Gastric cancer (GC) is the fourth most common malignancy in the world, after lung, breast and colorectal cancers and the second cause of cancer-related death in the world. Approximately 70% of GC cases occur in developing countries, especially in Eastern Asia. The preoperative gastric cancer staging and nodal involvement have relevant prognostic and therapeutic implications. A correct endoscopic tumor staging is particularly useful to decide the most appropriate treatment for patients; in fact “early gastric cancer” limited to the mucosa can benefit from endoscopic resection, instead when the disease is locally advanced, surgery is the only chance.

    A proper location of cancer, as described by Siewert [1], is useful to allocate multimodal therapy to esophageal and gastric cancer. In 1926, Borrmann [2] gave a still valid definition of type IV (scirrhus) of GC that remains an independent prognostic factor of patient’s survival [3]. The features mentioned above (type IV according Borrmann, location and extension of tumor in esophagus and in gastric wall according Siewert), are well defined by endoscopic ultrasonography (EUS), that is able to analyze the intestinal wall and adjacent structures, such us diaphragm. EUS is also useful to separate the intestinal wall in layers corresponding to histology and to view lymph nodes; therefore it is an excellent method to assess the loco-regional staging in particular T and N [4-5]. In the nineties some comparative studies with computed tomography (CT) demonstrated that, EUS is superior for the loco-regional staging (T and N), while it is less accurate than CT to assess distant involvement. Therefore authors concluded that CT and EUS were complementary methods for pre-operative staging [6-7]. Thanks to the continuous technical improvement and the planning of new multi detector CT and high definition magnetic resonance, (MRI) imaging methods have filled most of the gap existing with EUS in loco regional staging, [8] however, some recent systematic reviews and meta-analysis showed that, the ability of EUS to assess the wall still results in a better accuracy in the evaluation of T1 lesions. Especially, when probes at high frequency (>15MHz) with greater resolution for the surface layers are used, sensibility to discriminate T1 stage rather than more advanced stages is of 87% [9]. Although meta-analysis have heterogeneous results, linked to different centers experience and use of imaging modalities [9], a recent systematic review demonstrated that, EUS is particularly accurate to define T1 and T4 stages. EUS is able to discriminate patients that could benefit of endoscopic resection and those in which surgery has poor chance of cure. Probability of a correct staging in these patients is approximately 600 times (odds) superior than in those not subjected to EUS [10]. Accuracy of EUS to define metastatic lymph node is lower than the ability to define T stage correctly [11]. A recent study demonstrated that, the evaluation of the lymph nodes with EUS is lower than that obtained with new multi detector CT and MRI [12]. However EUS, thanks to the possibility to make a fine needle aspiration (FNA), can give more information about suspicious lymph nodes than traditional imaging technology [13-14]. EUS is also able to define, better than CT, advanced disease with peritoneal localizations, not only for the better detection, but also for the possibility to make targeted biopsy and to retrieve small amounts of peritoneal fluid [15-16].

    Until a short time ago, EUS was considered inferior to diagnostic laparoscopy, because of the better supposed ability of the latter to define peritoneal metastases. In a recent comparative study, no significant differences between the two diagnostic modalities have emerged, and EUS resulted the only independent factor associated with a peritoneal metastases diagnosis [18].Furthermore, EUS is also useful to identify patients to subject to laparoscopy, in fact, patients with a EUS staging T1-T2, N0 have a risk of peritoneal metastases of 4%, while the risk for patients staged T3-T4, N+ is about 25%. Therefore laparoscopy could be avoided in patients with EUS staging T2, N0 (predictive negative value of M1: 96%) [19].

    All these considerations have recently allowed EUS, although with some delay with respect to clinical practice, to be recognized in official guidelines as an important tool for the preoperative staging in patients with gastric cancer [17].

    High accuracy to identify tumors (T1), that could be removed by endoscopic mucosal resection (EMR) or endoscopic sub mucosal dissection (ESD), does not result in an equal ability to define sub mucosal infiltration (T1sm), also using high frequency probes [20-21]. This is a crucial point, because lymph node metastases are negligible, when tumors are confined to the mucosal, while they occur in about 20%, when the sub mucosal layer is involved [22].

    Operative endoscopy with EMR and ESD has not only a therapeutic role for early gastric cancer, but also a role of staging, thanks to the possibility to obtain an adequate specimen for histological examination. Histology is useful to value sub mucosal infiltration and then to decide if endoscopic treatment is definitive or, otherwise, to send patient to surgery [23].

    Despite evident advantages, EUS has relevant limitations. First of all it is not widespread in the territory; then, although apparently in recent years many centers offer EUS, they do not always have all the necessary tools [24]. Then EUS is influenced by operator experience, not always adequate, especially in low volume centers [25]. EUS is not accurate enough as other imaging (CT, MRI) in restaging after neo adjuvant radio or chemotherapy, because it is not able to discriminate between a cancer and an inflammatory or fibrotic effect [26-27]. A randomized trial, although with a small sample size, demonstrated a better survival in patients in whom down staging was indentified with EUS compared to those in which it was identified with CT, suggesting a better prognostic role of EUS after neo adjuvant treatment [28].

    In conclusions:

    EUS has an important role in staging of gastric cancer.

    EUS is the most accurate method for local GC staging; it should be performed together with radiologic methods such as CT, because they are complementary for a complete and correct pre-operative staging.

    EUS should be performed before diagnostic laparoscopy, because it identifies patients in whom it is not necessary.

    EUS should be performed before EMR and ESD, because it identifies better than other imaging methods, patients that could be treated with them.

    EMR and ESD should be performed after endoscopic and EUS evaluations and they have an important role in staging, because they provide an anatomical specimen for histological examination.

  • References


    1. Rudiger Siewert J, Feith  M, Werner M, Stein HJ. Adenocarcinoma of the esophagogastric junction: results of surgical therapy based on anatomical/topographic classification in 1,002 consecutive patients. Ann Surg 2000; 232:353.

    2. Borrmann R.Geshwulste des Magens und duodenums. In: “Handbuck der Spezieller pathologischen anatomie und istologie”. Henka F., Lubasch O. eds, Berlin J. Springer vol. 4:865; 1926.

    3. Ann JY,  Kang TH, Choi MG, et al. Borrmann Type IV: An independent prognostic factor for survival in gastric cancer. J Gastrointest Surg 2008  12:1364

    4. Saito N, Takeshita K, Habu H, Endo M. The use of endoscopic ultrasound in determining the depth of cancer invasion in patients with gastric cancer. Surg Endosc 1991; 5:14

    5. Caletti G, Ferrari A, Brocchi E, Barbara L. Accuracy of endoscopic ultrasonography in the diagnosis and staging of gastric cancer and lymphoma. Surgery 1993; 113: 14

    6. Botet JF, Lightdale CJ, Zauber AG, Gerdes H, Winawer SJ,Urmacher C, Brennan MF. Preoperative staging of gastric cancer: comparison of endoscopic US and dynamic CT. Radiology 1991; 181: 426

    7. Ziegler K, Sanft C, Zimmer T, Zeitz M,  et al .Comparison of computed tomography, endosonography,and intraoperative assessment in TN staging of gastric carcinoma. Gut 1993; 34: 604

    8. Kwee, RM, Kwee, TC. Imaging in local staging of gastric cancer: a systematic review. J Clin Oncol 2007; 25:2107.

    9. Kwee, RM, Kwee, TC. The Accuracy of Endoscopic Ultrasonography in Differentiating Mucosal from Deeper Gastric Cancer. Am J Gastroenterol 2008;103:1801

    10. Puli SR, Batapati Krishna Reddy J, Bechtold ML et al. How good is endoscopic ultrasound for TNM staging of gastric cancers? A meta-analysis and systematic review. World J Gastroenterol 2008; 14: 4011

    11. Willis S, Truong S, Gribnitz S et al. Endoscopic ultrasonography in the preoperative staging of gastric cancer: accuracy and impact on surgical therapy. Surg Endosc 2000; 14: 951

    12. Kwee RM, Kwee TC. Imaging in assessing lymph node status in gastric cancer. Gastric Cancer. 2009;12:6

    13. Vazquez-Sequeiros E, Wiersema MJ, Clain JE et al. Impact of lymph node staging on therapy of esophageal carcinoma. Gastroenterology. 2003;125:1626

    14. Chen VK, Eloubeidi MA. Endoscopic Ultrasound-Guided Fine Needle Aspiration is Superior to Lymph Node Echofeatures: A Prospective Evaluation of Mediastinal and Peri-Intestinal Lymphadenopathy. Am J Gastroenterol 2004; 99:628

    15. Canto M, Gislason G. Is extraluminal fluid (EFLUID) at endoscopic ultrasonography (EUS) as accurate marker of peritoneal carcinomatosis (PC)?A prospective study. Gastrointest Endosc 1998; 47:AB142.

    16. Nguyen PT, Chang KJ. EUS in the detection of ascites and EUS-guided paracentesis. Gastrointest Endosc 2001;54:336

    17. NCCN Clinical Practice Guidelines in Oncology™: Gastric Cancer Version 2.2013

    18. Lee YT, KWNg E, Hung LCT et al. Accuracy of endoscopic ultrasonography in diagnosing ascites and predicting peritoneal metastases in gastric cancer patients. Gut 2005;54:1541

    19. Power GD, Schattner MA, Gerdes H et al. Endoscopic Ultrasound Can Improve the Selection for Laparoscopy in Patients with Localized Gastric Cancer. J Am Coll Surg 2009; 208:173

    20. May A,Günter E,Roth F. Accuracy of staging in early oesophageal cancer using high resolution endoscopy and high resolution endosonography: a comparative, prospective, and blinded trial. Gut. 2004; 53: 634.

    21. Pech O, Günter E, Ell C. Endosonography of high-grade intra-epithelial neoplasia/early cancer. Best Pract Res Clin Gastroenterol. 2009; 23:639.

    22. Roviello, F, Rossi, S, Marrelli, D, et al. Number of lymph node metastases and its prognostic significance in early gastric cancer: a multicenter Italian study. J Surg Oncol 2006; 94:275.

    23. Conio M, Ponchon t, Blanchi S. Endoscopic Mucosal Resection. Am J Gastroenterol 2006;101:653

    24. Eloubeidi MA. Choosing from the expanding EUS armamentarium menu: high-frequency probes, radial or linear endosonography for staging of upper GI malignancy? Gastrointest Endosc. 2006 ;64:503.

    25. De Luca L, Bianchi M, Castellani D et al. Italian survey of endoscopic ultrasound. Dig Liv Dis 2009; 41, S151.

    26. Ajani JA, Mansfield PF, Lynch PM, et al. Enhanced staging and all chemotherapy preoperatively in patients with potentially resectable gastric carcinoma. J Clin Oncol. 1999;17:2403.

    27. Kelsen D, Karpeh M, Schwartz G, et al. Neoadjuvant therapy of high-risk gastric cancer: a phase II trial of preoperative FAMTX and postoperative intraperitoneal fluorouracilcisplatin plus intravenous fluorouracil. J Clin Oncol. 1996; 14:1818.

    28. Park SR, Lee JS, Kim CG et al. Endoscopic ultrasound and computed tomography in restaging and predicting prognosis after neoadjuvant chemotherapy in patients with locally advanced gastric cancer. Cancer 2008;112:2368.