PET scanning improves NSCLC staging compared to CT scanning. However, PET scans have a significant false-positive rate, and therefore tissue confirmation of PET-positive enlarged mediastinal lymph nodes is recommended. The authors prospectively evaluated 104 patients with NSCLC to determine the accuracy of EUS-FNA sampling of mediastinal lymph nodes compared to FDG-PET and CT staging of NSCLC. Only suspicious nodes in the posterior lymph node stations (#5, 7, 8, or 9) were evaluated. The endosonographer was blinded to the results of PET and CT scans. If EUS-FNA was benign (64%), patients underwent either thoracotomy with complete lymphadenectomy (61%), or long-term follow up (at least 6 months) with repeat imaging and clinical follow up (3%). The subcarinal space (level 7) was targeted 73% of the time and the median number of FNA passes was four. Granulomatous lung disease was the primary diagnosis by EUS-FNA in 17% and NSCLC in 57% The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EUS-FNA were 92.5%, 100%, 100%, 94%, and 97%, respectively. EUS-FNA had a higher positive predictive value than either PET or CT scan. There was a 50% false positive rate with PET scan. Subset analysis of those with proven lung cancer revealed 48% had cancer diagnosed by FNA of lymph nodes and 57% avoided invasive surgery. The authors concluded that EUS-FNA is a safe, accurate, and minimally invasive tool for staging NSCLC patients, and that it is more accurate and has a higher positive predictive value than either PET scan or CT scan for evaluating posterior mediastinal lymph nodes.

This study confirms previous studies showing that the main limitation of PET scan for evaluating malignant mediastinal lymph nodes is the high false-positive rate. PET scans have a very low false-negative rate, and therefore EUS-FNA is not needed in PET negative patients. However, in patients with mediastinal lymph nodes which are positive on PET scan, consideration should be given towards EUS-FNA to obtain tissue confirmation. This study also is consistent with several others showing the extremely high accuracy and safety of EUS-FNA for obtaining tissue diagnosis of enlarged posterior mediastinal lymph nodes.

It is estimated that one in five thoracotomies performed for lung cancer are “open and close” because of failure of pre-operative imaging studies to detect metastatic disease. The authors sought to determine the clinical impact of EUS in staging NSCLC in the absence of mediastinal lymphadenopathy on CT scan. The authors hypothesized that finding occult metastases with EUS may preclude unnecessary surgery. Patients were precluded from surgery if they had N3- contralateral lymph nodes or distant metastases by EUS-FNA. Cytology and clinical follow up were used as reference standards in those patients who did not undergo surgery. Seventy-six patients with NSCLC and no mediastinal lymphadenopathy were prospectively followed. There were no EUS related complications. Sixty-two (86%) of patients underwent surgery and 10 (14%) did not undergo surgery. Of the 10 patients who did not have surgery, 1 refused, and 9 were precluded based on EUS-FNA findings. Of the 9 patients, 5 had N3 disease and 2 had a positive celiac lymph node. EUS precluded surgery in 9 patients (12%) and altered management in 18 (25%). Of the 18 patients where EUS-FNA altered management, 8 patients had a benign left adrenal lesion and 5 had N3 disease. EUS imaging correctly staged 35 of 39 patients with negative mediastinal lymph nodes at surgery, resulting in a specificity of 90%. However, the overall specificity of EUS-FNA was 100% when suspicious appearing lymph nodes were included. Of the 6 patients with upper lobe NSCLC, only 1 of 6 had a positive mediastinal lymph node that was accessible to EUS imaging. On the contrary, 7 of 7 patients with lower lobe NSCLC, and 3 of 3 patients with hilar NSCLC had malignant lymph nodes by EUS imaging. EUS detected malignant mediastinal lymphadenopathy more frequently in patients with lower lobe and hilar cancers combined compared to upper lobe cancers. The authors estimate a direct cost savings of $300 million per year if 1 of every 8 of the 10,000 patients diagnosed with NSCLC every year were spared thoracotomy. The authors concluded that EUS played a significant role in patients with an unresectable (N3) NSCLC when adenopathy was not present on CT imaging, and is more sensitive in detecting lymph node and metastases in lower lobe and hilar than upper lobe NSCLC.

This important study shows that EUS-FNA can detect a significant number of patients with metastatic disease in NSCLC compared to CT scanning alone. The ability to detect suspicious appearing lymph nodes depends on the quality of the CT scanner and radiologist, and there is the potential that several malignant lesions were missed due to older technology missing lesions. Additionally, this study does not use PET scans in the diagnostic algorithm, and it would be interesting to know if that would have changed the results (acknowledging the high false-positive rate of PET). Finally, it is unknown if these patients with non-enlarged lymph nodes on CT, but who have “micro-metastases”, have a clinical outcome the same as other bulky N2 or N3 NSCLC, or if they would perhaps have these nodes removed anyway during thoracotomy and have a good clinical outcome. It is also unknown if this would be a subgroup which would benefit from pre-operative chemoradiation. An important observation of this study is noting the higher detection rate of mets in lower lobe and hilar NSCLC. Ultimately, the thoracic oncology community will need to determine if this information is important, and, if so, how it will change management.

The recurrence of cancer after the complete resection of early stage NSCLC may indicate that there are micro-metastases in lymph nodes at the time of resection. Wallace and colleagues determined if combining real time reverse transcriptase-polymerase chain reaction (RT-PCR) with EUS-FNA would enhance the preoperative detection of occult metastases. Eighty-seven patients with NSCLC with no metastases detected by CT and PET scan were evaluated. Lymph nodes were sampled for cytopathology and RT-PCR. Seventeen patients without cancer but with benign disease were used as the control group. Expression of six lung cancer-associated genes (CEA, CK19, KS1/4, lunx, muc1, and PDEF) were detected by RT-PCR. KS1/4 gene was above its clinical threshold in 25 of 27 (93%) of cytology-positive lymph nodes. KS1/4 was the most sensitive marker to detect micro-metastases. Of the cytology-negative patients, one of the six genes was overexpressed in 18 of 61 patients (30%) of which KS1/4 was overexpressed in 15 of these 18 patients. The authors predict that cytology-negative/marker positive NSCLC patients will have a high recurrence rate. Furthermore, KS1/4 is useful to detect over or occult metastatic non small cell lung cancer.

The evaluation of micrometastases as a clinical tool is in its infancy. This may be important for smaller nodes that evade detection by PET and CT. However, it remains to be determined how micrometastases detection will change the management of these patients compared to conventional cytology alone. In addition, it is unknown how the prognosis or treatment is changed when micromets are present and if the array of RT-PCR testing is cost-effective. It is also uncertain if patients will get adjuvant or neo-adjuvant chemo-radiation instead of lymph node dissection, and if lymph node dissection will remove the disease. Prospective outcomes studies will need to determine the answers to these issues.

Editor's Note: For those interested in more information regarding the utility of EUS in staging lung cancer, please see the review by Thomas J. Savides, M.D. and Richard Dobhan, M.D. by clicking here. Figure at right shows Regional Lymph Node Staging of Lung Cancer and is Figure 1A from Review, "EUS Staging of Lung Cancer," available by clicking the link above.

Figure

With the not so trivial morbidity (10-20%) and mortality (1-3%) rates of a major pancreatic resection for a cystic lesion, safer and less invasive means of treatment are being investigated. The purpose of this pilot study was to determine the safety and feasibility of EUS-guided ethanol lavage of pancreatic cystic lesions. Secondary outcomes were to determine the effects on cyst size and ablation. Asymptomatic patients with a pancreatic cystic lesion 1 cm to 5 cm in diameter were eligible. Cysts were collapsed first before lavage for 3 to 5 minutes. Cyst aspirate was sent for cytology, CEA, and amylase while viscosity of cysts was documented. In this prospective, single center study, 35% of 23 patients had complete cyst resolution on repeat imaging at 6-12 months, and 13% had a decreased size of the cyst. Five patients underwent cyst resection all of whom had histologic evidence of cyst ablation. Adequate cytology was obtained in 64% of patients and none of these were malignant. The authors concluded that EUS-assisted ethanol lavage of pancreatic cysts is safe and feasible.

This is an interesting, and potentially quite important, new application of interventional endosonography. The ability to use EUS-guidance to ablate lesions is potentially more important for definite neoplastic lesions, such as small neuroendocrine tumors or possibly unresectable adenocarcinoma. Because we do not know the natural history of most incidentally found cystic lesions of the pancreas, it is unclear whether the potential benefits of alcohol ablation are worth the risks. For now, this should continue to be considered purely an investigational technique.

The diagnosis of autoimmune pancreatitis can be difficult to make. Patients do not always have other autoimmune disease or elevated serum IgG4 levels. EUS-FNA alone does not always provide an adequate specimen to make the diagnosis. In this study, EUS-TCB was obtained in 3 patients with obstructive jaundice and suspected autoimmune pancreatitis. Nine features were collected which are closely related to autoimmune pancreatitis. A mean of 3.3 trucut biopsies were obtained per patient. Histologic review of the specimens established the diagnosis of AIP in 2 patients and identified chronic pancreatitis in a third patient. Other than transient abdominal pain in 1 patient, there were no complications. The authors conclude that EUS-TCB can safely diagnose AIP and help avoid unnecessary surgery.

EUS-guided trucut biopsies have the potential to obtain cores of tissue for pathologic evaluation, rather than just cells for cytologic evaluation. Unfortunately these needles are difficult to use for most endosonographers, especially when trying to obtain a trans-duodenal biopsy. This case-series suggests that perhaps it is worth the extra effort to obtain trucut biopsies when the immediate cytologic evaluation is uncertain for autoimmune pancreatitis. Furthermore, serology studies such as lactoferrin antibody and anticarbonic anhydrase II antibody, or empiric trials of steroids, may spare the need for TCB.