胃 癌 Gastric Cancer 浙江大学医学院附属第一医院 胃肠外科 于吉人 Ji-Ren Yu Zhejiang University 胃 癌 Gastric Cancer 浙江大学医学院附属第一医院 胃肠外科 于吉人 Ji-Ren Yu Department of GI Surgery The First Affiliated Hospital College of Medicine, Zhejiang University

Gastric Cancer Epidemiology Zhejiang University Gastric Cancer Epidemiology i) One of the most common cancer worldwide is surpassed only by lung cancer as the leading cause of cancer deaths; ii) higher rates in Eastern Asia, South America, Eastern Europe; Gastric carcinoma is one of the most common cancer worldwide ,which is surpassed only by lung cancer as the leading cause of cancer deaths. The incidence of gastric carcinoma is high in Eastern Asia, South America, Eastern Europe, and is low in Western Europe and the United States. iii) lower rates in Western Europe and the United States. 2

Epidemiology Incidence per 100,000 Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol 2006;12(3):354-362 Correa P Cancer Epidemiol Biomarkers Prev 2003;12:238s-241s

Gastric Cancer Risk Factors i) Nutrition Zhejiang University Risk Factors i) Nutrition A diet high in salty and smoked foods A diet low in fruits and vegetables Eating foods contaminated with aflatoxin fungus ii) Environment and Heredity Smoking Family history of stomach cancer Male Most epidemiologic studies investigating the role of diet in relation to the development of gastric cancer associate diets low in animal protein and fat, high in complex carbohydrates, high in salted meats and fish, and with high levels of nitrates or H. pylori in drinking water with an increased risk for gastric cancer. It appears that the long-term ingestion of nitrates in dried, smoked, salted food and cigarette smoking contributes to this increased risk. 4

Gastric Cancer Risk Factors iv) Medical iii) Social Zhejiang University Risk Factors iii) Social Low social class iv) Medical Prior gastric surgery Helicobacter pylori infection Gastric atrophy and gastritis Adenomatous polyps Pernicious anemia Other factors associated with an increased risk for gastric cancer include low socioeconomic status, male gender, and H. pylori infection. 5

Etiological Factors (Risk Factors) Etiological factors are presented in this figure. 6

A Model for the Pathogenesis of the Gastric Cancer A model of the pathogenesis of human gastric adenocarcinoma shows that Human gastric carcinogenesis is a multistep and multifactoral process 7

i) Early gastric cancer(EGC) Pathology Zhejiang University i) Early gastric cancer(EGC) Gastric cancer confined to the mucosa or submucosa, regardless of the presence or absence of lymph node metastasis ii) Advanced gastric cancer(AGC) Cancer cells infiltrate the proprial muscle layer or serosa

Pathology EGC IIc: superficially depressed I: protruded III: excavated The are Five types of early gastric cancinoma:type I: protruded type,type Iia :superficially elevated type,type IIb:superficially flat type ,type IIc: superficially depressed types and type III: excavated type. III: excavated IIa: superficially elevated IIb: superficially flat 9

EGC:Endoscopic images Endoscopic images of different types early gastric carcinoma. Type I Type II Type III 10

Pathology AGC: Borrmann’s classification Linitis plastica Normally, the Borrmann system divides gastric carcinoma into four types depending on the lesion's macroscopic appearance. Borrmann type 1 represents polypoid or fungating lesions; type 2, ulcerating lesions surrounded by elevated borders; type 3, ulcerating lesions with infiltration into the gastric wall and type 4, diffusely infiltrating lesions. Linitis plastica Borrmann's pathologic classification of gastric cancer based on gross appearance 11

T stage are defined by depth of penetration into the gastric wall Lamina propria T1a T1b T4a T4b T3 Subserosal connective tissue T stage are defined by depth of penetration into the gastrci wall, T1:Tumor invades lamina propria or submucosa, T2:Tumor invades muscularis propria or subserosa,T3: Tumor penetrates serosa (visceral peritoneum) without invasion of adjacent structures; T4: Tumor invades adjacent structures. 12

Staging N stage This picture shows the grouping of regional lymph nodes by location of primary tumor according to the Japanese classification of gastric carcinoma. Grouping of Regional Lymph Nodes (Groups 1-3) by Location of Primary Tumor According to the Japanese Classification of Gastric Carcinoma 15

M, lymph nodes regarded as distant metastasis   LOCATION OF PRIMARY TUMOR IN STOMACH LYMPH NODE STATION (NO.) DESCRIPTION Upper Third Middle Third Lower Third 1 Right paracardial 2 Left paracardial 3 M Lesser curvature 4sa Short gastric 4sb Left gastroepiploic 4d Right gastroepiploic 5 Suprapyloric 6 Infrapyloric 7 Left gastric artery 8a Anterior comm. hepatic 8p Posterior comm. hepatic 9 Celiac artery 10 Splenic hilum 11p Proximal splenic 11d Distal splenic 12a Left hepatoduodenal 12b,p Posterior hepatoduodenal 13 Retropancreatic 14v Superior mesenteric vein 14a Superior mesenteric artery 15 Middle colic 16al Aortic hiatus 16a2,b1 Para-aortic, middle 16b2 Para-aortic, caudal Lymph node stations are defined by the Japanese classification of gastric carcinoma. M, lymph nodes regarded as distant metastasis 16

Metastesis Direct invasion Lyphmatic metastesis Hematogenous metastasis Seeding metastasis Gastric carcinoma can spread to other organs via at least 4 different routines, which are direct invasion ,lyphmatic metastesis,hematogenous metastasis and seeding metastasis. 17

Clinical Presentation Lacks specific symptoms early: vague epigastric discomfort indigestion. Epigastric pain is constant, nonradiating, and unrelieved by food ingestion. Advanced disease may present with weight loss, anorexia, fatigue, or vomiting. Symptoms often reflect the site of origin of the tumor. Proximal tumors involving the gastroesophageal junction often present with dysphagia, whereas distal antral tumors may present as gastric outlet obstruction. Hematemesis, anemic. Very large tumors erode into the transverse colon, presenting as large bowel obstruction. Gastric cancer lacks specific symptoms at early period. Advanced disease may present with epigastric pain,weight loss, hematemesis.Very large tumors erode into the transverse colon,presenting as large bowel obstruction. 18

Physical signs i) a palpable abdominal mass, ii) a palpable supraclavicular (Virchow's) or periumbilical (Sister Mary Joseph's) lymph node, ii) peritoneal metastasis palpable by rectal examination (Blummer's shelf), iii) a palpable ovarian mass (Krukenberg's tumor). iv) as the disease progresses, patients may develop hepatomegaly secondary to metastasis, jaundice, ascites, and cachexia. Physical signs develop late in the course of the disease and are most commonly associated with locally advanced or metastatic disease. Patients may present with a palpable abdominal mass, a palpable supraclavicular (Virchow's) or periumbilical (Sister Mary Joseph's) lymph node, peritoneal metastasis palpable by rectal examination (Blummer's shelf), or a palpable ovarian mass (Krukenberg's tumor). As the disease progresses, patients may develop hepatomegaly secondary to metastasis, jaundice, ascites, and cachexia. 19

Examination Endoscopy M－SCT (multiple detector-row spiral CT) BUS & EUS double-contrast radiography MRI DL (diagnostic laparoscopy ) PET-CT

Clinicpathological Staging Laprascopy BUS CT EUS MRI PET-CT CT is the mainly procedure

Endoscopy Carcinoma in situ Advanced carcinoma When gastric cancer is suspected based on history and physical examination, flexible upper endoscopy is the diagnostic modality of choice Carcinoma in situ Advanced carcinoma 22

Double-Contrast Barium Upper GI Radiography Niche A Niche can be shown by double-contrast barium upper GI radiography in ulcerating tumor. 23

EUS EUS can detect the tumor infilltrated layer of the gastric wall. 24

EUS T N EUS aslo can detect the enlarged perigastric lymph nodes. 25

CT scan Borrmann I

CT Scan A B C T N H1 T4N2M1

PET-CT: T3N2

BUS left right Liver metastasis Krukenberg’s tumor Krukenberg‘s tumor and live metastasis are detected by peroperative B ultrasonograph. Liver metastasis Krukenberg’s tumor 29

Laparoscopy T T Abdominal metastasis Diagnostic laparoscopy detected metastases on the peritoneum and round ligaments of liver T Abdominal metastasis 30

Treatment for Gastric Cancer Surgery Endoscopic mucosal resection (EMR) Endoscopic submucosal dissection (ESD) Laparoscopic Surgery Open Surgery Chemotherapy Chemoradiotherapy Target therapy et,al

EMR for Earlier gastric cancer (EGC ) EMR represents a major advance in minimally invasive surgery for gastric carcinoma. Indicators for EMR include well-differentiated or moderately differentiated histology,tumors less than 30mm in size,absence of ulceration and no evidence of invasive findings. 32

Criteria for EMR NCCN 2011 V1. Japanese Gastric Cancer Association 1.Early gastric cancer (Tis or T1a tumors limited to mucosa) 2. Well-differentiated or moderately differentiated histology 3.Tumors less than 20mm in size, 4.Absence of ulceration and no evidence of invasive finding. Japanese Gastric Cancer Association ( Digestive Endoscopy. 2005,17, 54–58) differentiated adenocarcinoma; Intramucosal cancer; 20 mm in size; without ulcer finding EMR represents a major advance in minimally invasive surgery for gastric carcinoma. Indicators for EMR include well-differentiated or moderately differentiated histology,tumors less than 30mm in size,absence of ulceration and no evidence of invasive findings. 33

EMR

EMR

EMR

Limitation of EMR techniques 1. Difficult to resect large than 20mm tumor in size 2. Difficult to resect ulcerative lesions ESD has been developed

ESD for EGC EMR represents a major advance in minimally invasive surgery for gastric carcinoma. Indicators for EMR include well-differentiated or moderately differentiated histology,tumors less than 30mm in size,absence of ulceration and no evidence of invasive findings. 38

ESD Oita Digestive Organs Hospital

ESD Oita Digestive Organs Hospital

Criteria for ESD National Cancer Center Hospital In Japan (evaluation for histological curability) (indication for DST)

Surgical Treatment for Gastric Cancer Principles of radical operation for gastric cancer i) Negative margin (adequate margins ≥4 cm ) ii) D2 lymph node dissection for advance gastric cancer iii) Subtotal gastrectomy for distal gastric cancer iv)Total or proximal gastrectomy for proixmal gastric cancer Surgery is the only procedure to cure gastric cancer. The goal of a surgical cure requires complete resection to an R0 status, which approach to surgery is determined by 1) the negative margin, 2)the extent of lymph node dissection needed,3)the enbloc resection needed and 4) no distant metastasis. 42

Laparoscopic Resection A suitable procedure for ECG (Our experience) The efficacy and safety of this approach for advanc gastric carcinoma requires further investigation to be evaluated The efficacy and safety of laparoscopic resection need requires further investigation in larger randomized clinical trials. At present, laparoscopic resection is a suitable procedure for early gastric carcinoma. 43

Open Surgery for Advanced Gastric Cancer A suitable procedure for ACG R0 resection R1 resection R2 resection

Principles of advanced gastric cancer surgery Gastrectomy with regional lymphatics: perigastric lymph nodes(D1) and those along the named vessels of the celiac axis (D2), with a goal of examining 15 or greater lymph nodes Gastrectomy with D2 lymphadenectomy is the standard treatment for curable GC in eastern Asia

Gastrectomy and D2 lymphadenectomy for advanced gastric carcinoma For advance gastric carcinoma, open surgical resection are recommended. 46

The standard of surgical procedure varies worldwide, with most Asian countries encouraging extended lymphadenectomy. The majority of surgeons in the USA, on the other hand, excise the N1 lymph nodes, which are in the immediate perigastric region. This resection is called a D1 resection. A D2 resection, as described in the 2002 American Joint Committee on Cancer manual, includes nodes along the celiac access and its named branches and along the middle colic, superior mesenteric artery, and periaortic nodes. 47

Gastric resections are determined by tumor location Gastric resections are determined by tumor location. Reconstruction can be performed using a Billroth II or Roux-en-Y anastomosis. Distal gastrectomies are often done for distal tumors. A Roux-en-Y anastomosis tends to eliminate troublesome bile reflux. 48

Body and midstomach tumors typically require a total resection to gain adequate margins of at least 6 cm. 49

Left gastric A Hepatic A Splenic A No.11 LN

PORTAL VEIN

Tumor located at the midstomach which has invased into the spleen Tumor located at the midstomach which has invased into the spleen. Total gastrectomy in combination with splenoectomy was done. 52

Viedo of operation Ligaments of liver and stomach disection Right gastric arteries disection Right gastroepiploic arteries disection Ligaments of spleen-stomach disection esophagus disection N7,N8,N9 disection N7,N8,N9 disection N12，N13 disection

Adjuvant Therapy Chemotherapy Radiation Therapy Targeted Therapy Adjuvant therapy to potentially curative surgery in patients with locally advanced gastric cancer can contribute to the elimination of micrometastatic and increased survival. But substantial room for further improvement of outcomes are still remained.Adjuvant therapies to gastric cancer include Neoadjuvant chemotherapy, postoperative chemotherapy and postoperative chemoradiation. 56

Chemotherapy …… Regimens ECF: Epirubicin , Cisplatin, SOX: S-1, Oxaliplatin XELOX: Capecitabin, Oxaliplatin DCF: Docetaxel, Cisplatin, 5-Fu …… Preoperative Chemotherapy Postoperative Chemotherapy

Preoperative chemotherapy Our experience Before the neoadjvant chemotherapy Ulcerative mass at antrum of stomach，about 4*5cm in size After 3 courses FOLFOX6 The lesion is about 2.0*1.0cm in size

Our experience Before the neoadjvant chemotherapy After 3 courses of XELOX

Lymphadectomy of group 7,8,9 Our experience Lymphadectomy of group 7,8,9

Liver after Chemotherapy Our experience Liver after Chemotherapy

Our experience foam cells in lamina propria(40×10)

Targeted Therapy Herccptin Herb-2 receptor inhibitor Iressa EGFR inhibitor Avastin VEGFR inhibitor

Other Molecular Medicine Interventions of Gastric Cancer 1.Oncogene activation and targeted therapy 2.Tumor-suppressor-gene inactivation and related therapy 3. Apoptosis targeted therapy 4. Anti-metastasis therapy 5. Telomerase inhibition therapy 6. Gene directed chemotherapy 7. Immunotherapy

Palliative Treatment Surgical palliation resection or bypass alone or in conjunction with percutaneous, endoscopic, or radiotherapy techniques Nonoperative therapies laser recannulization and endoscopic dilation with or without stent placement Because 20% to 30% of gastric cancer patients present with stageIII or IV disease, clinicians must be familiar with different methods of palliative treatment. The goal of palliative treatment is the relief of symptoms with minimal morbidity. Surgical palliation of advanced gastric cancer may include resection or bypass alone or in conjunction with percutaneous, endoscopic, or radiotherapy techniques. Complete staging is necessary to determine the appropriate method of palliation for individual patients. In the presence of peritoneal disease, hepatic metastases, diffuse nodal metastases, or ascites, palliation of bleeding or proximal gastric obstruction would preferably be obtained nonoperatively. Nonoperative therapies include laser recannulization and endoscopic dilation with or without stent placement. Patients who undergo stent placement for gastric outlet obstruction are frequently able to tolerate solid foods and may not require additional interventions. 65

Cutting edge: gastric carcinoma H. pylori infection and gastric carcinoma Cyclooxygenase-2 Activation and gastric carcinoma Mini-invasive operation Sentinel node Neoadjunctive chemotherapy Micrometastasis Individualized treatment Molecular Targeted Therapies

QUESTIONS 1. Definition of the advanced gastric cancer and its metastatic way 2. Krukenburg’s tumor

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