 24.2% of NSCLC cases. The most common extension pattern is peribronchial. In ratio, proximal extension is observed in SCC more than AC and the extension pattern is mainly bronchial. Whereas in length, proximal extension occurs more in AC. Intraoperative frozen sections should verify clear margins for sleeve resections. Submucosal lymphatic extension occurs at a rate as low as 2.8%, which indicates that extensive resection of the tumors close to carina should be employed where possible. Finally, we strongly emphasize that even a bronchial resection of 1.5 cm in length will provide clear bronchial resection margins in 93% of NSCLC cases.

Acknowledgements We would like to extend our gratitude to Professor Yoh Watanabe, Chairman of Surgery Department in Kanazawa University, for critically reviewing the manuscript and to the surgeons of Thoracic Surgery Department of Ankara University Ibn-i Sina Hospital for their collaboration.

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