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(Chest. 2003;123:463-467.)
© 2003 American College of Chest Physicians

Lymph Node Size and Metastatic Infiltration in Non-small Cell Lung Cancer*

Klaus L. Prenzel, MD; Stefan P. Mönig, MD; Jan M. Sinning, MD; Stephan E. Baldus, MD; Hans-Georg Brochhagen, MD; Paul M. Schneider, MD and Arnulf H. Hölscher, MD

* From the Department of Visceral and Vascular Surgery (Drs. Prenzel, Mönig, Sinning, Schneider, and Hölscher), the Institute of Pathology (Dr. Baldus), and the Institute of Radiology (Dr. Brochhagen), University of Cologne, Cologne, Germany.

Correspondence to: Klaus L. Prenzel, MD, Department of Visceral and Vascular Surgery, University of Cologne, Cologne, Germany; e-mail: klausprenzel{at}hotmail.com


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Preoperative lymph node staging of lung cancer by CT relies on the premise that malignant lymph nodes are larger than benign ones. Lymph nodes > 1 cm in size are regarded as metastatic nodes. The surgical approach and potential application of neoadjuvant therapy regimens are dependent on this evaluation.

Patients and methods: In a morphometric study, hilar and mediastinal lymph nodes from 256 patients with non-small cell lung cancer (NSCLC) were analyzed. The lymph nodes were counted, the largest diameter of each lymph node was measured, and each lymph node was analyzed for metastatic involvement by histopathologic examination. The frequency of metastatic involvement was calculated and correlated with lymph node size. Preoperative CT scans of 80 patients were retrospectively analyzed by a staff radiologist. Lymph node size was measured, and lymph nodes were evaluated due to radiologic criteria. The radiologic evaluation was compared to the histopathologic diagnosis.

Results: A total of 2,891 lymph nodes were present in the 256 specimens examined for this study. One hundred thirty-nine patients had a pN0 status, whereas 117 patients had lymph nodes that were positive for cancer. Two thousand four hundred eighty-six lymph nodes (86%) were tumor-free, while 405 (14%) showed metastatic involvement on histopathologic examination. The mean (± SD) diameter of the nonmetastatic lymph nodes was 7.05 ± 3.75 mm, whereas infiltrated nodes had a diameter of 10.7 ± 4.7 mm (p = 0.005). One thousand nine hundred fifty-three of the tumor-free lymph nodes (79%) and 170 of the metastatic lymph nodes (44%) were < 10 mm in diameter. Of 139 patients with no metastatic lymph node involvement, 101 (77%) had at least one lymph node that was > 10 mm in diameter. Of 127 patients with metastatic lymph node involvement, 12% had no lymph node that was < 10 mm. The independent radiologic evaluation of the CT scans of 80 patients yielded a sensitivity of 57.1% and a specificity of 80.6%.

Conclusion: Lymph node size is not a reliable parameter for the evaluation of metastatic involvement in patients with NSCLC.

Key Words: CT imaging • lung cancer • lymph node metastasis • lymph node size


   Introduction
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 Abstract
 Introduction
Materials and Methods
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Lung cancer is the leading worldwide cause of death from malignant disease in both men and women.1 To determine resectability and prognosis for the patient with cancer, an accurate staging of the tumor, assessing the extent of local and distant disease, is necessary.2 Besides the location of the primary tumor and its infiltration of adjacent structures, lymph node status is of particular interest in the pretherapeutic staging of lung cancer. The surgical approach and planning of neoadjuvant therapies depend on this parameter. Metastases to ipsilateral hilar and mediastinal lymph nodes decrease survival rates but are not a contraindication to surgical resection. Patients with contralateral mediastinal, contralateral hilar, scalene, or supraclavicular lymph node metastases are considered to have unresectable stage IIIb lung cancer.3 The noninvasive evaluation of metastatic infiltration of hilar and mediastinal lymph nodes is based on CT scan or MRI. Lymph nodes > 1 cm in diameter are regarded as metastases.4 5 Most early articles6 7 reported a high sensitivity for detecting nodal metastases, whereas more recent studies8 9 10 have suggested that CT scanning and MRI have low sensitivities. Data from CT scanning and MRI are based on the assumption that malignant nodes will be larger than benign nodes, and that smaller lymph nodes are more likely to be benign. Therefore, we evaluated the size of lymph nodes in lymphadenectomy specimens from 256 patients and in the CT scans of 80 of these patients in order to specify whether it is possible to differentiate malignant from benign lymph nodes in patients with non-small cell lung cancer (NSCLC) by size.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
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Patients
The specimens included in this study were obtained from 256 consecutive patients, who underwent resections for NSCLC between 1992 and 1999 in the Department of Surgery at the University of Cologne. One hundred ninety-seven patients (77%) were men, 59 patients (23%) were women, and their ages ranged from 33 to 78 years (median age, 62 years). One hundred twenty-six patients (49%) were treated for squamous cell carcinoma, 113 patients (44%) were treated for adenocarcinoma, and 17 patients (7%) were treated for large cell carcinoma of the lung. Surgical procedures included pneumonectomy (38 patients; 15%), bilobectomy (18 patients; 7%), and lobectomy (200 patients; 78%). In all patients, an extended lymphadenectomy was performed. In no case was neoadjuvant radiation or chemotherapy employed.

Lymph Node Analysis
A total of 2,891 lymph nodes were resected from 256 specimens. The material was fixed in 5% formaldehyde and was embedded in paraffin. The nodes were counted, and the maximal diameter of each node was measured after preparation with a slide gauge. A series of sections from six levels of each node was selected and stained with hematoxylin and eosin, and the periodic acid-Schiff reaction. All dissected lymph nodes were analyzed microscopically for metastatic infiltration. Histologic findings were classified by the TNM International Union Against Cancer classification. To assess shrinkage due to fixation and staining, 36 lymph nodes from three lung cancer specimens were measured before and after fixation with hematoxylin-eosin.

Radiologic Analysis
The preoperative CT scans of 80 of 256 patients were available for a retrospective radiologic analysis. Spiral CT scans had been performed 2 weeks before surgical therapy (Somatom plus 4 or Somatom S; Siemens; Munich, Germany) using nonionic contrast fluid with a density of 300 mg iodine per milliliter. Slice thickness was 5 mm, pitch was 1.5, and the increment was 4 mm. Lymph nodes were grouped into the following four compartments: high mediastinal; aortic; low mediastinal; and hilar. The short-axis diameter size was measured, and a statement was given by the radiologist (HGB) about whether the lymph node appeared to be malignant or benign. The radiologic statement was compared with the histopathologic result.

Statistical Analysis
The relationship between lymph node size and the presence of metastases was evaluated statistically. Continuous variables were expressed as the mean ± SD and were analyzed using the Student t test. Frequencies were analyzed using the {chi}2 test. A p value of < 0.05 was considered to be significant. The mean shrinkage (95% confidence interval) was calculated. All calculations were performed using statistical software (SPSS; SPSS Inc; Chicago, IL).


   Results
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 Abstract
 Introduction
 Materials and Methods
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Discussion
 References
 
The relative size of 36 lymph nodes (from three lung cancer specimens) after fixing and staining was 8.36 ± 3.8 mm compared with 9.8 ± 4.1 mm before fixing and staining. Therefore, the shrinkage factor (mean, 0.6 mm; 96% confidence interval, 0.54 to 0.78) during the lymph node preparation was estimated to be about 10%. No significant difference in the amount of shrinkage between metastatic and nonmetastatic lymph nodes of any size was seen.

Two thousand eight hundred ninety-one lymph nodes were analyzed regarding size and metastatic infiltration. An average of 11.3 lymph nodes (range, 7 to 23 lymph nodes) per specimen were found. Four hundred five lymph nodes (14%) showed metastatic involvement, while 2,486 lymph nodes (86%) were free of tumor infiltration.

One hundred thirty-nine patients (54%) were staged as pN0, with 117 patients (46%) showing lymphatic spread of the tumor. Of these patients, 73 (29%) were staged as pN1 and 44 (17%) were staged as pN2, according to the 1997 TNM classification.11 The correlation of lymph node size and metastatic involvement is shown in Table 1 .


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  		Table 1.. Correlation of Lymph Node Size and Metastatic Involvement

 
The average size of the tumor-free lymph nodes was 7.05 ± 3.7 mm (Fig 1 ), while that of lymph nodes with metastatic involvement was 10.7 ± 4.7 mm (Fig 2 ). The difference was statistically significant (p < 0.005). Two thousand one hundred thirty-three lymph nodes (73.8%) were < 10 mm in diameter. One hundred eighty of these (8.4%) had tumor infiltration, while 1,953 (91.6%) were tumor-free. Seven hundred fifty-eight lymph nodes were >= 10 mm. Five hundred thirty-four of these (70%) had no metastatic involvement, while 224 (30%) contained metastases.



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  		Figure 1.. Size of tumor-free lymph nodes (2,486 nodes); mean size, 7.1 ± 3.75 mm.

 


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  		Figure 2.. Size of metastatic involved lymph nodes (405 nodes); mean size, 10.7 ± 4.72 mm.

 
Regarding the lymph nodes with histologic signs of metastases (405), 44% (180 lymph nodes) were < 10 mm. Nineteen percent (534 lymph nodes) of the tumor-free lymph nodes were >= 10 mm in size.

Of patients with lung cancer and no histopathologic sign of metastatic lymph node involvement (139 lymph nodes), 101 (73%) had at least one lymph node that was >= 10 mm. Fifteen of the patients (12%) with N1 or N2 disease had no lymph node that was > 10 mm.

Regarding only the mediastinal lymph nodes, 847 tumor-free nodes had a mean size of 7.07 ± 4.13 mm, whereas 113 infiltrated lymph nodes had a mean size of 11.31 ± 5.14 mm (p < 0.005).

In patients with mediastinal lymph node metastasis (44 patients), a median of 8.3 mediastinal lymph nodes were resected, and of those 2.6 had been infiltrated. There were 193 tumor-free lymph nodes, while 113 nodes showed metastatic infiltration. In eight of those patients (18.2%), no mediastinal lymph node was > 10 mm in size. Sixty-two patients (44.6%) with pN0 stage and 24 (32.9%) with pN1 stage had at least one mediastinal lymph node that was > 10 mm in size.

Lymph node involvement was present in 16% of patients with a squamous cell carcinoma and a large cell carcinoma. In adenocarcinoma patients, the rate of lymph node involvement was 12%. The size of lymph node metastases did not exhibit significant differences according to the tumor type, as follows: squamous cell carcinoma, 11.34 ± 4.98 mm; adenocarcinoma, 10.16 ± 4.39 mm; large cell carcinoma, 10.52 ± 4.81 mm (Fig 3 ).



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  		Figure 3.. Boxplot diagram of lymph node size according to tumor type. {circ} represents cases betwen 1.5 and 3.0 box lengths from the upper or lower edge of the box. * represents cases with values more than 3.0 box lengths from the upper or lower edge of the box. The box length is the interquartile range.

 
Independent retrospective radiologic assessment of 80 preoperative CT scans included 39 patients with pN0 stage disease, 31 with pN1 stage disease, and 10 with pN2 stage disease. The overall sensitivity and specificity were 57.1% and 80.6%, respectively. The positive predictive value was 30.8%, the negative predictive value 92.6%, and the accuracy was 77.5%


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The accurate preoperative assessment of lymph node involvement in patients with NSCLC has a crucial effect on therapy planning. Imaging modalities like CT scanning, MR, and transesophageal endosonography are limited in their predictive value to differentiate benign nodes from malignant ones.9 In the pretherapeutic lymph node staging of NSCLC, a correlation is assumed between node size and metastatic infiltration. In a study9 on 208 mediastinal lymph nodes from 40 patients, N2 nodes were present in 11 patients (28%). In seven of those nodes, lymph node metastases were misdiagnosed on CT scanning because of the presence of normal-sized N2 nodes. Kerr et al12 showed the lack of a statistically significant relationship between the size of the lymph nodes and the likelihood of malignancy in a series of 168 mediastinal lymph nodes from 56 patients. Similar results were reported by Vogel et al13 after investigating 162 lymph nodes from 83 patients.

In a study of 143 patients, McLoud et al14 showed that CT scanning has a sensitivity of 64% and a specificity of 62% when using 1 cm as the upper limit diameter and extensive nodal sampling. In our study, CT scanning had a sensitivity of 57.1% and a specificity of 80.6%. Despite these findings, CT scanning is still the method of choice when assessing lung cancer.8

In agreement with the studies mentioned above, our results do not show a definite correlation between metastatic involvement and lymph node size. Forty-four percent of lymph nodes with metastases are < 10 mm, and these nodes would have been staged as being falsely negative for disease with CT scanning. Fifteen patients with lymph node involvement had no node > 10 mm, whereas 101 patients (73%) without lymph node involvement had at least one node that was > 10 mm and would have been staged as falsely positive for disease by CT scanning. In patients with stage pN2 disease, 18% had no mediastinal lymph node > 10 mm in size. These results are based on the evaluation of 2,891 lymph nodes from 256 patients, which is the largest number in the literature so far.

The lack of correlation between lymph node size and metastatic infiltration has been reported in studies of other solid tumors. In a 1997 Japanese study15 regarding esophageal cancer, 36% of metastatic lymph nodes were < 5 mm in diameter. As we have demonstrated earlier16 in patients with gastric cancer, 55% of the metastatic lymph nodes were <= 5 mm in diameter. In patients with colorectal cancer, 50 to 65% of metastatic lymph nodes were <= 5 mm in size.17 18 19

Despite a significant difference in diameter between metastatic and nonmetastatic lymph nodes, the evaluation of lymph node metastasis in patients with lung cancer by nodal size is not accurate. An exact preoperative N-staging is therefore difficult to obtain. To distinguish between metastatic and normal lymph nodes, mediastinoscopy has the highest rates for sensitivity and specificity. Therefore, some authors20 perform this procedure previous to every resection for bronchogenic carcinoma. In cases in which the indication for resection is questionable because of a potential involvement of N3 lymph nodes, the N-staging should include mediastinoscopy to rule out metastases.

Preoperative CT scanning is useful for the evaluation of tumor invasion to the pleura and chest wall.6 Its accuracy in distinguishing between malignant and benign lymph nodes is too low for a sufficient preoperative staging. In several studies, positron emission tomography has shown a higher sensitivity and specificity than CT scanning regarding the nodal status.21 22 Our results have demonstrated in a larger series of patients that lymph node sampling based on lymph node size alone is not sufficient to provide a reliable pretherapeutic staging of NSCLC.


   Footnotes
 
Abbreviation: NSCLC = non-small cell lung cancer

Received for publication January 30, 2001. Accepted for publication August 30, 2002.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. . American Cancer Society. (1998) Cancer facts and figures, 1998. American Cancer Society Atlanta, GA.
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  3. Korst, RJ, Tsuchia, R Treatment of NSCLC: surgery. Hansen, HH eds. Textbook of lung cancer 2000,185-200 Martin Dunitz London, UK.
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  5. Gallardo, J, Naranjao, F, Cansino, M, et al Validity of enlarged mediastinal nodes as markers of involvement by non-small cell lung cancer. Am Respir Dis 1992;146,1210-1212
  6. Baron, RL, Levitt, RG, Sageless, SS, et al Computed tomography in preoperative evaluation of bronchogenic carcinoma. Radiology 1982;145,727-732[Abstract/Free Full Text]
  7. Osborn, DR, Korobkin, M, Ravin, CE, et al Comparison of plain radiography, conventional tomography, and computed tomography in detecting lymph node metastasis from lung cancer. Radiology 1982;142,157-161[Abstract/Free Full Text]
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  10. Bonomo, L, Ciccotosto, C, Guidotti, A, et al Lung cancer staging: the role of computed tomography and magnetic resonance imaging. Eur J Radiol 1996;23,35-45[CrossRef][ISI][Medline]
  11. Mountain, CF Revisions in the international system for staging lung cancer. Chest 1997;111,1710-1717[Abstract/Free Full Text]
  12. Kerr, KM, Lamb, D, Wathen, CG, et al Pathological assessment of mediastinal lymph nodes in lung cancer: implication for noninvasive mediastinal staging. Thorax 1992;47,337-341[Abstract]
  13. Vogel, P, Daschner, H, Lenz, J, et al Correlation of lymph node size and their infiltration by metastases in lung cancer. Langenbecks Arch Chir 1990;375,141-144[CrossRef][ISI][Medline]
  14. McLoud, T, Bourgounin, P, Greenberg, R, et al Bronchogenic carcinoma: analysis of staging the mediastinum with CT by correlative lymph node mapping and sampling. Radiology 1992;182,319-323[Abstract/Free Full Text]
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  16. Mönig, SP, Zirbes, TK, Schröder, W, et al Staging of gastric cancer: correlation of lymph node size and metastatic infiltration. AJR Am J Roentgenol 1999;173,365-367[Abstract/Free Full Text]
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  18. Kotanagi, H, Fukuoka, T, Shibata, Y, et al The size of lymph nodes does not correlate with the presence or absence of metastasis in lymph nodes in rectal cancer. J Surg Oncol 1993;54,252-254[ISI][Medline]
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