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

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1 Comparison Between Clinical and Pathologic Staging in 2,994 Cases of Lung Cancer Angel López-Encuentra, MD, Ricardo García-Luján, MD, Juan José Rivas, MD, Jesús Rodríguez-Rodríguez, MD, Juan Torres-Lanza, MD, Gonzalo Varela-Simo, MD, and the Bronchogenic Carcinoma Cooperative Group of the Spanish Society of Pneumology and Thoracic Surgery Pneumology Service, Hospital Universitario 12 de Octubre, Madrid, Spain 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 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 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. (Ann Thorac Surg 2005;79:974 9) 2005 by The Society of Thoracic Surgeons 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 Accepted for publication June 2, Address reprint requests to Dr López-Encuentra, Pneumology Service, Hospital Universitario 12 de Octubre, Ctta Andalucía 5.4, Madrid, Spain; lencuent@h12o.es. 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 2005 by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg LÓPEZ-ENCUENTRA ET AL 2005;79:974 9 CLINICAL AND PATHOLOGIC STAGING OF LUNG CANCER 975 during a period of time before the use of PET supposedly became common practice. Patients and Methods 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 mediastinoscopymediastinotomy 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 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%). The most common comorbidities were chronic obstructive pulmonary disease and hypertension. These data, together with the delay in therapy and its clinical value, have been reported previously [16, 17]. In 29% of cases (878 patients), lung cancer was diagnosed as a

3 976 LÓPEZ-ENCUENTRA ET AL Ann Thorac Surg CLINICAL AND PATHOLOGIC STAGING OF LUNG CANCER 2005;79:974 9 Table 1. General Characteristics Number, Percent Histological type Squamous 1,774, 59% Adenocarcinoma 759, 25% Large cell 190, 6% Nonsmall cell (unspecified) 138, 5% Bronchioloalveolar 84, 3% Small cell 49, 2% Resection type Complete (R0) 2,410, 80% Incomplete (R1 R2) 287, 10% Exploratory thoracotomy 297, 10% Extension of resection Lobectomy/bilobectomy 1,490, 55% Left pneumonectomy 497, 18% Right pneumonectomy 370, 14% Other resections 340, 13% casual radiologic finding. Fifty-one percent of the lung cancer cases were right-sided, involving the upper lobules in the majority of cases (1,489; 50%). 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). Comparison Between Clinical and Pathologic Classification Considering the classificatory criteria used in this paper for the clinical and the pathologic staging, and because Table 2. Clinical and Pathologic Staging Stages Clinical (n, %) Pathologic (n, %) IA 525, 20% 290, 11% IB 1453, 56% 997, 37% IIA 43, 2% IIB 373, 13.5% 401, 15% IIIA 74, 3% 524, 19% IIIB 139, 5% 413, 15% IV 42, 1.5% 42, 2% Total 2,606 2,710 both were available, it was possible to carry out a clinicopathologic comparison in 2,377 of the cases (79% of the total 2,994). This decrease in the number of cases was secondary, fundamentally, to the need to comply with classificatory certainty criteria in cn and pn [12, 13]. Both staging methods were in agreement in 1,108 cases (47%; Table 3). If the 42 cases in stage IV (in which thoracotomy is not supposed to modify that stage) were not to be taken into account, then the level of agreement would have been 46%. Kappa s index was for stages IA through IIIB. Taking pathologic staging as the gold standard, the percentage of accurate diagnosis by clinical stages was at its height in stage IV (100% of 42 piv) and nil for IIA (0% of 36 piia). Table 3 also shows the levels of agreement for the rest of stages (the penultimate row of data). It is worth mentioning the high level of agreement (75%) for stages IA and IB. Kappa s index was 0.56 in stages IA and IB. That is because according to T groups, the agreement for pt1 and pt2 was 74% to 76% and for pn0 it was 89%. Nevertheless, it is worth pointing out the low level of agreement in stages IIB and IIIB. Groups T3 and T4 are involved in these last stages; the level of agreement for these groups was 53% and 18%, respectively. With regard to the pn assessment, the agreement was 89% for pn0, nil for pn1 (by definition), and only 8% for pn2. 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 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

4 Ann Thorac Surg LÓPEZ-ENCUENTRA ET AL 2005;79:974 9 CLINICAL AND PATHOLOGIC STAGING OF LUNG CANCER 977 Table 3. Comparison of Clinical Stages and Pathologic Stages (c/p) Pathologic Stages pia pib piia piib piiia piiib piv Total cia cib ciia ciib ciiia ciiib civ Total ,337 Agreement c/p 75% 75% 23% 8% 22% Under estimation 15% 92% 74% 86% Over Estimation 10% 8% 3% 6% The figures on the c/p agreement diagonal are in bold letters. The c/p agreements are measured using the probability of clinical accuracy of the pathological stage, and considering this latter one as the reference gold standard (c/p ratio). 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]. Since 1990, the tendency has been to conduct comparative analyses between the clinical and the pathologic staging. The level of agreement between both classifications has ranged between 35% [7], 47% [6], and 55% [8, 9]. The level of agreement in our study is 47%, somewhere in between these two experiences, despite the fact that these studies [6, 8, 9] corresponded to cases retrieved with a 10-year difference with respect to cases compiled by the GCCB-S. When shown, Kappa s index was low (0.367), being more similar to the comparison between ct and pt (0.4) than to the comparison between cn and pn (0.242) [8]. 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]. Table 4. Comparison of Patient Characteristics With Surgical Lung Cancer Males Age (Mean) Squamous Lobectomy pia Netherlands [18] Poland [19] USA [20] Japan [21] Present study 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

5 978 LÓPEZ-ENCUENTRA ET AL Ann Thorac Surg CLINICAL AND PATHOLOGIC STAGING OF LUNG CANCER 2005;79:974 9 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. 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 1. Sobin LH, Wittekind Ch. UICC International Union Against Cancer, TNM classification of malignant tumours. 5th ed. 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J Clin Oncol 2003;21: 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, Ma-

6 Ann Thorac Surg LÓPEZ-ENCUENTRA ET AL 2005;79:974 9 CLINICAL AND PATHOLOGIC STAGING OF LUNG CANCER 979 drid); 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 INVITED COMMENTARY The importance of clinical staging for malignant disease cannot be overstated. Accurate clinical staging is a necessary prerequisite for treatment planning, prognostication, and for the rational design of clinical trials. The designation of a ctnm stage should incorporate all the information derived before thoracotomy from clinical evaluation, various imaging modalities, and invasive staging procedures such as mediastinoscopy. Ideally, clinical staging modalities should result in a ctnm stage that is highly predictive of the final pathologic stage as determined by pathologic examination of the excised lung parenchyma and the mediastinal lymph nodes. Unfortunately, clinical staging of non-small-cell lung cancer (NSCLC) falls short of that ideal. The degree of correlation between clinical and pathological staging varies between 35% and 50%. López-Encuentra and his colleagues compare clinical and pathologic staging in nearly 3000 cases of NSCLC that represent nearly 50% of all lung cancer cases operated on in Spain between 1993 and The authors should be commended for their huge effort, because this is probably the largest series to date that addresses this issue and is likely the most current. Sadly, however, the news is not good. Nearly a decade and several generations of computed tomography (CT) scanners after prior similar studies, the accuracy of clinical staging in predicting the final ptnm stage remains poor. In the current report it is less than 50%. Unfortunately, clinical staging in their study did not 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. include positron emission tomography (PET) scanning, which is rapidly becoming a common procedure in the United States, though perhaps not in Europe. The authors appropriately acknowledge this limitation of the study and conclude that this series should represent an adequate historical control for future studies that use PET scanning. The reader may be tempted, however, to conclude that the poor correlation merely reflects a lack of consistent use of mediastinoscopy. For example, 20% and 30% of patients clinically designated as having stages IA and IB, respectively, proved to have stage III disease and potentially did not benefit from primary resection. Similarly, approximately 20% of patients designated as stage IIIA and IIIB had earlier stages and may have been denied operative intervention. Given the suboptimal accuracy of CT scans in predicting nodal metastases, a more liberal application of mediastinoscopy could have added significantly to the accuracy of clinical staging. In an ideal world we should consistently use all of the modalities at our disposal to clinically stage patients with NSCLC. Only then will we establish a reliable historical control. Nasser Altorki, MD Department of Cardiothoracic Surgery Weill Medical College of Cornell University 525 East 68th St New York, NY nkaltork@med.cornell.edu by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur