Feb 222015

image: Olympus

Most lung cancers spread to the lymph nodes in the chest first. Unless distant spread to other organs (metastasis) is obvious, biopsy of any suspicious intrathoracic lymph nodes is necessary to stage and prognose lung cancer. The presence or absence of cancerous lymph nodes, and their location in relation to the lung cancer, determine whether someone can undergo potentially curative surgical resection and whether chemotherapy and radiation are needed.

In prognosis and staging of most lung cancer, location of positive lymph nodes is everything. A single positive lymph node (nodal metastasis) on the opposite side of the chest from the primary lung cancer can reduce the odds of 5-year survival to 5%. The key question in staging lung cancer (especially non-small cell lung cancer, the most common form) are whether N2-N3 nodes are affected.

Mediastinoscopy or VATS Often Done Despite Negative EBUS

In the old days (10 years ago), limited thoracic surgery (mediastinoscopy) was the only way to biopsy lymph nodes in the chest. Today, less-invasive transbronchial needle aspiration (TBNA) during bronchoscopy with endobronchial ultrasound (EBUS) has been proven accurate and safe, and has replaced mediastinoscopy as the first procedure for thoracic lymph node biopsy.

The problem comes when EBUS-guided biopsies of suspicious lymph nodes (>10 mm diameter or PET-positive) are negative. A negative EBUS done by experts rules out cancer with about 80-90% accuracy — not quite definitive enough. Patients with negative EBUS biopsies of suspicious lymph nodes are usually advised to then undergo mediastinoscopy or VATS, still considered the gold standard.

But those numbers imply that after a negative EBUS biopsy, 10 patients without metastasis may undergo mediastinoscopy/VATS to identify one with a positive lymph node. Almost half of patients undergoing EBUS for staging of non-small cell lung cancer have negative lymph node biopsies, so that’s a lot of unnecessary surgeries.

Some experts have questioned the practice, but it persists, because 1) we know EBUS-TBNA accuracy varies by skill of the operator, 2) patients with lung cancer are willing to go through mediastinoscopy to get more certainty in their prognoses, and 3) no surgeon wants to tell someone “we got it all” after surgery, and be wrong.

Are there factors that can predict whether cancer is present or absent in a suspicious lymph node that’s negative after EBUS biopsy? If so, it could spare some patients the pain and risk of unnecessary surgery for staging of lung cancer.

Risk-Stratifying Lymph Nodes with EBUS: What's the Evidence?

In 2010, the first large study of 1,061 EBUS-TBNA lymph node biopsies in 487 patients with lung cancer was published by Fujiwara et al. They found four independent predictors of nodal metastasis:

  • Heterogeneous echogenicity
  • Round shape (rather than oval)
  • Distinct margin
  • Coagulation necrosis sign (a hypoechoic “black hole” without blood flow, usually on a lymph node's edge)

No single factor predicted nodal metastasis reliably, and positron emission tomography (PET scan) data was not considered in the analysis. (Click here for image examples of these findings.)

A new study by Matthew Evison et al builds on Fujiwara et al’s work. Evison et al retrospectively studied 877 lymph nodes from 509 patients undergoing EBUS-TBNA at the University Hospital of South Manchester (UK).

All patients had a definite diagnosis of lung cancer (83% non-small cell; 17% small cell). In addition to lymph node morphology on ultrasound, authors integrated PET scan data: standardized uptake value (SUV) and the ratio of the lymph node’s SUV to the tumor’s SUV (calculated as a percentage, called SUV%).

In this analysis, three lymph node factors independently predicted the presence of nodal metastasis:

  • Heterogenous echogenicity of lymph node on EBUS (with an odds ratio of 48:1 favoring malignancy)
  • Lymph node PET scan SUV >4 (odds ratio of 10:1)
  • Lymph node SUV% >40 (odds ratio 9:1), and moreso for SUV% >60 (odds ratio 46:1).

They combined these 3 factors into a 0-5 point scoring model, stratified as low risk (0-1 points) or high risk (2-5 points). They then tested it on a derivation set and validation set of all the studied patients’ nodes.

Nodes classified as low risk had a 98-99% sensitivity for ruling out metastasis, while 65% of high risk nodes were malignant, in both the testing and validation groups.

Size >10 mm and round shape were not independent predictors of nodal metastasis. Loss of central hilar structures and the presence of a coagulation necrosis sign were strongly associated with malignancy, but occurred too infrequently to be included in the model.

Examples of low risk nodes would be enlarged, homogenous nodes with mildly elevated SUV uptake (>4), or significant SUV uptake but <=40% that of the primary tumor.

All nodes with heterogenous echogenicity or with SUV >60% that of the tumor were high risk.

The main limitation of the study was that only half the nodes deemed negative by EBUS-TBNA had surgical confirmation (many were poor surgical candidates or declined mediastinoscopy).

As with any screening test or scheme, its sensitivity depends on the true prevalence of the finding in the tested population. All these patients had lung cancer, and ~19% of the analyzed nodes were malignant. The study has no application to patients without lung cancer (e.g. EBUS for asymptomatic lymphadenopathy).

These results align with a 2012 study in which heterogeneous echogenicity had a 73% positive predictive value for malignancy, in a cohort of about 55:45 benign vs malignant lymph nodes.

How to Avoid Needless Mediastinoscopy After EBUS

"We need more tissue." It's easy for an oncologist to say after a negative EBUS-TBNA of a suspicious lymph node. It's guideline-compliant. It seems necessary to eliminate uncertainty.

But it's hard for a patient with lung cancer to hear, knowing it means yet another painful, stressful procedure. And the truth is, it might be safely avoided in many patients if we doctors got our act together.

How? EBUS-TBNA has become the standard at most academic centers in developed countries. Yet there's been almost no formal sharing of data among institutions. By creating a registry using the aforementioned predictors and other data (PET, molecular markers, etc), tens of thousands of patients' lymph nodes could be pooled and analyzed. A reliable predictive model, or the statistical power to rule out the possibility of one, should result -- either of which would advance the state of the art.

Such consortia are the obvious solution to the balkanization of the research enterprise, which produces endless series of inconclusive, small-scale studies. Under our feudal-like system, universities compete for prestige and research funding instead of collaborating to improve real health outcomes.

Absent such cooperation, this study will require the usual prospective replication, validation in larger cohorts, etc., etc., which may or may not ever occur. Until then, we who perform EBUS will be left to make our best guesses whether negative lymph node biopsies are truly benign. And people with lung cancer will continue to hear "we need more tissue," even if we don't.

Read more:

Nodal Staging in Lung Cancer: A Risk Stratification Model for Lymph Nodes Classified as Negative by EBUS-TBNA. Matthew Evison et al, Journal of Thoracic Oncology, January 2015, Vol. 10 - Issue 1: p 126–133.

Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.

The utility of sonographic features during endobronchial ultrasound-guided transbronchial needle aspiration for lymph node staging in patients with lung cancer: a standard endobronchial ultrasound image classification system. Chest. 2010 Sep;138(3):641-7. doi: 10.1378/chest.09-2006. Epub 2010 Apr 9.

Real-time prediction of mediastinal lymph node malignancy by endobronchial ultrasound. Hanaa Shafiek et al. Arch Bronconeumol. 2014;50:228-34. - Vol. 50 Num.06 DOI: 10.1016/j.arbr.2014.05.003

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Who needs mediastinoscopy after negative EBUS staging for lung cancer?