Prognostic Value of Histology in Resected Lung Cancer With Emphasis on the Relevance of the Adenocarcinoma Subtyping

GENERAL THORIC Prognostic Value of Histology in Resected Lung Cancer With Emphasis on the Relevance of the Adenocarcinoma Subtyping Marc Riquet, MD, PhD, Christophe Foucault, MD, Pascal Berna, MD, Jalal Assouad, MD, Antoine Dujon, MD, and Claire Danel, MD Service de Chirurgie Thoracique et d Anatomie Pathologique, Hôpital Européen Georges Pompidou, Paris, Centre Medico-Chirurgical du Cèdre, Boisguillaume, France Background. Adenocarcinoma () is the most common lung cancer, followed by squamous cell carcinoma (SCC). Controversy exists concerning both cell types. Our purpose was to compare their prognosis after resection and determine whether subtyping may have any significance. Methods. From 1993 to 2002, 574 patients with SCC and 565 with underwent a curative resection and were compared according to sex, age, type of resection, TNM system classification, and survival. One hundred fiftynine patients with s demonstrated a pure histologic pattern according to the 1999 World Health Organization classification, and 406 were of the mixed subtype including cell types with potentially different aggressiveness. Therefore, we compared subgroups according to presence or not of bronchioloalveolar carcinoma or solid adenocarcinoma with mucin component, or both. Results. Compared with s, SCCs had a higher number of males and older patients, and incidences of endobronchial tumors, pneumonectomies, and stage II tumors were higher. Global survival rates were not different. The s with solid with mucin components (n 239) were characterized by more males and stage IIB patients, and had poorer survival rates (38.6% vs 61.4%; p < 0.0014) than the s without solid with mucin component. When comparing these with SCCs, 5-year survival rates were: s without solid with mucin component (58.1%), SCCs (50.2%), and s with solid with mucin component (36.8%) (p < 0.000019). Multivariate analysis demonstrated these subgroups and SCCs to be independent factors of prognosis. Conclusions. Solid s with a mucin component demonstrated the poorest prognosis after resection. Further studies of this cell type, which should be looked for carefully, may help improve targetting adjuvant therapies. (Ann Thorac Surg 2006;81:1988 95) 2006 by The Society of Thoracic Surgeons Accepted for publication Jan 4, 2006. Address correspondence to Dr Riquet, Service de Chirurgie Thoracique, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75908 Paris Cedex 15, France; e-mail: marc.riquet@hop.egp.ap-hop-paris.fr. Lung cancer is the most frequent malignant neoplasm. The four main histopathologic types (squamous cell carcinomas [SCCs], adenocarcinomas [s], large cell undifferentiated carcinomas, and small cell undifferentiated carcinomas) account for more than 95% of diagnosed cases [1]. In contrast to generally declining squamous and small cell carcinoma rates among males, rates have risen in virtually all countries, with the increase exceeding 50%, and rates among females more than doubling in France [2]. A substantial amount of clinical and basic science research has focused on the prognostic factors for patients with lung cancer. The literature has grown rapidly and has identified more than 150 prognostic factors pertaining to the tumor, to the patient, or to the environment [3]. The survival of patients with nonsmall cell lung cancer who undergo a complete resection is closely correlated to the pathologic stage of disease [4]. Most studies generally comparing with SCC have not shown cell type to have independent prognostic value. However, some studies have concluded that has a negative impact on prognosis [3], whereas other more recent studies have reported that favorably influences the prognosis [5, 6]. Adenocarcinomas are highly and histologically heterogeneous, with only a minority of cases showing a pure histologic pattern [7]. Major new changes in the 1999 World Health Organization (WHO) classification include a strict definition of bronchoalveolar carcinomas (Bs) and the addition of a mixed type and several variant subtypes [7]. Bronchoalveolar carcinoma is the only subtype with a proven and more favorable prognosis [3, 7]. Subtypes of may influence prognosis; in 1978, Kemeny and colleagues [8] reported that patients with had a slightly poorer survival time than those with SCC but that this difference disappeared if all glandular cancers were analyzed as a group (ie, Bs and s). According to the 1999 WHO appraisal, further work is needed to better clarify the prognostic significance of subtyping based on cases studied with detailed histologic criteria. The purpose of our study was to compare the prognosis of both SCCs and s and attempt to determine how subtyping s may have significance. 2006 by The Society of Thoracic Surgeons 0003-4975/06/$32.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2006.01.021

Ann Thorac Surg RIQUET ET AL 2006;81:1988 95 PROGNOSTIC VALUE OF RESECTED LUNG ADENOCARCINOMA Material and Methods Patients Between January 1, 1993 and December 31, 2002, 1,878 consecutive patients underwent surgical resection for nonsmall cell lung cancer at Georges Pompidou European Hospital and Boisguillaume Surgical Center. The surgical procedure was a potentially curative complete resection with systematic hilar and mediastinal lymphadenectomy. Patients who had preoperative neoadjuvant therapy or palliative surgery, and patients with prior history of malignancy had been excluded from this study. Of these 1,878 patients, 574 (30.6%) had SCC and 565 (30.1%) had, which represents 1,139 patients forming the basis of this study. There were 915 males and 224 females. Adjuvant therapy was performed in 358 patients in a nonrandomized fashion according to specific management adopted by the different referring physicians (251 patients received adjuvant radiation therapy and 107 received radiation and chemotherapy or chemotherapy alone). The cell type was not taken into consideration in the indication for adjuvant therapy. Our institutional review board waived obtaining patient consent for this study, and information was obtained from hospital case records. Methods Squamous cell carcinoma patients were compared with patients in terms of age, sex, type of resection performed, characteristics of the tumor, and staging, but also the details of the TNM system classification [4], in addition to survival with overall survival rates and survival rates according to staging. For regional lymph node (LN) involvement, we used the classification of Mountain and Dresler [9] as follows: the N1 population was further divided into intralobar levels (12 or 13) and interlobar, extralobar, or hilar levels (10 or 11); the N2 population was divided into single station N2, which is N2 involving superior mediastinal LN (2R 4R or 3 or 4L) or aortic LN (5 or 6) or inferior mediastinal LN (7 or 8 or 9); and dual station N2, which is the involvement of any combination of two or more of the previously mentioned stations. The resected tumors were fixed routinely in 10% formalin, and selected samples of tumor were embedded in paraffin. All 4- m sections of the tumor were stained by hematoxylin and eosin, periodic acid-schiff with and without diastase digestion, and for immunochemistry with keratin antibodies. Adenocarcinoma was further classified according to the 1999 WHO proposals [7]. All surgical specimens of were reviewed by the same pathologist (CD). Of 565 s, 159 (28.1%) demonstrated a pure histologic pattern and 406 (71.9%) were of the mixed subtype. The pure B component was observed in 15 patients. The B component was present as a mixed subtype in 120 patients. Among these patients, 24 had a B component predominant with a microinvasion, also classified by the WHO as adenocarcinoma mixed bronchioloalveolar subtypes. This subgroup was studied separately. Pure histologic solid adenocarcinoma with mucin (SM) was observed in 33 patients. The SM component was present as mixed subtype in 206 patients, with 26 of them also having a B component. According to the 1999 WHO appraisal, tumor with a solid component will be poorly differenciated. Therefore, in the WHO classification, mixed subtype includes several different cell types of potentially variable aggressiveness. To determine whether subtyping may have an incidence on prognosis we distinguished subgroups among mixed subtypes according to presence or not of B or SM components, or both. These subgroups were compared with each other and with SCCs in the same terms that the SCC group was compared with the group. Follow-up information was obtained either from hospital case records, or from a questionnaire completed by the local chest physician or general practitioner, or from death certificates.the overall survival was the main outcome, which was defined as the time interval between the surgery date and the date of death or the last follow-up. Actuarial survival curves were estimated by the Kaplan-Meier method. Statistical comparisons were made using the log-rank test. Univariate and multivariate analyses were performed using the Cox proportionnal hazards model. Univariate analyses used the following explanatory variables: gender, age, type of surgical resection, histologic cell type and subtype, T and N status, and the stage of disease. Hazard ratios with their 95% confident interval were estimated. The cut off p value used for entering specific explanatory variables into the multivariate analysis was 0.05. The p values were adjusted according to the multiplicity of tests using the Bonferroni method for all tests. All data analyses were conducted with the two-sided test. A p value less than 0.05 was considered statistically significant. The statistical software used for analysis was SEM (C J. Perrin, Clermont Ferrand, France) [10]. Results 1989 Squamous cell carcinoma and patients presented significant differences (Table 1). The SCC group was observed to have more male patients, older patients, pneumonectomies and completion pneumonectomies, endobronchial tumors, larger sized tumors, more stage II and less stage I tumors than the group. Pathologic information is detailed in Table 2. Findings were more T3 tumors (due to bronchial involvement) and more N1 patients among SCCs, whereas patients demonstrated more T2 tumors, more visceral pleural involvement (VPI), more N0 and N2, more lymphatic invasion, and more associated nodules in homolateral lobes. The higher frequency of N2 in the group was due to a higher frequency of dual station involvement, and VPI and N2 involvement were correlated (N2 36.4%; 64 of 176 in cases of VPI vs N2 26.8%; 100 of 373). In cases without VPI the p value was 0.02, which was mainly due to dual station involvement of 15.9% (28 of 176) in cases of VPI versus 9.9% (37 of 373) in cases without VPI in which the p value was 0.04. However, overall long-term survival rates were the same between SCC and patients. GENERAL THORIC

GENERAL THORIC 1990 RIQUET ET AL Ann Thorac Surg PROGNOSTIC VALUE OF RESECTED LUNG ADENOCARCINOMA 2006;81:1988 95 Table 1. Main Characteristics of Squamous Cell Carcinomas, Adenocarcinomas, Solid Adenocarcinomas With Mucin Component, Bronchoalveolar Carcinoma With and Without Microinvasion Component SCC n 574 n 565 Without SM n 287 With SM n 289 B mic n 39 Without B n 526 n % n % p n % n % p n % n % Male 520 90.6 395 69.9 0.0000001 188 65.5 187 78.2 0.0013 20 51.3 375 71.3 Female 54 9.41 170 30.1 99 34.5 52 21.7 19 48.7 151 28.7 Age (yr) 64.2 9.8 60.1 10.6 0.0000001 60.6 10.7 59.1 10.6 0.11 62.0 9.5 59.9 10.6 Pneumo comp 257 44.8 94 16.6 0.0000001 44 15.3 46 19.2 0.24 4 10.3 90 17.1 Lob segment 317 55.2 471 83.4 243 84.7 193 80.7 35 89.7 436 82.9 Postop mortality 22 3.8 19 3.4 0.67 5 1.7 14 5.9 0.012 0 0 19 3.6 Endobronchial 352 61.3 88 15.6 0.0000001 54 18.8 30 12.6 0.051 4 10.3 84 16 Size (mm) 46.8 24.9 37.4 20.6 0.0000055 35.6 19.5 38.3 21.1 0.14 44.8 23.1 36.8 20.3 Stage I 245 42.7 304 53.9 0.0033 162 56.4 109 45.6 0.099 31 79.5 273 51.9 IA 98 17.1 116 20.6 0.17 66 23 39 16.3 0.056 9 23.1 107 20.3 IB 147 25.6 188 33.3 0.0057 96 33.4 70 29.3 0.31 22 56.4 166 31.6 Stage II 164 28.5 89 15.7 0.00000014 34 11.8 52 21.8 0.0022 3 7.7 86 16.3 IIA 26 4.5 20 3.5 0.38 9 3.1 11 4.6 0.38 0 0 20 3.8 IIB 138 2.4 69 12.2 0.00000017 25 8.7 41 17.2 0.0036 3 7.7 66 12.5 Stage IIIA 147 25.6 167 29.6 0.16 88 30.7 74 31 0.94 5 12.8 162 30.8 IIIB 14 2.4 5 0.9 0.039 1 0.3 4 1.7 0.27 0 0 0 0 Adjuvant ttt 183 31.9 176 31.2 0.79 88 30.7 84 35 0.27 3 7.7 172 32.7 5-year survival median (mo) 50.2% ( ) 49.7% (59) 0.8 61.4% ( ) 38.6% (38) 0.00014 70.3% ( ) 48.3% (56) B mic and without B have been listed for information and not compared. adenocarcinomas; B bronchoalveolar carcinomas; comp completion pneumonectomy; lob lobectomy; mic micro invasion component; pneumo pneumonectomy; postop postoperative; SM solid adenocarcinomas with mucin component; SCC squamous cell carcinomas; segment segmentectomy. Results were not modified by removing B from the. The main characteristics of the subtypes are shown in Table 3. There were not many differences between these subgroups even when the B subtype with a microinvasive component was included in the mixed subtypes. However, there were more large sized (p 0.018) and peripheral tumors in the B subtypes. The overall poorest long-term survival rates of pure histologic components were observed in acinar and SM subtypes, respectively, 48.5 and 34.6%; the difference between both these poorest subtypes approached significance (p 0.059). Mixed subtype subgroups according to presence or not of B or SM components, or both, are shown in Table 4. The mixed subtypes classified in this manner consisted of seven subgroups: (1) mixed acinar and papillary subtype (n 65; 11.5%); (2) mixed acinar or papillary and any variant (n 17; 3%); (3) mixed acinar or papillary, or both, and B component more than 20% (n 58; 10.3%); (4) mixed acinar or papillary, or both, and B component less than 20% (n 36; 6.4%); (5) SM mixed with acinar or papillary, or both, with or without variants component (n 180; 31.9%); (6) SM mixed with other components and B more than 20% (n 13; 2.3%); (7) SM mixed with other components and B less than 20% (n 13; 2.3%). Poorest long-term survival rates were observed when the SM component was present (Table 4). Consequently, with a pure histologic pattern (B excluded, n 15) and mixed subtypes (B with a microinvasive component excluded, n 24) were regrouped according to absence (287 patients) or presence (239 patients) of an SM component. Adenocarcinomas with an SM component were significantly characterized by more male patients, more stage II (mainly stage IIB), more T3 tumor (mainly parietal T3), and more lymphatic invasion. Patient demographics, pathologic information, and stage classification are shown in Tables 1 and 2. Five-year survival rates were highly different 38.6 versus 61.4% (p 0.00014) when the SM component was observed. In contrast, 5-year survival rates were not significantly different between all the s with a pure histologic subtype, including pure SMs (n 144), and all the s with mixed subtypes including the SM component (n 382): 47.6% and 48.6%, respectively (p 0.53), (ie, when the SM component was not individualized as a subgroup). Squamous cell carcinoma (n 574) and (n 565) 5-year survival rates were not different (50.2% and 49.7%, respectively; p 08), and were not modified by staging (Table 5). Nevertheless, in ptnm subgroups, best survival differences approaching significance were observed for stage IB s (63% vs 54.1%; p 0.08), stage IIB (T3

Ann Thorac Surg RIQUET ET AL 2006;81:1988 95 PROGNOSTIC VALUE OF RESECTED LUNG ADENOCARCINOMA Table 2. Main Characteristics of Squamous Cell Carcinomas, Adenocarcinomas, Solid Adenocarcinomas With Mucin Component, Bronchoalveolar Carcinoma With and Without Microinvasion Component SCC n 574 n 565 Without SM n 287 With SM n 239 B mic n 39 1991 Without B n 526 GENERAL THORIC n % n % p n % n % p n % n % T1 139 24.2 162 28.7 0.088 89 31.0 64 26.8 0.29 9 23.0 153 29.1 T2 305 53.1 341 60.4 0.014 174 60.6 139 58.2 0.57 28 71.8 313 59.5 VPI 109 24.5 176 35.0 0.00047 88 33.5 77 37.9 0.70 11 29.7 165 31.4 T3 117 20.4 57 10.1 0.0000014 23 8.0 32 13.4 0.045 2 5.1 55 10.5 T3p 50 8.7 43 7.6 16 5.6 25 10.5 0.037 2 5.1 41 7.8 T3 b m 67 11.7 14 2.5 14 2.7 T4 13 2.3 5 0.9 0.062 1 0.3 4 1.7 0.27 0 0 5 1.0 N0 304 53.0 333 58.9 0.042 173 60.3 128 53.6 0.12 32 82.0 301 57.2 N1 156 27.2 68 12.0 0.0000001 30 10.5 36 15.1 0.11 2 5.1 66 12.5 N2 114 19.9 164 29.0 0.00032 84 29.3 75 31.4 0.60 5 12.8 159 30.2 N2: 1 station 82 14.3 99 17.5 0.14 50 17.4 46 19.2 0.59 3 7.7 96 18.3 N2: 2 stations 32 5.6 65 11.5 0.00034 34 11.8 29 12.1 0.92 2 5.1 63 12.0 Lymphatic 28 4.9 71 12.5 0.0000041 29 10.1 39 16.3 0.034 3 7.7 68 12.9 invasion T4 and M1 19 3.3 58 10.3 0.000002 29 10.1 26 10.9 0.77 3 7.7 55 10.5 Vascular invasion 92 16.0 100 10.7 0.45 62 21.6 47 19.7 0.59 1 2.5 99 18.8 N1 EL 90 15.7 35 6.2 0.0000003 Visceral pleural involment (VPI); T3 parietal (T3p); T3 bronchial and mediastinal (T3 b m). T4 and M1 homolateral lung nodules; N1 EL extralobar and hilar N1. B mic and without B have been listed for information and not compared. adenocarcinomas; B bronchoalveolar carcinomas; mic micro invasion component; SM solid adenocarcinomas with mucin component. N0) s (54.5% vs 30.7%; p 0.07) and stage IIA SCCs (64.8% vs 36.6%; p 0.06). Survival rates were better in N0 patients (64.8% vs 56.3%; p 0.026), and in contrast, survival rates were better in N1 and T1 SCC patients (57.9% vs 42.4 %; p 0.046 and 68.8% vs 58.4%; p 0.033, respectively). In cases of N1 patients, the difference was mainly due to extralobar and hilar subgroups (SCCs [53.4%] vs s [21.4%]; p 0.020). In considering the size of the tumor, a difference in survival rates was observed for 3-cm tumors (SCCs [n 166; 69.2%] vs s [n 245; 57.2%], respectively; p 0.016), which was mainly due to the associated N1 patients (SCCs [n 33; 64.6%] vs s [n 29; 37.5%]; p 0.039). Among patients, long-term 5-year survival rates were the highest in cases with B subtypes (70.3%). The difference observed in cases with Bs with a microinvasion and Bs without a microinvasion (61.7% vs 84.8%) was not significant (p 0.096). The poorest longterm 5-year survival rates were observed when the SM component was present (39.1% vs 58.1%; p 0.00014, with postoperative mortality excluded) (Table 5); postoperative mortality was significantly higher in cases of the SM component (5.9% vs 1.7%; p 0.012) (Table 1). Differences in survival were highly significant only in stage I (Fig 2), and in cases of N0 and T1 patients: 50.5% vs 77.4% [p 0. 000004]; 52.4% vs 75% [p 0. 000071]; and 31% vs 79.3% [p 0.000001], respectively. Better survival rates were also observed for 3-cm tumors (without the SM component [n 140;70.8%] with B being excluded [n 15] vs tumors with the SM component [n 99; 36.6%]; p 0. 0000015), which was also significant in cases of N0 disease (82.8% vs 51.7%; p 0.00001) and N1 disease (67.7% vs 15.2%; p 0.018). Adjuvant therapy did not change the findings when included in the analysis. Survival after adjuvant therapy was not different between SCCs and s and between tumors with the SM component and tumors without the SM component. The type of adjuvant therapy (ie, chemotherapy, radiotherapy, or both radiotherapy and chemotherapy) did not influence these results. Squamous cell carcinoma survival rates were significantly better than rates when the SM component was present (p 0.0016), but were worse when the SM was absent (p 0.016) (Fig 1). Multivariate analysis demonstrated pt, pn, age, and histologic subtype were independent factors of prognosis (Table 6). Adenocarcinomas with the SM component were associated with a higher risk of death compared with s without the SM component (hazard ratio, 1.65). Comment In general, SCCs more frequently arise in the proximal bronchi, whereas s and their variants are more frequently peripherally located [11] as also observed in this study. This explains differences observed in pathologic features and staging. Squamous cell carcinomas are thus

GENERAL THORIC 1992 RIQUET ET AL Ann Thorac Surg PROGNOSTIC VALUE OF RESECTED LUNG ADENOCARCINOMA 2006;81:1988 95 Table 3. Main Characteristics of World Health Organization Adenocarcinoma Subtypes a B Acinar Papillary Variants SM B mic Mixed ( ) Mixed n 80 n 20 n 11 n 33 n 15 n 24 n 382 n 406 Male 59 14 6 27 7 13 269 282 Female 21 6 5 6 8 11 113 124 Age (yr) 60.6 11.0 62.7 8.4 53.6 8.4 59.4 10.5 57.8 10.0 67.7 8.1 60.0 10.7 60.2 10.6 Pneumo comp 16 4 2 5 1 3 63 66 Lob segment 64 16 9 28 14 21 319 340 Postop mortality 1 0 0 2 0 0 16 16 Endobronchial 17 7 3 4 2 2 53 54 Size (mm) 33.2 21.1 42.6 18.7 40.0 17.8 41.5 25.8 45.9 22.8 44.2 23.3 36.8 19.5 37.2 19.9 Stage I 41 9 6 19 15 16 194 210 IA 22 4 2 6 6 3 71 74 IB 21 5 4 13 9 13 123 136 Stage II 11 1 4 5 0 3 65 68 IIA 2 0 2 0 0 0 16 16 IIB 9 1 2 5 0 3 49 52 Stage III 26 10 1 9 0 5 121 126 IIIA 26 10 1 9 0 5 116 121 IIIB 0 0 0 0 0 0 5 5 5-year survival median (mo) 48.5% (59) 54.1% ( ) 72.7% ( ) 34.6% (25) 84.8% ( ) 61.7% ( ) 48.6% (56) 49.4% (59) a Acinar; papillary; B bronchoalveolar carcinoma; mic micro invasion component; mixed adenocarcinoma with mixed subtypes including B with mic; papillary; SM solid adenocarcinoma with mucin; variants various rare miscellaneous adenocarcinomas. B bronchoalveolar carcinomas; comp completion pneumonectomy; lob lobectomy; Mixed ( ) mixed subtypes, but excluding B with mic (added for information); pneumo pneumonectomy; postop postoperative; segment segmentectomy. characterized by a larger size, more endobronchial locations, more N1 involvement, and hence more stage II tumors and then more patients who require pneumonectomies (44.8% vs 16.6%). On the other hand, s demonstrate a more aggressive tendency to disseminate such as VPI, lymphatic invasion, satellite tumor nodule within the same lung, and N2 metastases, with N2 representing 70.7% (164 of 232) of all LN metastases, and more especially involving several stations. Predominant mediastinal N2 involvement in s has been previously mentioned [12], but we have not found other similar results in the literature, and we have no explanation for this predominance. Besides the hypothesis that desquamating cells from VPI of s may involve mediastinal LN by diaphragm pleural lymph reabsorbtion [13], another hypothesis may be that the biological behavior of itself plays an important role in mediastinal lymphatic dissemination. Despite such differences, the overall long-term 5-year survival rate was similar between both cell types, as also reported by many authors during the last 40 years [8, 12, 14 18]. Long-term 5-year survival rates were not modified by pathologic staging of the tumor, as already mentioned in tumors of stage I [19, 20], stages I and II [16], and stages I, II, and IIIA [21]. When a difference was demonstrated between cell type survival, SCC was most often reported as providing a better outcome, but in general the difference occurred in a particular stage or subgroup within one stage ie, in stage I [22], stage IA [23], and stage IB [24], and in stage II [25], stage IIB [21], and in stage IIIA of N2 groups [8, 26]. provides an overall best survival [6], or a best survival only in stage I [27]. The SCC long-term survival rate was better in cases of T1 tumors and N1 involvement, which was already indicated by Mountain [28] and Van Rens and colleagues [21] in the T2 N1 substage. This may denote a greater tendency of SCC to remain a local disease longer. In contrast, the long-term survival rate, which was better in cases of N0 patients, was similar to the SCC long-term survival rate in cases of N2, despite more dual station involvement, which demonstrates a different biological behavior of cell type. The ptnm classification fails to demonstrate these biological differences in which only pathologic studies could shed some light. Effectively, includes many cell types, and among them, B and SM are particular components. Bronchoalveolar carcinoma is the only subtype of with a substantially more favorable prognosis than the other subtypes, with survival rates varying from 81% [19] to 88% [27] to 100% [29]. Whatever the publications, the number of Bs remain small. The WHO proposal [7] reclassifies B as adenocarcinoma, mixed type with bronchioloalveolar features if stromal, vascular or pleural invasion is seen. In these cases we observed that the prognosis was better than in mixed type (Table 3), and we suggest subclassifying it as an with a pure histologic pattern, acinar, or papillary pattern not being obviously present and sufficient to acertain a mixed

Ann Thorac Surg RIQUET ET AL 2006;81:1988 95 PROGNOSTIC VALUE OF RESECTED LUNG ADENOCARCINOMA Table 4. Characteristics of Mixed Subtypes According to Presence or Not of Bronchoalveolar Carcinoma Component Given in % and Solid Adenocarcinoma With Mucin Component; G1 to G7 Subgroups of Adenocarcinoma Mixed Subtypes Referring to Text G1: Acinar Papillary G2: Other Mixed Subtype G3: Mixed B 20% G4: Mixed B 20% G5: Mixed With SM G6: Mixed SM B 20% G7: Mixed SM B 20% n 65 n 17 n 58 n 36 n 180 n 13 n 13 1993 GENERAL THORIC Male 46 9 31 23 143 9 8 Female 19 8 27 13 37 4 5 Age (yr) 61.0 10.2 58.2 11.6 61.5 11.1 60.8 10.3 59.1 10.8 59.0 9.7 59.2 8.4 Pneumo comp 15 4 1 2 40 0 1 Lob segment 50 13 57 34 140 13 12 Postop mortality 1 0 2 1 11 1 0 Endobronchial 19 3 1 4 23 3 0 Size (mm) 33.4 15.8 32.8 15.4 34.8 20.9 38.8 20.8 38.4 21.1 31.3 10.9 35.0 9.9 Stage I 28 8 44 24 77 8 5 IA 9 1 20 8 29 3 1 IB 19 7 24 16 48 5 4 Stage II 11 3 3 1 40 2 5 IIA 4 0 1 0 8 2 1 IIB 7 3 2 1 32 0 4 Stage III 26 6 11 9 63 3 3 IIIA 26 6 10 9 59 3 3 IIIB 0 0 1 0 4 0 0 5-year survival median (mo) 67.4% ( ) 46.5% (59) 63.1% ( ) 58.7% ( ) 38.1% (35) 20.5% (45) 46.2% (53) B bronchoalveolar carcinomas; comp completion pneumonectomy; lob lobectomy; pneumo pneumonectomy; SM solid adenocarcinomas with mucin component; segment segmentectomy. Table 5. Survival According to Main TNM Factors SCC n 574 n 565 without SM N 287 with SM n 239 B N 39 5-yr S % med m 5-yr S % med m p 5-yr S % med m 5-yr S % med m p 5-yr S % med m Stage I 60.8 ( ) 66.0 ( ) 0.25 77.4 ( ) 50.5 ( ) 0.000004 78.3 ( ) Stage II 49.9 60 46.2 53 0.81 52.1 ( ) 41.5 36 0.57 100 ( ) Stage IIIA 33.9 26 35.5 23 0.21 26.1 26 23.6 23 0.66 20 35 N0 56.3 ( ) 64.8 ( ) 0.026 75.0 ( ) 52.4 ( ) 0.000071 N1 57.9 ( ) 42.4 47 0.046 54.2 ( ) 31.1 34 0.12 100 ( ) N1 EL 58.1 ( ) 21.4 20 0.02 N2 27.9 22 23.2 23 0.95 27.4 30 21.7 23 0.4 20 35 N2: 1 station 28.1 24 30.5 35 0.43 36.8 36 26.2 31 0.33 N2 2 stations 26.0 16 10.3 17 0.54 11.6 18 13.7 17 0.8 T1 68.8 ( ) 58.4 ( ) 0.033 79.3 ( ) 31.0 37 0.000001 85.7 ( ) T2 51.2 ( ) 48.2 59 0.75 51.9 ( ) 44.6 47 0.22 63.4 ( ) T3 26.6 21 38.3 26 0.17 33.5 26 38.9 28 0.77 100 ( ) VPI 42.4 40 48.1 56 0.32 49.9 59 47.8 56 0.63 Overall survival 50.2 ( ) 49.7 59 0.8 58.1 ( ) 39.1 38 0.00014 70.3 ( ) adenocarcinoma; B bronchoalveolar carcinoma; med m median - month; N1 EL Extralobar N1; SM solid with mucin; SCC squamous cell carcinoma; VPI visceral pleural involvement; 5-yr S 5-year survival. Survival did not change when including postoperative deaths.

GENERAL THORIC 1994 RIQUET ET AL Ann Thorac Surg PROGNOSTIC VALUE OF RESECTED LUNG ADENOCARCINOMA 2006;81:1988 95 Fig 1. The 5-year survival according to the presence of a solid with mucin component stratified by stage. Difference was significant in stage 1 (St 1): 76% versus 47.3%. A difference persisted in stage 2 (St 2) and stage 3 (St 3), but was gradually smaller and not significant (NS). (SM solid adenocarcinoma with mucin.) pattern. In contrast, tumors with an SM component, either pure or mixed, seem to have the poorest prognosis. In 259 consecutive patients with advanced disease, Sorensen and colleagues [30] analyzed the prognostic implication of histopathologic subtyping of pulmonary s according to the 1981 WHO classification. Bronchoalveolar carcinoma had the longest median duration of response to chemotherapy (47 weeks), time to progression (33 weeks), and median survival (40 weeks), whereas corresponding values for solid carcinoma with mucus formation, which first appeared in the classification were 8, 12, and 22 weeks, respectively. In a similar study in patients with surgically treated stage I or II of the lung, Sorensen and Olsen [31] reported that there were no significant differences among the overall survival curves of the histopathologic subtypes. However, when the survival figures were analyzed in more detail, the same differences among the subtypes were revealed (ie, patients with solid carcinoma with mucin formation had an unfavorable prognosis). Fig 2. Overall survival: 5-year survival rates between squamous cell carcinoma (50.2%, curve 1), adenocarcinoma () without solid adenocarcinoma with mucin (58.1%, curve 2) and with solid adenocarcinoma with mucin (36.8%, curve 3) were not changed when excluding postoperative deaths (52.2%, 59.1%, and 39.1%, respectively; p 0.00014). In the 1999 WHO classification, mixed subtype with or without an SM component are considered as belonging to the same group, but nevertheless both groups seem to be separate on a prognosis point of view. When comparing with or without an SM component, presentation was not very different between both groups, except for an important increased frequency of male, pstage IIB and operative mortality in cases with with an associated SM component (Table 1). In detail, there was more parietal T3 involvement and peripheral lymphatic invasion (Table 2). The overall long-term survival Table 6. Multivariate Analysis of Survival According to Prognostic Variables Variables Coefficients HR Confidence Interval p Value N N0 0.43 1 0.0000001 N1 1.54 (1.39; 1.69) N2 2.36 (1.94; 2.80) T T1 0.42 1 0.0000001 T2 1.53 (1.34; 1.74) T3 T4 2.33 (1.79; 2.04) Age 31 61 0.42 1 0.0000011 62 88 1.53 (1.29; 1.81) Cell type without SM 0.26 1 0.000029 SCC 1.30 (1.15; 1.47) with SM 1.65 (1.32; 2.15) adenocarcinomas; HR hazard ratio; SM solid adenocarcinomas with mucin component.

Ann Thorac Surg RIQUET ET AL 2006;81:1988 95 PROGNOSTIC VALUE OF RESECTED LUNG ADENOCARCINOMA rate was lower mainly due to a better survival rate of pstage I well-differentiated, especially in cases of N0, T1, and 3-cm tumors. This suggests that the presence of an SM component directly influences the prognosis. The reason why is not explained, and unlike with the disease stage, the prognostic significance of histologic cell type by itself after resection of lung cancer in not clear [17]. In conclusion, the behaviors of SCCs and s differ, which becomes clearer when subtyping s. The SM component is an independent factor of prognosis. Further studies are needed to confirm and explain the behavior of this latter cell type. This component should be carefully researched and mentioned in pathology reports, and the mixed subtype group, including this histologic component should be separated for prognosis and therapeutic purposes. References 1. Hammar SP. Common neoplasms. In: Dail DH, Hammar SP, eds. Pulmonary pathology. New York: Springer Verlag, 1994: 1123 278. 2. Devesa SS, Bray F, Vizcaino AP, Pakin DM. International lung cancer trends by histologic type: male: female difference diminishing and adenocarcinomas rates rising. Int J Cancer 2005;117:294 9 3. Brundage MD, Davies D, Mackillop WJ. Prognostic factors in non-small cell lung cancer: a decade of progress. Chest 2002;122:1037 57. 4. Mountain CF. Revisions in the international system for staging lung cancer. Chest 1997;111:1710 7. 5. Rena O, Papalia E, Ruffini E, et al. Stage I pure bronchioloalveolar carcinoma: recurrences, survival and comparison with adenocarcinoma of the lung. Eur J Cardiothorac Surg 2003;23:409 14. 6. Okada M, Nishio W, Sakamoto T, et al. Evolution of surgical outcomes for non-small cell lung cancer: time trends in 1,465 consecutive patients undergoing complete resection. Ann Thorac Surg 2004;77:1926 31. 7. World Health Organization. Histological typing of lung tumors, 3rd ed. Geneva: WHO, Springer Verlag, 1999 8. Kemeny M, Block LK, Braun DW, Martini N. Results of surgical treatment of carcinoma of the lung by stage and cell type. Surg Gynecol Obstet 1978;147:865 71. 9. Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest 1997;111,1718 23. 10. Kwiatkowski F. SEM (Statistiques, Epidemiologie, Medecine): un outil de gestion informatique et statistique adapté à la recherche en cancérologie. Bull Cancer 2000;87: 715 21. 11. Maddaus MA, Gimberg RJ. Clinical features, diagnosis and staging of lung cancer in thoracic surgergy, 2nd ed. Pearson FG, Cooper JD, Deslauriers J, et al, eds. Philadelphia: Churchill Livingstone, 2002:813 36. 12. Paulson DL Reisch JS. Long-term survival after resection for bronchogenic carcinoma. Ann Surg 1976;184:324 32. 13. Manac h D, Riquet M, Medioni J, Le Pimpec Barthes F, Dujon A, Danel C. Visceral pleura invasion by non-small cell 1995 lung cancer: an underrated bad prognostic factor. Ann Thorac Surg 2001;71:1088 93. 14. Higgins GA, Beebe GN. Bronchogenic carcinoma: factors in survival. Arch Surg 1967;94:539 49. 15. Shields TW, Conn JH, Robinette CD. Relationship of cell type and lymph node metastasis to survival after resection of bronchial carcinoma. Ann Thorac Surg 1975;20:501 10. 16. Ludwig Lung Cancer Study Group. Adverse effect of intrapleural corynebacterium parvum as adjuvant therapy in resected stage I and II non-small cell carcinoma of the lung. J Thorac Cardiovasc Surg 1985;89:842 7. 17. Kadri MA, Dusseck JE. Survival and prognosis following resection of primary non-small cell bronchogenic carcinoma. Eur J Cardiothorac Surg 1991;5:132 6. 18. Alkattan K, Sepsas E, Townsen ER, et al. Factors affecting long term survival following resection for lung cancer. Thorax 1996;51:1266 9. 19. Williams DE, Pairolero PC, Davis CS, et al. Survival of patients surgically treated for stage I lung cancer. J Thorac Cardiovasc Surg 1981;82:70 6. 20. Gail MH, Eagan KT, Feld R, et al. Pronostic factors in patients with resected stage I non-small cell lung cancer. Cancer 1984;54:1802 13. 21. Van Rens MTM, Brutel de la Riviere A, Elbers HRJ, Van Den Bosch JMM. Prognostic assessment of 2,361 patients who underwent pulmonary resection for non-small cell lung cancer stage I, II and IIIA. Chest 2000;117:374 9. 22. Wu YC, Lin CFJ, Hsu NH Huang BS Huang MH, Wang LS. Long-term results of pathological stage I non-small cell lung cancer: validation of using the number of totally removed lymph nodes as a staging control. Eur J Cardiothorac Surg 2003,24:994 1001. 23. Read RC, Yoder G, Schaeffer RC. Survival after conservative resection for T1 N0 M0 non-small cell lung cancer. Ann Thorac Surg 1990;49:391 400. 24. Padilla J, Calvo V, Penalver JC, et al. Survival and risk model for stage IB non-small cell lung cancer. Lung Cancer 2002; 36:43 8. 25. Ichinose Y, Yano T, Asoh H, Yokoyama H, Hoshino I, Katsuda Y. Prognostic factors obtained by a pathologic examination in completely resected non-small cell lung cancer: an analysis in each pathologic stage. J Thorac Cardiovasc Surg 1995;110:601 5. 26. Kirsh MM, Sloan H. Mediastinal metastases in bronchogenic carcinoma: influence of postoperative irradiation, cell type and location. Ann Thorac Surg 1982;33:459 63. 27. Rena O, Oliaro A, Cavallo A, et al. Stage I non-small cell lung carcinoma: really an early stage? Eur J Cardiothorac Surg 2002;21:514 9. 28. Mountain CF. Surgery for stage IIIa-N2 non-small cell lung cancer. Cancer 1994;73:2589 98. 29. Sakurai H, Dobashi Y, Mizutani E, et al. Bronchioloalveolar carcinoma of the lung 3 centimeters or less in diameter: a prognostic assessement. Ann Thorac Surg 2004;78:1728 33. 30. Sorensen JB, Hirsch FR, Olsen J. The prognostic implication of histopathologic subtyping of pulmonary adenocarcinoma according to the classification of the World Health Organization. An analysis of 259 consecutive patients with advanced disease. Cancer 1988;62:361 7. 31. Sorensen JB, Olsen J. Prognostic implications of histopathologic subtyping in patients with surgically treated stages I or II adenocarcinoma of the lung. J Thorac Cardiovasc Surg 1989;97:245 51. GENERAL THORIC