Lung cancer staging with EUS

This article is about lung cancer staging "methods" emphasizing the use of EUS (endoscopic ultrasound) whereas the companion article Non-small cell lung carcinoma staging is about the staging "system" (TNM).

Endoscopic ultrasound (EUS) is an endoscopic technique that allows a miniaturized ultrasound-probe to be driven though the mouth into the upper gastrointestinal tract to investigate organs and structures close to the esophagus, stomach or duodenum. The first paper describing the use of EUS to diagnose and stage lung cancer appeared in 1993.Wiersema M et al. Real-time endoscopic ultrasound-guided fine-needle aspiration of a mediastinal lymph node. Gastrointest Endosc 1993, 39(3):429-431] This is done by advancing a fine needle through the esophagus into adjacent lymph nodes. Since that time numerous studies have been performed that show that this methodology is effective, very safe, minimally-invasive, and very well tolerated. In fact, this approach offers so many advantages that many authorities in the field think that EUS together with EBUS (endobronchial ultrasound) will lead to profound changes in the way lung cancer is being diagnosed and staged.Annema J, Rabe K: State of the art lecture: EUS and EBUS in pulmonary medicine. Endoscopy 2006, 38 Suppl 1:S118-122 ]

The importance of accurate lung cancer staging

Correct staging of lung cancer is of paramount importance for the treatment planning process. Treatment choices are highly complex even for physicians with much experience in the field and they largely depend on the stage of the disease: Surgery yes or no, now or later. Radiation therapy combined with chemotherapy or chemotherapy alone,chemotherapy and radiation before surgery or after, or both. There is a no less bewildering array of staging methods available which all have their advantages and disadvantages. Many cancer treatment centers present the majority of their newly diagnosed patients to an inter-disciplinary chest tumor board where radiologists, oncologists, surgeons, pulmonologists, pathologists and EUS-specialists (endosonographers) discuss the relative merits of the available modalities and make a choice by consensus. This article will focus on the role endoscopic ultrasound plays in the staging and diagnosis of lung cancer with an emphasis on the most common type of lung cancer, non-small cell lung cancer (NSCLC) .

The progression of lung cancer occurs in stages

Lung cancer can start in various portions of the lung. From there it spreads in fairly predictable pattern. Typically, close-by lymph nodes are involved first by spreading cancer cells, followed by lymph nodes further away located between the lungs in a space called the mediastinum. In the mediastinum the lung cancer tends to first stay on the side where the original tumor started, once it crosses the midline, it becomes surgically unresectable. Lung cancer can also spread to distant organs, for example, the liver or adrenal glands, which constitutes the most advanced stage of the disease called stage IV. The results of staging are summarized in an internationally agreed upon shorthand notation system called the TNM system, where T stands for tumor, N for lymph node an M for distant metastasis (distant spread) [http://www.emedicine.com/radio/images/Large/62316231cb1281832001.jpg] . Staging information which is obtained prior to surgery, for example by x-rays and endoscopic ultrasound , is called clinical staging and staging by surgery is known as pathological staging. Pathologic staging is more accurate than clinical staging, but clinical staging is the first and sometimes the only staging type. For example, if clinical staging reveals stage IV or IIIB disease, surgery is not helpful and no pathological staging information will be obtained.

Clinical staging is done by a combination of imaging and sampling (biopsies), or stated differently, non-invasive (radiological) and invasive (biopsy) methods. Patients with lung cancer may have biopsies taken for two different reasons:
*1) Diagnosis:To find out whether an abnormality seen on a chest x-ray or CT scan is indeed lung cancer, and what histological type it is (small cell or non-small cell).
*2) Staging: To find out whether a structure, most often a lymph node in the mediastinum, has already been invaded by cancer or not. It is often possible, with proper planning, to obtain both diagnostic and staging information with a single biopsy procedure.

The limitations of Non-Invasive Staging

The mainstay of non-invasive staging is a CT scan of the chest followed by metabolic imaging with a PET scan. The CT scan shows abnormalities such as a lung nodule or enlarged lymph nodes whereas the PET scan reveals increased metabolism such as occurs in structures which contain rapidly growing cancer cells. Unfortunately, when it comes to the important lymph nodes in the mediastinum, the accuracy of these two methods is disappointing even if combined. The reasons for this are as follows:
*1.Radiologists evaluate lymph nodes on CT scans only by size. Any lymph node larger than 1 cm in short axis is called “pathologically enlarged” (suspicious). The problem is that very small lymph nodes (3-4 mm) can contain cancer and very large lymph nodes can be benign.
*2.Although PET scans are a big improvement over CT alone, they also have false-positive and false-negative results. PET scans evaluate metabolic activity, not the presence of cancer. For example, many smokers with abnormal lungs have chronic bronchitis and this inflammation can lead to inflamed lymph nodes which light up on a PET scan. Conversely, a small lymph node with cancer will not have enough activity to register on the PET scan.

According to the American College of Chest Physicians (ACCP) Non-Invasive Staging Guidelines for Lung Cancer (2007),Silvestri G et al. Noninvasive staging of non-small cell lung cancer: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest 2007, 132(3 Suppl):178S-201S ] the pooled sensitivity and specificity of CT scanning for identifying mediastinal lymph node metastasis are 51% and 85%, respectively and for PET scanning 74 % (95% CI, 69 to 79%) and 85% (95% CI, 82 to 88%), respectively. In other words, where one to rely on the results of non-invasive staging alone, between 21 to 31 percent of patients would be understaged (the cancer is more advanced than it seems) and between 12 and 18 percent of patients would be overstaged ( the cancer is in fact in an earlier stage than it seems). In many clinical situations confirmation of the results of the status of the mediastinal nodes by sampling will therefore be necessary and is recommended by the ACCP.Detterbeck F et al. Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007, 132(3 Suppl):202S-220S.]

The mediastinal lymph nodes

The American Thoracic Society has standardized the nomenclature of lymph nodes in the chest [http://www.euswiki.com/MediawikiDirectory/mediawiki-1.8.2/index.php?title=Lymph_Node_Map_for_EUS ATS Lymph Node Map] . There are fourteen numbered nodal stations. Lymph nodes considered to be in the mediastinum are stations 1 – 9. If cancer involves any of these mediastinal lymph node, these lymph nodes are designated N2 if they are on the same side as the original tumor, and N 3 if they are on the other. The presence of N3 lymph nodes affects the clinical stage very significantly.

Staging modalities

There are numerous modalities which allow staging of mediastinal lymph nodes. In the following table they are arranged from the most to the least invasive.

Staging Procedure	Advantages	Disadvantages
Thoracotomy (surgical opening of the chest)	Allows the most thorough inspection and sampling of lymph node stations, may be followed by resection of tumor, if feasible	Most invasive approach, not indicated for staging alone, significant risk of procedure-related morbidity
Left parasternal mediastinotomy (Chamberlain procedure)	Access to station 5 (aortopulmonary window lymph node)	Limited applications, invasive.
Cervical mediastinoscopy	Still considered the gold standard by many, excellent for 2 RL 4RL	Does not cover all medastinal lymph node stations, invasive
Video-assisted thoracoscopy	Good for inferior mediastinum, station 5 and 6 lymph nodes	Invasive, does not cover superior anterior mediastinum
Transthoracic percutaneous Fine Needle Aspiration (FNA) under CT guidance	More widely available than some other methods	Traverses a lot of lung tissue, therefore high pneumothorax risk, some lymph node stations inaccessible
Bronchoscopy with blind trans-bronchial FNA (Wang needle)	Less invasive than above methods	Relatively low yield, not widely practiced, bleeding risk
Endobronchial US (EBUS)	Direct visualization of lymph node stations. Complements EUS: covers lymph node stations 2R and 4R which are difficult to access by EUS	More invasive than EUS, few practitioners, but rapidly growing in popularity
Endoscopic Ultrasound (EUS)	Least invasive modality, uses the esophagus to access mediastinal lymph nodes, excellent for station 5, 7, 8 lymph nodes. Useful for station 2L and 4L, L adrenal, celiac lymph node	Cannot reliably access right sided paratracheal lymph node stations 2 R and 4R

EUS (endoscopic ultrasound) as minimally-invasive staging modality

A metaanalysis published in 2007 of EUS-guided FNA for the staging of NSCLC examines the performance of EUS in patients who have enlarged lymph nodes on CT, which, as we know, frequently does not mean cancer, and those who have no enlargement on CT, which -conversely- does not necessarily mean no cancer. Micames C et al. [http://www.chestjournal.org/cgi/content/full/131/2/539 Endoscopic ultrasound-guided fine-needle aspiration for non-small cell lung cancer staging: A systematic review and metaanalysis] . Chest 2007, 131(2):539-548. ] : The first group consisting of 8 studies comprised patients who had enlarged discrete mediastinal lymph nodes on CT: In this scenario, the pooled sensitivity was 90 % (95% CI, 84 to 94%) and the specificity 97% (95% CI, 95 to 98%) which are excellent results. In four studies with patients without enlarged mediastinal lymph nodes on CT the pooled sensitivity was 58 % (95 % CI, 39 to 75%). A total of 1,201 patients were included in the analysis from 18 eligible non-overlapping studies. Sixteen of these were prospective. Only 10 patients had minor complications (0.8%), the majority which were reported from one center, and no major complications were recorded. The performance of EUS in patients without enlarged mediastinal lymph nodes with a sensitivity of 58% appears disappointing. Nevertheless, if EUS is performed in this context, as a first staging test, it will help avoid more invasive staging procedures or surgery if positive. In other words, an EUS with a positive result showing cancer will avoid further needless surgery whereas a result not showing cancer may be false-negative requiring an excisional biopsy technique for confirmation such as VATS or mediastinoscopy.The ACCP guidelines recommend invasive staging for patients with or without mediastinal lymph node enlargement on CT regardless of the PET scan findings. If needle techniques are used (such as EUS-NA, TBNA, EBUS-NA, or TTNA) a non-malignant result should be further confirmed by mediastinoscopy as explained above.

EUS can reliably reach the lymph node stations 5, 7, 8 and 9. In the superior mediastinum the trachea is somewhat to the right of the esophagus which makes it often possible to reach left-sided area 2 and 4 lymph nodes and, less often, right sided paratracheal lymph nodes.Larsen S et al. Endoscopic ultrasound guided biopsy versus mediastinoscopy for analysis of paratracheal and subcarinal lymph nodes in lung cancer staging. Lung Cancer 2005, 48(1):85-92. ] In general, EUS is most appropriate for evaluation of the posterior inferior mediastinum while mediastinoscopy or EBUS are best for the anterior superior mediastinum. The feasibility of EUS-FNA of aorto-pulmonary window (subaortic) lymph nodes (station 5) is a major advantage of EUS. Evaluation of this station has traditionally required a paramedian mediastinotomy (Chamberlain procedure).EUS can easily sample celiac lymph nodes which cannot be reached by the other mediastinal staging methods. In one recent study an unexpectedly high incidence of celiac lymph node metastasis (11 %) was noted.Singh P et al. Endoscopic ultrasound as a first test for diagnosis and staging of lung cancer: a prospective study. Am J Respir Crit Care Med 2007, 175(4):345-354. ] EUS has also the advantage that left adrenal metastases can be biopsied whereas the right adrenal is mostly inaccessible.DeWitt J et al. Endoscopic ultrasound-guided fine-needle aspiration of left adrenal gland masses. Endoscopy 2007, 39(1):65-71.] A topic which will require further work is the utility of EUS-FNA in the restaging of the mediastinum in patients who have undergone chemotherapy and radiotherapy for N-3 disease (lymph nodes on the contralateral side). The idea behind this is that patients who previously were not operative candidates may have responded to chemotherapy and radiation so much that they now may be operative candidates. Rather than just going in which could lead to an “open and close” thorax surgery the staging, including invasive staging, should be repeated. If the initial mediastinal staging included a mediastinoscopy, most surgeons try to avoid a repeat mediastinoscopy after radiation treatment because of scarring. Restaging by PET and CT scanning may help to provide targets for biopsies but, as we know, even PET-negative mediastinums need to be sampled. EUS-FNA and EBUS-FNA appear to clearly offer the best risk-benefit ratio in these patients.Cerfolio R, Bryant A, Ojha B: Restaging patients with N2 (stage IIIa) non-small cell lung cancer after neoadjuvant chemoradiotherapy: a prospective study. J Thorac Cardiovasc Surg 2006, 131(6):1229-1235]

EBUS (endobronchial ultrasound) a complementary technique to EUS

As mentioned in the table, EUS cannot reliably access right sided paratracheal lymph node stations 2 R and 4R and may not be optimal for the left sided paratracheal lymph node stations either. An adaptation of the endoscopic ultrasound scope originally designed for the gastrointestinal tract is known as endobronchial ultrasound (EBUS). The instrument is inserted into the trachea rather than the esophagus. There are actually two types of EBUS bronchoscopes available: Radial catheter probe and convex probe EBUS (CP-EBUS).Yasufuku K et al. Endobronchial ultrasonography: current status and future directions. J Thorac Oncol 2007, 2(10):970-979. ] Only the latter will concern us here. The early experience for this instrument in mediastinal lymph node staging appears very promising with sensitivities ranging from 92 to 96 percent in 4 series comprising from 70 to 502 patients.Yasufuku K et al. Real-time endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal and hilar lymph nodes. Chest 2004, 126(1):122-128 ] Yasufuku K et al. Endobronchial ultrasound guided transbronchial needle aspiration for staging of lung cancer. Lung Cancer 2005, 50(3):347-354 ] Herth F et al.: Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes. Thorax 2006, 61(9):795-798.] Herth F et al.: Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically normal mediastinum. Eur Respir J 2006, 28(5):910-914 ]

Current Research: Complete medical mediastinoscopy with EUS and EBUS in combination

EBUS-FNA and EUS-FNA are complementary techniques. EBUS is strongest for the superior anterior mediastinum and EUS has the highest yield in the posterior inferior mediastinum. Some lymph node stations can only be accessed by one method and not the other (for example, station 2 and 4 L and 3 are hard or impossible to see by EUS, stations 5 and 8 cannot be biopsied by EBUS). Together, EBUS and EUS cover the entire mediastinum (except possibly station 6) and complete mediastinal staging should be possible with a combination of these two procedures. This combination could not only eliminate the need for most surgical mediastinoscopies but would in fact be more comprehensive. Many patients will, if given a choice, prefer an instrument which is inserted into the esophagus (EUS) over one which is inserted into the trachea (EBUS). Furthermore, many patients with suspected lung cancer will have other smoking related illnesses, such as emphysema or COPD, which makes a bronchoscopy-like procedure (EBUS) a higher risk than an upper endoscopy through the esophagus (EUS). An area of active and emerging research concerns the value of combining EUS and EBUS in a single session, one specialist following the other, or -even more convenient- a dual trained operator doing one or the other – or both- as needed. Preliminary data concerning “complete medical mediatinoscopy”were presented in an ongoing prospective blinded trial presented in part at the Digestive Diseases Week 2007. Sixty patients with lung tumors and/or enlarged mediastinal lymph nodes underwent combined EUS-FNA, EBUS-FNA and bronchocopy-FNA. The combination of EUS and EBUS was completed in an average of 52 minutes with conscious sedation only. EUS-FNA alone and EBUS-FNA alone both had sensitivities of 83% but both combined detected all but one patient with malignancy except for one, who had a lymph node anterior to the aortic arch (station 6) resulting in a sensitivity of 97%Wallace M et al. A Prospective Double Blind Comparison of Endoscopic Ultrasound, Endobronchial Ultrasound, and Bronchoscopic Fine Needle Aspiration for Malignant Mediastinal Lymph Nodes. Gastrointestinal Endoscopy 2007, 65(5):AB101 ] . This study has in the interim been published in its final form in the Journal of the American Medical Association now including a total of 138 patients. The authors conclude that EUS plus EBUS may allow near-complete minimally invasive mediastinal staging in patients with suspected lung cancer Wallace M et al. Minimally invasive endoscopic staging of suspected lung cancer.JAMA. 2008 Feb 6;299(5):540-6 ] .

References

External links

* Vilmann P, Larsen SS. [http://erj.ersjournals.com/cgi/reprint/25/3/400 Endoscopic ultrasound-guided biopsy in the chest: little to lose, much to gain] .Eur Respir J. 2005 Mar;25(3):400-1. Review

* [http://www.gi-guy.com/endoscopic_ultrasound_resources.html Endoscopic Ultrasound Resources]