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Published online before print January 17, 2007, 10.1148/radiol.2423051707
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(Radiology 2007;242:882-888.)
© RSNA, 2007

Thoracic Imaging

Clinical Predictors of Metastatic Disease to the Brain from Non–Small Cell Lung Carcinoma: Primary Tumor Size, Cell Type, and Lymph Node Metastases1

Amol Mujoomdar, MD, John H. M. Austin, MD, Rohin Malhotra, MD, Charles A. Powell, MD, Gregory D. N. Pearson, MD, PhD, Maria C. Shiau, MD and Haralambos Raftopoulos, MD

1 From the Departments of Radiology (A.M., J.H.M.A., R.M., G.D.N.P., M.C.S.) and Medicine (C.A.P., H.R.), Columbia University Medical Center, New York, NY. From the 2000 RSNA Annual Meeting. Received October 19, 2005; revision requested December 9; revision received February 28, 2006; accepted March 28; final version accepted May 31. Supported by the Saskatchewan Lung Association, the CRH Foundation, and the Department of Radiology, Columbia University. Address correspondence to A.M., Department of Radiology, Montreal General Hospital, McGill University, 1650 Cedar Ave, Room C5 118, Montreal, QC, Canada H3G 1A4 (e-mail: amm921{at}hotmail.com).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To retrospectively assess possible clinical predictors of metastatic disease to the brain in patients with non–small cell lung carcinoma (NSCLC).

Materials and Methods: Institutional review board approval was obtained, informed consent was waived, and data and other information were obtained prior to implementation of HIPAA. A review was performed of 264 patients (mean age, 65 years; 158 men and 106 women) with NSCLC who had undergone imaging studies of the chest and head. Hierarchical logistic regression was used to determine the predicted probability of metastatic disease to the brain as a function of patient age and sex and of size, cell type, peripheral versus central location, and lymph node stage of the primary NSCLC.

Results: Ninety-five (36%) patients had evidence of metastatic disease to the brain. Mean diameter of the primary tumors was 4.0 cm ± 2.2 (standard deviation). Cell types included adenocarcinoma (136 [52%] patients), undifferentiated (68 [26%] patients), and squamous (47 [18%] patients), for which metastatic disease to the brain occurred in 43%, 41%, and 13% (P = .003) of patients, respectively. The predicted probability of metastatic disease to the brain correlated positively with size of the primary tumor (P < .001), cell type (adenocarcinoma and undifferentiated vs squamous, P = .001), and lymph node stage (P < .017) but did not correlate with age, sex, or primary tumor location. For primary adenocarcinoma without lymph node spread, the predicted probabilities of metastatic disease to the brain from 2- and 6-cm primary tumors were .14 (95% confidence interval: .06, .27) and .72 (95% confidence interval: .48, .88), respectively (P < .02).

Conclusion: The probability of metastatic disease to the brain from primary NSCLC is correlated with size of the primary tumor, cell type, and intrathoracic lymph node stage.

© RSNA, 2007


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Distant metastatic disease is present at the time of initial diagnosis of lung cancer in approximately 43% of patients (1). Metastatic disease to the brain is common for lung cancer and occurs in approximately 32% (range, 25%–38%) of patients with non–small cell lung carcinoma (NSCLC) (2–4). Among the cell types of NSCLC, nonsquamous cell tumors are especially associated with metastatic disease to the brain (44%–54% of nonsquamous cell tumors) (2–5).

The TNM staging system for lung cancer allows correlations between survival and stage and includes a distinction between T1 (≤3-cm diameter) and T2 (>3-cm diameter) tumors (6). However, beyond these two categories, considerations of the risk of metastatic disease on the basis of tumor size are not within the purview of that system. The probability of metastatic disease to the brain from NSCLC can be presumed to depend on many factors, including genetic aspects of the tumor (7,8) and possibly its size (2,9,10), lymph node spread (5,11,12), and the degree of tumor-related angiogenesis (9,10,13). In an era of interest in computed tomographic (CT) screening for lung cancer (14–17), defining a relationship between characteristics of an NSCLC and the probability of spread to the brain is of importance both for screening algorithms and for routine evaluation.

Controversy currently exists between two concepts: The first concept is that detection of small "early" lung cancers will lead to improved prognosis (18–21). The second concept is that once an NSCLC is of a size that is detected with contemporary CT scanning (20,21), the presence of angiogenesis, which develops by the time a tumor is 1–2 mm and enables tumor cells to enter the bloodstream (13), will render futile the detection of a lung cancer (22,23).

Because magnetic resonance (MR) imaging or CT of the head is performed in most patients with NSCLC at our institution, we undertook this study to retrospectively assess possible clinical predictors of metastatic disease to the brain in patients with NSCLC.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Study Group
The institutional review board of Columbia University Medical Center approved the study protocol and waived the need for informed consent for our retrospective study, which was performed entirely at Columbia University Medical Center. The data and other information were all obtained prior to implementation of the Health Insurance Portability and Accountability Act. A retrospective search of the center's clinical database for cases from 1998 to 1999 was used to identify 414 patients with the diagnosis of NSCLC as determined by means of cytologic and/or histopathologic analysis of material obtained from sputum, bronchoscopy, percutaneous needle biopsy, surgical exploration, and/or autopsy. The classification of each tumor on the basis of findings at light microscopy was assigned according to the 1999 World Health Organization criteria (24). Thirteen patients with bronchial carcinoid tumors and eight patients with noninvasive bronchioloalveolar cell carcinoma were excluded from study because of the low metastatic potential of these tumors.

Among the 393 patients remaining, 373 (94.9%) had relevant information, including findings from chest imaging at our institution, in the medical center database. Of these 373 patients, 298 (79.9%) also underwent an imaging study of the brain at our institution for which images had been interpreted as showing the presence or absence of metastatic disease. Therefore, 95 (24.2%) of 393 potential patients for the study were excluded because of lack of head imaging (n = 75) or lack of other relevant data (n = 20).

Brain metastases were recorded as present whether they were seen at the time of initial presentation or developed later during the course of the disease. Central nervous system imaging was performed with MR after intravenous administration of gadopentetate dimeglumine (Magnevist; Schering, Berlin, Germany) in 207 patients (69.5%) and with CT after intravenous administration of contrast medium in 52 patients (17.4%). Thirty-nine patients (13.1%) underwent head CT examinations with no intravenous injection of iodinated contrast material. Of those 39 patients, four had new onset of neurologic symptoms and multiple brain masses at head CT that were interpreted as metastatic NSCLC, and one patient had a diagnosis of NSCLC in 1992 and a normal CT scan of the head in 1999 and is alive and well some 14 years later; these five patients were accepted for inclusion in the study. However, because head CT without use of intravenous contrast material is less sensitive in the detection of carcinomas metastatic to the brain than both (a) head CT with intravenous contrast material and (b) head MR imaging after intravenous injection of gadopentetate dimeglumine, the remaining 34 patients (11.4%) were not accepted for inclusion in the series. Therefore, 264 patients (mean age, 65 years; range, 23–99 years; 158 men, 106 women) remained for further analysis.

Characteristics of Primary Cancers
Review of all clinical, imaging, and pathologic data was performed separately by two of the authors (A.M., J.H.M.A.), with any differences resolved by means of consensus. The reports from each chest imaging study were reviewed with respect to size of the primary cancer and central versus peripheral location, each determined by means of the tumor appearance on images obtained immediately prior to initial therapy for the cancer. The size of each primary cancer was determined as follows: as the mean of all three dimensions, when available; otherwise, as the mean of two dimensions, when available; or otherwise, as a single diameter, which was applied for tumors of spherical or nearly spherical shape. Central location was defined as any lesion at or proximal to the level of the origin of a segmental bronchus. Peripheral location was defined as any location that was not central. If a tumor had both peripheral and central components, it was classified as central.

Whenever radiography and CT differed in terms of the interpretation of any of these findings, the CT report was accepted for analysis. The pathologic tumor size, if available, was used for those tumors that were excised. In the absence of size data from any of those sources, the original CT or chest radiographic images were reviewed by two of three thoracic radiologists (J.H.M.A., G.D.N.P., M.C.S., with 6–36 years of experience), the size of the tumor was measured in three dimensions, and the mean of the two assessments was accepted as the size of the tumor. The primary tumor cell type was reviewed in the pathology reports. TNM staging was performed by using the 1997 formulation by Mountain (6). Lymph node staging was assessed by means of review of reports of light microscopic analysis of lymph node tissue obtained at thoracotomy, mediastinal exploration, or bronchoscopic needle sampling of subcarinal lymph nodes; when any of those procedures had not been performed, then CT reports were reviewed and any lymph nodes with a short-axis diameter of 1.0 cm or larger were considered as positive for the presence of metastatic disease.

Statistical Analysis
Initial analyses of the data included an examination of descriptive statistics for the dependent variable (metastatic disease to the brain) and six independent variables (ages and sexes of the patients and cell types, sizes, lymph node stages, and locations of the tumors). Because the mean tumor size (4.0 cm ± 2.2 [standard deviation]) was larger than the median tumor size (3.5 cm) and because this difference was largely owing to 22 (8.3%) tumors larger than 7.0 cm (range, 7.2–14.2 cm), subsequent logistic regression analysis was based on log tumor size in order to minimize skew from the very largest tumors. The {chi}2 test was used to compare the prevalence of metastatic disease to the brain among the major histopathologic subtypes: adenocarcinoma, undifferentiated NSCLC, and squamous cell NSCLC. Differences with P values of less than .05 were accepted as statistically significant. Statistical analysis was performed by using statistical software (SAS, version 8.2; SAS Institute, Cary, NC).

Next, bivariate relationships between the presence or absence of brain metastases and the six predictors were investigated by using both Pearson correlation coefficients and bivariate logistic regression analysis within the subgroups of patients with adenocarcinoma, undifferentiated NSCLC, and squamous cell NSCLC. Finally, hierarchical logistic regression analysis was used to explore the possible existence of both "main effects" and higher-order interactions among the six predictors. Because no higher-order interactions were found to be statistically significant, the statistically insignificant main effects of age, sex, and tumor location (peripheral vs central) were deleted from the final model, which therefore included tumor size, cell type, and lymph node stage.

We also compared the sizes of the primary tumors for the 264 patients included in the study and for the 95 patients who otherwise met entry criteria for analysis but were excluded because of insufficient data (two-sample comparison of median values).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
The size of the primary cancer (Table 1) was assessed by means of measurements from CT scans in 236 (89.4%) patients and from a surgical specimen in 28 (10.6%) patients. Intrathoracic lymph node status (Table 1) was assessed by means of histopathologic analysis of surgically resected tissue in 136 (51.5%) patients, from cytologic analysis of aspirated lymph nodes in three (1.1%) patients, and by means of CT assessment in 125 (47.3%) patients.


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  		Table 1. Patient Characteristics

 
Brain Metastasis
Metastatic disease to the brain as a function of size and major cell types of the primary NSCLC (Table 2) shows, on visual inspection, a positive trend between tumor size and the presence of metastatic disease to the brain for all cell types (n = 264), as well as for invasive adenocarcinoma (n = 136) and squamous cell NSCLC (n = 47). However, the undifferentiated NSCLC subgroup (n = 68) shows no clear pattern. To confirm or refute these impressions, bivariate logistic regression models to predict the likelihood of metastatic disease to the brain from (log) mean tumor size were estimated. The above relationships were confirmed as statistically significant, except for the undifferentiated NSCLC subgroup (P < .06) (Table 3). The predicted probabilities exhibited an increasing pattern of greater frequency of metastatic disease to the brain as sizes of the primary tumors increased, although for tumors larger than 5 cm, the likelihood of brain metastases increased at a decreasing rate (Figure). The probability of metastatic disease to the brain did not correlate with sex ({chi}2 = 0.64, P = .42) (Table 1).


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  		Table 2. Size of Primary Cancer, Cell Types, and Presence of Metastatic Disease to the Brain

 

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  		Table 3. Predicted Probability of Brain Metastasis according to Cell Type

 

Figure 1
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  		Graph shows predicted probability of metastasis to the brain at selected sizes of primary tumors by controlling for cell type and nodal stage for NSCLCs ({chi}2 = 11.28, P = .001). Bars = 95% confidence interval (CI).

 
Metastatic disease to the brain was more common for adenocarcinoma and undifferentiated NSCLC than for squamous NSCLC (Tables 2, 3). The percentage of patients with prevalence of brain metastases from adenocarcinoma of the lung was 43%. Compared with squamous cell NSCLC, for which the percentage of patients with metastatic disease to the brain was 13%, the difference ({chi}2, df = 1) was statistically significant (P < .001). The percentage of patients with metastatic disease to the brain from undifferentiated NSCLC was 41%; compared with primary squamous cell NSCLC, the difference ({chi}2, df = 1) was also statistically significant (P < .002). The predicted probabilities of metastatic disease to the brain, controlling for size of the tumor and nodal stage, were comparable for both adenocarcinoma and undifferentiated NSCLC (Table 3).

Increasing lymph node stage was also correlated with the presence of metastatic disease to the brain (controlling for cell type and size of the primary tumor) (Table 4).


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  		Table 4. Predicted Probability of Brain Metastasis according to Nodal Stage

 
Given that the mean tumor diameter in our study was 4.0 cm ± 2.2, we defined "small" primary tumors as 2 cm and "large" primary tumors as 6 cm. For small primary tumors of the most common cell type—that is, adenocarcinoma (n = 136, 51.5%)—nodal stages N0 and N3 showed significantly different probabilities of metastatic disease to the brain, but the large primary adenocarcinomas did not show a corresponding significant difference (Table 5).


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  		Table 5. Adenocarcinoma of Lung: Predicted Probability of Brain Metastasis as a Function of the Interaction between (Log) Tumor Size and Nodal Stage

 
Included and Excluded Patients
For the 359 patients who were potentially acceptable for inclusion in this study (264 patients who were included in the study plus 95 who were excluded), mean tumor size for the included patients (4.0 cm ± 2.2) was larger than that for the excluded patients (3.1 cm ± 1.8; two-sample median test, {chi}2 = 6.2, df = 1, P < .02).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
Our study showed three main findings: (a) The probability of metastatic NSCLC to the brain increased as the size of the primary cancer increased, (b) adenocarcinoma and undifferentiated cell types of NSCLC spread more commonly to the brain than did squamous NSCLC, and (c) increasing lymph node stage (TNM system) was associated with increased probability of spread to the brain.

Size of NSCLC is widely recognized as being of prognostic significance in the TNM system, in which patients with early-stage primary tumors larger than 3 cm in diameter are well recognized to have poorer survival after resection than are those with smaller tumors (6,10,25–27). Results of the present study amplify that observation by showing increasing probability of metastatic disease to the brain as the sizes of primary tumors increased. These results are also consistent with those of a number of studies in which prognosis was assessed in terms of sizes of NSCLC other than "smaller or larger than 3 cm" (18,19,28–32); in these studies, increasing sizes correlated with decreased survival. Nevertheless, authors of one major surgical series (23), to our knowledge, found no prognostic differences among size categories for resected NSCLC with diameters of 3 cm or smaller; results of that study, however, showed such excellent survival rates (84% 5-year survival) that the study has been criticized by others as being underpowered (19).

The largest study of survival in terms of size of NSCLC, to our knowledge, is an analysis of 84 152 tumors from the Surveillance, Epidemiology, and End Results Registry in the United States. In that study, as primary tumor sizes increased, the proportion of stage I tumors decreased: The proportion ranged from 54.1% (95% confidence interval: 52.9%, 55.2%) for cancers 1.5 cm or smaller to 46.5% (95% confidence interval: 45.8%, 47.3%) for 1.6–2.5-cm cancers, 34.4% (95% confidence interval: 33.7%, 35.2%) for 2.6–3.5-cm cancers, 25.2% (95% confidence interval: 24.4%, 25.9%) for 3.6–4.5-cm cancers, and 14.7% (95% confidence interval: 14.3%, 15.5%) for cancers larger than 4.5 cm (P < .001) (28).

In general, the positive association in our study between size of the primary tumor and the probability of metastatic disease to the brain showed no statistical evidence of nonlinearity. However, toward the upper end of the spectrum of sizes of primary tumors, nonlinearity is suggested: As tumor size increased from 5 to 6 cm, the predicted probability increased by only .04. This "tailing off" probably represents a manifestation of tumor kinetics in which tumors beyond a certain level of growth attain a phase of retarded growth (33). The findings in our series suggest a parallel pattern for the metastatic potential of a tumor.

Our study findings confirmed that adenocarcinoma is a cell type of NSCLC that is well recognized to metastasize commonly to the brain (2–5), but, to our knowledge, comparable rates of undifferentiated NSCLC metastasizing to the brain have not been described previously. For the 68 undifferentiated NSCLCs in the present study, the prevalence of 41% for metastatic disease to the brain is nearly identical to the prevalence of 43% for the 136 adenocarcinomas. However, by controlling for size of the cancer and nodal stage, the predicted probability of metastatic disease to the brain was .43 (95% confidence interval: .35, .52) for adenocarcinoma and .36 (95% confidence interval: .25, .48) for undifferentiated NSCLC; these confidence intervals overlap considerably.

For adenocarcinoma of the lung, the predicted probability of metastatic disease to the brain from adenocarcinoma of the lung varied greatly by size—for example, for nodal stage 0, probability varied from .14 (95% confidence interval: .06, .27) for a primary tumor 2 cm in diameter to .72 (95% confidence interval: .48, .88) for a tumor 6 cm in diameter. To our knowledge, these considerable differences have not previously been described.

Metastasis from lung cancer to lymphatics and to visceral organ beds by way of the systemic circulation is the result of stepwise properties of tumor cells. These steps include enzyme-mediated invasion of organ stroma, circulation in lymphatic or vascular channels, and extravasation and proliferation in distant organ beds (8). By using various high-throughput genomic strategies, the molecular programs driving the tumor-stromal interactions that lead to metastases are becoming well characterized (7). It is tempting to speculate that early-stage NSCLC genomic profiles may become defined that are highly predictive of brain metastases, and, if so, it may be possible to select patients with these tumor profiles to receive further therapy, such as adjuvant chemotherapy and prophylactic cranial irradiation (12).

Results of our study confirm the known much lesser risk for metastatic disease to the brain from squamous cell NSCLC than from primary adenocarcinomatous NSCLC (2–5). Although mechanisms for the different rates of metastatic disease to the brain among the major cell types of NSCLC appear to relate to genetic characteristics of the primary tumors, these characteristics as yet remain incompletely defined (34,35).

Findings of our study also corroborate those of previous studies that show intrathoracic spread of NSCLC to intrathoracic lymph nodes correlates with metastatic disease to the brain (5,11,12). Whatever mechanisms are involved in lymphatic spread of NSCLC to intrathoracic lymph nodes, it appears they may also be associated with the mechanisms of bloodborne spread of NSCLC. However, our data show that, for adenocarcinomas, the association does not hold at the larger end of the clinical spectrum of tumor sizes, because for 6-cm adenocarcinomas, the probability of metastatic disease to the brain was in the range of 60%–70% regardless of nodal stage.

CT screening to detect lung cancer is a contemporary controversy for which the results of the present study offer potentially important implications. Most screening-detected NSCLC are detected and resected when smaller than 2 cm (20,21), so screening detection of NSCLC does offer distinctly favorable odds of sparing the patient the complication of metastatic disease to the brain. Nevertheless, an unfavorable subset remains: Node-negative adenocarcinoma of 2 cm in diameter showed a .14 (95% confidence interval: .06, .27) probability of metastatic disease to the brain.

Limitations of this study include its retrospective design and that we assessed lymph node metastatic disease by means of tissue sampling in 52.7% of patients and by means of CT assessment of nodal sizes in 47.3% of patients. Histologic sampling is widely accepted in clinical practice, but immunohistochemical techniques not infrequently show occult nodal metastatic NSCLC (36), so our histologic nodal assessments may possibly have understaged disease. Furthermore, CT assessments of mediastinal nodal metastatic disease determined on the basis of size criteria show accuracy in only the 75% range (37,38) because of a mix of overcalling enlarged inflammatory nodes and undercalling positive nodes of normal size.

Another limitation of the study is that 95 (26.5%) of 359 potential patients for this study were excluded because of a lack of head imaging data (n = 75) or a lack of other relevant data (n = 20), and the tumor sizes in these patients were significantly smaller (P < .02) than the tumor sizes in the 264 included patients. If those 95 excluded patients had been included in the series, the mean tumor size for the series would have been 3.7 cm ± 2.2 rather than 4.0 cm ± 2.2. We can therefore presume that the total percentage of patients with metastatic disease to the brain would have been somewhat less than the value of 36.0% for the patients who did have data from head imaging. However, this overall prevalence of 36.0% of brain metastases in our study is within the reported range of 25%–38% (2–4), and in the context of the contemporary epidemic of adenocarcinomatous NSCLC (51.9% of the patients in the present study), the percentages of brain metastases from all NSCLC certainly can be expected to be at least in this range.

A further limitation of this study is that, although we considered a number of variables as possible predictors of the outcome variable (metastatic disease to the brain: yes or no), it is possible that other variables that we did not assess may also be related to the outcome. The study findings do show that spread of lung cancer to the thoracic lymphatic system was associated with increased probability of metastatic disease to the brain, so it is entirely plausible that spread to the brain may also relate to the presence of distant metastatic disease in other organs (eg, bone) or to various genetic aspects of tumor growth that were beyond the purview of this study.

Current TNM staging of lung cancer is based only on size and location of the primary tumor, regional nodal involvement, local invasion, and distant metastatic disease (6). Refining the T classification of this system to include separate categories for tumors of 2.0 cm or smaller, 2.1–3.0 cm, 3.1–5.0 cm, and larger than 5.0 cm in diameter is now under active consideration (29–31). The results of our study lend support to consideration of such a reclassification.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   ACKNOWLEDGMENTS
 
We thank Marc Glassman, PhD, for statistical analysis of the data.


   FOOTNOTES
 

Abbreviations: NSCLC = non–small cell lung carcinoma

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, A.M., J.H.M.A.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, A.M., J.H.M.A., C.A.P.; clinical studies, J.H.M.A.; statistical analysis, J.H.M.A.; and manuscript editing, all authors


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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