Gastric Cancer: Epidemiology Surgery and Regional Therapy Gastric cancer is second leading cause of cancer Timothy J. Kennedy, MD specific mortality world wide (989,600 cases; 738,000 Montefiore Medical Center deaths) accounting for 8% new cancer cases Assistant Professor of Surgery Fourth leading cause of cancer death in the United Upper Gastrointestinal and Pancreas Surgery States (21,320 cases; 10,540 deaths) December 15, 2012 Incidence in Japan 8x higher than US More common in men More common in Asians, blacks, native americans and US hispanics Peak age is 7th decade Incidence of proximal gastric cancer increasing 1 Risk factors Etiology H-pylori infection (90% intestinal type and 30% diffuse type) Exposure to carcinogens (tobacco, salt, nitrites) Pernicious anemia Obesity Adenomatous Polyp Previous gastric surgery Familial history of gastric cancer 4 Molecular Pathogenesis Molecular Pathogenesis Diffuse Type (linitis plastica) Histologic Types (Lauren Classification) Poorly differentiated signet ring cells Intestinal Type (well differentiated) Loss of expression of E-cadherin, a key intercellular Arises from gastric mucosa adhesion molecule which maintains organization of Most common in high risk patient populations epithelial tissue Related to environmental factors Arises within lamina propria of stomach wall and grows in infiltrative/submucosal pattern Associated with older patients and distal tumors Associated with females, younger patients and Incidence is decreasing proximal tumors Better prognosis Associated with early metastases Incidence is increasing 5 6 Gastric carcinogenic sequence Hereditary Diffuse Gastric Cancer Inherited form of diffuse type gastric cancer QRUPDOJDVWULFPXFRVD CDH1 mutations identified in 30-50% of affected ൻ ൸+S\ORULLQIHFWLRQ kindreds DWURSKLFJDVWULWLV Autosomal dominant trait with high penetrance ൻ Lifetime cumulative risk for gastric cancer is between LQWHVWLQDOPHWDSODVLD 40 and 67% in men and 60-83% in women ൻ Affected patients develop gastric cancer at early age G\VSODVLD (average 38) ൻ Asymptomatic carriers of germline truncating mutations LQYDVLYHDGHQRFDUFLQRPD in E-cadherin should have prophylactic gastrectomy, aalthough age is unclear 8 Clinical Features Diagnosis Clinical Presentation Upper gastrointestinal endoscopy is best test for Vague abdominal pain, weight loss, anemia and anatomic localization of tumor and tissue diagnosis early satiety are most common presenting During endoscopy any gastric ulcer should be biopsied symptoms Single biopsy has 70% sensitivity for diagnosing an Massive bleeding and perforation rare existing gastric cancer 25% of patients have a gastric ulcer Seven biopsies from ulcer base and margin All gastric ulcers should be followed to complete increases sensitivity to >98% healing and those that do not heal should undergo Diagnosis of diffuse type gastric cancer endoscopically resection can be difficult because it is submucosal lesion Screening not cost effective in low risk groups 9 10 Staging Clinical Staging Two major classification systems Directs the initial approach to therapy Most elaborate is the Japanese classification , Patients with locoregional disease (Stage I-III) are based upon anatomic location, particularly of lymph potentially curable node stations If tumor invades through submucosa (T2 or higher) or Most commonly used pathologic staging system is there is high suspicion of nodal involvement patient AJCC/UICC system should be referred for multidisciplinary evaluation T Stage – depth of gastric wall invasion Patients with stage IV disease are usually referred for N Stage – number of nodal metastases identified palliative therapy depending on symptoms and functional status M Stage – presence of distant metastases 11 12 Abdominopelvic CT Endoscopic Ultrasound (EUS) Dynamic CT imaging should be performed to evaluate for Most reliable nonsurgical method for evaluating depth of Regional and distant nodal disease invasion of primary gastric cancers. Local extension to adjacent organs Accuracy of EUS for differentiation of individual tumor Liver metastases stages (T1 to T4 tumors) ranges from 77% to 93%. Peritoneal metastases Experience of operator markedly influences these rates. CT accurately assess T stage in only 50-70% of patients; EUS provides a more accurate prediction of T stage than Sensitivity for regional nodal metastases is limited for nodes CT. <0.8cm; in addition false positives can be attributed to In contrast accuracy for nodal staging (65 to 90%) is only inflammatory lymphadenopathy slightly greater than CT Sensitivity for nodal metastases ranges from 65 to 97% EUS guided FNA of suspicious nodes adds to this and specificity from 49 to 90% accuracy 13 14 FDG-PET Imaging Diagnostic laparoscopy Role of PET is controversial and evolving Utilized to assess for small volume peritoneal carcinomatosis Can be used to confirm malignant involvement of CT detected lymphadenopathy Peritoneal cytology utilized to look for microscopic free peritoneal tumor cells Most diffuse type gastric cancers are not FDG avid 25% of patients with T3 – T4 or N(+) have radiographic More sensitive than CT for detection of distant occult disease identified by laparoscopy metastases but poor for peritoneal carcinomatosis Only 4% of T1 – T2 or N0 disease have any findings on May be useful in assessment of response of tumors to laparoscopy neoadjuvant treatment Utilized prior to administration of neoadjuvant chemotherapy 15 16 Peritoneal Cytology Peritoneal Cytology Bentrem. Ann Surg Oncol 2005 371 R0 resections with staging laparoscopy and washings Incidence, Risk factors, Prognostic value of positive cytology Peritoneal Cytology T Stage Correlates with (+) LN Positive peritoneal washings as only site of M1 disease T1a - <5% and patients with gross metastatic disease fare equally T1b – 20% poorly T2 – 50% Surgical resection with therapeutic intent in the presence T3 – 70% of known M1 disease portends a poor outcome T4 – 90% The absence of detectable M1 disease after systemic chemotherapy is associated with a survival benefit 20 TNM Classification Stage Grouping Stage T N M Tis: Cancer cells only in mucosa N0: No spread to LN 0 Tis N0 M0 T1a: into lamina propria or muscularis mucosa N1: 1-2 regional LN IA T1 N0 M0 T1b: into the submucosa N2: 3-6 regional LN IB T1 N1 M0 T2: into muscularis propria N3: >7 regional LN T2 N0 M0 T3: into the subserosa II T1 N2 M0 T4a: into serosa T2 N1 M0 T4b: into nearby organs or structures T3 N0 M0 IIIA T2 N2 M0 T3 N1 M0 T4 N0 M0 Mo: No distant mets IIIB T3 N2 M0 M1: Distant mets IV T4 N1–3 M0 T1–3 N3 M0 Any T Any N M1 21 22 Survival by AJCC stage – curative resection 1.0 0.8 Surgical Management I N=659 0.6 II N=385 III N=583 IV N=131 0.4 Dysplasia 0.2 0.0 0 24 48 72 96 120 144 168 Months 24 Progression of LGD/HGD to Cancer Progression of Dysplasia __________________________ $XWKRU \HDU /*'SURJUHVVLRQ PHDQLQWHUYDO +*'SURJUHVVLRQ PHDQLQWHUYDO Progression in low grade dysplasia is from 0% - 23% in 6DUDJDHWDO \HDUV PRQWKV various studies /DQVGRZQHWDO 1$ PRQWKV Progression in high grade dysplasia is 60 - 85% in 5XJJHHWDO \HDU PRQWKV multiple studies 'L*UHJRULRHWDO \HDUV PRQWKV Most experts recommend endoscopic surveillance in )HUWLWWDHWDO PRQWKV PRQWKV patients with LGD 5XJJHHWDO \HDUV PRQWKV Most experts recommend endoscopic or surgical .RNNRODHWDO 1$ PRQWKV resection for management of patients with evidence of 5XJJHHWDO PRQWKV PRQWKV HGD <DPDGDHWDO PRQWKV PRQWKV 26 Progression of Dysplasia > 1 year endoscopic followup of 90 low-grade and 16 high-grade gastric dysplasia cases Low-grade: 53.3% regression 31.1% no change Surgical Management 15.4% progression 8.8% progression to cancer (mean 48 months [21-85]) High-grade: 0/16 regression Early Gastric Cancer 5/16 no change 11/16 progression to cancer (mean 34 months [13-72]) Rugge, et al., Gut 2003 28 Early Gastric Cancer (EGC) Endoscopic Resection of EGC Developed 20 years ago, defined over the last two EGC defined as adenocarcinoma limited to mucosa decades as an alternative to gastrectomy for early and submucosa regardless of LN involvement (T1Nx) gastric cancers Reflects that EGC represents a more favorable/curable Endoscopically developing a plane submucosally and subset of gastric cancers compared to more invasive resecting affected tissue in one piece gastric cancers (T2-T4Nx) Advantages include decreased morbidity and mortality, EGC identified more often now with the upward trend potential increased quality of life post procedure reflecting mass screening and improved technology Disadvantages include increased risk of nodal disease, Still uncommon in US given lack of screening metachronous disease, incomplete resection endoscopy in low risk patient population Early Gastric Cancer (EGC) In Western countries early gastric cancers comprise <15% of gastric cancers diagnosed Frequency of early gastric cancer: Surgical Management Japan - 78 cases/100,000 United States - 10 cases/100,000 Locoregional Disease 31 32 Gastrectomy Indicators of Unresectability Distant metastatic disease Resection offers best chance for survival for patients with localized gastric cancer Invasion of major vascular structure such as aorta, celiac axis, hepatic artery or proximal splenic artery As previously discussed adjuvant or perioperative chemotherapy or chemoradiotherapy can improve Bulky lymphadenopathy fixed to pancreatic head that outcomes over surgery alone may require pancreaticoduodenectomy Optimal therapy depends on accurate staging of extent Lymph nodes considered