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Ann Thorac Surg 2005;79:974-979
© 2005 The Society of Thoracic Surgeons

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Original article: General thoracic

Comparison Between Clinical and Pathologic Staging in 2,994 Cases of Lung Cancer

Pneumology Service, Hospital Universitario 12 de Octubre, Madrid, Spain
Department of Cardiothoracic Surgery, Weill Medical College of Cornell University, 525 East 68th St, New York, NY 10021

Accepted for publication June 2, 2004.

^* Address reprint requests to Dr López-Encuentra, Pneumology Service, Hospital Universitario 12 de Octubre, Ctta Andalucía 5.4, 28041 Madrid, Spain

	Abstract

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BACKGROUND: The accuracy of clinical staging in lung cancer may be evaluated by comparing it against the gold standard of pathologic staging. The objective of this paper is to compare these two staging methods in a series of 2,994 lung cancer cases operated on consecutively in Spain between 1993 and 1997.

METHODS: The raw frequency of agreement was used to compare clinical against pathologic staging and to assess the agreement. Kappa's index was used to determine the random effect of agreement.

RESULTS: Ninety-three percent of the entire population were men, with a mean age of 64 years (median, 66; SD, 9.6). The majority of cases were classified as squamous tumors (1,774; 59%), with complete resection (2,410; 80%), and with lobectomy or bilobectomy (1,490; 55%). The most frequently found pathologic stage was pIB (997; 37%), followed by pIIIA (524; 19%). Considering the 2,377 cases with clinical and pathologic staging data, a classification coincidence was observed in 1,108 cases (47%; Kappa's index 0.248 for stages IA through IIIB). Considering the pathologic staging as the gold standard, the agreement was 75% for stages IA-IB (Kappa's index 0.56). In general, downstaging is more frequent than upstaging.

CONCLUSIONS: This recent series of lung cancer showed the low diagnostic accuracy of the clinical staging as compared with the pathologic staging. Diagnostic accuracy was found to be much higher in the initial IA-IB stages, as illustrated by Kappa's index.

	Introduction

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The staging of lung cancer has been modified and updated on several occasions, being the 1997 classification the latest version [1].

The clinical staging is based on the information provided by any given method before thoracotomy, including clinical, imaging, or endoscopic methods. Endoscopic methods include bronchoscopy, thoracoscopy, and the surgical exploration of the mediastinum (mediastinoscopy, mediastinotomy) [1]. The pathologic staging is based on the information gathered in the previous phase (clinical staging), together with the information obtained during the actual surgical procedure, after pathologic analysis of the excised surgical specimen [1]. The clinical staging makes it possible for the clinician to make therapeutic decisions. The pathologic staging provides greater certainty in the estimation of prognosis and can also prove useful when making decisions on adjuvant therapy after surgery.

In recent years, numerous clinical staging methods have become increasingly available. Computed tomography (CT) and bronchoscopy have been systematically used in clinical staging. Mediastinoscopy has also been used in certain situations [2, 3]. Positron emission tomography (PET) provides better results than CT in mediastinal nodal staging [4]; and more recently, new PET technology [5] has made it possible to make a better assessment of the original tumor (T)

This increased use of new techniques should lead to decreased classification error of clinical staging when compared against the available gold standard of pathologic staging.

In the 1990s, several studies comparing both staging methods were carried out. Agreement was found in the T, N, or TN staging in 35% to 55% of the cases, with thoracic CT in all cases [6, 7] or with an indication for CT in all central lung cancer [8, 9].

Our series of 2,994 consecutive cases (operated on between 1993 and 1997) was selected after clinical staging, based on very similar methods [10], had been performed in all the Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery (GCCB-S) centers. (A complete list of GCCB-S members is given in the Appendix.) It should be pointed out that PET was employed in clinical staging only in one center and only toward the end of the study.

The objective of this paper is to describe this series of cases and to compare clinical against pathologic staging during a period of time before the use of PET supposedly became common practice.

	Patients and Methods

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Patients
All the patients included in the study had lung cancer in initial stages and had undergone thoracotomy with intent to cure in hospitals pertaining to the Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery [11].

We included prospectively all patients treated surgically from October 1993 to September 1997 in hospitals participating in the GCCB-S. The annual cumulative number of cases was close to 50% of surgical cases occurring in Spain. The participating GCCB-S centers had a wide variety of activities, including a representative range in the number of beds, teaching or research activities (university and nonuniversity hospitals), public and private ownership, and in the number of interventions per year (from 8 to 100 interventions were performed in participating center for this disease). The sample was complete, as verified by the inclusion of all patients undergoing surgery in the registry, including incomplete resections and exploratory thoracotomy.

Operative mortality was understood to include all deaths directly related to the surgical procedure, regardless of when the death occurred. The final number of cases included in the study was 2,994.

Methods and Analysis
The 1997 TNM staging classification currently in effect was used in this study [1]. The degree of certainty of the TNM staging classification relies on the diagnostic methods used; according to some international organizations, postmortem study yields the maximum certainty and the clinical findings yield the minimum certainty. The methods for affirming maximum classificatory certainty for each of the components (size, local invasion) of each category (T, N, M [maximum possible clinical certainty adjusted for each problem]) [12, 13] were established by consensus among the members of the GCCB-S coordinating group (central review board composed of two thoracic surgeons and one pneumologist). Lymph node categories (N) were evaluated using different diagnostic criteria of classificatory certainty. To confirm a cN0 classification, the absence of lymph node enlargement or lymph node enlargement of less than 1 cm in diameter had to be confirmed by CT in lymph node areas 4, 7, and 10 [14]. There had to be no lymph node enlargement in either the aortopulmonary window nor in the anterior mediastinal area (areas 5 and 6) if the lung cancer was left-sided (upper lobule or main left bronchus). If these criteria were not met, negative mediastinoscopy-mediastinotomy or negative fine-needle aspiration biopsy (transbronchial, transthoracic, or transesophageal) of these areas was required. The cN1 classification was confirmed by cytohistologic evidence (transbronchial fine-needle biopsy, hilioscopy). To confirm a cN2 classification, cytohistologic evidence was required (mediastinoscopy, mediastinotomy, fine needle aspiration biopsy using any approach).

Surgical pathologic N0 was classified by radical mediastinal lymph node dissection or sampling of at least four lymph node areas (2 [only in right lung cancer], 4, 7, and 10 on the same side as the tumor), especially in pT3 [13]. This criterion is similar to that defended in recently proposed guidelines, such as the six hilar-mediastinal enlarged lymph nodes in the latest UICC (International Union Against Cancer) tumoral classification [1].

Internal and external audits were made to survey the ratio between the number of patients undergoing surgery and the number of cases included in the registry (standard > 95%), and to determine the presence and validity of the data recorded for each case (standard > 70%), including the consistency of tumoral staging [12, 15]. The criterion used to assess the validity of the survival data were the existence of a documented follow-up of 85%, or more, of the cases registered in each hospital. In the hospitals that did not meet these criteria, the cases corresponding to the irregular period of time were excluded. Finally, correct data transmission by a single central office from the paper record to the computer database was verified.

These procedures were designed to control the selection bias of surgical cases, registered cases out of the total number of surgical cases, sample size, type of hospital, prognostic migration due to the prolonged period of case recruitment, classification with low or deficient degrees of certainty, contamination of data from incomplete series, or incorrect data, and loss of long-term follow-up.

The raw frequency of agreement was used to compare clinical against pathologic stages and to assess agreement. Kappa's index was used to determine the random effect of agreement.

	Results

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Descriptive Study
The majority of patients were male (2,771; 93%), mean age was 64 years (SD, 9.6; median, 66; minimum, 30; maximum, 91; 25th percentile, 59; 50th percentile, 66; 75th percentile, 71). Eighty-seven percent of cases were smokers or ex-smokers; in 2,585 patients it was possible to determine the level of smoking, with a mean of 57.5 package-year (SD, 30; median, 50). Of the 2,994 patients, 57% admitted being an active smoker.

Table 1 shows the rest of the characteristics for these cases. The histologic typing of the tumor was based on the pathologic analysis of the surgical specimen in 2,983 cases (97%), and in the remaining 101 cases, on preoperative histology. Operative death occurred in 236 patients (7.9%).

Table 2 shows the distribution by clinical and pathologic stages. In 6 cases, the clinical classification was in situ or hidden carcinoma (TXN0M0). There were no cIIA cases owing to the necessity to have a prethoracotomy cytohistologic confirmation to be able to confirm cN1, as required by the study design [12]. There were 106 cases with a suspected cN1 image. For cN2 and cN3, these same reasons are at play and explain the number of cIIIA and cIIIB cases, and the total number of cases with clinical classification (n = 2,606). Diagnostic imaging showed 393 suspected cN2, and 103 had cytohistologic evidence. In the pathologic classification, to the problems encountered in the pN0 staging [13], we need to add the absence of correct staging in cases of exploratory thoracotomy. The total number of cases classified using the pathologic staging was 2,710 (91% of the total series of 2,994 cases).

In the comparison by stages, clinical staging was frequently found to underestimate the pathologic staging rather than vice versa. Obviously, both classificatory extremes (IA and IIIB) make the clinically misdiagnosed cases move necessarily into one single direction of overestimation or underestimation, respectively. In pIB, the percentage relation between underestimation and overestimation is 15 and 10 (in percentages; see Table 3, last row of data); in IIA it is 92 and 8; in IIB it is 74 and 3; and in IIIA it is 86 and 6.

	Comment

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The main objective of this study on a recent series of 2,994 lung cancer cases compiled by the GCCB-S is to analyze the accuracy of the clinical staging by comparing it against the best gold standard, pathologic staging. Of the three staging components, this comparison is only valid for T and for N, given that thoracotomy, the gold standard for this staging, can hardly modify the M clinical classification. This study shows that both staging methods coincide in fewer than half of cases, with a higher accuracy in stages IA and IB (75%) than in stages IIB and IIIB (between 8% and 23% of agreement).

The basic characteristics of our series are very similar to other European experiences [18, 19], but different from characteristics observed in the United States [20] or Japan [21] (Table 4). Recently, a joint comparison among various authors from three continents (America, Asia, and Europe) [22] was carried out, controlling the type of tumor (nonsmall cell lung cancer) and taking into account cases with resection. This comparative analysis showed a common low frequency of pIIA (2% to 4%) in the proportion of pIIIB (15% to 20%) and pIIIA (18% to 26%), with greater differences in the pIA/pIB ratio coefficient, which ranges between 0.93 and 1.21 in the United States and Japan and between 0.29 and 0.43 in Spain and Germany [22].

The majority of reported experiences, including this one, show a deterioration of the clinicopathologic agreement that is directly related to the increase in T and N categories (Table 3). Taking the pathologic classification as the gold standard, the accuracy in the T category changes from 92% for T1% to 52% for T3, and from 87% for N0% to 4% for N2 [6],

When the different stages are assessed by the same method, the 75% level of agreement found in our study is similar to the 72% reported by another recent study for initial stages [23] and lower than the 91% agreement for IA reported in 1990 and 75% for IB [6].

Overestimation or underestimation of the staging varies greatly among experiences and stages, with overestimation tending to be more frequent in the more initial stages and underestimation more frequent in the most advanced stages, due to, among other causes, obvious reasons in the distribution of the stage spectrum. Moreover, there are differences in the working methods used for the staging of patients. For example, the majority of patients undergo routine CT, but in some, CT is only carried out for central tumors [8]. There are also differences in the judgments and in the decisions made. For instance, in some cases, cN2 patients are not operated on, and thus comparison with the pathologic classification is not possible in this subset of the population [6].

In our series, the prospective registry of all the variables of all the cases provided different data that made it possible to control the classificatory reliability of the T and N categories. Thus, out of clinical interest, it was decided to classify cN1 and cN2 only on the basis of cytohistologic criteria [12]. This decision was motivated by the high number of false-positive results yielded by CT in these cases [24]. Also, in the absence of systematic nodal dissection in all the cases and in all the hospitals, a minimal nodal staging of the mediastinum (see Methods) was required to classify pN0 [13], given that for pN1 and pN2 the pathologic certification was obvious. For the objectives of the pN0 and pN2 classification, this minimal staging appears to be adequate not to include pN2 hidden in an apparent pN0 classification [25, 26].

This study presents several limitations, the most important being the presence of some population characteristics (scarce number of women), tumor characteristics (high rate of squamous type tumors), and stage characteristics (low relative frequency of pIA) different from those reported in other countries. Furthermore, in our series, there was a 5% of cases with induction therapy, which could have caused a downstaging in some cases, although, at an overall level, with little effect on the final outcome.

No improvement in the accuracy capacity of clinical staging was observed over 2 decades (1980 and 1990) when compared with pathologic staging. It is probable—and desirable—that integrated PET [5] substantially improves the classificatory certainty of the T and N clinical staging. The values of the clinicopathologic agreement of the TN classification shown in this paper, based on a series of cases compiled between 1993 and 1997, can serve as a reference point—as the historical control—to determine whether integrated PET improves the TN staging.

	Appendix

 
Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery
Coordinators: José Luis Duque, MD (Hospital Universitario, Valladolid); Angel López Encuentra, MD (Hospital Universitario 12 de Octubre, Madrid); Ramón Rami Porta, MD (Hospital Mutua de Terrassa, Barcelona).

Local Representatives: Julio Astudillo, MD; López de Castro, MD (Hospital Germans Trias i Pujol, Barcelona); Emilio Canalís, MD; Jose Belda, MD (Hospital Clinic, Barcelona); Antonio Cantó, MD (Hospital Clínico, Valencia); Juan Casanova, MD (Hospital de Cruces, Bilbao); Jorge Cerezal, MD (Hospital Universitario, Valladolid); Antonio Fernández de Rota, MD (Hospital Carlos Haya, Málaga); Federico González Aragoneses, MD; Nicolas Moreno, MD (Hospital Gregorio Marañón, Madrid); Jorge Freixinet, MD (Hospital Doctor Negrin, Las Palmas); Nicolás Llobregat, MD (Hospital Universitario del Aire, Madrid); Nuria Mañes, MD (Fundación Jiménez Díaz, Madrid); Miguel Mateu, MD (Hospital Mutua de Terrassa, Barcelona); José Luis Martín de Nicolás, MD (Hospital Universitario 12 de Octubre, Madrid); Nuria Novoa (Complejo Hospitalario, Salamanca); Jesús Rodríguez, MD (Complejo Hospitalario, Oviedo); Antonio José Torres García, MD (Hospital Universitario San Carlos, Madrid); Mercedes de la Torre (Hospital Juan Canalejo, La Coruña); Abel Sanchez-Palencia, MD; Javier Ruíz-Zafra, MD (Hospital Virgen de las Nieves, Granada); Andrés Varela Ugarte, MD; Mar Cordoba, MD (Clínica Puerta de Hierro, Madrid); Yat Wah Pun, MD; Lorenzo Fernández, MD (Hospital de la Princesa, Madrid).

Data Analysis: Agustín Gómez de la Cámara, MD; Francisco Pozo Rodriguez, MD.

	Acknowledgments

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Supported in part by FIS Grant 97/0011, FEPAR-1995 Grant, RTIC-03/11-ISCIII-Red-Respira Grant, and with financial aid from the Castilla-León Regional Government and the Menarini Foundation.

	References

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