Having less invasiveness compared to mediastinoscopy and VATS, EUS-FNP has a high power to clarify the nature of unspecified mediastinal lymphadenopathy or other lesions. To tap the full potential, it should include all histologic, immunochemical, molecular-biological, and bacteriological methods (◘ Table 5.1). A close collaboration with the corresponding laboratory and pathology physician and the use of appropriate transport media for specialized examination is crucial.

Likewise, EUS-FNP can be used for difficult accessible lesions of the retroperitoneum (including adrenal gland, kidney, pancreas), of the spleen, and of the left liver lobe including the liver hilum (◘ Table 5.2, ◘ Fig. 5.1). Additionally, para-aortic lymph nodes and lesions such as morbus Ormond are accessible up to the level of the aortic bifurcation using a transduodenal approach. EUS-FNP should be taken into account if liver lesions are not clarified by contrast imaging and are not accessible transcutaneously (Dumonceau et al. 2011; Adler et al. 2007).

Solid masses of the adrenal glands most often consist of nonfunctional, benign adenomas or hyperplastic nodules that do not require any histologic assessment (so-called incidentalomas). There are, however, some adrenal masses ranging from 3 to 6 cm in size that may require further workup (according to certain diagnostic algorithms) upon exclusion of hormonal activity from these tumors. EUS-guided fine-needle aspiration (or core-needle) biopsy (EUS-FNA) should only be performed after pheochromocytoma has been ruled out, for instance, by 24-h-sampling of urine to measure catecholamine and metanephrine levels. Most EUS-FNA biopsies with cytohistologic analysis are being carried out to search for metastasis into the adrenal glands in lung cancer, colonic cancer, and others. The left adrenal gland is readily accessible for EUS-FNA in virtually all cases (◘ Fig. 5.2), while the right adrenal gland shows variable accessibility and cannot be seen by EUS in approximately 30–40% of cases.

Locoregional staging by EUS-FNA exerts a significant impact on the further clinical decision-making in cancer patients when cytohistologic proof of malignant disease stages a tumor up (or down, if true negative results are revealed). This is frequently the case in patients with lung cancer (NSCLC) – particularly when EUS-FNA reveals metastasis to the adrenal glands or retroperitoneal lymph nodes or when PET-negative, contralateral lymph nodes have been proved to be infiltrated by cancer (N3 situation). In such circumstances and disease stage, surgical procedures are most often deemed unnecessary and too aggressive since they do not offer any chance of healing to the affected patients but expose the patients to a high risk of postoperative complications (including postoperative mortality ranging from 2% to 4%, pulmonary complications in approximately 15% of cases).

Since both EUS-FNA and EBUS-TBNA exhibit a far superior safety and convenience profile for patients and investigators (when compared with thoracic surgery including mediastinoscopy/thoracotomy), major diagnostic surgery has almost become obsolete. Therefore, most patients do not need any surgical staging procedure. EUS-FNA and EBUS-TBNA are complementary procedures that allow for accurate oncologic tumor staging in almost every patient with lung carcinoma. Up to 25% of patients who are PET-negative do still have carcinomatous infiltrates within their regional lymph node stations, which can be detected by fine-needle biopsy in most instances. Hence, such positive N2- or N3-categories preclude patients from unnecessary operations. EUS-FNA also has the potential to disclose previously undiagnosed distant metastases such as adrenal gland involvement and/or small metastatic nodules in the liver or infradiaphragmatic lymph nodes. In summary, staging of lung carcinoma has been greatly simplified and improved by the use of endoscopic staging procedures including EUS-FNA and EBUS-TBNA (◘ Table 5.2 and ◘ Table 5.3) (Jenssen and Hollerbach 2013; Hollerbach et al. 2010; Moehler et al. 2011). Modern contemporary staging concepts reserve surgical mediastinoscopy or VATS for the few remaining clinical cases in which EUS could not be properly performed or which were invariably negative due to technical difficulties or repeated sampling errors (Jenssen and Hollerbach 2013; Sharples et al. 2012). The clinical impact of EUS biopsy results in oncologic treatment algorithms in lung cancer, and other malignancies has been clearly proven by numerous clinical studies and can be considered evidence-based (Sharples et al. 2012).

EUS-FNA is also helpful and accurate for cytohistologic assessment of pancreatic tumors that – based on radiologic or endosonographic imaging findings and surgical judgment – appear to be unresectable at time of diagnosis (Dumonceau et al. 2011; Jenssen et al. 2011a; Moehler et al. 2011). Such findings preclude patients from unnecessary surgery and facilitate decision-making for neoadjuvant or palliative treatment decisions.

Approximately 10–15% of pancreatic tumors are not ductal adenocarcinomas but consist of other malignant (or semi-malignant) entities such as neuroendocrine tumors, metastases, lymphomas, or solid-papillary pancreatic tumors (young women). In all cases of doubt, EUS-FNA can be very helpful to establish a definite diagnosis prior to individual therapy, to rule out benign disease such as autoimmune pancreatitis, to assess prognosis of cancer patients, to plan surgical strategy, and – most recently – to allow for novel therapeutic studies that investigate new regimes for neoadjuvant therapy in pancreatic cancer.

EUS-FNA techniques can be helpful for assessment and definite diagnosis of subepithelial tumors (SET) in the upper and lower GI tract (◘ Fig. 5.5). EUS needles, however, have a limited diagnostic accuracy – particularly in small tumors (<1.5 cm) – that is superior to other approaches such as «button-hole» forceps biopsies during EGD (Dumonceau et al. 2011; Jenssen et al. 2011a; Jenssen and Hollerbach 2013; Jenssen and Dietrich 2008) but still doesn’t exceed >65–70% in this setting, which is not satisfying as yet. Accuracy can possibly be enhanced by using novel biopsy devices such as the «shark core» needle, but the potential of such techniques remains to be substantiated by ongoing clinical trials.

In patients suffering from ampullary or biliary neoplasias including bile duct and gall bladder carcinomas, EUS-FNA achieves better results than other diagnostic approaches including brush biopsies or biliary forceps biopsies. Even small neoplasias are clearly visible and detectable by EUS and can be punctured with high diagnostic accuracy.

In some other malignancies including focal liver tumors such as hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCC), or scirrhous gastric cancer, EUS-FNA can be used (with high diagnostic accuracy) as an alternative technique to obtain histologic proof of disease and tissue-based diagnosis for targeted oncologic therapies and treatment planning (Dumonceau et al. 2011; Jenssen et al. 2011a; Jenssen and Hollerbach 2013; Hollerbach et al. 2010).

Detection and locoregional biopsy of suspicious retroperitoneal lymph nodes are also very important in other cancers such as biliary carcinoma, hepatocellular carcinoma, and neuroendocrine tumors, as shown in several clinical studies.

In contrast, locoregional involvement of peripancreatic lymph nodes does not change current treatment protocols including radical surgery as single most important measure, whereas novel neoadjuvant treatment studies are currently on their way that may possibly change the dismal clinical course and prognosis of affected patients.

In patients with esophageal, gastric, duodenal, and rectal cancer, however, the overall survival and prognosis are highly dependent on lymph node (micro-)metastasis, as shown in numerous clinical studies. The presence of lymph node spread (= N+ situation) in such cancers dramatically reduces the 5-year survival rate of affected patients by more than 50%. If stage N+ and/or advanced T stages are found during EUS staging in such cancer patients, neoadjuvant treatment protocols should be the strategy of choice in most instances. Therefore, German clinical S3 guidelines recommend EUS staging for esophageal, gastric, and rectal cancer in combination with imaging studies (CT, MRT, PET), whereas the exact role of FNA has not yet been fully addressed in these guidelines. Accuracy of N-staging can be substantially improved by EUS-FNA (Moehler et al. 2011). If FNA is performed by passing the needle through the tumor into a regional lymph node, this biopsy is often contaminated by tumor cells arising within the GI wall layers but not from the lymph node itself (Jenssen et al. 2011a; Levy et al. 2010). This problem must be avoided during EUS-FNA by choosing different pathways for the biopsy needle that do not go straight or laterally through tumor-infiltrated GI layers, and by removing the stylet of the needle only after the needle tip is clearly visible within the lymph node.

Lymph nodes should only be biopsied, however, during EUS staging if the results have a high likelihood to change the individual treatment strategy in all patients, for instance, decisions in favor of palliative versus surgical treatment.

Distant metastasis is only rarely detectable by EUS techniques in GI cancers because of the locoregional character of this technique and limited access to distant organs and compartments. However, in up to 12–15% of EUS staging cases with esophageal, gastric, pancreatic, and biliary cancers, EUS may detect previously unknown – or unclear – focal lesions that were not clearly visible, or mistaken, during CT or MRT imaging (= «obscure» metastasis). Examples include distant suspicious lymph nodes in pancreatobiliary cancer such as mediastinal lesions, small liver metastasis <5 mm in patients with esophageal or gastric or colorectal cancer, small adrenal noduli, pancreatic lesions, and peritoneal or pleural masses. In such cases of doubt, needle biopsy should be undertaken or attempted since histologic proof of advanced disease may dramatically change treatment decisions, including surgical interventions that are no longer indicated. Knowledge of TNM staging classification for each subtype of GI cancer is absolutely necessary (Sobin et al. 2009) before oncologic treatment plans can be made with accurate certainty.

For therapeutic interventions, advanced expertise arising from advanced experiences with EUS techniques is the principal requirement prior to introduction of such techniques. ◘ Table 5.4 demonstrates the current status of therapeutic EUS techniques in the clinical setting, of which several techniques should still be regarded as strictly experimental.

In addition, patients with severe plasmatic coagulopathies (INR >1.75, significantly prolonged activated prothrombine time PT), or those presenting with severe thombopenias (thrombocyte count <50,000), should not be deliberately subjected to EUS-FNA in terms of a pre-diagnostic risk assessment. In contrast, aspirin (ASS) treatment is no longer considered to be a major obstacle to EUS-FNA.

Other absolute contraindications of EUS-FNA include lack of informed consent by patients or lack of visibility during needle biopsy. To minimize risk of bleeding, interpolated vessels located within the needle tract should always be avoided during EUS-FNA.

The general clinical condition of the individual patient needs always to be considered, while EUS-FNA is planned during clinical risk assessment strategies. If EUS-FNA results do not look likely to impact further clinical decision-making, its indication should always be critically reassessed. ◘ Tables 5.5 and 5.6 demonstrate absolute and relative contraindications for EUS-FNA.

The overall rate of complications of diagnostic endosonography (without FNA) is reported to lie somewhere in the range between 0.03% (retrospective questionnaires) and 0.22% (prospective studies). Complications of EUS-FNA are somewhat more frequent: one systematic analysis of 51 EUS-FNA studies including 10,941 patients reported a cumulative complication rates of 0.98%. Looking at the 31 existing prospective studies only, however, sheds a – probably more realistic – light on the clinical situation: in this analysis the cumulative rate of complications reached 1.71% of cases (Polkowski et al. 2012; Wang et al. 2011; Gottschalk et al. 2012; Jenssen et al. 2011b). Similar data could be obtained from the prospective German Endosonography Register, which reported overall complication rates around 2.05% of diagnostic cases (► www.​eus-degum.​de) (Gottschalk et al. 2012). Mortality rates, in contrast, have only been reported in extremely rare circumstances.