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(Chest. 2005;127:1136-1139.)
© 2005 American College of Chest Physicians

Stage of Lung Cancer in Relation to Its Size*

Part 2. Evidence

Juan P. Wisnivesky, MD, MPH; David Yankelevitz, MD and Claudia I. Henschke, PhD, MD, FCCP

* From the Divisions of General Internal Medicine and Pulmonary, Critical Care, and Sleep Medicine (Dr. Wisnivesky), Mount Sinai School of Medicine, New York; and Department of Radiology (Drs. Yankelevitz and Henschke), New York-Presbyterian Hospital-Weill Cornell Medical Center, New York, NY.

Correspondence to: Claudia I. Henschke, PhD, MD, FCCP, Department of Radiology, New York-Presbyterian Hospital, Weill Cornell Medical Center, 520 East 70th St, Starr Bldg, New York, NY 10021; e-mail: chensch{at}med.cornell.edu


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objective: To assess the relationship between tumor size and disease stage at the time of diagnosis in non-small cell lung cancer.

Methods: From the Surveillance, Epidemiology and End Results registry, we identified all cases of primary non-small cell lung cancer diagnosed prior to autopsy. Among these, we focused on 84,152 cases diagnosed in 1988 or later and documented as to tumor size and disease stage at diagnosis. The distribution of disease stage within categories of tumor size was determined.

Results: The smaller the tumor was, the more likely the disease was stage I. For tumors < 15 mm in diameter, the proportion of stage I was 54%, compared with 46% for 16 to 25 mm, 34% for 26 to 35 mm, 25% for 36 to 45 mm, and 15% for cases > 45 mm, with all of these proportions being very precise.

Conclusions: Tumor size has substantial bearing on disease stage in non-small cell lung cancer.

Key Words: diagnosis • non-small cell lung cancer • screening • stage distribution


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The lung cancer cure rate is dismal and has remained essentially unchanged over the past 3 decades.1 The stage of disease at diagnosis represents one of the most powerful determinants of outcome in non-small cell lung cancer, with earlier-stage patients having a better chance of cure.2 Unfortunately, only a small proportion of the cases are diagnosed at an early stage.

Recently, low-dose CT has been suggested as the initial test in a screening regimen as a way to diagnose early stage lung cancers, which are more commonly cured by resection, to improve patient outcomes.3456 The rationale is that CT can lead to the detection of cancer when they are smaller than can be detected with chest radiography or when symptom prompted, and that these smaller cancers will more commonly be early stage. As reviewed in part 1 of this article, the association between size and stage has been questioned based on the results of a single study using data from a tertiary care center tumor registry.7 This study was conducted to further evaluate the association between size and stage at the time of diagnosis using a large database with a broader representation of the population.


   Materials and Methods
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 Introduction
 Materials and Methods
Results
 Discussion
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The Surveillance, Epidemiology and End Results (SEER) program is a National Cancer Institute-funded database that has been collecting clinicopathologic data on all incident cancer cases in selected geographic areas of the United States since 1973. From SEER registry 2004, we identified all cases of non-small cell lung cancer (tumor site codes 34.0–34.9 and International Classification of Diseases for Oncology, Second Edition morphology codes 8010–8040, 8050–8076, 8140, 8143, 8250–8260, 8310, 8320, 8323, 8470–8490, 8550–8573), diagnosed in 1988 or later, as the histologic and staging classification in SEER had significantly changed.8 Among these cases, we narrowed the focus to microscopically confirmed primary cancers diagnosed prior to autopsy. There were 158,794 such cases.

These cases were classified according to stage using the American Joint Committee on Cancer criteria2: T1 (noninvasive tumor of diameter ≤ 3 cm, without evidence of invasion more proximal than the lobar bronchus; SEER tumor extent code 10); T2 (tumor with any of the following features of size or extent: > 3 cm in dimension, involves main bronchus, ≥ 2 cm 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; SEER tumor extent codes 20 and 40); T3 (tumor of any size that directly invades any of the following: chest wall, diaphragm, mediastinal pleura, parietal pericardium, or tumor in the main bronchus < 2 cm distal to the carina, but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung; SEER tumor extent codes 50 and 60); or T4 (tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina; or separate tumor nodules in the same lobe; or tumor with a malignant pleural effusion; SEER tumor extent codes 25, 65–77, 79, and 80). Lymph node involvement was classified as follows: N0 (absence of lymph node metastasis; SEER lymph node code 0); N1 (metastasis to ipsilateral peribronchial and/or hilar, and intrapulmonary nodes; SEER lymph node code 1); N2 (metastasis to ipsilateral mediastinal and/or subcarinal lymph nodes; SEER lymph node codes 2); or N3 (metastasis to contralateral mediastinal or hilar, scalene, or supraclavicular lymph nodes, SEER lymph node code 6). Cancers were classified as M0 (no distant metastasis; SEER tumor extension < 80) or M1 (distant metastasis present; SEER extension code 85). Tumor size as defined by its greatest diameter was based (in priority order) on those recorded in the pathology report, operative report, or radiographic report. Histology was identified according to the World Health Organization definition published in 1990.9

Among the 158,794 cases of primary lung cancer identified in the SEER registry, 74,642 cases (47.0%) were unclassified as to stage or tumor size, while 84,152 cases (53.0%) had adequate documentation of tumor size and stage. The mean age, gender, ethnicity, and tumor histology were similar for those who had adequate documentation of tumor size and stage compared to those who did not (Table 1 ).


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  		Table 1. Demographic Characteristics of Patients With Non-Small Cell Lung Cancer in the SEER Registry*

 
Cases were classified into five tumor size categories: ≤ 15 mm, 16 to 25 mm, 26 to 35 mm, 36 to 45 mm, and > 45 mm in diameter. A {chi}2 test was used to examine the overall relation between tumor size and disease stage10; a p value of 0.05 was used to define statistical significance. The analyses were performed using a statistical package (SAS, version 8.2; SAS; Cary, NC).


   Results
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 Abstract
 Introduction
 Materials and Methods
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Discussion
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Among the 84,152 cases with adequate documentation of tumor size and stage, 24,880 cases (29.6%) were as stage I, 5,113 cases (6.1%) were stage II, 10,218 cases (12.1%) were stage IIIA, 14,832 cases (17.6%) were stage IIIB, and 29,109 cases (34.6%) were stage IV. By size, 7,327 cases (8.7%) were found to be ≤ 15 mm in diameter, 15,853 cases (18.8%) were 16 to 25 mm, 16,394 cases (19.5%) were 26 to 35 mm, 12,955 cases (15.4%) were 36 to 45 mm, and 31,623 cases (37.6%) were > 45 mm (Table 2 ).


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  		Table 2. Distribution of Disease Stage According to Tumor Size*

 
Among these 84,152 cases, we found that a decreasing proportion of cases were stage I with increasing tumor size (p < 0.0001). For cancers ≤ 15 mm in size, the proportion of stage I was 54.1% (95% confidence interval [CI], 52.9 to 55.2%), compared to 46.5% (95% CI, 45.8 to 47.3%) for 16 to 25 mm, 34.4% (95% CI, 33.7 to 35.2%) for 26 to 35 mm, 25.2% (95% CI, 24.4 to 25.9%) for 36 to 45 mm, and only 14.7% (95% CI, 14.3 to 15.5%) for > 45 mm (Fig 1 ).



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  		Figure 1. Proportion of stage I tumors according to tumor size at diagnosis. The percentage of stage I cases linearly decreased as the diameter of the primary tumor at the time of diagnosis increased from < 15 to > 45 mm.

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
A number of studies3411121314 of CT screening for lung cancer have reported that CT detects cancers at smaller size than chest radiography and that they were typically stage I. The potential benefit of finding smaller tumors has been discussed in part 1 of this article. This study shows a significant association between the size of lung tumors at the time of diagnosis and the proportion of stage I disease. Using a large population-based registry, we found that the smaller the tumor size at diagnosis the more likely it is to be stage I. Notably, this association was significant even for tumors ≤ 3 cm in greatest diameter.

Our results contrast to those of the Patz and Goodman group,7 who found a similar stage distribution for lung tumors < 1 cm, 1 to 2 cm, and 2 to 3 cm in diameter, using 620 patients from their tumor registry. As discussed in part 1, their study had many limitations. Notably, patients included in their study were obtained from a tumor registry of a tertiary center, in all essence a surgical registry, with size restricted to cancers < 3 cm in diameter and only 25 patients having cancers < 1 cm.

The present study used data from the SEER registry that collects data on all cases of lung cancer diagnosed in six standard metropolitan statistical areas (Atlanta, Detroit, San Francisco-Oakland, Seattle-Puget Sound, Los Angeles, and San Jose-Monterrey) and five states (Connecticut, Utah, New Mexico, Iowa, and Hawaii).8 Thus, selection bias was minimized in the assembly of the study cohort. Another advantage of using the SEER registry is that the large numbers of patients with lung cancer in the registry allows for precise estimation of the stage distribution even in the smallest size category.

The proportion of early stage cancers in a particular size range that are clinically diagnosed is related to how frequently they cause symptoms. Symptoms are more common when cancers are large or when metastasis are present, particularly for small cancers.15 This is because small cancers are not likely to cause local symptoms and would remain mostly undetected unless they have disseminated. Conversely, large cancers may produce symptoms due to local invasion or compression and thus be diagnosed even in the absence of metastasis. For example, if tumors of a certain size develop metastases 50% of the time and the probability of detection when metastases are present is nine times greater than for those without metastases, then the observed frequency of metastasis for this tumor size will be about 90%. This mechanism likely leads to an overestimation of the rate of dissemination of the smaller cancers, as they are less likely to be symptomatic in the absence of metastasis. Thus, it is probable that the rate of stage I malignancies for tumors < 15 mm in a screening population (asymptomatic) is even greater than the 58% found in this study, and that the association between tumor size and stage is more striking.

This study has several limitations. There was inadequate documentation in the SEER registry about the cancer size and/or stage distribution for approximately 72,000 cases of non-small cell lung cancer. The demographic data and tumor histology of these cases, however, was similar to those included in the analysis that had complete documentation. Beside random error in coding and documentation, the most likely factor related to lack of documentation is whether the tumor was resected. For early stage tumors, accurate size and stage information is generally available from the operative report or pathology specimen. Conversely, lack of information regarding size is probably more common for unresected tumors, particularly if they are poorly defined on imaging studies. As large, advanced tumors are most likely to fall into this category, it is unlikely that the association between size and stage found in this study was due to lack of their inclusion, as the potential bias would have been in the opposite direction and made the association even more positive.

In summary, this study revealed that within a population-based database, cancer size at diagnosis is associated with the proportion of cancers that are stage I. These findings contradict the results of the Patz and Goodman group.


   Footnotes
 
Abbreviations: CI = confidence interval; SEER = Surveillance, Epidemiology and End Results

Received for publication May 14, 2004. Accepted for publication October 13, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Smith, RA, Glynn, TJ (2000) Epidemiology of lung cancer. Radiol Clin North Am 38,453-470[CrossRef][ISI][Medline]
  2. Mountain, CF Revisions in the International System for Staging Lung Cancer. Chest 1997;111,1710-1717[Abstract/Free Full Text]
  3. Henschke, CI, McCauley, DI, Yankelevitz, DF, et al Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354,99-105[CrossRef][ISI][Medline]
  4. Henschke, CI, Naidich, DP, Yankelevitz, DF, et al Early lung cancer action project: initial findings on repeat screenings. Cancer 2001;92,153-159[CrossRef][ISI][Medline]
  5. Henschke, CI, Yankelevitz, DF CT screening for lung cancer. Radiol Clin North Am 2000;38,487-495viii[CrossRef][ISI][Medline]
  6. Lam, S, Lam, B, Petty, TL Early detection for lung cancer: new tools for casefinding. Can Fam Physician 2001;47,537-544[Abstract/Free Full Text]
  7. Heyneman, LE, Herndon, JE, Goodman, PC, et al Stage distribution in patients with a small (< or = 3 cm) primary nonsmall cell lung carcinoma: implication for lung carcinoma screening. Cancer 2001;92,3051-3055[CrossRef][Medline]
  8. Surveillance, Epidemiology, and End Results (SEER) Program Public-Use Data (1973–2001), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2004, based on the November 2003 submission. Available at: www.seer.cancer.gov. Accessed March 11, 2005
  9. Percy, C Van Holten, V Muir, C eds. International Classification of Diseases for Oncology 2nd ed. 1990 World Health Organization. Geneva, Switzerland:
  10. Rosner, B Fundamentals in biostatistics. 1995 Wadsworth Publishing. Belmont, CA:
  11. Diederich, S, Wormanns, D, Semik, M, et al Screening for early lung cancer with low-dose spiral CT: prevalence in 817 asymptomatic smokers. Radiology 2002;222,773-781[Abstract/Free Full Text]
  12. Sone, S, Li, F, Yang, ZG, et al Results of three-year mass screening programme for lung cancer using mobile low-dose spiral computed tomography scanner. Br J Cancer 2001;84,25-32[CrossRef][ISI][Medline]
  13. Swensen, SJ, Jett, JR, Sloan, JA, et al Screening for lung cancer with low-dose spiral computed tomography. Am J Respir Crit Care Med 2002;165,508-513[Abstract/Free Full Text]
  14. Sobue, T, Moriyama, N, Kaneko, M, et al Screening for lung cancer with low-dose helical computed tomography: anti-lung cancer association project. J Clin Oncol 2002;20,911-920[Abstract/Free Full Text]
  15. Kimmel, M, Flehinger, BJ Nonparametric estimation of the size-metastasis relationship in solid cancers. Biometrics 1991;47,987-1004[CrossRef][ISI][Medline]



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