The tumor-node-metastasis (TNM) system is

LUNG CARCINOMA STAGING PROBLEMS Philip T. Cagle, MD a,b, * KEYWORDS Lung Carcinoma Staging Tumor-node-metastasis TNM system ABSTRACT The tumor-node-metastasis (TNM) system is the most commonly used staging system for cancers, including lung cancer. The TNM descriptors and the stage groupings reflect differences in patient prognosis and choices for specific therapies. Generally, the higher the T, N, or M, and the higher the stage grouping, the worse the prognosis is for patients in that category. TNM stage is traditionally the most important factor predicting survival of lung cancer patients. The tumor-node-metastasis (TNM) system of the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC) is the most commonly used staging system for cancers, including lung cancer. The specific stage group representing the anatomic extent of a patient s disease is determined by combining the T (primary tumor size and local invasiveness), N (extent of nodal metastases) and M (presence or absence of distant metastases). Patients in the same stage group have similar prognoses and are candidates for similar therapy. Higher stage is usually associated with worse prognosis. 1 21 TNM stage is traditionally the most important factor predicting survival of lung cancer patients. 4,10,11 Staging may be clinical or pathologic. Pathologic TNM (ptnm) staging is typically derived from the gross and histologic examination of cancer resection specimens by the surgical pathologist, although, if the highest T and N categories or the M1 category can be verified by biopsies, the criteria for pathologic staging can be met. 20,21 The first TNM staging system for lung cancer was adopted in 1973 by the AJCC and in 1974 by the UICC. 1 3,10,13 In 1999, the International Association for the Study of Lung Cancer (IASLC) began a multinational study to delineate and validate a new TNM staging system with a larger, more representative database of 81,015 patients from 45 sources in 20 countries on 4 continents. 5 9,12 21 The new TNM staging for lung cancer was published in the seventh edition of the AJCC Cancer Staging Manual in October 2009 and implemented in January 2010. 20 The changes to the TNM descriptors proposed by the IASLC are summarized as key features. GROSS FEATURES The pathologic staging of lung cancer begins with the gross examination of the resection specimen, CHANGES TO T DESCRIPTORS PROPOSED BY IASLC AND ADOPTED BY THE SEVENTH EDITION OF THE AJCC CANCER STAGING MANUAL T1 subclassified as T1a and T1b according to size T2 subclassified as T2a and T2b according to size T2 tumors larger than 7 cm reclassified as T3 Tumors previously classified as T4 for multiple tumor nodules in the primary lobe reclassified as T3 Tumors previously classified as M1 for multiple tumor nodules in a different lobe of the ipsilateral lung reclassified as T4 a Department of Pathology and Laboratory Medicine, Weil Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA b Department of Pathology, The Methodist Hospital, Main Building, Room 227B, 6565 Fannin Street, Houston, TX 77030, USA * Department of Pathology, The Methodist Hospital, Main Building, Room 227B, 6565 Fannin Street, Houston, TX 77030. E-mail address: pcagle@tmhs.org Surgical Pathology 3 (2010) 61 69 doi:10.1016/j.path.2010.03.008 1875-9181/10/$ see front matter ª 2010 Elsevier Inc. All rights reserved. surgpath.theclinics.com

62 Cagle CHANGES TO N DESCRIPTORS PROPOSED BY IASLC AND ADOPTED BY THE SEVENTH EDITION OF THE AJCC CANCER STAGING MANUAL Existing N categories were found to be valid in the IASLC database N0, N1, N2 and N3 as previously described were found to identify prognostically distinct groups of patients IASLC found that patients can be placed into 4 prognostically distinct categories, depending on the extent of nodal metastases: Single-zone N1 Multiple-zone N1 Single-zone N2 Multiple-zone N2 Overall disease burden is suggested to have the most important influence on outcome, rather than just the anatomic location of lymph node involvement and several problems may be encountered. 20 23 First, the surgeon must provide adequate sampling, including appropriate lymph node stations. If the surgeon follows guidelines for pathologic staging this problem should be solved. Second, the pathologist should seek assistance from the surgeon if there are ambiguities about the surgical margins. Surgical margins include staple lines for wedge resections and some larger specimens, bronchial and vascular margins for lobectomies and pneumonectomies, and occasionally other surfaces when extrapulmonary tissues are CHANGES TO M DESCRIPTORS PROPOSED BY IASLC AND ADOPTED BY THE SEVENTH EDITION OF THE AJCC CANCER STAGING MANUAL Tumors previously classified as T4 for pleural dissemination (malignant pleural effusions, pleural nodules) reclassified as M1a M1 subclassified as M1a (malignant pleural effusion present or tumor nodules in the opposite lung) and M1b (distant metastases present) Tumors previously classified as M1 for tumor nodule(s) in the ipsilateral lung (nonprimary lobe) reclassified as T40 PROBLEMS IN GROSS EXAMINATION OF LUNG RESECTION SPECIMENS FOR STAGING Adequate sampling including appropriate lymph node stations Ambiguities about the surgical margins Grossly exaggerated tumor dimensions because of firm, discolored peritumoral reactions Specific gross measurements may not be possible for the distance of a main bronchus tumor from the carina Specific gross measurements may not be possible for the extent of associated atelectasis or obstructive pneumonia resected en bloc. Surgical margins are first examined grossly and, to assist with histologic evaluation of grossly equivocal margins, margins may be inked. Third, determination of gross tumor size may be problematic because many lung cancers have firm, discolored peritumoral reactions that may give a gross impression that they are part of the cancer, resulting in exaggerated tumor dimensions. These peritumoral reactions may include organizing pneumonia, lipid pneumonia, interstitial pneumonia, and desquamative interstitial pneumonialike reactions. As a result, gross measurements must be confirmed with histologic measurements. Fourth, specific measurements that may not be possible with the gross examination of the resection specimen, including distance of a main bronchus tumor from the carina and the extent of associated atelectasis or obstructive pneumonia. These features may require correlation with imaging studies. MICROSCOPIC FEATURES In addition to the gross findings, the surgical pathologist examines the resection specimen microscopically for specific features of the primary tumor (size and location, invasion of visceral pleura and other structures, associated atelectasis and obstructive pneumonia, separate tumor nodules), lymph nodes (presence of metastases), and distant metastases if appropriate diagnostic tissue is provided. 20 23 In addition to confirmation of tumor size, location, and associated features such as atelectasis

Lung Carcinoma Staging Problems 63 MICROSCOPIC FEATURES EXAMINED FOR STAGING Primary tumor Size, location, cell types and subtypes Invasion of visceral pleura and other structures Associated atelectasis and obstructive pneumonia Separate tumor nodules Lymph nodes: presence of metastases Distant metastases if appropriate diagnostic tissue is provided. and obstructive pneumonia, microscopic examination of the primary tumor includes determination of cell type and subtypes. Treatment of lung cancer is increasingly based on detailed diagnosis of these cell types and subtypes that are associated with specific targets of molecular therapy. Most lung cancers are heterogeneous, consisting of mixed subtypes and often mixed major cell types. Therefore, microscopic examination must include adequate sampling to determine not only the T descriptor but also a thorough classification of the cell types and subtypes. 4,10,11,24,25 Changes to the classification of pulmonary adenocarcinoma have been proposed, in particular by the IASLC. 26 30 The differential diagnosis of specific problem areas of the T descriptors (invasion of visceral pleura and multiple separate tumor nodules) is discussed later. 20 23,31 33 There are histologic findings that may affect prognosis but do not change the TNM descriptors. Lymphovascular invasion is reported to be an unfavorable prognostic finding in lung cancer specimens. When lymphovascular invasion is equivocal, immunostains such as CD31 and CD34 for vascular endothelial cells and D2-40 for lymphatic endothelial cells can be performed. Extension of a lung cancer metastasis outside a mediastinal lymph node capsule (extranodal extension) is also considered to be an unfavorable prognostic finding, but, again, it does not change the TNM status. 20,21 DIFFERENTIAL DIAGNOSIS Differential diagnoses of multiple tumor nodules and of visceral pleural invasion are 2 areas of lung cancer staging that are notoriously problematic. 20 23,31 33 Several aspects of the staging of pleural involvement by a subpleural primary tumor that were vague in previous TNM staging systems have been clarified in the new TNM staging system. It is now recognized that visceral pleural invasion is determined by penetration of its external elastic lamina. Visceral pleural invasion is absent if a cancer fails to penetrate the external elastic lamina (Figs. 1 and 2) and pleural invasion is present if the cancer penetrates this layer (Figs. 3 and 4), regardless of whether or not it extends all the way to the visceral pleural surface. Prognosis seems to be the same whether a tumor extends to the visceral pleural surface or it penetrates the visceral pleural external elastic lamina without extending to the pleural surface. In either case, a lung cancer that is otherwise staged as a pt1 cancer is upstaged to a pt2 cancer. 20 23,31,32 Assessment of visceral pleural invasion depends on identification of the external elastic lamina and the relationship of the cancer to it. On hematoxylin and eosin (H&E) stains, the external elastic lamina appears as a comparatively thick, refractile line that extends in the connective tissue of the visceral pleura and often seems incomplete because of tangential sectioning. Elastic stains (eg, Verhoeff-van Gieson [VVG]) can be used to highlight the external elastic lamina, which stains as a comparatively thick black line. In many cases, particularly when invasion of the visceral pleura by cancer is present, identification of the external elastic lamina may be difficult or impossible. This Differential Diagnosis VISCERAL PLEURAL INVASION Absent if cancer does not penetrate the external elastic lamina Present if cancer penetrates the external elastic lamina, whether or not the cancer extends all the way to the visceral pleural surface Elastic stains may highlight the external elastic lamina to assist with assessment of visceral pleural invasion With visceral pleural invasion, a pt1 lung cancer is upstaged to pt2 Elastotic changes of the visceral pleura and underlying lung due to cancer invasion, fibrosis, and other pathology may disrupt or destroy the external elastic lamina, making confirmation of visceral pleural invasion impossible

64 Cagle Fig. 1. No visceral pleural invasion is observed on this medium-power hematoxylin and eosin (H&E) stained section. The external elastic lamina appears as a wavy, eosinophilic, refractile line. An adenocarcinoma can be observed beneath the external elastic lamina of the visceral pleura without penetration of the lamina. The visceral pleural surface has been stained with black ink. quandary is a common problem in the differential diagnosis of lung cancer staging. The visceral pleura has elastic fibers in addition to the external elastic lamina, and these blend with elastic fibers in the subpleural lung tissue. In many pathologic conditions, fibroelastotic changes of the visceral pleura and adjacent lung result in duplication and distortion of the elastic fibers, obliterating the Fig. 2. This medium-power Verhoeff-van Gieson (VVG) stained section shows the external elastic lamina as a thick, wavy, black line. An adenocarcinoma is present beneath the lamina and does not penetrate it. No visceral pleural invasion is present.

Lung Carcinoma Staging Problems 65 Fig. 3. Visceral pleural invasion can be seen in this medium-power H&Estained section in which adenocarcinomais present on both sides of the external elastic lamina. normal elastic fiber infrastructure and eradicating recognition of the external elastic lamina. In this situation, there may be cancer distributed among fragmented elastic fibers with significant disruption of the external elastic lamina or without any recognizable external elastic lamina. 20 23,31,32 A frequent dilemma in the differential diagnosis of staging lung cancers involves the presence of 2 or more cancer nodules in the resection specimen. One or more additional cancer nodules could represent metastasis from a single primary cancer or it could represent multiple synchronous primary tumors. The additional nodule(s) may be located in the same lobe, in the same lung but in different lobes, or in the opposite lung. Currently, there are histologic criteria for differentiating synchronous primary lung cancers from intrapulmonary metastatic lung cancers when more than 1 cancer nodule is present. Nodules with different cell types that are physically distinct and separate are presumed to be synchronous primary lung cancers. Nodules that show similar histologic features but are physically distinct and separate are considered to be synchronous primary lung cancers if they display an origin from carcinoma in situ, lack lymphangitic spread of carcinoma in the lymphatics common to both nodules, and lack extrapulmonary metastases at the time of diagnosis. The T descriptor for multiple synchronous lung cancers is based on the size of the largest cancer. In this situation, the number of primary cancers or, alternatively, the suffix m for multiple is provided in parentheses with the T descriptor. 20 23,33 A second cancer nodule is considered to be a metastasis if it has similar histology, is physically distinct and separate from the other cancer nodule, and lacks the criteria given earlier for synchronous primary lung cancers. Metastatic Differential Diagnosis MULTIPLE TUMOR NODULES Nodules with different cell types 1 physically distinct and separate 5 synchronous primary lung cancers Nodules with similar histologic features 1 physically distinct and separate 1 origin from carcinoma in situ 1 lack spread of carcinoma in the lymphatics common to both nodules 1 lack extrapulmonary metastases at the time of diagnosis 5 synchronous primary lung cancers Nodules with similar histology 1 physically distinct and separate 1 lack criteria for synchronous primary lung cancers 5 metastasis T descriptor for multiple synchronous lung cancers is based on the size of the largest cancer 5 pt(m) Metastatic nodules in the same lobe are staged as T3 Metastatic nodules in ipsilateral separate lobes are staged as T4

66 Cagle Fig. 4. In this high-power VVG-stained section, visceral pleural invasion is indicated by the presence of adenocarcinoma on both sides of the black, wavy, external elastic lamina. nodules in the same lobe are staged as T3 and metastatic nodules in ipsilateral separate lobes are staged as T4. 20 23,33 Problems in the differential diagnosis of multiple synchronous primary lung cancers versus intrapulmonary lung cancer metastases arise because the principal histology in a metastasis may represent a minor histologic component of the primary cancer and, thus, seem to differ from the principal histology of the primary cancer. This apparent histologic dissimilarity suggests multiple synchronous primary lung cancers rather than a metastasis. Another problem with this differential diagnosis occurs in cases in which sampling fails to include areas of lymphovascular spread between 2 lung cancer nodules and, even if properly sampled, lymphangitic spread is difficult to discern on H&E sections. In the latter situation, Pitfalls MULTIPLE TUMOR NODULES! Principal histology in a metastasis may represent a minor histologic component of the primary cancer; apparent histologic dissimilarity suggests multiple synchronous primary lung cancers rather than a metastasis! Sampling fails to include areas of lymphovascular spread between 2 lung cancer nodules! Lymphovascular spread is sometimes difficult to discern on H&E sections; immunostains for endothelial markers may be helpful

Lung Carcinoma Staging Problems 67 TNM PATHOLOGIC DESCRIPTORS FOR LUNG CANCER ADOPTED BY THE SEVENTH EDITION OF THE AJCC CANCER STAGING MANUAL Primary tumor (pt) ptx: cannot be assessed, or tumor proven by presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy pt0: no evidence of primary tumor ptis: carcinoma in situ pt1a: tumor 2 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (ie, not in the main bronchus); or superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus pt1b: tumor greater than 2 cm, but 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (ie, not in the main bronchus) pt2a: tumor greater than 3 cm, but 5 cm or less in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (ie, not in the main bronchus), or tumor 5 cm or less in greatest dimension with any of the following features of extent: involves main bronchus, 2 cm or more distal to the carina; invades the visceral pleura; associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung pt2b: tumor greater than 5 cm, but 7 cm or less in greatest dimension pt3: tumor greater than 7 cm in greatest dimension; or tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumor of any size in the main bronchus less than 2 cm distal to the carina but without involvement of the carina; or tumor of any size associated with atelectasis or obstructive pneumonitisoftheentirelung;ortumorsofany size with separate tumor nodule(s) in same lobe pt4: tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina; or tumor of any size with separate tumor nodule(s) in a different lobe of ipsilateral lung Regional lymph nodes (pn) pnx: cannot be assessed pn0: no regional lymph node metastasis pn1: metastasis in ipsilateral peribronchial or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension pn2: metastasis in ipsilateral mediastinal or subcarinal lymph node(s) pn3: metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s) Distant metastasis (pm) Not applicable pm1a: separate tumor nodule(s) in contralateral lung; tumor with pleural nodules or malignant pleural (or pericardial) effusion pm1b: distant metastases outside the lung/pleura From Edge SB, Byrd DR, Compton CC, et al, editors. AJCC cancer staging manual. 7th edition. New York: Springer; 2009; with permission. TNM STAGE GROUPINGS FOR LUNG CANCER ADOPTED BY THE SEVENTH EDITION OF THE AJCC Stage IA T1a N0 M0 T1b N0 M0 Stage IB T2a N0 M0 Stage IIA T1a N1 M0 T1b N1 M0 T2a N1 M0 T2b N0 M0 Stage IIB T2b N1 M0 T3 N0 M0 Stage IIIA T1a N2 M0 T1b N2 M0 T2a N2 M0 T2b N2 M0 T3 N1-2 M0 T4 N0-1 M0 Stage IIIB T1a N3 M0 T1b N3 M0 T2a N3 M0 T2b N3 M0 T3 N3 M0 T4 N2-3 M0 Stage IV Any T Any N M1a or M1b CANCER STAGING MANUAL From Edge SB, Byrd DR, Compton CC, et al, editors. AJCC cancer staging manual. 7th edition. New York: Springer; 2009; with permission.

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