EUS in mediastinal and lung lesions/EBUS

Enclosed between the sternum, the lungs and the vertebral column, the mediastinum is one of the least accessible areas of the body; the need to explore mediastinal structures is mainly represented by lymph nodal investigations for staging of non small cell lung cancer (NSCLC), detection of direct mediastinal involvement in lung cancer (LC), and the diagnosis of indeterminate mediastinal masses. Mediastinal lymph nodes can be investigated with different techniques, each one carrying advantages and limitations. Contrast enhanced computed tomography (CT) is recommended as first diagnostic step, although it is poorly sensitive in the diagnosis of small lymph nodes (≥ 1cm); moreover, reactive lymph nodes larger than 1 cm. may present additional diagnostic difficulties. Positron emission tomography (PET) is highly effective in staging advanced disease but is less specific in the diagnosis of metastatic lymph nodes because of a significant false positive rate (>20%)—hence its specificity is too low to be used as the sole criteria for surgery exclusion. Mediastinoscopy (MS) is considered the gold standard for mediastinal investigation and is generally recommended before LC therapeutic surgery; however, MS requires general anaesthesia, is associated with a significant rate of false negatives (10/15%) mainly related to the difficulties in exploring the posterior mediastinum but has a low complication rate (2/3%). As in primary LC, broncoscopic techniques fail to diagnose up to 30% of LC: in fact, the overall sensitivity of bronchoscopy (FB) in the diagnosis of LC is about 80%, but this percentage decreases in case of peripheral lesions. Therefore histological or cytological evaluations are still necessary to accurately diagnose and stage LC and other mediastinal masses, despite the variable sensitivity of blind transbronchial FNA and transthoracic FNA. Trans-oesophageal endoscopic ultrasound (EUS) combined with fine-needle aspiration (EUS-FNA) and, more recently, endobronchial ultrasound guided trans-bronchial needle aspiration (EBUS-TBNA) have completely changed the diagnostic approach to mediastinal masses and lymph nodes. Both techniques have demonstrated very high sensitivity and specificity, with sensitivity values ranging between 80% - 90%y for EUS-FNA and 90% - 100% for EBUS-TBNA according to different series, proving to be the best performing methods compared to others. In addition to the advantages shared by the two techniques, EUS allows better access to the posterior/inferior mediastinum, namely to sub carinal and paraoesophageal (7 and 8 levels) lymph nodes and to the masses proximal to the oesophagus; EBUS allows better access to peritracheal nodes(?) and to the regions adjacent to the main bronchi, and seems to be more useful for right-sided lymph nodes. Selection of EUS or EBUS to sample specific lymph node stations should be performed on the basis of PET and CT scans, and the availability of both techniques might, in a very near future, replace MS. Moreover since lymphadenopathy after treatment of malignancy is not a definitive sign of recurrence, preliminary studies have used EUS and EBUS to restage mediastinal LN after CHEMO-XR therapy in NSCLC patients.From a cytopathological point of view, the first task is to assess the adequacy of the diagnostic material and its management. In this perspective, the on site evaluation is considered indispensable—albeit time consuming—and requires that the different work schedules coincide. Liquid-based-thin-layer cytological technique provides high-quality specimens for diagnostic purposes; this approach might produce high-quality specimens without the need for direct on-site evaluation, although at present there is only limited experience supporting this solution. In some institution cytotechnologists are deputed to this task whereas(although??) cytological interpretation of the corresponding samples may be complex even for experienced cytopathologists. Adequacy criteria are not well established: the quantitative evaluation of lymphocytes is generally considered a criteria of adequacy for EUS/EBUS lymph node specimens(?) whereas, in metastatic lymph node smears, lymphocytes may be scanty or even absent. Oesophageal or bronchial cells contamination is frequently observed in these cytological samples and should not bear on adequacy. As for the diagnostic difficulties, bronchial contamination, especially by metaplastic or dysplastic cells, can cause problems in the differential diagnosis, as epithelial cells may lead to “atypical” or even false positive diagnoses. Therefore recognizing bronchial or oesophageal contamination is important to avoid diagnostic pitfalls. At the same time, dense lymphoid groups with large cells intermingled with mature lymphocytes, possibly combined with crushed nuclei, can be confused with small-cell LC. Technical factors may also represent additional difficulties: as in other cytological samples, air drying and poor preservation may blur the cytological features of contaminant epithelial cells and reserve cell hyperplasia. Cell block sections are helpful in clarifying these cytological difficulties, but incorrect on-site evaluation may determine the need for repeat testing, thus delaying the final diagnosis. Therefore, whenever possible, adequacy evaluation and cytological diagnoses should be performed by experienced cytopathologists. In fact, reproducibility of the cytological diagnosis obtained by EBUS-TBNA and EUS-FNA has proven to be excellent among experienced cytopathologists; cytopathologists with less experience in this type of sampling have shown a steep learning curve and, after specific training, the reproducibility of their diagnoses was markedly improved. Therefore it seems that on-site evaluation performed by experienced pathologists is necessary to keep high levels of sensitivity and specificity. The need for experienced cytopathologists is also related to the increasing variety of possible targets and corresponding pathological processes: metastases from different sites, sarcoidosis, mesenchimal tumours and other pathological processes, diagnosed by EUS-FNA, have been described, and their evaluation requires specific cytopathological experience. As for the diagnosis of primary LC and mediastinal masses, the task of the cytopathologist is to identify the histotype, especially with regard to the distinction between small-cell and non-small LC, and to diagnose mediastinal masses. In these cases, other than adequacy, on site evaluation should determine the management of residual FNA and possible repetition to obtain additional diagnostic material. Paraffin embedded cell blocks of formalin fixed cells and small tissue fragments generally provide excellent material to visualize dense cell groups, as well as for the immunocytochemical determinations necessary to diagnose “solid” tumours and Hodgkin lymphoma. In case of non-Hodgkin lymphoma, residual cells and/or additional passes may be suspended in buffered solution or RMPI for flow-cytometric evaluation. Therefore, considering the generally scanty diagnostic material available, its management during the on-site evaluation is an important step of the diagnostic algorithm. Finally, new targeted therapies appear promising for an improved prognosis of NSCLC, and phenotypic and genetic profiles are necessary to assess their biological features. At the same time, an accurate cytological diagnosis on EUS-EBUS specimens, avoiding MS or unnecessary surgical treatments, reduces the need to collect additional biologic material in up to 50% of the cases. Therefore, in these instances, FNA provides the only diagnostic material to be utilized for molecular assessment.In conclusion, among the diagnostic procedures available for mediastinal pathologies, EUS-FNA and EBUS-TBNA are accurate, minimally invasive, and relatively expensive. Immediate assessment of adequacy and specific experience in cytopathology are necessary for an optimal outcome of the whole diagnostic procedure.