Anatomy, Biology and Concepts, Pertaining to Lung Cancer Stage Classification

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1 COMMENTARY Anatomy, Biology and Concepts, Pertaining to Lung Cancer Stage Classification Frank C. Detterbeck, MD,* Lynn T. Tanoue, MD,* and Daniel J. Boffa, MD* Abstract: The proposed lung cancer stage classification system remains grounded in anatomic characteristics, although the large patient database contributing to this revision has dramatically expanded our body of knowledge. Predictably this has led to increased complexity due to the identification of an increasing number of subpopulations of patients. Patterns of clinical presentation characterizing these subgroups may provide clues about the propensity of tumors within a subgroup toward a particular pattern of biologic behavior. This article explores concepts regarding tumor biology that can be applied to the anatomically based new staging system. Key Words: Lung cancer, Anatomy, Biology, Concepts, Stage. (J Thorac Oncol. 2009;4: ) A stage classification system provides a common nomenclature about patients with a particular type of cancer. A common language facilitates communication among different centers, allowing observations from different sources to be combined and thereby enhance our collective knowledge. As knowledge is gained, further details of a staging system can be defined, and thus the system requires periodic revision and refinement. In lung cancer, a major effort led by the International Association for the Study of Lung Cancer (IASLC) Staging Committee was undertaken to inform a revision of the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system, 1 5 involving an unprecedented extent of data collection and scientific analysis. 1 5 This has prompted us to reflect on the goals of a staging system, the limitations of our current understanding of the biology of lung cancer, and how underlying concepts can help or hinder our ability to make new observations. Inherent in the development of the nomenclature of a staging system is the ability to define homogeneous patient cohorts. This raises the question of how homogeneity is *Thoracic Oncology Program, Yale Cancer Center; Division of Thoracic Surgery Department of Surgery, Yale University; and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Yale University, New Haven, Connecticut. Disclosure: The authors declare no conflicts of interest. Address for correspondence: Frank C. Detterbeck, MD, Division of Thoracic Surgery, Yale University School of Medicine, 330 Cedar St., BB 205, New Haven, CT frank.detterbeck@ yale.edu Copyright 2009 by the International Association for the Study of Lung Cancer ISSN: /09/ defined. While many measures can be considered, the one most commonly used is prognosis. Indeed, this is the primary end point used in the analysis and staging recommendations of the IASLC staging committee. 2,6,7 Another common expectation of a staging system is to define patient cohorts for which the same treatment approach is appropriate. However, it must be recognized that prognosis and treatment approaches are not static. There is an incessant quest to define treatments that lead to better outcomes. Moreover, prognosis is continually changing due to progress in aspects other than treatment. Advances in imaging affect the prognosis of stage groups through the resultant stage migration. 8,9 Changing methods of detection (e.g., computed tomography screening) also affect prognosis by altering the spectrum of disease that is encountered. 10 Therefore, grouping patients by prognosis alone carries the risk that some patients will be grouped together because they happen to have the same prognosis at the current time, even though they are inherently different. For example, within stage IIIa the IASLC staging revision groups together patients with N2 involvement, those with a T4N0M0 tumor and those with additional nodules of cancer in a different ipsilateral lobe. 2 As we explore new treatment approaches, we may find that the optimal treatment and resultant prognosis for subpopulations of patients within a stage group or even a T,N, and M descriptor group may be divergent. The ideal stage classification system would reflect the biology of the tumor, because patients grouped by tumor biologic characteristics will probably continue to share many similarities even as treatment approaches, staging procedures and outcomes change. This suggests that classification by molecular biologic characteristics may be more useful than by anatomic characteristics. However, our current ability to predict tumor biology is rudimentary, and we have a poor understanding of which biologic characteristics of a tumor are really the key factors There was no choice for the IASLC staging committee but to describe patient cohorts using anatomic characteristics. Nevertheless, as we look to the future we should use whatever means we currently have available to define biologic behavior. This article proposes a categorization of lung cancer by patterns of clinical presentation, which are postulated to reflect biologic behavior. This approach has the advantage that it can be used with the currently available anatomic descriptors as defined by the proposed IASLC stage classification system, which are summarized in Tables 1 and 2. Journal of Thoracic Oncology Volume 4, Number 4, April

2 Detterbeck et al. Journal of Thoracic Oncology Volume 4, Number 4, April 2009 TABLE 1. Definitions for T,N,M Descriptors in the IASLC Staging Classification a TNM Descriptions Subgroup b T (Primary Tumor) T0 No primary tumor T1 Tumor 3 cm c, surrounded by lung or visceral pleura, not more proximal than the lobar bronchus T1a Tumor 2 cm c T1a T1b Tumor 2 but 3 cm c T1b T2 Tumor 3 but 7 cm c or tumor with any of the following d : Invades visceral pleura, involves main bronchus 2 cm distal to the carina, atelectasis/obstructive pneumonia extending to hilum but not involving the entire lung T2a Tumor 3 but 5 cm c T2a T2b Tumor 5 but 7 cm c T2b T3 Tumor 7 cm c T3 7 or directly invading chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, T3 Inv or tumor in the main bronchus 2 cm distal to the carina e, T3 Centr or atelectasis/obstructive pneumonitis of entire lung, T3 Centr or separate tumor nodule(s) in the same lobe T3 Satell T4 Tumor of any size with invasion of: heart, great vessels, trachea e, recurrent laryngeal nerve, esophagus, T4 Inv vertebral body, or carina e ; or separate tumor nodule(s) in a different ipsilateral lobe T4 Ipsi Nod N (regional lymph nodes) N0 No regional node metastasis N1 Metastasis in ipsilateral peribronchial and/or perihilar lymph nodes and intrapulmonary nodes, including involvement by direct extension N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph node(s) M (distant metastasis) M0 No distant metastasis M1a Separate tumor nodule(s) in a contralateral lobe; M1a Contr Nod or tumor with pleural nodules or malignant pleural dissemination f M1a Pl Dissem M1b Distant metastasis M1b Special situations: TX, NX, MX T, N, or M status not able to be assessed Tis Focus of in situ cancer Tis T1 e Superficial spreading tumor of any size but confined to the wall of the trachea or mainstem bronchus T1 SS a Reflects the IASLC staging Committee s recommendations and not necessarily the UICC 7th Edition Staging System. b These subgroup labels are not defined in the IASLC publications, but are added here to facilitate a clear discussion. Goldstraw et al., J Thorac Oncol 2007;2: ; Rami-Porta et al., J Thorac Oncol 2007;2: ; Postmus et al., J Thorac Oncol 2007;2: ; Rusch et al., J Thorac Oncol 2007;2: c In greatest dimension. d T2 tumors with these features are classified as T2a if 5 cm. e The uncommon superficial spreading tumor in central airways is classified as T1. f Pleural effusions are excluded that are cytologically negative, nonbloody, transdative, and clinically judged not to be due to cancer. IASLC, International Association for the Study of Lung Cancer; TNM, tumor, node, metastasis. Proposed Categories of Biologic Behavior Because our understanding is limited, an attempt at characterization of tumors according to biologic behavior is inherently speculative. We postulate that there are four types of biologic behavior: tumors with a primary propensity for direct local invasion, those with a propensity for spread to regional lymph nodes, those with a propensity to develop additional foci of cancer within the lung(s), and those with a propensity for systemic dissemination (Table 3). These categories fit commonly observed patterns of clinical presentation, e.g., patients presenting with large tumors and no metastases, others with small tumors and metastatic deposits in nodes and/or distant sites, and patients with multiple foci of cancer within the lung parenchyma in the absence of any extrapulmonary involvement. In Table 4 the new IASLC stage groups and tumor, node, metastasis descriptors are depicted aligned according to these clinical patterns. Categorization according to patterns of clinical presentation may be an important concept that allows us to recognize differences among patients within a stage grouping and similarities among patients in different groups. In Table 4, the patterns of presentation (and the presumed patterns of biologic behavior) are aligned vertically, while the stage groupings are aligned horizontally. This underscores that some stage groups combine patients with very different clinical presentations, and that there are similarities between subgroups of patients that belong to different stage groups. 438 Copyright 2009 by the International Association for the Study of Lung Cancer

3 Journal of Thoracic Oncology Volume 4, Number 4, April 2009 Anatomy, Biology and Concepts TABLE 2. Stage Groups in the IASLC Staging Classification a Stage group T N M I Ia T1a,b N0 M0 Ib T2a N0 M0 II IIa T1a,b N1 M0 T2a N1 M0 T2b N0 M0 IIb T2b N1 M0 T3 N0 M0 III IIIa T1 3 N2 M0 T3 N1 M0 T4 N0,1 M0 IIIb T4 N2 M0 T1 4 N3 M0 IV T Any N Any M1a,b a Reflects the IASLC staging Committee s recommendations and not necessarily the UICC 7th edition staging system. IASLC, International Association for the Study of Lung Cancer; TNM, tumor, node, metastasis. TABLE 3. Cancer Proposed Patterns of Biologic Behavior of Lung Tumors marked by: Propensity for local growth/invasion Propensity for lymph node involvement Propensity for multifocal disease in lung parenchyma Propensity for systemic dissemination Attempting to predict biologic behavior is fraught with more uncertainty than identifying clinical patterns of presentation. It seems reasonable, however, to use characteristics observed in individual tumors at presentation to estimate the future behavior. In very early tumors, there may be insufficient growth or development to form the basis for a prediction. In tumors presenting somewhat later in their development we think that the predominant pattern observed at presentation may well predict future behavior. Anatomic descriptors remain the most studied aspects of lung cancers, and are the only characteristics for which data exists in a large number of patients. Furthermore, the proposed categorization shown in Table 4 has the advantage that it is readily applicable around the world (without genomic analysis). Therefore it seems that this might be a useful tool to investigate how well we are able to predict biologic behavior. There is ample clinical experience indicating that some tumors primarily grow and invade locally, and seem to have a diminished propensity for nodal or systemic dissemination. Many reports substantiate that patients with local invasion of additional structures exhibit good survival after resection, particularly when a complete resection is accomplished. The good outcome with local therapy alone corroborates the postulated decreased propensity for dissemination. A common example are tumors invading the chest wall (consistent 50 60% 5 years survival for T3N0M0 tumors after R0 resection). 14 Good survival has been reported after complete resection of T4 inv N0M0 tumors invading the vertebral column or carina However, much of the data is difficult to interpret because of inclusion of patients with nodal involvement and incomplete resections. In the extensive database of the IASLC staging project, the good survival of patients with locally invasive or large tumors without significant nodal involvement was clearly documented. In summary, although there may be difficulties in the ability to deliver effective local therapy to tumors marked by local invasion, there is data to support the postulated decreased propensity for nodal or systemic metastases in this subgroup. Patients with tumors involving lymph nodes seem to have a higher propensity for both regional and systemic recurrence. Treatment increasingly involves both more aggressive local therapy as well as more aggressive systemic therapy. This includes adjuvant chemotherapy after completely resected stage II(N1) and IIIa(N2) tumors, exploration of the role of surgery in addition to chemotherapy and radiotherapy in stage IIIa(N2), and the use of high dose three-dimensional conformal radiotherapy together with chemotherapy for stage III(N2,3) tumors. 22 The category that is the most obviously distinct, yet also the hardest to accurately define, are the patients with additional nodules of tumor in the lungs. It has long been recognized that a satellite focus of cancer in the same lobe carries a good prognosis, only slightly different than that of the same tumor without a satellite Similarly, multiple studies have suggested relatively good outcomes for patients with an additional focus of tumor in an ipsilateral different lobe, clearly better than for patients with other forms of distant spread. 23,25 30,32,33 Frequently such patients have multiple additional malignant foci in the lungs. 27,28,33,34 An extreme example of this process may be those patients with what is termed a pneumonic type of adenocarcinoma, meaning diffuse involvement of a portion of the lung parenchyma A mechanism for how such spread occurs is not readily apparent, but the clinical observations do not seem to fit the concepts of either lymphatic or hematogenous dissemination. It appears that a better concept for the behavior of these tumors is not spread from one area to another, but the development of multifocal disease. This may be due to field cancerization, or it may be a yet obscure change in the host microenvironment that sets the stage for this pattern of tumor development. These tumors appear to have a lower propensity for nodal involvement or distant dissemination. 29,33,37 40 Data regarding the proportions of patients entered into the IASLC database (Table 5) shows that the majority of patients fall into the category defined by the extent of nodal involvement (57%). A smaller group is characterized by the extent of the primary tumor (28%). The patients whose stage is characterized by the presence of additional nodules of tumor account for only a small proportion (2.5%). Although a population-based registry is needed to define the true Copyright 2009 by the International Association for the Study of Lung Cancer 439

4 Detterbeck et al. Journal of Thoracic Oncology Volume 4, Number 4, April 2009 TABLE 4. Stage Group IASLC Stage Grouping Aligned by Patterns of Biologic Behavior a Local Growth and Invasion Nodal Involvement Multifocal Disease (Additional Nodules) T N T N T N I a T1a,b N0 M0 I b T2a N0 M0 II a T2b > 5 N0 M0 T1a,b N1 M0 T2a N1 M0 II b T2b > 5 N1 M0 T3 b inv,> 7 N0 M0 T3 Satell N0 M0 III a T3 b inv,> 7 N1 M0 T4 inv N0,1 M0 T1 3 Any N2 M0 T3 Satell N1 M0 T4 Ipsi Nod N0,1 M0 III b T4 inv N2 M0 T1 4 Any N3 M0 T4 Ipsi Nod N2 M0 Systemic Dissemination IV M1a c Contr Nod M1a c PlDissem M1b c a Reflects the IASLC staging Committee s recommendations and not necessarily the UICC 7 th Edition Staging System. b T3 Cent is included whenever T3 inv is denoted; it is not separately recorded in order to simplify the table. c Any T, Any N. M incidence of these categories of patients, the IASLC database provides a rough estimate of the proportions. This rough estimate points out that the impression of complexity in the IASLC staging system is created primarily by relatively small subsets of patients. DISCUSSION A critical examination of accepted clinical concepts is important because so much of how we approach patients, and even how we conduct research, is driven by preconceived beliefs (often in the absence of data). Viewing the IASLC stage subgroups from the perspective of patterns of clinical presentation has several potential benefits. There is reason to think that these patterns of clinical presentation may well correlate with biologic behavior of the tumor. This categorization may have implications for the relevance of local and systemic therapies as well as of specific pretreatment staging procedures. It may turn out that a particular treatment strategy that addresses a pattern of biologic behavior may be useful for many patients within a vertical category outlined in Table 4, even though the patients fall within different stage groups. We should consider these concepts as we analyze the results of new treatments so that we do not overlook an observation because we are focused only on horizontal stage groups as a whole. What exactly is meant by biologic behavior of a tumor? From a clinical standpoint, the relevant issues are the rapidity of growth of the tumor and the pattern of spread into adjacent organs or distant sites. By definition, a cancer has the ability to grow in an unlimited fashion, to invade other normal tissues, and/or to metastasize and grow in sites distant from the primary tumor. It is the aggressiveness of the tumor and the pattern of dissemination that have the greatest influence on prognosis and on the general approach to treatment. On a cellular level, biologic behavior includes the genetic, regulatory and metabolic factors that determine cellular growth. It also includes the interactions between tumor cells, the local tissue microenvironment and the host in general. We have by necessity focused on the macroscopic aspects of tumor biology rather than cell signaling or genomic aspects. Clearly major advances are being made into understanding cellular mechanisms of tumor growth At present, however, these insights are limited to small groups of patients. More importantly, characterization of tumors by cellular biologic features requires sophisticated laboratory analysis, and thus from a practical standpoint is not easy to incorporate in clinical practice. Furthermore, cellular biologic features are not currently readily grafted onto the lung cancer staging system, which remains grounded in anatomic features. This is not meant to imply that molecular biologic 440 Copyright 2009 by the International Association for the Study of Lung Cancer

5 Journal of Thoracic Oncology Volume 4, Number 4, April 2009 Anatomy, Biology and Concepts TABLE 5. Relative Proportion of IASLC Stage Grouping by Patterns of Biologic Behavior a Stage Group I a I b TNM Classification T1a,b N0 M0 T2a N0 M0 II a T2b 5 N0 M0 4 T1a,b N1 M0 T2a N1 M0 Relative Proportion (% of all patients) b Tumor Extent Nodal Involvement Multifocal (Add l Nodules) Systemic Dissemination II b T2b 5 N1 M0 2 T3 c inv,> 7 N0 M0 13 T3 Satell N0 M0 0.6 III a T3 c inv,> 7 N1 M0 6 T4 inv N0,1 M0 2 T1 3 Any N2 M0 20 T3 Satell N1 M0 0.3 T4 Ipsi Nod N0,1 M0 0.4 III b T4 Inv N2 M0 1 d T1 4 Any N3 M0 3 e T4 Ipsi Nod N2M0 0.3 IV M1a f Contr Nod 0.9 M1a f Pl Dissem 3 M1b f 10 Total (%) a Reflects the IASLC staging Committee s recommendations and not necessarily the UICC 7 th Edition Staging System. b Proportion of patients in IASLC database as defined by best stage (pathologic, if available, otherwise clinical). 2 Values are a percentage, rounded to the nearest integer (or nearest 10th when less than 1). This incidence of patients within the IASLC database does not necessarily represent the true incidence of each stage group, because the data came from a variety of source types, and exclusion criteria may have disproportionately excluded more patients in certain subgroups (e.g. incomplete data may be more common among M1 patients). c T3 Cent is included whenever T3 inv is denoted; it is not separately recorded in order to simplify the table. d Including T4N3M0. e Excluding T4N3M0. f Any T, Any N characterization is less important; in fact it may become the dominant factor at some point in the future. It is simply less broadly applicable across the world and less readily applicable to the lung cancer stage classification system at this time. Adding biologic categorization to the anatomic grouping of the staging system may be most helpful in patients in the stage III group. These patients comprise a large percentage of patients with NSCLC and a group whose optimal care has been particularly difficult to define, perhaps because stage III includes a variety of T and N subgroups. The clinical pattern of presentation may help guide the selection of appropriate treatment. For example, an extensive surgical resection may be curative for a T4 Inv N0M0 tumor but less beneficial in patients with a T1-3N2M0 tumor. Conversely systemic treatment with a new targeted agent may be of benefit in patients with a T1-3N2M0 tumor but not for those with a T4 Inv N0M0 tumor. A limited (sublobar) resection may be of value for a T4 Ipsi Nod N0M0 tumor but not a T1N2M0 tumor. There is reason to consider a propensity for nodal involvement separately from a propensity for distant metastases. Although increasing nodal stage is clearly associated with an increased incidence of distant metastases, dissemination via the lymphatic system is no longer considered the mechanism for the development of distant metastases. Clinical experience certainly documents many patients who develop distant metastases after an apparent curative resection, but never have any evidence of nodal involvement. Multiple studies have shown that tumor cells are commonly present in the bone marrow or peripheral blood, even in patients with early stage lung cancer, when assessed by sensitive assays Moreover, the ability to detect these cells does not correlate with the nodal stage, although it is significantly associated with a higher distant recurrence rate The development of metastases is determined by a complex interplay of characteristics of the tumor cell population, the host microenvironment and the interactions between them. 50 It is best to consider a propensity for nodal involvement and for systemic metastases separately, although both factors may be at play in many patients. The proposed categorization within the IASLC stage groupings seems logical when dealing with tumors at the ex- Copyright 2009 by the International Association for the Study of Lung Cancer 441

6 Detterbeck et al. Journal of Thoracic Oncology Volume 4, Number 4, April 2009 tremes (e.g., a T1N3M0 or a T4 Inv N0M0 tumor), but it is less obvious how some other subgroups should be viewed. For example, should a T4 Inv N2M0 (stage IIIb) tumor be categorized predominantly by the invasive nature of the primary tumor or by a propensity for lymphatic involvement? In this example there may be a difference between direct extension of the primary tumor into a node versus spread to noncontiguous nodes via lymphatic channels. The same reasoning may be applicable to T2b 5 N1M0, T3 Inv N1M0 and T4 Inv N1M0 tumors: i.e., there may be a difference between direct lymph node invasion and involvement of noncontiguous nodes. Another group of patients in whom the clinical presentation does not lend itself easily to speculation about the biologic behavior are those patients with multifocal disease as well as node involvement. For T3 Satell N1M0orT4 Ipsi N1M0 tumors it is easier to accept the multifocal characteristic as being the most distinctive feature. However, patients with a T4 Ipsi N2M0 tumor may be much more likely to actually have multiple metastases, with the additional parenchymal nodule being the only distant site that was apparent at presentation. 23,24 In other words, such patients may, in fact, turn out to fit better with patients with a propensity for nodal and for systemic spread, similar to the T1-3 Any N2M0 or T Any N Any M1b patients. Reclassifying such patients in this manner, however, is in conflict with the IASLC staging committee s findings and recommendations. Furthermore, only a minority of patients with additional pulmonary foci of cancer present with N2 nodal involvement. 2,29 Therefore, it seems most appropriate to view the T4 Ipsi N2M0 patients among other patients with multifocal disease and as a subgroup of stage IIIb, consistent with the IASLC staging committee s recommendations, at least until significant data is generated that supports a different view. Whether pleural dissemination should be viewed as a form of direct invasion, of multiple nodules or of distant dissemination is also unclear. It may be that there are different types of patients with pleural involvement (e.g., those with otherwise limited disease and no effusion but with several visceral pleural nodules, and those with a malignant pleural effusion, who often have large tumors with significant nodal involvement). The fact that patients with pleural dissemination but no nodal metastases have exhibited good survival after resection (25 30% 5 year survival) corroborates this speculation. 3,51 However, most patients with pleural dissemination have extensive tumors, multiple metastases, and poor survival. Therefore, we think it is best to consider these patients as having a form of distant metastatic spread, at least until we can develop a valid way to subclassify them. Other methods of defining the biologic behavior of a lung cancer do not appear to be close to being ready for clinical application. There have been many reports that positron emission tomography (PET) intensity correlates with prognosis, suggesting that PET intensity may be a marker for the metabolic rate of a tumor as well as the propensity to metastasize. 52 However, these studies have generally not accounted for other prognostic factors such as tumor size or stage. The only carefully controlled, prospective study found that PET intensity offers no significant independent prognostic information, and that size and stage are the dominant factors. 11 Much attention has also been given to characterization of genetic changes in tumor cells. 53,54 However, most of the studies have had significant methodological flaws, and clinical application appears elusive. 55 Furthermore, different studies have identified different genes as predictive of the same outcome with only rare overlap. 56 In general, the prognostic prediction based on genetic characterization does not outperform conventional clinical and pathologic factors at this time. 12,56 The IASLC staging committee also considered this issue, and concluded that molecular characterization of tumors was insufficiently studied to be included in the current staging revision. 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