Commentary (Brugge): Endoscopic Ultrasound Fine-Needle Aspiration in the Staging of Non-Small-Cell Lung Cancer

October 1, 2006

Precise mediastinal staging of non-small-cell lung cancer is extremely important, as mediastinal lymph node metastases generally indicate unresectable disease. Reliance on computed tomography (CT) and positron-emission tomography (PET) alone to stage and determine resectability is limited by false-positive results. Whenever possible, pathologic confirmation of metastases is desirable. Mediastinoscopy and transbronchial fine-needle aspiration are widely established but imperfect modalities. Endoscopic ultrasound fine-needle aspiration (EUS-FNA) has emerged as a diagnostic and staging tool because of its safety, accuracy, and patient convenience. We reviewed 13 prospective studies evaluating the comparative performance of EUS for staging lung cancer. We conclude that EUS is a valuable staging modality. Further studies of the role of EUS compared to other modalities such as integrated PET/CT and endobronchial ultrasound (EBUS) are forthcoming.

 Drs. Ogita, Robbins, Blum, and Harris have reviewed the various invasive and noninvasive staging modalities used for the staging of patients with non-small-cell lung cancer (NSCLC). The authors represent the specialties of oncology, gastroenterology, and thoracic surgery at a major medical center. The accuracy of noninvasive staging via computed tomography (CT) and positron-emission tomography (PET) scanning is reviewed using a retrospective review of a large number of published series. Additional attention is focused on the results of more invasive procedures, including mediastinoscopy, endoscopic ultrasound fine-needle aspiration (EUS-FNA), and endobronchial ultrasound FNA (EBUS-FNA). Astute readers may wonder why a gastroenterologist would be writing about lung cancer staging and why a gastroenterologist would be writing this editorial.

Gastroenterologists are the major source of controversy in lung cancer staging. The performance of EUS-FNA by gastroenterologists has demonstrated an accuracy rate superior to any other staging modality in lung cancer. How could an endoscopic procedure designed for the upper GI tract have such success in the staging of lung cancer? Let's examine some of the key features of EUS-FNA.

Origins of EUS

EUS was initially designed to provide an imaging modality for the staging of esophageal and gastric cancer. In the original configuration of the device, a high-frequency ultrasound probe was placed on the tip of an endoscope. High-resolution, cross-sectional images were obtained of the relationship between the malignant mass and the wall of the esophagus or stomach. Intramural lesions (T1-2) were found to be localized to the wall, whereas transmural lesions (T3-4) were found to be invading through the muscularis propria.[1]

Not only did EUS provide highly accurate tumor staging, EUS also provided detailed imaging of mediastinal lymph nodes. In the traditional radial EUS configuration, only imaging of lymph nodes was possible. With the recent introduction of linear EUS, FNA has become standard and has dramatically improved the accuracy of lymph node staging.

Principles of EUS-FNA

EUS-FNA has dramatically increased the accuracy of esophageal cancer staging through lymph node aspiration. What are the principles used in the aspiration of lymph nodes? The first principle of EUS-FNA is the safety of the procedure.[2] When small-gauge needles (22 or 25 gauge) are placed across the esophagus, the rate of complications (such as bleeding, infection, pneumomediastinum) is surprisingly rare. The esophagus (and the rest of the GI tract) has proven to be a remarkable window for FNA. The small tracts made by the passage of the needle are quick to close and seal over completely.[3] Bleeding is rare because the endoscopist is able to guide the needle very accurately with Doppler imaging and avoid blood vessels.

The second principle of EUS-FNA is the high quality of aspiration cytology. Despite the needle passing through the echoendoscope, into the esophageal lumen, and across the esophageal wall, the quality of cytology of the aspirated lymph node is relatively high.[4] There are several key characteristics of EUS-FNA that assure high-quality cytology. Most importantly, the aspiration needle is occluded by a stylet when it is passed through the esophageal wall, preventing the passage of gastroesophageal mucosal material into the needle. Aspiration of lymph nodes provides highly recognizable cytologic material for the cytologist. It is rare for gastroesophageal contamination to cause falsely negative or positive cytology.

The third principle of EUS-FNA is the least secured one. Although EUS imaging readily detects lymph nodes along the esophagus (for distances up to 5 cm) and it is technically easy, there is some uncertainty as to how well aspiration cytology detects malignancy. In the original studies of a large spectrum of patients with mediastinal lymphadenopathy, the accuracy of EUS-FNA was 94% in the detection of malignancy in enlarged lymph nodes.[5] In the staging of esophageal cancer, the accuracy of EUS-FNA for detecting malignancy in celiac lymph nodes has proven to be highly sensitive (90%).[6] Aspiration cytology is dependent upon the ability of the cytologist to recognize malignant cells within lymphocytes.

Accuracy in Staging Mediastinal Lymph Nodes

How accurate is EUS FNA for the evaluation of mediastinal lymph nodes? While EUS can provide detailed imaging of lymph nodes, FNA cytology is superior to the use of imaging criteria for malignancy.[7] Although EUS was traditionally used to evaluate mediastinal lymphadenopathy, EUS-FNA was recently found to detect advanced malignancy in nearly 25% of lung cancer patients who had no evidence of adenopathy on CT scanning.[8] When EUS-FNA is used preoperatively, 70% of patients will not be candidates for surgery, based on the finding of malignancy in aspirated lymph nodes.[9] Even when patients are excluded based on positive PET scanning, an additional 22% of patients will have a positive EUS-FNA cytology.[10] When using the results of surgical exploration, EUS-FNA was found to have an overall accuracy rate of 94% in the detection of malignant lymph nodes.[11]

Although EUS is best at the detection of posterior mediastinal lymph nodes, the vast majority of malignant adenopathy is detectable by EUS-FNA.[12,13] Furthermore, recent evidence has demonstrated the superiority of EUS-FNA over mediastinoscopy in the staging of anterior mediastinal lymph nodes. The sensitivity for lymph node metastases in region 2/4L and/or 2/4R and/or 7 was 96% for EUS-FNA vs 24% for mediastinoscopy.[14]

Recently, EUS-FNA has been used not only preoperatively, but also after chemoradiation therapy. The presence of malignant aspiration cytology was found to be predictive of response to chemoradiotherapy.[15]

Transferring the Technology

Despite these impressive results of EUS-FNA, the technology has not been widely accepted by oncologists and thoracic surgeons. Drs. Ogita, Robbins, Blum, and Harris have done an excellent job of summarizing the literature, and it is becoming clear that EUS-FNA offers the best means for lung cancer staging. How can we transfer this technology to thoracic surgeons and/or pulmonologists?

It appears that thoracic surgeons or pulmonary physicians would be appropriate for providing lung cancer staging since they are intimately involved with the patients. It is difficult to incorporate gastroenterologists in this process, as the focus of their patient care is so different. Since thoracic surgeons are more comfortable with esophageal endoscopy, it would seem that thoracic surgeons are the best candidates for the adoption of EUS-FNA.

There are several barriers to the transfer of EUS-FNA from gastroenterology to the pulmonary and thoracic specialties. The transfer of technical skills is a small hurdle, as EUS-FNA is relatively easy. A host of other professional challenges stand in the way, including tradition, "turf battles," privileges, and malpractice insurance. Nevertheless, these bumps in the road should not stand in the way of what is best for the patient who requires lung cancer staging.

 

-William R. Brugge, MD

References:

1. Brugge WR, Lee MJ, Carey RW, et al: Endoscopic ultrasound staging criteria for esophageal cancer. Gastrointest Endosc 45:147-152, 1997.

2. Kramer H, van Putten JW, Douma WR, et al: Technical description of endoscopic ultrasonography with fine-needle aspiration for the staging of lung cancer. Respir Med 99:179-185, 2005.

3. Wiersema MJ, Vilmann P, Giovannini M, et al: Endosonography-guided fine-needle aspiration biopsy: Diagnostic accuracy and complication assessment. Gastroenterology 112:1087-1095, 1997.

4. Gress FG, Hawes RH, Savides TJ, et al: Endoscopic ultrasound-guided fine-needle aspiration biopsy using linear array and radial scanning endosonography. Gastrointest Endosc 45:243-250, 1997.

5. Fritscher-Ravens A, Sriram PV, Bobrowski C, et al: Mediastinal lymphadenopathy in patients with or without previous malignancy: EUS-FNA-based differential cytodiagnosis in 153 patients. Am J Gastroenterol 95:2278-2284, 2000.

6. Parmar KS, Zwischenberger JB, Reeves AL, et al: Clinical impact of endoscopic ultrasound-guided fine needle aspiration of celiac axis lymph nodes (M1a disease) in esophageal cancer. Ann Thorac Surg 73:916-921 (incl discussion), 2002.

7. Schmulewitz N, Wildi SM, Varadarajulu S, et al: Accuracy of EUS criteria and primary tumor site for identification of mediastinal lymph node metastasis from non-small-cell lung cancer. Gastrointest Endosc 59:205-212, 2004.

8. Wallace MB, Ravenel J, Block MI, et al: Endoscopic ultrasound in lung cancer patients with a normal mediastinum on computed tomography. Ann Thorac Surg 77:1763-1768, 2004.

9. Annema JT, Versteegh MI, Veselic M, et al: Endoscopic ultrasound-guided fine-needle aspiration in the diagnosis and staging of lung cancer and its impact on surgical staging. J Clin Oncol 23:8357-8361, 2005.

10. Sawhney MS, Kratzke RA, Lederle FA, et al: Endoscopic ultrasound and positron emission tomography for lung cancer staging. Clin Gastroenterol Hepatol 4:846-851, 2006.

11. Caddy G, Conron M, Wright G, et al: The accuracy of EUS-FNA in assessing mediastinal lymphadenopathy and staging patients with NSCLC. Eur Respir J 25:410-415, 2005.

12. Cerfolio RJ, Bryant AS, Ojha B, et al: Improving the inaccuracies of clinical staging of patients with NSCLC: A prospective trial. Ann Thorac Surg 80:1207-1214 (incl discussion), 2005.

13. Fernandez-Esparrach G, Gines A, Belda J, et al: Transesophageal ultrasound-guided fine needle aspiration improves mediastinal staging in patients with non-small cell lung cancer and normal mediastinum on computed tomography. Lung Cancer 54:35-40, 2006.

14. Larsen SS, Vilmann P, Krasnik M, et al: Endoscopic ultrasound guided biopsy versus mediastinoscopy for analysis of paratracheal and subcarinal lymph nodes in lung cancer staging. Lung Cancer 48:85-92, 2005.

15. Varadarajulu S, Eloubeidi M: Can endoscopic ultrasonography-guided fine-needle aspiration predict response to chemoradiation in non-small cell lung cancer? A pilot study. Respiration 73:213-220, 2006.