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• W2009449310 abstract "Lobectomy and mediastinal lymph node dissection is the standard surgical management of early stage non-small cell lung cancer (NSCLC) because more limited resections have been associated with a higher risk of local recurrence. Nevertheless, recent lung cancer screening studies have led to the detection of an increasing number of “very early” NSCLC (defined as less than 2 cm in size) and of good-prognosis histologic subtypes, bronchioloalveolar carcinoma (BAC), and adenocarcinoma (AC), mixed subtypes that are potentially appropriate for sublobar resection. The precise indications for sublobar resection remain unclear and are the subject of ongoing clinical trials, but it seems that very early, peripherally located, node-negative AC of a predominantly BAC pattern may be adequately treated in this manner. Multifocal AC and BAC, either synchronous or metachronous, are also effectively treated by complete resection, using limited resections whenever possible. The pneumonic form of BAC, the rarest variant of this disease spectrum, continues to have a poor prognosis despite complete resection. Very limited experience suggests that lung transplantation leads to prolonged survival in highly selected patients with this histologic subtype. To improve our management of very early AC, much more information is needed about the molecular abnormalities of AC and their relationship to clinical outcomes. Lobectomy and mediastinal lymph node dissection is the standard surgical management of early stage non-small cell lung cancer (NSCLC) because more limited resections have been associated with a higher risk of local recurrence. Nevertheless, recent lung cancer screening studies have led to the detection of an increasing number of “very early” NSCLC (defined as less than 2 cm in size) and of good-prognosis histologic subtypes, bronchioloalveolar carcinoma (BAC), and adenocarcinoma (AC), mixed subtypes that are potentially appropriate for sublobar resection. The precise indications for sublobar resection remain unclear and are the subject of ongoing clinical trials, but it seems that very early, peripherally located, node-negative AC of a predominantly BAC pattern may be adequately treated in this manner. Multifocal AC and BAC, either synchronous or metachronous, are also effectively treated by complete resection, using limited resections whenever possible. The pneumonic form of BAC, the rarest variant of this disease spectrum, continues to have a poor prognosis despite complete resection. Very limited experience suggests that lung transplantation leads to prolonged survival in highly selected patients with this histologic subtype. To improve our management of very early AC, much more information is needed about the molecular abnormalities of AC and their relationship to clinical outcomes. During the past decade, thoracic surgeons have been confronted with demographic and pathological shifts in the group of non-small cell lung cancers (NSCLC) that are potentially resectable.1Read WL Page NC Tierney RM et al.The epidemiology of bronchioloalveolar carcinoma over the past two decades: analysis of the SEER database.Lung Cancer. 2004; 45: 137-142Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar In many countries, adenocarcinoma (AC) has become the most common NSCLC histology. The proportion of women with lung cancer has increased dramatically; in some institutions, half of all patients are female. The number of patients who have never smoked or who have minimal past tobacco exposure is also increasing, especially in North America, because of tobacco control efforts. The widespread use of computed tomography (CT) for lung cancer screening has also led to increased detection of “very early” NSCLC, generally defined as tumors that are 2 cm or less in size, which are usually ACs of mixed subtype or bronchioloalveolar carcinomas (BAC) and which tend to have an indolent clinical behavior. These epidemiologic shifts have led thoracic surgeons to reexamine the accepted tenets of surgical management of early-stage NSCLC. As part of the November 2004 symposium on BAC, which is the subject of this supplement, a group of thoracic surgeons were asked to review the current management of BAC and very early ACs, focusing especially on the role of sublobar resection. This paper summarizes the discussions held at the symposium and provides updated information on relevant clinical trials. BAC has long been recognized as a distinct form of AC associated with a favorable prognosis. In 1989, the North American Lung Cancer Study Group (LCSG) reviewed 1635 patients who had undergone resection of AC, 235 of whom had BAC. Resectable BAC occurred more frequently in never-smokers, was diagnosed at an earlier disease stage, and was associated with a better survival rate than invasive AC.2Grover FL Piantadosi S The Lung Cancer Study Group. Recurrence and survival following resection of bronchioloalveolar carcinoma of the lung - the Lung Cancer Study Group experience.Ann Surg. 1989; 209: 779-790Crossref PubMed Scopus (77) Google Scholar During the last 40 years, improved understanding of the pathology of lung AC has prompted substantial changes in the histologic subclassification by the World Health Organization (WHO), which are summarized by Travis et al.3Travis WD Garg K Franklin WA et al.Evolving concepts in the pathology and CT imaging of lung adenocarcinoma and bronchioloalveolar carcinoma.J Clin Oncol. 2005; 23: 3279-3287Crossref PubMed Scopus (231) Google Scholar in their report from the pathology panel of this symposium (Table 1). From 1967 to 1999, multiple subcategories were added to reflect increasing knowledge about the histologic heterogeneity of AC. Significant changes in the 1999 WHO classification included the addition of atypical adenomatous hyperplasia (AAH) as a preinvasive lesion for lung AC, and the requirement that all BACs demonstrate pure lepidic growth without invasion of stroma, blood vessels, or pleura. In 2004, AC mixed subtype was moved to the top of the list of subcategories in recognition that this is now the most common subtype.4Travis WD Brambilla E Müller-Hermelink HK Harris CC World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon, France2004Google ScholarTABLE 1History of Lung Adenocarcinoma Subclassification According to the World Health OrganizationFrom Travis WD, Garg K, Franklin WA, et al. Evolving concepts in the pathology and CT imaging of lung adenocarcinoma and bronchioloalveolar carcinoma. J Clin Oncol 2005;23:3279–3287. Used with permission.1967 Bronchogenic AcinarPapillaryBronchioloalveolar1981 Acinar adenocarcinomaPapillary adenocarcinomaBronchioloalveolar carcinomaSolid carcinoma with mucus formation1999 AcinarPapillaryBronchioloalveolar carcinoma NonmucinousMucinousMixed mucinous and nonmucinousSolid adenocarcinoma with mucinAdenocarcinoma with mixed subtypesVariants Well-differentiated fetal adenocarcinomaMucinous (colloid) adenocarcinomaMucinous cystadenocarcinomaSignet-ring adenocarcinomaClear-cell adenocarcinoma2004 Adenocarcinoma, mixed subtypeAcinar adenocarcinomaPapillary adenocarcinomaBronchioloalveolar carcinoma NonmucinousMucinousMixed nonmucinous and mucinous or indeterminateSolid adenocarcinoma with mucin productionFetal adenocarcinomaMucinous (colloid) adenocarcinomaMucinous cystadenocarcinomaSignet-ring adenocarcinomaClear-cell adenocarcinoma Open table in a new tab In 1995, Noguchi proposed a six-tier histologic subclassification (types A through F) for small ACs of the lung, recognizing the excellent prognosis associated with BACs (with a purely lepidic growth pattern), the adverse prognostic importance of central fibrosis in BACs, and the pathologic heterogeneity of invasive ACs (Table 2).5Noguchi M Morikawa A Kawasaki M et al.Small adenocarcinoma of the lung. Histologic characteristics and prognosis.Cancer. 1995; 75: 2844-2852Crossref PubMed Scopus (1137) Google Scholar Although the 2004 WHO classification is the internationally accepted system, Noguchi deserves credit for an early attempt to refine the classification and to correlate it with clinical outcomes. As discussed below, the Noguchi system is still used by Japanese investigators to select patients for sublobar resection in ongoing clinical trials. More recently, Noguchi showed that these histologic subtypes have corresponding molecular abnormalities.6Aoyagi Y Yokose T Minami Y et al.Accumulation of losses of heterozygosity and multistep carcinogenesis in pulmonary adenocarcinoma.Cancer Res. 2001; 61: 7950-7954PubMed Google Scholar Areas of histologic types A, B, and C extracted by microdissection from resected ACs were examined by multiplex PCR-LOH and were found to have a progressive rise in the incidence of allelic losses. Deletions of 3p, 17p, 18q, and 22q increased significantly from types A to C, consistent with a model of malignant progression.TABLE 2Noguchi's Histology Typing of Small Adenocarcinoma of the LungFrom Noguchi M, Morikawa A, Kawasaki M, et al. Small adenocarcinoma of the lung. Histologic characteristics and prognosis. Cancer 1995;75:2844–2852. Used with permission.TypeDescriptionALocalized bronchioloalveolar carcinomaBLocalized bronchioloalveolar carcinoma with foci of collapse of alveolar structureCLocalized bronchioloalveolar carcinoma with foci of active fibroblastic proliferationDPoorly differentiated adenocarcinomaETubular adenocarcinomaFPapillary adenocarcinoma with compressive and destructive growth Open table in a new tab Several Japanese studies now confirm that the histologic subtype correlates with CT findings and clinical outcome.3Travis WD Garg K Franklin WA et al.Evolving concepts in the pathology and CT imaging of lung adenocarcinoma and bronchioloalveolar carcinoma.J Clin Oncol. 2005; 23: 3279-3287Crossref PubMed Scopus (231) Google Scholar, 7Kodama K Higashiyama M Yokouchi H et al.Natural history of pure ground-glass opacity after long-term follow-up of more than 2 years.Ann Thorac Surg. 2002; 73: 386-393Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 8Nakata M Sawada S Saeki H et al.Prospective study of thoracoscopic limited resection for ground-glass opacity selected by computed tomography.Ann Thorac Surg. 2003; 75: 1601-1606Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 9Shimizu K Yamada K Saito H et al.Surgically curable peripheral lung carcinoma. Correlation of thin-section CT findings with histologic prognostic factors and survival.Chest. 2005; 127: 871-878Crossref PubMed Scopus (51) Google Scholar, 10Ohde Y Nagai K Yoshida J et al.The proportion of consolidation to ground-glass opacity on high resolution CT is a good predictor for distinguishing the population of non-invasive peripheral adenocarcinoma.Lung Cancer. 2003; 42: 303-310Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 11Nakamura H Saji H Ogata A et al.Lung cancer patients showing pure ground-glass opacity on computed tomography are good candidates for wedge resection.Lung Cancer. 2004; 44: 61-68Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 12Asamura H Suzuki A Watanabe S-I et al.A clinicopathological study of resected subcentimeter lung cancers: a favorable prognosis for ground glass opacity lesions.Ann Thorac Surg. 2003; 76: 1016-1022Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, 13Watanabe S-I Watanabe T Arai K et al.Results of wedge resection for focal bronchioloalveolar carcinoma showing pure ground-glass attenuation on computed tomography.Ann Thorac Surg. 2002; 73: 1071-1075Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 14Kodama K Higashiyama M Yokouchi H et al.Prognostic value of ground-glass opacity found in small lung adenocarcinoma on high-resolution CT scanning.Lung Cancer. 2001; 33: 17-25Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 15Matsuguma H Yokoi K Anraku M et al.Proportion of ground-glass opacity on high-resolution computer tomography in clinical T1 N0 M0 adenocarcinoma of the lung: A predictor of lymph node metastasis.J Thorac Cardiovasc Surg. 2002; 124: 278-284Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 16Takashima S Maruyama Y Hasegawa M et al.Prognostic significance of high-resolution CT findings in small peripheral adenocarcinoma of the lung: A retrospective study on 64 patients.Lung Cancer. 2002; 36: 289-295Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 17Okada M Nishio W Sakamoto T et al.Correlation between computed tomographic findings, bronchioloalveolar carcinoma component, and biologic behavior of small-sized lung adenocarcinomas.J Thorac Cardiovasc Surg. 2004; 127: 857-861Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 18Suzuki K Asamura H Kusumoto M et al.“Early” peripheral lung cancer: Prognostic significance of ground glass opacity on thin-section computed tomographic scan.Ann Thorac Surg. 2002; 74: 1635-1639Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar, 19Higashiyama M Kodama K Yokouchi H et al.Prognostic value of bronchiolo-alveolar carcinoma component of small lung adenocarcinoma.Ann Thorac Surg. 1999; 68: 2069-2073Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar The results of Kodama exemplify these investigations (Table 3). Taken as a whole, these studies suggest that: 1) pure ground-glass opacities (GGO) on CT usually represent BAC without any areas of invasive AC, whereas lesions that show both GGO and solid components on CT (part solid, part nonsolid) are mixtures of BAC and invasive ACs; and 2) small (less than 2 cm in size) tumors with >50% GGO are associated with a 100% chance of being node negative, have an excellent chance of long-term survival after treatment, and probably can be managed by limited resection rather than lobectomy. However, the appropriateness of limited resection for part solid/part nonsolid lesions is unclear and is the subject of clinical trials in Japan. Tumors that are more than 50% GGO on CT seem to have a better prognosis and may potentially be managed by sublobar resection, but preoperative high-resolution CT and intraoperative frozen-section analysis still do not always accurately identify tumors that have a poorer prognosis. Our uncertainties with respect to the optimal surgical management of these lesions reflect the highly variable presentation and behavior of lung ACs, the limitations of CT findings in predicting pathologic findings, and our lack of knowledge of the histologic and molecular features that predict a poor prognosis.TABLE 3Prognosis in Relationship to Appearance (% GGO)Adapted from Kodama K, Higashiyama M, Yokouchi H,. Prognostic value of ground-glass opacity found in small lung adenocarcinoma on high-resolution CT scanning. Lung Cancer 2001;33:17–25. Used with permission.GGO < 50%GGO > 50%pPatients5252—Size13.712.30.09Node involvement800.01% local resection50%70%0.001Relapse90—DFS72%100%—GGO, ground-glass opacity; DFS, disease-free survival. Open table in a new tab GGO, ground-glass opacity; DFS, disease-free survival. In NSCLC, the size of the primary tumor is known to correlate with the likelihood of lymph node metastases and, therefore, to influence consideration of sublobar resection. The frequency of nodal disease in very early NSCLC has been studied extensively.20Ohta Y Oda M Wu J et al.Can tumor size be a guide for limited surgical intervention in patients with peripheral non-small cell lung cancer? Assessments from the point of view of nodal micrometastasis.J Thorac Cardiovasc Surg. 2001; 122: 900-906Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 21Ikeda N Maeda J Yashima K et al.A clinicopathological study of resected adenocarcinoma 2 cm or less in diameter.Ann Thorac Surg. 2004; 78: 1011-1016Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 22Sakurai H Dobashi Y Mizutani E et al.Bronchioloalveolar carcinoma of the lung 3 centimeters or less in diameter: A prognostic assessment.Ann Thorac Surg. 2004; 78: 1728-1733Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 23Naruke T Significance of lymph node metastases in lung cancer.Sem Thorac Cardiovasc Surg. 1993; 5: 210-218PubMed Google Scholar, 24Asamura H Nakayama H Kondo H et al.Lymph node involvement, recurrence, and prognosis in resected small, peripheral, non-small cell lung carcinomas: Are these carcinomas candidates for video-assisted lobectomy?.J Thorac Cardiovasc Surg. 1996; 111: 1125-1134Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 25Konaka C Ikeda N Hiyoshi T et al.Peripheral non-small cell lung cancers 2.0 cm or less in diameter: Proposed criteria for limited pulmonary resection based upon clinicopathological presentation.Lung Cancer. 1998; 21: 185-191Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 26Takizawa T Terashima M Koike T et al.Lymph node metastasis in small peripheral adenocarcinoma of the lung.J Thorac Cardiovasc Surg. 1998; 116: 276-280Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 27Sugi K Nawata K Fujita N et al.Systematic lymph node dissection for clinically diagnosed peripheal non-small cell lung cancer less than 2 cm in diameter.World J Surg. 1998; 22: 290-295Crossref PubMed Scopus (182) Google Scholar, 28Wu J Ohta Y Minato H et al.Nodal occult metastasis in patients with peripheral lung adenocarcinoma of 2.0 cm or less in diameter.Ann Thorac Surg. 2001; 71: 1772-1778Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 29Okada M Sakamoto T Nishio W et al.Characteristics and prognosis of patients after resection of nonsmall cell lung carcinoma measuring 2 cm or less in greatest dimension.Cancer. 2003; 98: 535-541Crossref PubMed Scopus (79) Google Scholar, 30Nonaka M Kadokura M Yamamoto S et al.Tumor dimension and prognosis in surgically treated lung cancer for intentional limited resection.Am J Clin Oncol. 2003; 26: 499-503Crossref PubMed Scopus (27) Google Scholar, 31Oda M Watanabe Y Shimizu J et al.Extent of mediastinal node metastasis in clinical stage I non-small cell lung cancer: The role of systematic nodal dissection.Lung Cancer. 1998; 22: 23-30Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 32Miller DL Rowland CM Deschamps C et al.Surgical treatment of non-small cell lung cancer 1 cm or less in diameter.Ann Thorac Surg. 2002; 73: 1545-1551Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar Although lymph node involvement is relatively uncommon in small AC, approximately 10% of tumors that are 1 cm or smaller and 20% of tumors that are 1 to 2 cm in size have nodal metastases (TABLE 4, TABLE 5). Relative to AC, squamous cell carcinomas less than 2 cm in size seem to be associated with a lower risk of nodal disease.20Ohta Y Oda M Wu J et al.Can tumor size be a guide for limited surgical intervention in patients with peripheral non-small cell lung cancer? Assessments from the point of view of nodal micrometastasis.J Thorac Cardiovasc Surg. 2001; 122: 900-906Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar These findings complicate the selection of patients for limited pulmonary resection because we do not fully understand which patients with very early lung AC may have disease in the intralobar lymphatics or regional nodes. A better understanding of the molecular features in early AC and their relationship to clinical outcome is needed to allow accurate decisions about the use of sublobar resection.TABLE 4Prevalence of Nodal Disease in Solid Nodules <2 cm in Sizen% Positive Nodes% N2Naruke (1993)23Naruke T Significance of lymph node metastases in lung cancer.Sem Thorac Cardiovasc Surg. 1993; 5: 210-218PubMed Google Scholar2874050Asamura (1996)24Asamura H Nakayama H Kondo H et al.Lymph node involvement, recurrence, and prognosis in resected small, peripheral, non-small cell lung carcinomas: Are these carcinomas candidates for video-assisted lobectomy?.J Thorac Cardiovasc Surg. 1996; 111: 1125-1134Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar1742060Konaka (1998)25Konaka C Ikeda N Hiyoshi T et al.Peripheral non-small cell lung cancers 2.0 cm or less in diameter: Proposed criteria for limited pulmonary resection based upon clinicopathological presentation.Lung Cancer. 1998; 21: 185-191Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar17117.566Takizawa (1998)26Takizawa T Terashima M Koike T et al.Lymph node metastasis in small peripheral adenocarcinoma of the lung.J Thorac Cardiovasc Surg. 1998; 116: 276-280Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar15717NSSugi (1998)27Sugi K Nawata K Fujita N et al.Systematic lymph node dissection for clinically diagnosed peripheal non-small cell lung cancer less than 2 cm in diameter.World J Surg. 1998; 22: 290-295Crossref PubMed Scopus (182) Google Scholar1151966Wu (2001)28Wu J Ohta Y Minato H et al.Nodal occult metastasis in patients with peripheral lung adenocarcinoma of 2.0 cm or less in diameter.Ann Thorac Surg. 2001; 71: 1772-1778Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar13622NSOkada (2003)29Okada M Sakamoto T Nishio W et al.Characteristics and prognosis of patients after resection of nonsmall cell lung carcinoma measuring 2 cm or less in greatest dimension.Cancer. 2003; 98: 535-541Crossref PubMed Scopus (79) Google Scholar2651855Nonaka (2003)30Nonaka M Kadokura M Yamamoto S et al.Tumor dimension and prognosis in surgically treated lung cancer for intentional limited resection.Am J Clin Oncol. 2003; 26: 499-503Crossref PubMed Scopus (27) Google Scholar462870Average23NS, not stated. Open table in a new tab TABLE 5Prevalence of Nodal Disease in Solid Nodules 1 cm or Less in SizenPatients with Positive Nodes (%)Naruke (1993)23Naruke T Significance of lymph node metastases in lung cancer.Sem Thorac Cardiovasc Surg. 1993; 5: 210-218PubMed Google Scholar208(16)Oda (1998)31Oda M Watanabe Y Shimizu J et al.Extent of mediastinal node metastasis in clinical stage I non-small cell lung cancer: The role of systematic nodal dissection.Lung Cancer. 1998; 22: 23-30Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar220 (0)Konaka (1998)25Konaka C Ikeda N Hiyoshi T et al.Peripheral non-small cell lung cancers 2.0 cm or less in diameter: Proposed criteria for limited pulmonary resection based upon clinicopathological presentation.Lung Cancer. 1998; 21: 185-191Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar190 (0)Ohta (2001)20Ohta Y Oda M Wu J et al.Can tumor size be a guide for limited surgical intervention in patients with peripheral non-small cell lung cancer? Assessments from the point of view of nodal micrometastasis.J Thorac Cardiovasc Surg. 2001; 122: 900-906Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar114 (4)Miller (2002)32Miller DL Rowland CM Deschamps C et al.Surgical treatment of non-small cell lung cancer 1 cm or less in diameter.Ann Thorac Surg. 2002; 73: 1545-1551Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar1007 (7)Average9 Open table in a new tab NS, not stated. A prospective randomized multicenter trial reported by the LCSG in 1995 established lobectomy as the standard approach to resection for T1N0 NSCLC (LCSG trial 821). Sublobar resection, either wedge resection or segmentectomy, for carefully selected patients who had thorough intraoperative evaluation of the extent of the primary tumor and of the N1 and N2 lymph nodes, was associated with a tripling of the local recurrence rate and a 30% increase in the overall death rate. Within the T1 stage category, tumor size did not seem to influence the risk of recurrence, but the numbers of patients who had tumors less than 2 cm in size were small.33Ginsberg RJ Rubinstein LV Randomized trial of lobectomy versus limited resection for T1N0 non-small cell lung cancer. Lung Cancer Study Group.Ann Thorac Surg. 1995; 60: 615-622Abstract Full Text PDF PubMed Scopus (2067) Google Scholar The increasing incidence of very early NSCLC seen in thoracic surgical practice, primarily via CT screening for lung cancer,1Read WL Page NC Tierney RM et al.The epidemiology of bronchioloalveolar carcinoma over the past two decades: analysis of the SEER database.Lung Cancer. 2004; 45: 137-142Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar has reopened the debate about the use of sublobar resection. This debate is especially relevant to BAC and to some AC of mixed subtype because of their indolent clinical behavior and known propensity for multifocality. Patients with these AC histologic subtypes often have synchronous or metachronous primary tumors that are best managed by resection. Preservation of lung function through the proper use of limited resection can be a critical aspect of achieving prolonged survival and maintaining patients’ functional capacity.34Ebright MI Zakowski MF Martin J et al.Clinical pattern and pathologic stage but not histologic features predict outcome for bronchioloalveolar carcinoma.Ann Thorac Surg. 2002; 74: 1640-1647Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 35Roberts PF Stranicka M Lara PN et al.Resection of multifocal non-small cell lung cancer when the bronchioloalveolar subtype is involved.J Thorac Cardiovasc Surg. 2003; 126: 1597-1602Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 36Battafarano RJ Meyers BF Gurthrie TJ et al.Surgical resection of mltifocal non-small cell lung cancer is associated with prolonged survival.Ann Thorac Surg. 2002; 74: 988-994Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar Several retrospective studies and prospective clinical trials suggest that the sublobar resection may be an appropriate operation for very early AC.11Nakamura H Saji H Ogata A et al.Lung cancer patients showing pure ground-glass opacity on computed tomography are good candidates for wedge resection.Lung Cancer. 2004; 44: 61-68Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, 13Watanabe S-I Watanabe T Arai K et al.Results of wedge resection for focal bronchioloalveolar carcinoma showing pure ground-glass attenuation on computed tomography.Ann Thorac Surg. 2002; 73: 1071-1075Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 37Okada M Yoshikawa K Hatta T et al.Is segmentectomy with lymph node assessment an alternative to lobectomy for non-small cell lung cancer of 2 cm or smaller?.Ann Thorac Surg. 2001; 71: 956-961Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 38Koike T Yamato Y Yoshiya K et al.Intentional limited pulmonary resection for peripheral T1N0M0 small-sized lung cancer.J Thorac Cardiovasc Surg. 2003; 125: 924-928Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar, 39Yoshikawa K Tsubota N Kodama K et al.Prospective study of extended segmentectomy for small lung tumors: The final report.Ann Thorac Surg. 2002; 73: 1055-1059Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 40Watanabe T Okada A Imakiire T et al.Intentional limited resection for small peripheral lung cancer based on intraoperative pathologic exploration.Jpn J Thorac Cardiovasc Surg. 2005; 53: 29-35Crossref PubMed Scopus (55) Google Scholar The parameters that currently seem to allow proper selection of patients for limited resection include tumor size (less than 2 cm and especially 1 cm or less) in combination with tumor histology (BAC or AC, mixed subtype with 50% or greater BAC component or AC, Noguchi types A or B), peripheral tumor location, and absence of N1 or N2 disease based on thorough intraoperative staging. The presence of GGO or of part solid, part nonsolid appearance on CT reflects these tumor characteristics. In ways that are not yet fully understood (aside from the presence of EGFR mutations in some tumors), these clinical and pathologic features represent tumors that most likely have an indolent biological behavior. The adequacy of wedge resection versus anatomical resection via segmentectomy remains undefined, although segmentectomy has been favored in Japanese studies because it provides an optimal deep margin of resection and removes the local lymphatic bed associated with the primary tumor.39Yoshikawa K Tsubota N Kodama K et al.Prospective study of extended segmentectomy for small lung tumors: The final report.Ann Thorac Surg. 2002; 73: 1055-1059Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar Japanese investigators have sought to confirm these selection criteria for sublobar resection through prospective multicenter clinical trials. JCOG trial 0201 (Figure 1), reported at the 2006 meeting of the American Society of Clinical Oncology (ASCO), enrolled patients with clinical stage IA AC.41Suzuki K Koike T Shibusa T et al.Evaluation of radiologic diagnosis in peripheral clinical IA lung cancers - a prospective study for radiological diagnosis of peripheral early lung cancer (JCOG 0201).J Clin Oncol. 2006; 24: 419sCrossref PubMed Scopus (193) Google Scholar The primary endpoint was to determine the specificity of high-resolution CT (HRCT) in diagnosing noninvasive AC, using the final pathologic findings as the reference standard. A pathological noninvasive AC was defined as a tumor with no lymph node metastases or lymphatic or vascular invasion. Preoperative evaluation included HRCT to assess the presence of GGO and to calculate the ratio of GGO to solid component of the tumor. Patients then underwent lobectomy and mediastinal lymph node dissection. Final pathological findings were compared with the HRCT features to determine whether the CT could be used to select patients appropriately for sublobar resection. Of the 811 patients enrolled, 545 eligible patients had undergone lobectomy and central data review at the time of the ASCO presentation. Comparison of the CT with the pathological findings showed that HRCT had a specificity of 98.3% but a sensitivity of only 24.7% for the diagnosis of noninvasive AC. The results of JCOG 0201 have been utilized to develop two new prospective trials. Patients found to have AC 2cm or less in size that are predominantly GGO by HRCT (solid component less than 25% of entire tumor) will be entered on a single arm Phase II trial testing the use of wedge resection for these highly curable indolent tumors. Patients found to have AC 2cm or less in size that have a larger solid component on HRCT (more than 25% but less than 100% of the entire tumor) will be eligible for a prospective randomized comparing lobectomy to limited resection (Figure 2). These trials might also help define which tumors do not require lymph node dissection or sampling, although this is not a planned study endpoint. At the current time lymph node sampling or systematic nodal dissection (SND) remains a key part of accurate tumor staging.42Goldstraw P Report on the international workshop on intrathoracic staging. London, October 1996.Lung Cancer. 1997; 18: 107-111Abstract Full Text Full Text PDF Google Scholar In North America, the Cancer and Leukemia Group B (CALGB), in collaboration with the American College of Surgeons Oncology Group (ACOSOG), is planning a prospective randomized trial comparing lobectomy versus limited resection (wedge or segmentectomy) for patients with AC 2 cm or less in size. This trial does not incorporate the nuanced radiological and histologic selection criteria used in Japanese studies, depending instead on simple size criteria and the basic diagnosis of AC. Designed to reproduce the LCSG 821 trial, but with a focus on smaller tumors, the CALGB trial uses intraoperative assessment of tumor size, tumor location, and nodal involvement, followed by randomization to lobectomy or limited resection. Because of the large numbers of patients and long follow-up time required to identify a survival difference between these two resectional approaches, results from this trial will probably not be available for about 8 years. Most BAC or AC, mixed subtype present as either a single nodule or as multiple lung nodules (synchronous or metachronous) that behave in an indolent manner and are best managed surgically.34Ebright MI Zakowski MF Martin J et al.Clinical pattern and pathologic stage but not histologic features predict outcome for bronchioloalveolar carcinoma.Ann Thorac Surg. 2002; 74: 1640-1647Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 36Battafarano RJ Meyers BF Gurthrie TJ et al.Surgical resection of mltifocal non-small cell lung cancer is associated with prolonged survival.Ann Thorac Surg. 2002; 74: 988-994Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 43Regnard JF Santelmo N Romdhani N et al.Bronchioloalveolar lung carcinoma. Results of surgical treatment and prognostic factors.Chest. 1998; 114: 45-50Crossref PubMed Scopus (63) Google Scholar The least common variant of this BAC-AC disease spectrum is generally termed the pneumonic form because it presents as a progressive lobar consolidation with mucinous AC filling the alveolar spaces. Resection does not seem to alter the very poor prognosis of this disease, which inevitably progresses to consolidation of both lungs and death from respiratory failure.34Ebright MI Zakowski MF Martin J et al.Clinical pattern and pathologic stage but not histologic features predict outcome for bronchioloalveolar carcinoma.Ann Thorac Surg. 2002; 74: 1640-1647Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, 43Regnard JF Santelmo N Romdhani N et al.Bronchioloalveolar lung carcinoma. Results of surgical treatment and prognostic factors.Chest. 1998; 114: 45-50Crossref PubMed Scopus (63) Google Scholar Systemic therapy has also been relatively ineffective in this disease. Thus, most surgeons are reluctant to consider pulmonary resection for this biologically aggressive form of AC. Lung transplantation has been suggested as a potential treatment option. First reported by Zorn et al., lung transplantation in nine patients (single lung in two and bilateral transplants in seven patients) was associated with a poor outcome.44Garver Jr, RI Zorn GL Wu X et al.Recurrence of bronchioloalveolar carcinoma in transplanted lungs.N Engl J Med. 1999; 340: 1071-1074Crossref PubMed Scopus (85) Google Scholar, 45Zorn GL McGiffin DC Young KR et al.Pulmonary transplantation for advanced bronchioloalveolar carcinoma.J Thorac Cardiovasc Surg. 2003; 125: 45-48Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Only two patients survived long term, whereas the other patients experienced cancer recurrence in the transplanted lungs. More recently, the Toronto group reported their experience with transplantation in 29 patients.46de Perrot M Chernenko S Waddell TK et al.Role of lung transplantation in the treatment of bronchogenic carcinomas for patients with end-stage pulmonary disease.J Clin Oncol. 2004; 22: 4351-4356Crossref PubMed Scopus (82) Google Scholar Five-year survival was 51%, and recurrence developed in 13 of the transplanted lungs. Although transplantation was performed for advanced multifocal BAC, it is not entirely clear how many of these patients truly had the pneumonic form of mucinous AC. Thus, lung transplantation potentially remains an option for selected patients, but it is associated with a significant risk of recurrent disease and requires further study. Lobectomy and lymph node sampling or systematic nodal dissection remain the standard surgical treatment for patients with early stage NSCLC. However, limited resection may be an appropriate option for patients with very early AC and BAC based on tumor size, location, and relative proportion of BAC to AC. Very small BAC are probably appropriately treated by limited resection. Accurate criteria for selecting patients for limited pulmonary resection await the results of ongoing clinical trials and an improved understanding of NSCLC biology in relationship to clinical outcome." @default.
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