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The potential of contrast-enhanced ultrasonography to evaluate lymphadenopathy

      Abbreviations:

      CE-EUS (contrast-enhanced EUS), CEUS (contrast-enhanced US), TIC (time intensity curve)
      In a prospective multicenter study, Yoshida et al
      • Yoshida K.
      • Iwashita T.
      • Uemura S.
      • et al.
      Efficacy of contrast-enhanced EUS for lymphadenopathy: a prospective multicenter pilot study (with videos).
      evaluated the diagnostic performance of contrast-enhanced endoscopic ultrasonography (CE-EUS) in differentiating malignant from benign lymphadenopathy. The echo features on B-mode EUS and the vascular and enhancement patterns in CE-EUS were qualitatively evaluated in 100 patients undergoing cytologic or histologic lymph node assessment. The change of echo intensity in the lymph nodes over 60 seconds after the injection of contrast material was also quantitatively evaluated by time intensity curve (TIC) analysis. CE-EUS combining qualitative and quantitative analyses might be useful for evaluation of lymphadenopathy to complement conventional EUS and EUS-guided sampling.
      • Yoshida K.
      • Iwashita T.
      • Uemura S.
      • et al.
      Efficacy of contrast-enhanced EUS for lymphadenopathy: a prospective multicenter pilot study (with videos).
      EUS for lymph node evaluation has a wide spectrum of indications and several established techniques. For diagnosis of lymphadenopathy, conventional B-mode, color Doppler imaging, and elastography have been used, but EUS-guided sampling with cytologic and histologic evaluation remains the criterion standard to confirm malignancy.
      • Jenssen C.
      • Hocke M.
      • Fusaroli P.
      • et al.
      EFSUMB guidelines on interventional ultrasound (INVUS), part IV - EUS-guided interventions: general aspects and EUS-guided sampling (short version).
      • Dumonceau J.M.
      • Deprez P.H.
      • Jenssen C.
      • et al.
      Indications, results, and clinical impact of endoscopic ultrasound (EUS)-guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline - updated January 2017.
      By contrast, exclusion of malignant lymph node infiltration is much more limited because up to one third of lymph node metastases are found in lymph nodes <5 mm in diameter that cannot be reliably detected.
      • Monig S.P.
      • Baldus S.E.
      • Zirbes T.K.
      • et al.
      Lymph node size and metastatic infiltration in colon cancer.
      • Prenzel K.L.
      • Holscher A.H.
      • Vallbohmer D.
      • et al.
      Lymph node size and metastatic infiltration in adenocarcinoma of the pancreatic head.
      The main criteria needed for lymph node evaluation are these:
      • Hocke M.
      • Ignee A.
      • Dietrich C.
      Role of contrast-enhanced endoscopic ultrasound in lymph nodes.
      • Knowledge of underlying malignant or inflammatory diseases (eg, sarcoidosis, tuberculosis) with regional or systemic lymphadenopathy
      • Knowledge of the regional lymph node anatomy
      • B-mode imaging (localization, size, shape, distribution, echogenicity, architecture)
      • EUS-guided sampling with cytologic and histologic evaluation avoiding nonvital tissue
      Contrast-enhanced US (CEUS) and CE-EUS can be performed on both Doppler mode with high mechanical index and contrast-specific mode with low mechanical index.
      • Dietrich C.F.
      • Ignee A.
      • Frey H.
      Contrast-enhanced endoscopic ultrasound with low mechanical index: a new technique.
      CEUS is helpful for the detection and characterization of small intranodal vessels, which is valuable information for the characterization of lymphadenopathy. Improved imaging of the microvasculature might have additional value under certain circumstances. CE-EUS allows real-time analysis of all vascular phases and enable visualization of intranodal avascular areas that are necrosed.
      • Sidhu P.S.
      • Cantisani V.
      • Dietrich C.F.
      • et al.
      The EFSUMB guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: update 2017 (long version).
      Quantification software analyzing TICs may be helpful for the differential diagnosis of benign and malignant lymph nodes by adding information on perfusion.
      • Dietrich C.F.
      • Averkiou M.A.
      • Correas J.M.
      • et al.
      An EFSUMB introduction into dynamic contrast-enhanced ultrasound (DCE-US) for quantification of tumour perfusion.
      To understand the potential of CE-EUS, knowledge of lymph node vascularity is important. Normal lymph nodes have a single hilum and, therefore, a single vascular pedicle including arteries, veins, and lymphatic vessels. The intranodal normal lymph node vessel architecture is characterized by regularly branching arterial vessels, sinuous capillaries at the lymph node cortex, and counterdirected venous vessels. This typical vessel architecture does not significantly change in most inflammatory processes. Tissue-destructive processes are not common in inflammatory disease, but there are exceptions. For example, damaged vessel architecture has been described in tuberculosis and atypical mycobacteriosis. Malignant infiltration may be circumscribed in highly differentiated carcinoma, whereas aggressive tumors tend to infiltrate lymph nodes diffusely. Therefore, malignant lymphadenopathies in the very early stages may still display the original vessel architecture, and vascularity may be increased as a result of local inflammatory immune reaction. Destruction or distortion of vessel architecture is explained by the mass forming neoplastic infiltration with or without desmoplastic reaction, necrosis, or both. Neoplastic infiltration of the lymph node cortex is associated with peripheral hypervascularity, which is demonstrated by tortuous and aberrant capsular vessels. The production of angiogenetic factors by tumor cells at the lymph node periphery also leads to neovascularity with capsule-penetrating vessels that can be visualized by CE-EUS. Typical CEUS features of malignant lymph nodes, therefore, include heterogenous contrast enhancement, differences in the velocity of reduction for homogeneous lesions (washout), and the demonstration of capsule-penetrating vessels. CE-EUS with contrast-specific imaging mode is also helpful to identify nonenhancing areas and therefore to guide biopsy to avoid necrosis. At least theoretically, CE-EUS also has the potential to identify circumscript malignant areas within lymph nodes for targeted biopsy.
      Contrary to contrast-enhanced CT and contrast enhanced magnetic resonance imaging, CEUS uses strict intravascular contrast agents, eg, SonoVue (Bracco, Milano, Italy), but also Sonazoid (GE Healthcare, Amersham, UK), as in the study by Yoshida et al.
      • Yoshida K.
      • Iwashita T.
      • Uemura S.
      • et al.
      Efficacy of contrast-enhanced EUS for lymphadenopathy: a prospective multicenter pilot study (with videos).
      CEUS is also a promising technique for the assessment of treatment response of malignant neoplasia in solid organs and potentially also in malignant lymphadenopathy because it shows changes in vascularity and perfusion very early during antiangiogenic and antiproliferative treatment. The role of CE-EUS for the evaluation of treatment response in lymphoma has not yet been studied.
      • Dietrich C.F.
      • Averkiou M.A.
      • Correas J.M.
      • et al.
      An EFSUMB introduction into dynamic contrast-enhanced ultrasound (DCE-US) for quantification of tumour perfusion.
      We need improved imaging and reliable characterization of lymph nodes to avoid the need for invasive diagnostic tests in benign lymphadenopathy. Ideally, a test with a negative predictive value for malignancy of almost 100% would be the goal. This goal cannot be achieved because up to one third of malignant lymph nodes are not detectable by imaging methods. Moreover, owing to sampling error, EUS-guided sampling will fail to prove malignancy in approximately 10% to 15% of cases with detectable lymph nodes.
      • Jenssen C.
      • Hocke M.
      • Fusaroli P.
      • et al.
      EFSUMB guidelines on interventional ultrasound (INVUS), part IV - EUS-guided interventions: general aspects and EUS-guided sampling (short version).
      On the other hand, sampling might also be necessary for the diagnosis of benign lymphadenopathy where treatment is needed, such as tuberculosis and sarcoidosis. In addition, detection of malignant lymph node infiltration would ideally have a positive predictive value >90%. In the mediastinum, >50 lymph nodes are typically found in anatomic studies. An imaging method should be able to identify individual lymph nodes with malignant infiltration.
      Most importantly, any imaging method in the mediastinal area should have a high predictive value because further assessment requires highly invasive tissue sampling. For example, lymph node station 6 cannot usually be reached by EUS-guided biopsy, and tissue sampling needs a more invasive procedure such as video-assisted thoracoscopy. The analysis of TIC is time consuming, and preselection techniques should preferably use B-mode–dependent criteria, which are routinely available. Therefore, only very few cases would be suitable for contrast-enhanced TIC analysis, and the B-mode criteria will remain the main definitive criteria for lymph node sampling.
      The third important issue is to avoid false positive results of tissue sampling based on US-guided fine-needle sampling before neoadjuvant treatment strategies in upper GI cancers.
      • Gleeson F.C.
      • Kipp B.R.
      • Caudill J.L.
      • et al.
      False positive endoscopic ultrasound fine needle aspiration cytology: incidence and risk factors.
      The use of CE-EUS for this is promising to avoid false positive biopsy results.
      Fourth, improved imaging is needed to indicate the need for recurrent biopsy in the case of false negative tissue findings. Such a method should have also a positive predictive value >90%. In addition, CE-EUS might be helpful to guide core-needle biopsy in lymph node metastasis in the case of tumors with unknown primary because it will yield a larger amount of tissue allowing immunohistochemical staining and will help avoid necrotic areas. This issue has not been examined in the study featured, nor has the use of faster methods such as purely B-mode–guided strategies and EUS elastography. Comparative study designs should be chosen in future studies to include measurement of examination time.
      Tumor response evaluation after neoadjuvant treatment should be an additional goal of a CEUS method, and this is again not addressed in the featured study.
      The high number of lymphomas in the featured study might have resulted in preselection bias because both entities (lymphoma and metastases) have very different perfusion characteristics.
      In conclusion, CEUS has the potential to improve the diagnostic performance in differentiating between benign and malignant lymphadenopathy. Before CE-EUS is applied, all clinical information about underlying malignant or inflammatory diseases should be available, and the results of staging by CT should be carefully studied. B-mode US is often sufficient to indicate EUS-guided sampling with cytologic and histologic evaluation. CE-EUS can support the biopsy guidance to avoid nonenhancing necrosis.

      Disclosure

      The author disclosed no financial relationships relevant to this publication.

      References

        • Yoshida K.
        • Iwashita T.
        • Uemura S.
        • et al.
        Efficacy of contrast-enhanced EUS for lymphadenopathy: a prospective multicenter pilot study (with videos).
        Gastrointest Endosc. 2019; 90: 242-250
        • Jenssen C.
        • Hocke M.
        • Fusaroli P.
        • et al.
        EFSUMB guidelines on interventional ultrasound (INVUS), part IV - EUS-guided interventions: general aspects and EUS-guided sampling (short version).
        Ultraschall Med. 2016; 37: 157-169
        • Dumonceau J.M.
        • Deprez P.H.
        • Jenssen C.
        • et al.
        Indications, results, and clinical impact of endoscopic ultrasound (EUS)-guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline - updated January 2017.
        Endoscopy. 2017; 49: 695-714
        • Monig S.P.
        • Baldus S.E.
        • Zirbes T.K.
        • et al.
        Lymph node size and metastatic infiltration in colon cancer.
        Ann Surg Oncol. 1999; 6: 579-581
        • Prenzel K.L.
        • Holscher A.H.
        • Vallbohmer D.
        • et al.
        Lymph node size and metastatic infiltration in adenocarcinoma of the pancreatic head.
        Eur J Surg Oncol. 2010; 36: 993-996
        • Hocke M.
        • Ignee A.
        • Dietrich C.
        Role of contrast-enhanced endoscopic ultrasound in lymph nodes.
        Endosc Ultrasound. 2017; 6: 4-11
        • Dietrich C.F.
        • Ignee A.
        • Frey H.
        Contrast-enhanced endoscopic ultrasound with low mechanical index: a new technique.
        Z Gastroentero. 2005; 43: 1219-1223
        • Sidhu P.S.
        • Cantisani V.
        • Dietrich C.F.
        • et al.
        The EFSUMB guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: update 2017 (long version).
        Ultraschall Med. 2018; 39: e2-e44
        • Dietrich C.F.
        • Averkiou M.A.
        • Correas J.M.
        • et al.
        An EFSUMB introduction into dynamic contrast-enhanced ultrasound (DCE-US) for quantification of tumour perfusion.
        Ultraschall Med. 2012; 33: 344-351
        • Gleeson F.C.
        • Kipp B.R.
        • Caudill J.L.
        • et al.
        False positive endoscopic ultrasound fine needle aspiration cytology: incidence and risk factors.
        Gut. 2010; 59: 586-593

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