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J Thorac Cardiovasc Surg 2001;122:907-912
© 2001 The American Association for Thoracic Surgery

General Thoracic Surgery (GTS)

T2 tumors larger than five centimeters in diameter can be upgraded to T3 in non–small cell lung cancer

From the Division of Thoracic Surgery,^a National Cancer Center Hospital, Tokyo, Japan; the Department of General and Thoracic Surgery,^b University of Genoa, School of Medicine, Genoa, Italy; and the Department of Mathematics,^c Science University of Tokyo, Tokyo, Japan.

This research was financially supported by the Foundation for Promotion of Cancer Research, The National Cancer Center, Tokyo, Japan.

Received for publication Dec 20, 2000. Revisions requested April 4, 2001; revisions received April 19, 2001. Accepted for publication April 24, 2001. Address for reprints: Emanuela Carbone, MD, Department of General and Thoracic Surgery, University of Genoa, School of Medicine, Largo Rosanna Benzi 8, 16132 Genoa, Italy (E-mail: gmotta{at}unige.it).

Abstract

Objective: Among the TNM criteria, tumor size is a well-assessed factor in the prognosis of small tumors. A 3-cm cutoff point separates T1 from T2 tumors, whereas a size larger than 3 cm is not ascribed any prognostic value. Instead, N2 is considered to be the worst prognostic factor for intrathoracic extended disease.
Method: The prognosis of 545 patients with non–small cell lung cancer larger than 3 cm in diameter (T2, T3, and T4) was studied. These tumors were completely resected by pneumonectomy (n = 126) or lobectomy (n = 411) or were partially resected (n = 8). Survivals were compared according to the following factors: tumor size (3.1-5 cm, 5.1-7 cm, >7 cm), nodal status, age, sex, histologic type, degree of pleural involvement, operative procedure, stage, and T factor. For the multivariate analysis, the Cox proportional hazard model was used with the same variables.
Results: The univariate analysis showed that age, sex, degree of pleural involvement, operative procedure, tumor size, nodal status, and stage were all significant prognostic factors. Further comparison of survival between different tumor sizes (5 cm vs >5 cm) in the same nodal category demonstrated a significantly poor prognosis for larger tumors in N0 (P = .00374) and N2+N3 (P = .0157), but not in N1 (P = .3452). T2 tumors (n = 349) were divided, according to size, into T2a (n = 238) and T2b (n = 111), and survival was compared with those in T3 and T4. The 5-year survivals were 51.3%, 35.1%, 47.8%, and 25.3%, respectively. The difference between T2a and T2b was statistically significant (log-rank P = .0170, Breslow P = .0055).
Conclusions: A tumor size of more than 5 cm in diameter was indicative of a poor prognosis in non–small cell lung cancer, because patients with T2b tumors had a significantly different survival from that of patients with T2a tumors, and the survival curve was located between those for patients with T3 and T4 tumors. Consequently, T2b might be upgraded to at least T3.

Although many reports on the prognostic factors of non–small cell lung cancer (NSCLC) have been published, ^1-6 and even though a large tumor size has been thought to be an important factor in a poor prognosis, as shown in a recent review, ⁷ in the TNM classification provided by the International Union Against Cancer, tumor size has prognostic value only for small tumors. According to the latest revision of the International System for Staging Lung Cancer in 1997, ⁸ a cutoff point of 3 cm divides patients with T1 N0 M0, stage IA disease, who have the best expectation for survival, from patients with T2 N0 M0, stage IB disease, who have a significantly lower probability of survival.

In this context, many reports have been published on the poor survival for larger NSCLCs and better survival for smaller tumors. Several important contributions appeared in the 1960s and 1970s, when many studies considered size as an autonomous factor in the prognosis: Steele ⁹ in 1964, Wellons and associates ¹⁰ in 1968, Jackman and colleagues ¹¹ in 1969, Yashar and Yashar ¹² in 1975, and Soorae and Abbey Smith ¹³ in 1977 emphasized the very short survival in patients with bulky tumors. The reports in the late 1970s by Soorae and Abbey Smith ¹³ and in 1984 by Ogata and Naruke ¹⁴ described the strong correlation between tumor diameter and lymph node involvement, with the frequency of N2 and N3 increasing in conjunction with an increase in tumor size. These reports raised the possibility that survival, even in patients affected by bulky tumor, basically depended on nodal involvement, because N0 and N1 tumors had a clearly better prognosis than N2-N3 tumors.

However, surgical experience shows an adverse prognosis even for larger N0-N1 tumors that are completely resected. This suggests that tumor size directly affects survival independent of lymph node involvement.

The aim of this study was to determine whether tumor size can be considered an independent factor that affects survival in NSCLC. We analyzed 545 patients with tumors of more than 3 cm in maximum diameter and their survival with regard to size, nodal status, age, sex, pleural involvement, operative procedure, histologic type, stage, and T factor.

Patients and methods

Patients
From January 1985 to December 1994, a total of 1543 pulmonary resections were performed at the National Cancer Center Hospital, Tokyo, Japan. Of these, 545 patients (35.3%) who had NSCLC more than 3 cm in maximum diameter were selected and included in this retrospective study. Table 1 shows the patients' characteristics with 5-year survivals.

Excluded from the analysis were patients with tumors smaller than 3 cm (T1), patients with distant metastasis (stage IV), and patients in whom pathologic examination disclosed infiltration of the bronchial resection margin, low-grade malignant tumors (carcinoids, adenoid cystic carcinomas, mucoepidermoid carcinomas), sarcomas, carcinosarcomas, and bronchioloalveolar carcinomas. Double primary tumors and Nx conditions were also excluded.

Statistical analysis ^17,18
The following 9 prognostic factors, which have been reported to influence survival, were analyzed by univariate and multivariate analyses: age, sex, histologic type, operative procedure, degree of pleural involvement, tumor size, lymph node involvement, T factor, and stage. The Kaplan–Meier method was used to estimate survival and its 95% confidence interval. The univariate statistical comparison was made by the log-rank and Breslow tests; the day of the operation was considered the beginning day for the analysis, and all deaths, including 30-day postoperative deaths, were included. For the multivariate analysis, the Cox proportional hazard model ¹⁹ was used to identify variables that were significantly associated with survival. SPSS version 10 statistical software (SPSS, Inc, Chicago, Ill) was used for the analysis.

Results

Univariate analysis
The overall survival curve for all 545 patients is shown in Figure 1, and the 5-year survival was 43%. On the basis of the univariate analysis, a significantly worse prognosis was found for patients more than 60 years old (log-rank P = .0000; Breslow P = .0001), men (Breslow P = .0105), tumor invasion through the visceral pleura and extending to the parietal pleura (P2 and P3) compared with P0 (log-rank P = .0442; Breslow P = .0126; Figure 2), pneumonectomy (log-rank P = .0015; Breslow P = .0002), and an advanced stage of disease (log-rank and Breslow P = .0000). There was no evidence of statistically significant differences among the histologic types

View larger version (12K): [in this window] [in a new window]   Fig. 1. Survival curve for 545 patients with tumors larger than 3 cm. The 5-year survival is 43%

View larger version (19K): [in this window] [in a new window]   Fig. 2.Survival according to the degree of pleural involvement. The survival curves show a significantly worse prognosis for tumor invading through the visceral pleura(P2)and the parietal pleura(P3).

View larger version (17K): [in this window] [in a new window]   Fig. 3. Survival curves according to tumor size. The 5-year survivals for group A (3.1-5 cm), group B (5.1-7 cm), and group C (<7 cm) are 48%, 37% and 31.6%, respectively. A statistically significant difference was found between groups A and B (log-rank>P= .0377, Breslow P= .0085) and A and C (log-rank P= .0039, Breslow P= .0002), but not between B and C (log-rank P= .1929, Breslow P= .0928).

Prognosis by tumor size in the same nodal category
Different tumor sizes (group A vs group B+C) were compared within the same nodal category: N0, N1, and N2+N3. A statistically significant difference was found by the Breslow test in N0 (P = .0374; Figure 4) and in N2+N3 (P = .0157; Figure 5), whereas no statistically significant difference was found in N1.

View larger version (17K): [in this window] [in a new window]   Fig. 4. Stratified analysis for patients with NO disease (n = 236). The 5-year survivals for tumors of 3.1 to 5 cm and more than 5 cm are 61.9% and 51.3%, respectively. A statistically significant difference was found by the Breslow testP= .0374).

View larger version (15K): [in this window] [in a new window]   Fig. 5. Stratified analysis for patients with N2+N3 disease (n = 166). The 5-year survivals for tumors of 3.1 to 5 cm and more than 5 cm are 27.8% and 15.9%, respectively. A statistically significant difference was found by the Breslow testP= .0157).

View larger version (22K): [in this window] [in a new window]   Fig. 6. Survival curves according to T factor. The 5-year survivals for T2a (3.1-5 cm), T2b (<5 cm), T3, and T4 are 51.3%, 35.1%, 47.8%, and 25.3%, respectively. A statistically significant difference was found between T2a and T2b (log-rank>P = .0170, Breslow P = .0055), between T2a and T4 (log-rank and Breslow P = .0000), and between T3 and T4 (log-rank P = .0037, Breslow P = .0042). No difference was found between T2a and T3, T3 and T2b, or T2b and T4. *Statistically significant; —, not statistically significant.

In the TNM Classification for Lung Cancer, tumor size is considered to affect the prognosis only for small tumors (stage I, <3 cm), whereas larger sizes are not thought to have a direct influence on survival, as reported in a recent review by Mountain. ²⁰ In the advanced stage of the disease, invasion of visceral pleura, associated atelectasis, obstructive pneumonia, and extension of tumor within the lung as well as to adjacent structures and organs all represent local progression and are responsible for a poor prognosis, rather than tumor diameter. Therefore, tumor size has not been considered to reflect locally advanced T status. On the other hand, a strong correlation has been shown between tumor size and lymph node involvement, ^13,14,21 with a higher percentage of N2 in larger tumors and a proportionally worse prognosis for patients with N2 tumors. ^22-25

Our results show that tumor size directly affects survival, with a significantly worse prognosis for tumors larger than 5 cm than for those ranging from 3 to 5 cm. We also found a significantly poorer survival for patients with T2b tumors, closer to that for patients with T4 tumors, with 5-year survivals of 35.1% and 25.3%, respectively. These results suggest that tumor size may be considered an independent factor in determining the prognosis, that tumor size is distinct from other features characterizing T2, T3, and T4 status, and that T2 tumors larger than 5 cm should be upgraded to at least T3. Similar results were reported by Watanabe and associates, ²⁶ who found, in patients with T2 N0 M0 disease, 5-year survivals of 61.0% and 46.3% for tumors less than 5.0 cm and more than 5.1 cm, respectively.

Although lymph node involvement has been shown to significantly affect survival, this analysis found a significant "additive" effect with tumor size, and no significant interaction was found when both variables were considered together, as confirmed by a generalized Wilcoxon test in a stratified univariate analysis. Despite the relationship between size and nodal status, with a cumulative worsening of the 5-year survival, tumor size has an independent effect on the prognosis. In fact, the 5-year survival for N0 patients with tumors larger than 5 cm (51.3%) is significantly less than that for tumors smaller than 5 cm (61.9%). This finding supports the possibility of autonomous spreading, ¹³ which seems to follow routes different from the more anatomic lymphatic routes. These results are confirmed by the proportional hazard model, in which the estimated relative risk associated with size increases for tumors larger than 5 cm (risk = 1.430).

In conclusion, tumor size was studied independent of other variables in T3 and T4 of the TNM classification and was shown to affect survival independent of nodal metastases. Tumor size appears to play a fundamental role in the prognosis of lung cancer, and a new cutoff point of 5 cm divides tumors larger than 3 cm into 2 groups with significantly different survivals. In addition, the 5-year survival of patients with T2 tumors larger than 5 cm (T2b) is between those for patients with T3 and T4 tumors and actually closer to that for patients with T4 tumors. Thus, T2 tumor larger than 5 cm might be upgraded to at least T3 in the TNM classification.

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