Lesson 9, Volume 15—Revised International Staging System for Lung Cancer

By Jamie C. Hey, MD

Objectives

1. Describe the critical role the TNM system plays in the evaluation of non-small cell lung cancer.
2. Review the historical development of the Revised International System for Staging Lung Cancer.
3. Review, in detail, the TNM subsets and stage classifications.
4. Describe the differences between clinical and surgical-pathologic staging.
5. Introduce new areas of research regarding prognosis and possibly treatment.

Key words

CT scan; lung neoplasm; oncogenes; positron emission tomography; TNM staging; tumor markers

Abbreviations

NSCLC = non-small cell lung cancer

The American Cancer Society predicted there would be more than 164,000 new cases of lung cancer in the United States this year.¹ Obviously, this is a disease that routinely confronts physicians in all areas of adult medicine. Practitioners who focus on diseases of the chest need to be well-versed in the evaluation and treatment of lung cancer. This can be a challenge as the disease presentation can range from an asymptomatic, subcentimeter nodule to disseminated disease, with a multitude of possibilities in between. The TNM staging system provides us with a guide with which to approach the process. It points out which features of the disease are important in regard to outcome and are therefore crucial to ascertain with certainty. In most cases, if there is doubt regarding one of the staging points, further investigation is necessary. When the staging process is complete, the physician and patient have reliable prognostic information that is based on the outcomes of thousands of patients. An appropriate treatment plan may then be constructed. The TNM system also provides standardization of reporting across various research centers. This allows for improved epidemiologic data as well as more reliable treatment evaluation. The current International System for Staging Lung Cancer is used to assess all cases of non-small cell lung cancer (NSCLC) and although it may be applied to small cell lung cancer as well, its use in that disease is not universal. This update will focus on the staging of NSCLC.

Background

Table 1 outlines the increase in complexity of the TNM system as it has gone through two major revisions. The additional classifications should not intimidate clinicians attempting to better understand the approach to lung cancer evaluation. The more complex the system, the less uncertainty there is regarding how each patient should be managed. The best way to become comfortable with this type of information is to review its development. The first widely used TNM system for lung cancer staging was published by Mountain et al² in 1974. It was based on data from more than 2,000 cases of bronchogenic carcinoma with at least 4 years of follow-up for survivors. Analysis of this data delineated tumor characteristics that were associated with outcome including size, bordering structures and invasion, location, secondary pneumonic complications, and presence of malignant pleural effusions. Thus, T1 lesions were small (< 3 cm), in a peripheral location (distal to main bronchi) and exhibited no invasion of surrounding structures. T2 lesions either were larger, were more proximal (but still > 2 cm distal to carina), or created some amount of atelectasis or pneumonitis. The T3 grouping was much broader and included all other tumors. Thus, a localized tumor within 2 cm of the carina and a large tumor invading the superior vena cava with a malignant pleural effusion would both be classified as T3. Lymph node involvement was also separated into three simple groupings: N0 had no nodal involvement, N1 involved ipsilateral hilar nodes, and N2 cases had spread to the mediastinal nodes on either side. The distant metastasis classification in this early system included some nodal spread. M1 included metastasis not only to bone, brain, liver, etc., but also to scalene, cervical, or contralateral hilar nodes. Three stages for invasive carcinoma were assigned as follows: stage I included T1 tumors with either no nodal involvement (N0) or ipsilateral hilar involvement (N1) and T2 tumors with no nodal spread; stage II included T2N1 tumors only; and all others were classified as stage III. This system was successful in separating patient groups with different survival odds; however, whereas stage II was narrowly defined and therefore relatively accurate for patients included, stage III was extremely broad in its definitions and therefore less accurate for each individual patient. Variations of this system were adapted by professional oncology organizations. Although there was much overlap, the presence of multiple accepted staging formats made standardization for reporting and research difficult.

In 1986, Mountain³ published a revised staging system that was accepted by the American Joint Committee on Cancer and the Union Internationale Contre Cancer as an International Staging System for Lung Cancer. The data for this work came from more than 3,000 total cases of lung cancer in two separate databases. It focused on the problem of including patients with a wide array of expected outcomes in the same stage. The primary tumor (T) descriptor for small, parenchymal tumors remained unchanged, while the more advanced lesions were divided into T3 and T4 to separate possible surgical and nonsurgical cases. The T3 classification no longer included tumors with direct invasion to vital structures. The T3 lesion could involve the chest wall, diaphragm, or the mediastinal pleura, but if the heart, major vessels, vertebral bodies, or carina were involved it became T4. Malignant pleural effusions were also classified as T4. A new nodal descriptor was added because ipsilateral and contralateral mediastinal involvement were found to convey different survival effects. Ipsilateral mediastinal and subcarinal nodes remained N2, while contralateral mediastinal and hilar nodes became N3. The scalene and supraclavicular nodes that had been included in the distant metastasis descriptor previously (M1) were now included in N3. Although spread to these nodal areas on either side portends a poor prognosis, they are covered within a local treatment field. The new staging system included stage 0 (carcinoma in situ), two subdivisions of stage III (A and B), and a separate stage for M1 cases, stage IV. Stage I no longer included N1 lesions and defined a group with excellent survival odds. Stage II cases involved ipsilateral hilar nodes (N1) but were localized tumors (T1, T2). The division of the stage III category aimed to separate patients with locally advanced disease into a group who had potential for cure (A) from those who had a similar outcome to M1 patients (B). Stage IIIA included ipsilateral mediastinal lymph node spread (N2) for T1 to T3 tumors as well T3 lesions with no nodal involvement (N0) or spread to hilar nodes (N1). Stage IIIB included all T4 and N3 cases, and stage IV was reserved for distant metastases (M1).

The International System for Staging Lung Cancer underwent a major revision in 1997.⁴ This most recent edition serves as our current guideline for staging and should be familiar to all pulmonary clinicians. It was developed using two large databases with more than 5,000 total cases evaluated. The primary objective was further refinement of stages to minimize outcome variation. There was only minimal change made to the T classification and none to N or M (Table 2). Previously, tumor nodules that were noncontiguous with the primary tumor were felt to represent metastatic spread and were labeled M1. Under the revised classification, satellite nodules that are within the same lobe as the primary tumor dictate a T4 classification while nodules outside of that lobe are still M1. Satellite nodules are relatively uncommon and studies addressing their prognostic importance contain small numbers of patients. The issue is complicated by the fact some of these nodules represent synchronous primary tumors rather than metastasis. Differentiating these two scenarios can be difficult. There have been publications evaluating this change in T staging and the results are varied.^5,6 Most cases of satellite nodules occur in the setting of significant nodal involvement and their inclusion in stage IIIB is appropriate based on outcome. However, the rare case of a satellite nodule within the same lobe as the primary tumor that does not have advanced nodal involvement may have a much better chance for survival than other stage IIIB cases.⁶ As always, the TNM system is a guide but each case needs to be evaluated individually using all available data before determining a treatment course.

The most significant changes in the 1997 revision involved the stage groupings (Table 3). The original International Staging System had addressed the broadest group, stage III, and had developed the A and B subsets. The 1997 revision took a similar approach to stages I and II because of data showing notable disparity in outcome. For stage I (N0) and stage II (N1) cases, there was a significant difference in survival between T1 lesions and T2 (67 vs 57% 5-year survival for N0 cases and 55 vs 39% 5-year survival for N1 cases).⁴ Given the advances in adjuvant therapies, these differences are crucial to recognize to help separate patients who may benefit from more aggressive treatments from those who should be expected to do well with surgical resection alone. Thus, stages I and II were subdivided into A and B subsets based on the T status. This change didn’t alter the stage II population greatly because T1N1M0 (IIA) cases are uncommon. Most stage II cases by the 1986 system would be classified as IIB under the revised system. A more significant adjustment to stage II was the addition of T3N0M0 cases. Recall that in the original classification the T3 lesion dictated a stage III grouping along with metastatic disease and that under the 1986 system it was "upgraded" to IIIA with or without N1 spread. The data analysis for the current revision revealed that the outcome for surgically treated T3N0M0 cases was similar to that of T2N1M0 cases with a 38% 5-year survival. The finding of N1 disease with a T3 lesion remained within the IIIA group.

Clinical and Surgical-Pathologic Staging

One of the most important issues in lung cancer staging involves the methods used to obtain the TNM data. Although the stage classifications are fixed, the predicted outcomes vary depending on whether the staging is clinical or surgical-pathologic.⁴ Clinical staging involves data collected with noninvasive means such as radiographic techniques and is less reliable than pathologic staging. Although pathologic findings can up- or down-stage individual cases because of inaccurate radiographic findings, survival within a given stage group is generally better for surgical-pathologic staged populations compared with clinically staged populations. Thus it is crucial to be as accurate as possible in staging evaluation. CT scanning has become the radiographic staging tool most widely employed. Unfortunately, nodal staging by CT has been repeatedly shown to be imperfect, with a significant number of cases of false-positive and false-negative scans.^7-9 Therefore, most cases of lung cancer require pathologic staging and all surgical cases must have a complete mediastinal lymph node evaluation at the time of surgery. Positron emission tomography scanning has a reported sensitivity and specificity of 91% and 86%, respectively, for the detection of mediastinal and distant spread of NSCLC.¹⁰ As this application becomes more universally available, there may be a decrease in the need for preoperative pathologic staging, although nodal staging at the time of surgery should continue to be the standard of care.

Future Directions for Staging

Although the further subdivision of the various TNM stages decreases the heterogeneity within each group, the TNM system cannot be the only prognostic tool used to determine treatment. There will continue to be a variety of clinical presentations that will be classified together based on the level of tumor progression but whose long-term outcomes vary significantly. Some of the differences are obvious and are used routinely to help with treatment decisions because they relate to potential for long-term survival or to ability to withstand treatment toxicity and inconvenience. These factors include age, sex, performance status, comorbid illnesses, and others.¹¹ However, there are also newer tools that show some promise as markers for tumor aggressiveness or sensitivity to treatment that may someday be helpful in determining a treatment strategy.

Serum markers of tumor presence and spread are used for screening and or monitoring several common malignancies including carcinoma of the prostate and colon. No such marker is currently in general use in the evaluation and treatment of NSCLC although several have been under investigation, including carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC Ag), and CA 125. Rubins et al¹² found carcinoembryonic antigen to be an independent prognostic factor in a prospective cohort analysis of 130 patients; a finding consistent with other published data.¹³ Diez et al¹⁴ reported similar findings using CA 125 in serum of patients undergoing surgical resection. Squamous cell carcinoma antigen, although frequently elevated in lung cancer patients, was not shown to be an independent predictor of survival.^13,15

Immunohistochemical analysis of tumor cells for the presence of specific antigens has also been utilized. The presence of blood group antigens that stain with the MIA-15-5 antibody was shown to correlate with survival in a retrospective analysis of surgical patients.¹⁶ Although this finding raised hopes about new prognostic tools, it has not translated into common practice, and indeed, more recent research has reported the opposite association between these antigens and survival.¹⁷

The understanding of specific DNA alterations that can lead to cell transformation has progressed rapidly in recent years. There are now many recognized oncogenes and oncoproteins and several of these are found in NSCLC. Numerous researchers have evaluated the use of these mutations or aberrant proteins as markers for a poor clinical outcome. The most frequently studied markers include the dominant oncogenes K-ras and HER-2/neu and the tumor suppressor p53.¹⁸ Two problems prevent the routine use of oncogene markers in the prognostic evaluation of patients. First, the techniques for their identification are not readily available to most clinicians. Second, the clinical studies of these markers are generally small and conflicting results abound. It is prudent, however, to be aware of these types of markers. As more genetic alterations are found, it is very possible that one or a combination of mutations will be recognized as a reliable prognostic tool. They may also form the basis for direct curative therapies.

Conclusions

The TNM system for lung cancer staging has progressed over the years based on statistics derived from large, reliable databases. The current Revised International System for Staging Lung Cancer plays several roles pertinent to the care of patients with NSCLC. First, it provides the individual clinician with a road map for evaluation of NSCLC, incorporating many different factors into an easily understandable system. Second, it provides accurate prognostic information that is necessary to develop an appropriate treatment plan. Third, it provides a standard that is used around the world such that ongoing research is not confused by varying case definitions. As this system continues to undergo evaluation and revision, it is important for all physicians involved in the diagnosis, staging, and treatment of NSCLC to be well-versed in its details. In addition, one needs to be aware of new areas of interest such as novel prognostic tools and imaging techniques that may be helpful in patient care and that may be incorporated into future revisions.

References

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