Advances in Anatomic Pathology:
An Update on Lung Cancer Staging
Jones, Kirk D. MD
Department of Anatomic Pathology, University of California, San Francisco, CA
Reprints: Kirk D. Jones, MD, UCSF Department of Pathology, 505 Parnassus Avenue, Rm M545, San Francisco, CA 94143 (e-mail: email@example.com).
Abstract: The staging committee of the International Association for the Study of Lung Cancer has recently published, in collaboration with the International Union Against Cancer and the American Joint Committee on Cancer, the recommendations for the upcoming 7th edition of the tumor, node, metastasis classification and staging manual. This article reviews the changes in criteria for the tumor, node, metastasis components and discusses the issues that will be faced by pathologists when examining lung cancer specimens, including recommendations for tumor measurement, differentiation of multiple primary tumors versus metastases, and visceral pleural invasion.
Accurate staging of lung cancer has several benefits. It provides for international collaboration and comparison of cases, it allows for determination of prognosis, and it allows for planning treatment and evaluating the results of treatment. The International Association for the Study of Lung Cancer (IASLC) recently published the Staging Manual in Thoracic Oncology that will provide the criteria for the 7th edition of the American Joint Commission on Cancer (AJCC)/International Union Against Cancer Manual for Staging of Cancer.1 The data for this new staging system are the result of the IASLC Staging Project, which collected over 100,000 international cases of lung cancer, of which over 81,000 were included in the analysis.2 Several changes were made in the tumor, node, metastasis (TNM) lung cancer staging system as a result of this project.3 In addition, several controversial parameters of invasion and metastasis were defined to aid future evaluation and diagnosis (Table 1).4
T COMPONENT—THE SIGNIFICANCE OF SIZE
Tumor size is an important prognostic indicator in the lung. Its longevity is apparent in its inclusion as a criterion for lung cancer staging in both the 1974 article by Mountain, Carr, and Anderson5 and in the 1977 first edition of the AJCC Manual for Staging of Cancer.6 This importance is further expanded in the 7th edition TNM system by the subdivision of the former T1 and T2 groups into T1a, T1b, T2a, T2b, and T3 based on tumor diameter.7
An evaluation of tumor size was a major component of the IASLC Staging Project. During analysis of prognosis, several statistically significant breakpoints were identified at tumor diameters of 2 cm, 3 cm, 5 cm, and 7 cm. As shown in Table 2, this resulted in subdivision of T1 tumors into T1a (less than or equal to 2 cm) and T1b (greater than 2 but less than or equal to 3 cm), and in subdivision of T2 tumors into T2a (greater than 3 but less than or equal to 5 cm), T2b (greater than 5 but less than or equal to 7 cm), and T3 (greater than 7 cm).7 Several subsequent studies have shown the system to be prognostically valid.8–10
MEASURING TUMOR DIAMETER
The importance of tumor diameter has led to some understandable trepidation about the proper method of tumor measurement. The current recommendation is to measure the tumor before formalin fixation. It is difficult to ascertain the impact of fresh measurement. A recent study showed that the majority of cases (90%) did not change their diameter significantly after fixation; however, 10% of the cases showed changes that led to down-staging from T2 to T1.11 If measurement is unable to be done until after the tumor is fixed, do not despair. The fact that this study compared fresh measurement by the surgeon with postfixation measurement by the pathologist (including subtraction of areas of pneumonia/atelectasis at the time of microscopy) suggests that while concerning, the 10% may be an overestimation of the significance of the effect. Therefore, while measuring the diameter of the tumor, one should attempt to measure the fresh tumor, when possible, then subtract out regions of adjacent organizing pneumonia or obstructive pneumonia during microscopic examination. Regions of the central scarring or necrosis often represent portions of collapse or degeneration within a tumor and should be included in the measurement of the diameter.12
T-COMPONENT: MULTIPLE TUMOR NODULES
A second major change in the T-component is in the classification of multiple tumor nodules within the ipsilateral lung. In the 6th TNM staging system, the presence of additional nodules in the same lobe was classified as T4, and additional nodules in ipsilateral separate lobes were designated as M1 disease. Analysis of prognosis in the IASLC Staging Project revealed that multinodular disease within the same lobe showed similar survival to T3 tumors, and ispsilateral multinodular disease in separate lobes showed similar survival to T4 tumors. Although it is still important to use histologic criteria to try to distinguish synchronous primary tumors from intrapulmonary metastases, the difference in staging (changing from stage IV to stage IIIA in node-negative disease, for example) allows the clinician to consider surgery as a primary treatment option even when tumors are considered intrapulmonary metastases.
DIFFERENTIATION OF MULTIPLE PRIMARY TUMORS FROM METASTASES
In the past, the onus upon the pathologist to use “the criteria of Martini and Melamed” was an occasionally arduous endeavor to find description of these criteria, first laid out in 1975.13 In the current 7th TNM staging system, criteria for differentiating multiple primary tumors from metastases are more explicitly stated and reflect the subsequent findings of a study by Girard et al, which used comprehensive assessment of histologic features in comparison with mutational profiling to determine metastatic status.14 Most multiple nodules represent metastatic disease and should be staged as T3, if they are in the same lobe, T4, if in an ipsilateral separate lobe, or M1a if present in the contralateral lung. If the tumors have different histologic types (eg, squamous vs. adenocarcinoma) or have marked variation in their components (eg, papillary adenocarcinoma vs. solid type adenocarcinoma) or cytologic/stromal features and lack mediastinal lymph node metastasis or tumor within shared lymphatics, then these tumors may be considered synchronous primary tumors.15 Synchronous primary tumors are designated by the highest T status, followed by a parenthetical description of either multiplicity or exact number of tumors [eg, T3(m) or T3(2)—it is sometimes helpful to add a text comment in these cases to assist the reader of the report, if they are unfamiliar with this less-often used modifier].
T-COMPONENT: PLEURAL INVASION
Pleural invasion is a complicated topic because of the fact that it was not defined histologically in the initial staging guides. Subsequently, it has been interpreted by various definitions.16 The visceral pleura is composed of several layers, some easily recognizable, others not so easily (Fig. 1). Moving from the pleural space into the lung, one traverses: (1) the mesothelial layer, (2) a layer of loose submesothelial connective tissue, (3) a well-defined elastic layer, the external elastic lamina, (4) a layer of loose connective tissue containing small vessels and lymphatics, and (5) an often poorly defined elastic layer, the internal elastic lamina.17 Most anatomists consider the internal elastic layer as a part of the distal alveolar wall, as this layer develops in synchrony with the remainder of the pulmonary alveolar elastic tissue.18 Various criteria used in assessment of invasion include gross pleural puckering, tumor invasion through internal elastic layer, tumor invasion through external elastic layer, and tumor present on pleural surface.
This problem of differing definitions of pleural invasion by various pathologists led to the publication of a consensus statement that defined pleural invasion as a tumor crossing the prominent visceral pleural elastic layer.19 Whereas some might still wonder whether this refers to the internal elastic layer or external elastic layer, for most cases, this is the external elastic layer. These criteria for pleural invasion are similar to those used by Hammar20 and the Japan Lung Cancer Society21 and can be subdivided into tumors that invade the visceral pleural elastica (PL1), extend to the mesothelial surface (PL2), or invade into the parietal pleura/chest wall (PL3). The use of the external elastic layer as the boundary for assessing visceral pleural invasion is in accordance with studies performed by Shimizu et al22 and Osaki et al,23 which showed that tumors with invasion through the external elastic layer (visceral pleural elastica) showed similar prognosis to tumors that extended to the visceral pleural surface (mesothelial layer), and worse prognosis than those which did not penetrate the elastica. Although it is intriguing to wonder whether invasion of the internal elastic layer might have a worse prognosis (owing to access to subpleural lymphatics), the data are limited, and often this layer is obscure and difficult to recognize.24
The use of stains to highlight the elastic layer is more important now that this landmark is the boundary that determines pleural invasion. Several authors have commented on the utility of these stains.25–27 Even in cases, in which invasion seems obvious, a stain often changes “seemingly obvious” to simply obvious (Fig. 2).
Occasionally a tumor will invade through the pleura at the interlobar fissure into the adjacent lobe. This leads to confusion whether this represents pleural invasion (thus T2), tumor in different lobes (thus T4), or perhaps some happy medium. Studies have shown the prognosis in these cases to be similar to T2 or T3 cancers.28–31 In the current system, these tumors will be staged as T2.19
N COMPONENT: CONSOLIDATION OF LYMPH NODE MAPS
There will be no changes in the N component of the TNM staging system.32 As was the case earlier, ipsilateral peribronchial, hilar, and intrapulmonary lymph nodes are designated as N1, subcarinal and ipsilateral mediastinal lymph nodes are designated as N2, and supraclavicular, scalene, and contralateral mediastinal lymph nodes are designated as N3 (Table 3).
Before the 7th TNM staging system, several lymph node maps were being used to define the various nodal stations. These included the Naruke map used by the Japan Lung Cancer Society, and the Mountain-Dreseler modification of the American Thoracic Society map that was included in the 6th TNM staging system. An important development in the 7th TNM staging system is a new map defining the anatomic boundaries of the lymph node stations.33 This was developed to bring the various lymph node maps into agreement. In addition, the concept of nodal zones was introduced which combined lymph node stations into anatomic compartments.33 This will allow for future analysis of both nodal stations and zones in future iterations of the TNM staging system.34
N COMPONENT: A SIMPLE WARNING ON DESIGNATION
Although it seems trivial, I have seen some near errors in which a level 11 lymph node has been termed level II, and a particularly sloppily written level 10 lymph node was erroneously designated as level IV. Roman numerals are often used in the designation of lymph node stations of the head and neck, but they have no place in the thorax. When it comes to pathologic staging of lung cancer: caveo numeros Romanorum-beware of Roman numerals.35
M COMPONENT: LOCAL VERSUS DISTANT METASTASES
Several changes were made in the M component, the most obvious of which is the splitting of M1 into M1a and M1b based on whether the disease was confined to the lung, pleura, and pericardium (local), or extended past these confines (distant), respectively (Table 4).36 As mentioned above, tumors, classified earlier as M1 owing to multiple nodules in ipsilateral separate lobes, are now down-staged to T4. The presence of metastatic nodules in contralateral lung tissue is classified as M1a.
In the 6th TNM staging system, pleural effusions were classified as T4 tumors. Prognostic analysis of pleural effusions (and pleural nodular metastases) done by the IASLC Staging Project showed a significantly worse survival of these lesions when compared with other T4 tumors. Based on this finding, both pleural and pericardial dissemination are reclassified as M1a in the 7th TNM staging system and subsequently changed to stage IV disease. Cytologic examination of pleural and pericardial fluid thus has a greater significance in the current system than it had in previous staging systems. Fortunately, complete cytologic evaluation (Papanicolaou, MGG, and cell block preparations) has a sensitivity of greater than 90% and a specificity near 100% for detection of carcinoma in pleural fluid.37 In difficult cases, immunohistochemical markers for epithelial differentiation (eg, CEA, MOC-31)or tissue specific markers (eg, TTF-1) or histochemical markers for mucin (eg, PAS-D) may be used to aid in diagnosis.
APPLYING THE TNM STAGING SYSTEM TO SMALL CELL CARCINOMA AND BRONCHOPULMONARY CARCINOID TUMORS
For several decades, physicians split small cell carcinoma into either limited disease or extensive disease. After analysis of over 8000 patients with small cell carcinoma, including 349 with complete pathologic TNM staging, the IASLC Staging Project found that TNM staging revealed differences in prognosis. TNM staging of small cell carcinoma is encouraged and appropriate.38,39
During the collection of the many cases of lung carcinoma, over 500 cases of carcinoid tumor were obtained and analyzed. Whereas the prognosis in these cases is much better than for lung cancer, TNM staging stratifies cases into significantly different prognostic groups. TNM staging of carcinoid tumors seems valid and useful.40
LUNG CANCER STAGING: WHERE IS THE NEXT STEP?
The IASLC Lung Cancer Staging Project used a large data set of over 100,000 patients to do a retrospective analysis that formed the basis of the current 7th TNM staging system recommendations. The next phase of this project is prospective and has the primary objective of refining future TNM classifications.41,42 Several objectives have been defined for prospective analysis in each of the TNM components. In addition, other components, such as impact of histologic type, surgical resection status, clinical factors, such as pulmonary function tests, and radiologic factors, such as maximum standardized uptake value, will be analyzed. These data will be used as a source of recommendations for the 8th edition of the TNM classification by the UICC and AJCC in 2016.
1. Goldstraw P. Staging Manual in Thoracic Oncology. Orange Park, FL: Editorial Rx Press; 2009.
2. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol. 2007;2:706–714.
3. Groome PA, Bolejack V, Crowley JJ, et al. The IASLC Lung Cancer Staging Project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol. 2007;2:694–705.
4. Goldstraw P. The 7th Edition of TNM in Lung Cancer: what now? J Thorac Oncol. 2009;4:671–673.
5. Mountain CF, Carr DT, Anderson WA. A system for the clinical staging of lung cancer. Am J Roentgenol Radium Ther Nucl Med. 1974;120:130–138.
6. American Joint Committee for Cancer Staging and End Results Reporting. Manual for Staging of Cancer 1977. Chicago, IL: American Joint Committee; 1977:59–64.
7. Rami-Porta R, Ball D, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the T descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol. 2007;2:593–602.
8. Ye C, Masterman JR, Huberman MS, et al. Subdivision of the T1 size descriptor for stage I non-small cell lung cancer has prognostic value: a single institution experience. Chest. 2009;136:710–715.
9. Kassis ES, Vaporciyan AA, Swisher SG, et al. Application of the revised lung cancer staging system (IASLC Staging Project) to a cancer center population. J Thorac Cardiovasc Surg. 2009;138:412–418.
10. Ruffini E, Filosso PL, Bruna MC, et al. Recommended changes for T and N descriptors proposed by the International Association for the Study of Lung Cancer-Lung Cancer Staging Project: a validation study from a single-centre experience. Eur J Cardiothorac Surg. 2009. [Epub ahead of print].
11. Hsu PK, Huang HC, Hsieh CC, et al. Effect of formalin fixation on tumor size determination in stage I non-small cell lung cancer. Ann Thorac Surg. 2007;84:1825–1829.
12. Shimosato Y, Suzuki A, Hashimoto T, et al. Prognostic implications of fibrotic focus (scar) in small peripheral lung cancers. Am J Surg Pathol. 1980;4:365–373.
13. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg. 1975;70:606–612.
14. Girard N, Deshpande C, Lau C, et al. Comprehensive Histologic Assessment Helps to Differentiate Multiple Lung Primary Nonsmall Cell Carcinomas From Metastases. Am J Surg Pathol. 2009. [Epub ahead of print].
15. Travis WD, IASLC Staging Committee. Reporting lung cancer pathology specimens. Impact of the anticipated 7th Edition TNM classification based on recommendations of the IASLC Staging Committee. Histopathology. 2009;54:3–11.
16. Butnor KJ, Vollmer RT, Blaszyk H, et al. Interobserver agreement on what constitutes visceral pleural invasion by non-small cell lung carcinoma: an internet-based assessment of international current practices. Am J Clin Pathol. 2007;128:638–647.
17. Hiroshima K, Yusa T, Kameya T, et al. Malignant pleural mesothelioma: clinicopathology of 16 extrapleural pneumonectomy patients with special reference to early stage features. Pathol Int. 2009;59:537–545.
18. Nagaishi C. Functional Anatomy and Histology of the Lung. Baltimore, MD: University Park Press; 1972:254–259.
19. Travis WD, Brambilla E, Rami-Porta R, et al. Visceral pleural invasion: pathologic criteria and use of elastic stains: proposal for the 7th edition of the TNM classification for lung cancer. J Thorac Oncol. 2008;3:1384–1390.
20. Hammar SP. Common Tumors. In: Dail DH, Hammar SP, eds. Pulmonary Pathology. 2nd ed. New York: Springer-Verlag; 1994:1123–1278.
21. The Japan Lung Cancer Society. Classification of Lung Cancer. Tokyo: Kanehara Publishing; 2000.
22. Shimizu K, Yoshida J, Nagai K, et al. Visceral pleural invasion classification in non-small cell lung cancer: a proposal on the basis of outcome assessment. J Thorac Cardiovasc Surg. 2004;127:1574–1578.
23. Osaki T, Nagashima A, Yoshimatsu T, et al. Visceral pleural involvement in nonsmall cell lung cancer: prognostic significance. Ann Thorac Surg. 2004;77:1769–1773;discussion 1773.
24. Warth A, Muley T, Herpel E, et al. A Histochemical Approach to the Diagnosis of Visceral Pleural Infiltration by Non-small Cell Lung Cancer. Pathol Oncol Res. 2009. [Epub ahead of print].
25. Butnor KJ, Cooper K. Visceral pleural invasion in lung cancer: recognizing histologic parameters that impact staging and prognosis. Adv Anat Pathol. 2005;12:1–6.
26. Flieder DB. Commonly encountered difficulties in pathologic staging of lung cancer. Arch Pathol Lab Med. 2007;131:1016–1026.
27. Taube JM, Askin FB, Brock MV, et al. Impact of elastic staining on the staging of peripheral lung cancers. Am J Surg Pathol. 2007;31:953–956.
28. Miura H, Taira O, Uchida O, et al. Invasion beyond interlobar pleura in non-small cell lung cancer. Chest. 1998;114:1301–1304.
29. Okada M, Tsubota N, Yoshimura M, et al. How should interlobar pleural invasion be classified? Prognosis of resected T3 non-small cell lung cancer. Ann Thorac Surg. 1999;68:2049–2052.
30. Nonaka M, Kataoka D, Yamamoto S, et al. Outcome following surgery for primary lung cancer with interlobar pleural invasion. Surg Today. 2005;35:22–27.
31. Demir A, Gunluoglu MZ, Sansar D, et al. Staging and resection of lung cancer with minimal invasion of the adjacent lobe. Eur J Cardiothorac Surg. 2007;32:855–858.
32. Rusch VW, Crowley J, Giroux DJ, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2007;2:603–612.
33. Rusch VW, Asamura H, Watanabe H, et al. The IASLC Lung Cancer Staging Project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2009;4:568–577.
34. Pisters KM, Darling G. The IASLC Lung Cancer Staging Project: “the nodal zone”. J Thorac Oncol. 2007;2:583–584.
35. Gibbon E. The Decline and Fall of the Roman Empire. New York: Alfred A. Knopf; 1993.
36. Postmus PE, Brambilla E, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for revision of the M descriptors in the forthcoming (seventh) edition of the TNM classification of lung cancer. J Thorac Oncol. 2007;2:686–693.
37. Johnston WW. The malignant pleural effusion: a review of cytopathologic diagnoses of 584 specimens from 472 consecutive patients. Cancer. 1985;56:905–909.
38. Shepherd FA, Crowley J, Van Houtte P, et al. The International Association for the Study of Lung Cancer lung cancer staging project: proposals regarding the clinical staging of small cell lung cancer in the forthcoming (seventh) edition of the tumor, node, metastasis classification for lung cancer. J Thorac Oncol. 2007;2:1067–1077.
39. Vallieres E, Shepherd FA, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals regarding the relevance of TNM in the pathologic staging of small cell lung cancer in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol. 2009;4:1049–1059.
40. Travis WD, Giroux DJ, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the inclusion of broncho-pulmonary carcinoid tumors in the forthcoming (seventh) edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2008;3:1213–1223.
41. Giroux DJ, Rami-Porta R, Chansky K, et al. International Association for the Study of Lung Cancer International Staging Committee. The IASLC Lung Cancer Staging Project: data elements for the prospective project. J Thorac Oncol. 2009;4:679–683.
42. Chansky K, Sculier JP, Crowley JJ, et al. The International Association for the Study of Lung Cancer Staging Project: prognostic factors and pathologic TNM stage in surgically managed non-small cell lung cancer. J Thorac Oncol. 2009;4:792–801.
tumor; node; metastasis classification; staging system; lung cancer; carcinoma; tumor size; pleural invasion
© 2010 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.