Context.—Lung cancer is the leading cause of cancer mortality worldwide. Despite technological, therapeutic, and scientific advances, most patients present with incurable disease and a poor chance of long-term survival. For those with potentially curable disease, lung cancer staging greatly influences therapeutic decisions. Therefore, surgical pathologists determine many facets of lung cancer patient care.
Objective.—To present the current lung cancer staging system and examine the importance of mediastinal lymph node sampling, and also to discuss particularly confusing and/or challenging areas in lung cancer staging, including assessment of visceral pleura invasion, bronchial and carinal involvement, and the staging of synchronous carcinomas.
Data Sources.—Published current and prior staging manuals from the American Joint Committee on Cancer and the International Union Against Cancer as well as selected articles pertaining to lung cancer staging and diagnosis accessible through PubMed (National Library of Medicine) form the basis of this review.
Conclusions.—Proper lung cancer staging requires more than a superficial appreciation of the staging system. Clinically relevant specimen gross examination and histologic review depend on a thorough understanding of the staging guidelines. Common sense is also required when one is confronted with a tumor specimen that defies easy assignment to the TNM staging system.
THE STAGING SYSTEM
Lung cancer staging is not the most exciting topic in lung pathology, but its importance cannot be overstated. The pathologic staging of lung tumors aids clinicians in determining optimal patient treatment, allows for reasonable prognostication, and facilitates comparisons between patient groups in clinical studies. Current investigations into early detection and adjuvant chemotherapy for early lung cancer rely heavily on proper staging of the patient's tumor. In addition, the pathologist's staging abilities reflect strongly on his or her perceived competency. Although many pathologists believe that staging is the clinicians' responsibility, many departments and all cancer programs that are approved by the Commission on Cancer of the American College of Surgeons include TNM designations in diagnostic reports.1
The international staging system for lung cancer was developed for the 1987 TNM classification and revised in 1997.2,3 This system, which is accepted by the International Union Against Cancer and the American Joint Committee on Cancer (AJCC), is based on more than 5000 clinically and pathologically staged patients followed for at least 5 years.3 Regional lymph node station classification was also standardized in 1997 (Table 1).4
This staging system is, in general, a universally valid and reproducible prognostic and investigational tool. The most recent revisions from 1997 concerned stage groupings. Stage I was split into IA and IB, stage II into IIA and IIB, and T3 N0 M0 patients were reassigned from stage III to IIB. The 1997 classification also restaged satellite tumor nodule(s). Although it is not perfect, shortcomings and new prognostic indices will be addressed and revisions will be suggested by the International Association for the Study of Lung Cancer Staging Committee in the coming months.5,6
Although surreal, the largest problem with the current staging system is deciphering if, when, and where pathologic findings belong in the system. The revised 1997 staging guidelines are confusing, stating, “Most patients are not treated surgically, and elements that can be determined only from pathologic examination of resected specimens are not included in the definitions and stage grouping rules.” 3
This statement seems to exclude the very tissue samples required for accurate patient staging and has great implications for the pathologic staging of synchronous carcinomas in lung cancer resections. The current AJCC manual mirrors these comments, despite the fact that, by convention, clinical staging (cTNM) is performed before definitive treatment with all available clinical tools.7,8 The International Association for the Study of Lung Cancer Staging Committee should clarify this issue.
Pathologic staging (pTNM) is based on gross and microscopic examination of the tumor and additional tissue submitted for examination. This is usually established on the entire resection specimen, but may be designated on a biopsy specimen if that tissue is adequate to evaluate the highest pT category. The pN category requires evaluation of lymph nodes that is adequate to document the presence or absence of nodal metastases, and the pM category requires histologic confirmation of metastatic disease. Although this TNM system can be applied to small cell carcinoma, most thoracic surgical, medical, and radiation oncologists prefer the Veterans Administration Lung Study Group System, which assigns patients to either limited-stage or extensive-stage disease categories.9
According to the AJCC staging system, primary lung carcinomas are subdivided into 4 categories (T1 to T4) depending on size, location, and other findings. Lymph nodes are identified according to anatomic location, and involvement is divided into bronchopulmonary (N1), ipsilateral mediastinal (N2), and contralateral mediastinal or supraclavicular disease (N3). Metastases are designated as M1 (Table 1).
Although it is no surprise to surgical pathologists that pathologic staging is more reliable than clinical staging, the assigned pathologic stage is only as good as the patient's surgeon and the surgeon's pathologist.10,11 The status of thoracic lymph nodes is the main determinant of outcome for patients with resectable lung cancer, but a recent Commission on Cancer of the American College of Surgeons study, which included more than 11 000 surgically treated lung cancer patients, reported that only 27% of surgical patients had preoperative mediastinoscopy, only 47% of those had mediastinal nodal biopsies, and that a surprisingly low percentage (58%) of all surgical patients had mediastinal lymph node sampling during surgery (Figure 2, A and B).12
The International Union Against Cancer TNM Classification of Malignant Tumours states that a classification of pN0 requires histologic examination of at least 6 hilar and mediastinal lymph nodes, but adds that if fewer than 6 lymph nodes are sampled and are negative, the nodal status should be classified as pN0.13 Thus, an Nx designation can be reported only in resections without nodal sampling. The International Association for the Study of Lung Cancer Staging Committee, however, suggests that the pathologist should dissect and histologically examine intrapulmonary and hilar nodes, and the surgeon should sample at least 3 mediastinal nodal stations, depending on the lobar location of the carcinoma.14
Whether complete mediastinal lymphadenectomy, as opposed to nodal sampling, becomes the recommended treatment will depend on the results of the American College of Surgeons Oncology Group multicenter trial Z0030, which is 4 to 5 years from completion. According to early results from this trial, mediastinal lymph node dissection does not result in higher morbidity or mortality, as compared with mediastinal lymph node sampling.15 Although it is uncertain how many lymph node stations and total number of lymph nodes should be examined, from a staging perspective, the more extensive the sampling, the greater the likelihood that patients will be “upstaged.” 16,17 More extensive sampling also results in better survival rates for each stage and more accurate data for clinical research studies.18
Although pathologists have no control over the astounding number of lung cancer resections that are performed without nodal sampling, the 1996 College of American Pathologists “Q-Probes study of lung carcinoma surgical pathology report adequacy” listed ways pathologists contribute to inadequacies in lung cancer staging.19 More than 8300 reports from 464 institutions noted that 10% of reports lacked a procedural type, 3% lacked a tumor size, 25% of gross descriptions did not mention regional lymph nodes, and the status of lymph nodes was not stated in 4% of reports. These results empowered both the College of American Pathologists and the Association of Directors of Anatomic and Surgical Pathology to publish practice protocols.20,21 Uniform reporting (ie, checklists or synoptic reports) may be unpleasant for many pathologists, but certain data must be included in lung cancer pathology reports. In many instances, deciding whether a carcinoma involves visceral pleura, comes within 2.0 cm of the carina, or has metastasized within the lungs can be problematic. The remainder of this article addresses these issues.
ASSESSING THE VISCERAL PLEURA
Remarkably, 17% of reports from lung resection specimens reviewed in the College of American Pathologists study did not describe the visceral pleura and 33% of reports did not comment on the presence or absence of visceral pleural involvement by carcinoma. These results, combined with the recent explosion of publications on this topic, highlight the importance of visceral pleural invasion in lung cancer staging.
The visceral pleura is a complex anatomic structure with five histologic layers that blur in the presence of underlying lung disease (Figure 3). A single layer of mesothelial cells without a basement membrane rests on a submesothelial layer of loose connective tissue, approximately as thick as the mesothelial cell layer. The third layer is a well-defined elastic layer (external elastic lamina) and the fourth layer is the interstitial or loose connective tissue layer containing lymphatics, large capillaries, and collagen. The final layer is composed of elastic fibers (internal elastic lamina) and fibrous tissue that merges with underlying lung.22
Even the earliest TNM lung cancer staging system recognized that carcinoma involving the visceral pleura was a significant adverse prognostic finding, and the T category reflects this fact.23 Visceral pleural invasion in carcinomas that are 3.0 cm or less in size increases the pT category from T1 to T2, and thus increases the stage designation from IA to IB, or IIA to IIB. Survival rates differ for these subgroups, and in some centers adjuvant chemotherapy is offered to patients with T2 lesions.24 Recent evidence also suggests that pT2 carcinomas larger than 3.0 cm with visceral pleural invasion behave similarly to pT3 tumors.25
Complaints that the AJCC staging system lacks a definition of “pleural invasion” are misplaced.26–30 Although one can certainly criticize that staging system for its complete silence on interlobar pleural invasion—whether such cases should be designated T2 or T3 is unknown31–33 (Figure 4)—an explanation of pleural invasion is not at all necessary. Invasion into visceral pleura means just that. The classification of visceral pleural invasion proposed by Hammar,34 which was first presented in 1988 and later co-opted by the Japan Lung Cancer Society,35 separates visceral pleural invasion into cases in which tumor invades into but not through visceral pleura (p1) and cases in which tumor penetrates to the visceral pleural surface without involvement of parietal pleura (p2). This subclassification may appear more informative than simply noting the presence or absence of pleural invasion, but recent studies have demonstrated that there is no prognostic difference between tumors that invade into and those that invade through visceral pleura.26,28 In fact, visceral pleural invasion not otherwise specified is associated with a higher frequency of lymph node involvement.27,36–38 One hopes that the College of American Pathologists and the Association of Directors of Anatomic and Surgical Pathology consider these findings when revising their lung specimen–reporting protocols.
Academic arguments aside, the evaluation of pleural invasion can be difficult or impossible owing to distortion of the pleura and/or fibroelastotic change associated with many peripheral lung carcinomas.39 In specimens with visible pleural pathology, including puckers and adhesions, the entire abnormal area should be submitted for histologic evaluation. When reactive pleural fibrosis overlies a carcinoma, the low-magnification impression of uninvolved visceral pleura may be erroneous (Figure 5, A). Although carcinoma appears to be several millimeters from the pleura, tumor cells may actually infiltrate the pleura (Figure 5, B and C).40 Because local angiolymphatic invasion and single-cell spread beneath the pleura are suggested morphologic predictors of visceral pleural invasion,29 serial sections and deeper levels of tissue blocks in these areas are recommended. Lowering the microscope condenser in order to highlight the elastic tissue layer can be helpful.
Hematoxylin-eosin–indeterminate cases should be further studied with elastic tissue stains (Figure 6, A through C). In one retrospective study, 10% of hematoxylin-eosin– indeterminate cases were resolved with an elastic tissue stain.29 Infiltration through the elastic layer can be demonstrated with Movat or Verhoeff-van Gieson stains. Tumor cells can penetrate individually or in small clusters and, as a consequence, the internal elastic lamina can be distorted, displaced, or retracted, or penetrated and destroyed. Desmoplastic response accompanying tumor infiltration is rarely appreciated on hematoxylin-eosin– stained sections, but elastic tissue stains may demonstrate elastic duplication or fusion of the internal and external elastic laminae. In these instances, it may be very difficult or impossible to discern visceral pleura from underlying fibroelastotic lung and, consequently, impossible to unequivocally diagnose visceral pleural invasion.
Intraoperative pleural lavage or postsurgical pleural saline rinses appear to offer results when traditional histomorphology fails.41–48 Data suggest that both methods are highly sensitive and specific for pleural invasion and detect pleural invasion in a significant number of cases lacking histologic evidence, but the results of multi-institutional trials (Cancer and Leukemia Group B 159902: “Markers of Pleural Involvement in Non–Small Cell Lung Cancer” and American College of Surgeons Oncology Group Z40040: “Prognostic Significance of Occult Metastases in Non–Small Cell Lung Cancer”) are not yet known.49 The labor-intensive nature of specimen procurement and the need for immunohistochemical stains to differentiate mesothelial cells from carcinoma also dampen enthusiasm for this modality.
ASSESSING BRONCHIAL AND CARINAL INVOLVEMENT
Bronchial involvement by carcinoma of any size ensures at least pT2 designation, except for superficial spreading tumors with invasion confined to the bronchial wall (which would be designated as pT1). If the tumor comes within less than 2.0 cm of the carina, a pT3 designation is applied, and carinal involvement necessitates a pT4 assignment. In these instances, preoperative or intraoperative bronchoscopy provides an exact location of the carcinoma and biopsies are often used to delineate the extent of disease.
Several comments regarding bronchial anatomy are warranted. Although staging manuals illustrate symmetric right and left main bronchi, the right main bronchus is usually less than 2.0 cm in length and the right upper lobe bronchus can even be at the carina. Thus, virtually all right main bronchial and many right upper lobe bronchial tumors are T3 lesions. Because the left main bronchus is usually longer than the right, these main and lobar bronchial tumors may be T2 lesions.
Only when handling a pneumonectomy specimen can one definitely comment on whether a carcinoma involves a main bronchus. But even in these circumstances, it may be impossible to ascertain from the specimen whether the tumor comes within 2.0 cm of the carina. With some parenchyma-sparing operations, such as sleeve lobectomy, the pathologist cannot comment on either main bronchial involvement or tumor distance from the carina. The surgeon should be consulted before assigning a T category; however, one should recognize that complete surgical resection and nodal status, rather than the T category, are the most important determinants of long-term survival in such cases.50,51
Superficial spreading tumors of any size involving segmental, lobar, or main bronchi 2.0 cm or more from the carina with invasion limited to the bronchial wall are pT1 lesions, unless the tumor causes atelectasis or obstructive pneumonitis, which would necessitate a T2 designation if incomplete or T3 if involving the entire lung. Although several studies reported 5-year survival rates of at least 75% for superficial spreading, node-negative tumors less than 2.0 cm from the carina, these lesions are classified as pT3, and carinal involvement necessitates a pT4 designation (Figure 7).30,52,53 As long as these carcinomas do not invade into mediastinal structures, invasion into peribronchial adipose tissue does not require a T4 designation. Many true early hilar lung cancers are cured with complex surgical resections.54,55
In all these instances, pathologists should be prepared to perform and interpret frozen sections of surgical margins and should be aware that salivary gland tumors and, occasionally, carcinoid tumors have the highest incidence of positive margins.56 With non–small cell lung cancers, the pattern of involvement most likely to be encountered at frozen section is mucosal involvement, but one should also search for submucosal, lymphatic, and peribronchial carcinoma. In situ carcinoma, unlike microscopic invasive or peribronchial disease at the margin, has a negligible effect on survival.50,51,57,58
STAGING SYNCHRONOUS CARCINOMAS
The staging of cancers from patients with incidental satellite tumor nodules is by far the most confusing and weakest aspect of the International Union Against Cancer and AJCC staging system. Rules are difficult to interpret, our ability to discern intrapulmonary metastases from synchronous carcinomas is suspect, and stage designations may not accurately reflect the natural history of these cancers.
Perhaps this entire issue serves as a good example of medical progress. The current staging system predates the technological advances that facilitated computed tomography lung cancer screening protocols. In the late 1980s and early 1990s, the incidence of synchronous lung tumors was 0.5% to 2.0% and satellite nodules were associated with large (>6.0 cm) central tumors.59–62 However, up to 25% of patients with computed tomography–detected carcinomas, most of which are smaller than 3.0 cm, have more than one tumor in their resection specimen.33,63,64
In earlier versions of the AJCC staging system, a patient with a T1 tumor that was found to have a satellite lesion in the same lobe was upstaged to T2, while additional nodules in another ipsilateral lobe qualified as T4.65 The current classification designates the presence of satellite tumor nodule(s) in the primary tumor–bearing lobe as pT4 (stage IIIB) or an ipsilateral non–primary tumor-bearing lobe as M1 (stage IV) (Figure 1, F and G; Table 1). As previously discussed, the lung staging rules do not include pathologic findings in the definitions and stage grouping rules.3 Thus, there is uncertainty as to whether incidental tumors identified at either gross examination or under the microscope should be included in the TNM designation. The AJCC manual offers some guidance in its Pathologic Staging section: “Multiple synchronous tumors should be considered separate primary lung cancers, and each should be staged separately. … Synchronous tumors may be identified according to the criteria originally proposed by Martini and Melamed.7 ”
Although this sounds simple, the 1975 Martini and Melamed61 criteria are empirical and based on only 7 synchronous squamous cell carcinomas and a single resection with synchronous adenocarcinomas (Table 3).
Intrapulmonary metastases are thus defined as (1) tumors with the same histology, (2) located in at least different lobar segments, (3) demonstrating carcinoma in lymphatics common to both tumors, (4) lacking an in situ component, and (5) occurring in the setting of extrapulmonary metastases.
Because adenocarcinomas are histologically heterogeneous, one may not be comfortable suggesting that 2 carcinomas with unequal percentages of acinar, papillary, solid, or lipidic growth patterns are “related” 66 (Figure 8, A through D). Furthermore, in situ adenocarcinoma of the lung is not nearly as well defined as in situ squamous cell carcinoma. Lastly, the identification of lymphatic invasion is often a fortuitous finding, and it is uncertain how vigilantly one should search for a feature that lacks statistical significance with regard to resolving the issue of synchronous adenocarcinomas.67
Molecular studies assessing the clonality of synchronous lung cancers offer a more precise method of discerning intrapulmonary metastases from synchronous primaries, but are not yet practical ancillary tests. Studies focusing on the loss of heterozygosity demonstrate that synchronous, histologically similar adenocarcinomas of the lung represent a very heterogeneous group at the genetic level.67–70 Although tumors that are molecularly homogeneous most likely represent intrapulmonary metastases, the nature of heterogeneous tumors is unclear because of the uncertainty as to whether heterogeneity is a consequence of multiple tumor clones or genetic instability continuing after metastatic spread of a primary single clone. It is hoped that large multicenter studies will standardize microsatellite markers and the definition of homogenous and heterogeneous tumors on the basis of percentage of discordance, as well as elucidate the relationship between tumor genotype and clinicopathologic characteristics and prognosis. In the future, gene expression profiling may become clinically useful.71,72
Thankfully, clinicians recognize the shortcomings of these designations.73–80 Most lung cancer patients with T4 or M1 tumors on the basis of intrapulmonary metastases are treated with surgery and have better outcomes than lung cancer patients with “traditional” stage IIIB or IV tumors (eg, tumors that are designated as T4 on the basis of invasion of mediastinal structures). Published literature on synchronous lung tumors indicate 5-year survival rates of 17% to 67% (including both T4 and M1 lesions), which are higher than those expected for traditional T4 (stage IIIB) or M1 (stage IV) diseases, with reported survival rates of 7% and 1%, respectively (Figure 9, A and B). Also, there may not be a survival difference between patients with synchronous tumors in one lobe or those with an intrapulmonary metastasis in a non–primary tumor-bearing lobe.75 Prognosis in these cases may depend on the presence or absence of lymph node involvement.81
Our confidence in applying staging criteria to patients with multiple tumors suffers another blow when faced with multifocal bronchioloalveolar carcinoma. The 1997 staging system predates the 1999 World Health Organization revised definition of bronchioloalveolar carcinoma and therefore lacks supporting data and authority. The 2002 AJCC staging manual acknowledges this, yet does not suggest a practical solution such as discussing tumor multifocality in a surgical pathology report comment, but rather instructs that cases should be staged according to the current rules.7 Even if one could determine whether cases of multifocal bronchioloalveolar carcinoma represent synchronous primary carcinomas or intrapulmonary metastases, the observed outcomes for such patients is better than would be expected from published T4 tumor survival rates.76,78,82 Further investigations are sorely needed to formulate an appropriate classification scheme for bronchioloalveolar carcinoma.
In summary, the staging of lung cancers can be challenging, and surgical pathologists need more than a superficial appreciation of the staging system in order to properly guide patient therapy. One must especially be aware of nuances that can upstage seemingly obvious early stage tumors. Future revisions in the staging system should improve its utility and make our task easier.
The author has no relevant financial interest in the products or companies described in this article.
Presented at the Pulmonary Pathology Society Evening Session held during the annual meeting of the United States and Canadian Academy of Pathology, Atlanta, Ga, February 11, 2006.
Corresponding author: Douglas B. Flieder, MD, Department of Pathology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111-2497 (Douglas.Flieder@fccc.edu)
Reprints not available from the author.