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1 Gastric Cancer Core Curriculum Lecture: Mamie Dong, Pradipta Ghosh February 16, 2010 I Introduction: • 95% of gastric cancers are adenocarcinomas • The remaining 5% are lymphomas (second most common, includes MALT lymphomas), sarcomas (including leiomyosarcomas and Kaposi’s sarcomas), GISTs, carcinoids, and squamous cell carcinomas • distinct histologic subtypes of gastric adenocarcinomas: intestinal, diffuse (discussed in more detail later) Intestinal type – retained glandular structure, more localized Diffuse type – no glandular structures, more spread out Gastric Adenocarcinoma II Epidemiology • Cancer status Worldwide: 4th most common cancer, 2nd leading cause of cancer death In the US: 14th most common cancer, 7th most common cancer death Incidence of intestinal type has declined rapidly over the recent few decades ? due to invention of refrigerators, with better food storage and reduced need for salt-based preservation Incidence of diffuse type has declined more gradually Incidence of distal gastric cancers has decreased, but proximal (cardia) cancers have increased (some propose that these cancers are a separate entity, more closely resembling Barrett’s associated esophageal adenocarcinoma) • Cancer Geography Diffuse type has similar frequencies in all geographic locations Intestinal type: ♦ Highest incidence in Eastern Asia, Andean regions of South America, and Eastern Europe ♦ Lowest rates are in North America, Northern Europe, Africa, Southeast Asia ♦ Higher geographic latitudes are associated with higher risk ♦ Migration studies of patients born in high risk countries and moving to low risk countries shows that the risk is diminished but still significantly higher than those who are ethnically from a high risk country but born in a low risk country, indicating that early environmental exposure, rather than genetic factors, have a greater influence on risk • Race – In the US, Asian and Pacific Islanders have the highest incidence, followed by black, Hispanic, white, and American Indian • Gender • Intestinal type is more common in males, 2:1 ratio worldwide Diffuse type is equally distributed between males and females Age – Median age in the US at diagnosis is 70 for men and 74 for women III Brief Review of Gastric Anatomy IV Pathophysiology and Genetics • Intestinal type – sequence of molecular events is incompletely understood, but there seems to be s stepwise progression of neoplastic stages Chronic Gastritis There may be temporary episodes of spontaneous regression to a less advanced stage, though overall there is stepwise progression Chronic Atrophic Gastritis Many patients remain at this stage Loss of chief and parietal cell mass Hypochlorhydria Intestinal Metaplasia Dysplasia Carcinoma Allows colonization of bacteria capable of converting dietary nitrates to mutagenic N-nitroso compounds Increase in serum gastrin, which is a potent inducer of gastric epithelial cell proliferation Decrease in luminal vitamin C, which is an antioxidant à à à Non-atrophic gastritis predominates in the gastric antrum ♦ Presence of PMNs correlates closely with active colonization by H.pylori Chronic atrophic gastritis – loss of gastric glands ♦ This is the first histopathologic lesion of the preneoplastic cascade Intestinal metaplasia ♦ Abnormal glands first appear at the junction of the antrum and corpus, particularly in the incisura angularis ♦ Over time, foci of metaplasia becomes larger and more numerous ♦ Initially, glands resemble those in the small intestines (multiple microvilli, mucus-producing goblet cells) – this is Type I or complete ♦ At more advanced stages, glands resemble those in the colon – this is Type II or incomplete, also called colonic metaplasia Dysplasia ♦ Western definition - dysplastic cells which not penetrate the basement membrane ◊ Rate of progression from low grade dysplasia to carcinoma is 0-23% ◊ Rate of progression from high grade dysplasia to carcinoma is 60-85% ♦ Japanese definition – there is no specific lesion called “dysplasia” ◊ Western definition of low grade dysplasia would be termed “adenoma” by the Japanese ◊ Western definition of high grade dysplasia would be termed “carcinoma” by the Japanese Invasive Carcinoma ♦ Western definition – atypical cells invading the stroma ♦ Japanese definition – atypical cells in any location Genetics – complicated and not well defined ♦ ♦ ♦ ♦ ♦ • Oncogenes – K-ras, c-met Tumor suppressor genes – p53, APC, TFF Cell cycle regulatory molecules – cyclin E, p27 Morphogenesis regulatory molecules – beta-catenin/Wnt signaling Cancer cells may actually be migrating bone marrow derived cells rather than gastric epithelial cells Diffuse type – main carcinogenic event is loss of expression of E-cadherin, a key cell surface protein for establishing intercellular connections CDH1 gene mutations are found in 50% of diffuse type cancers Hypermethylation of the E-cadherin tumor promoter may be present in >80% of tumors that lack specific mutations in CDH1 Hereditary Diffuse Gastric Cancer ♦ Autosomal dominant, very high penetrance ♦ Lifetime cumulative risk is 40-67% in men, 60-83% in women ♦ Average age at diagnosis is 38 ♦ Affected women are also at increased risk of lobular breast cancer ♦ Consensus criteria for diagnosis of Hereditary Diffuse Gastric Cancer by the IGCLC (International Gastric Cancer Linkage Consortium) ◊ >2 cases of diffuse type gastric cancer in 1st/2nd degree relative with at least one relative 3 cases of diffuse type gastric cancer in 1st/2nd degree relatives of any age V Risk Factors • Environmental / Lifestyle Factors – more associated with intestinal type Diet ♦ Risk: Salted, pickled, smoked foods, dietary nitrates ♦ Protective: Fruits and raw vegetables rich in vitamin C and betacarotene (reduces formation of N-nitroso compounds inside the stomach) Smoking ♦ Risk: dose-dependent ♦ Risk diminishes with smoking cessation > 10 years Obesity – increases risk of gastric cardia cancers Helicobacter pylori infection – The strongest risk factor WHO classified group carcinogen ♦ Increases risk for both intestinal and sporadic diffuse type cancers ♦ Risk is estimated at approximately cases per year for every 10,000 infected persons ♦ May be particular strains of H.pylori are associated with malignancy ♦ H.pylori has an affinity for normal mucosa but not metaplastic, dysplastic, or malignant tissue, so biopsy of lesions may miss H.pylori • ♦ Infection in early life tends to lead to chronic inflammation ♦ Longer duration of infection increases risk Ebstein-Barr virus – role in carcinogenesis is still unclear ♦ EBV is detected in 5-15% of gastric cancers worldwide ♦ Male predominance ♦ Preferential location in the gastric cardia or postsurgical gastric stump ♦ Diffuse type, lymphocytic infiltration Radiation exposure – in animal models can induce intestinal metaplasia Host Factors Maybe particular genotype of interleukin may pose particular risk from H.pylori infection Blood group A patients are at 20% excess risk of cancer Previous gastric surgery ♦ Partial gastrectomy promotes hypochlorhydria ♦ Bile reflux also stimulates intestinal metaplasia (so risk is higher with Billroth II than Billroth I) ♦ Risk highest 15-20 years after surgery and increases with time ♦ But notably, chronic hypochlorhydria induced by H2 blockers or PPIs does not lead to increased risk of cancer Reproductive hormones are thought to have a protective role (risk is lower in women) High risk conditions or lesions ♦ Chronic atrophic gastritis, intestinal metaplasia, dysplasia ♦ Gastric polyps ◊ Fundic gland polyps associated with polyposis syndromes (those that are sporadic or PPI-associated have virtually no malignant potential) ◊ Hyperplastic polyps, particularly those >2cm have a small malignant potential ◊ Adenomatous polyps have malignant potential ◊ ASGE guidelines: hyperplastic polyps >2cm and all adenomatous polyps should be completely resected and EGD repeated in year ♦ Pernicious anemia – a result of autoimmune chronic atrophic gastritis ◊ Associated with increased risk of intestinal type cancer ◊ Also associated with increased risk of gastric carcinoids ◊ ASGE guidelines: Single endoscopy should be performed as screening, not enough data to support subsequent surveillance endoscopies ♦ Gastric ulcers – risk of malignancy is increased in patients with benign gastric ulcers, but unclear if there is malignant potential or whether this reflects common risk factors (such as H.pylori) ◊ Gastric cancer risk is decreased among patients with benign duodenal ulcers (? different H.pylori strains) ◊ Do we need to repeat EGDs on all gastric ulcers to document healing? Ž No consensus, old ASGE guidelines (now no longer available on their website) says repeat EGD in 8-12 weeks with re-biopsy of any remaining ulcers No updated guidelines since then Ž Some studies support second look EGD, others conclude that there is no added benefit if adequate numbers of biopsies were taken (ie, 7) on the first EGD ♦ Various immunodeficiency syndromes ♦ Hypertrophic gastropathy (enlarged gastric folds), including Menetrier disease (multiple sheet-like adenomas with associated foveolar hyperplasia) • Genetic Factors – more associated with diffuse type Approximately 10% are familial (independent of H.pylori infection) Diffuse type – strongly correlated with mutations in E-cadherin gene, CDH1 (see above) Intestinal type – genetic factors not so well established Hereditary syndromes – HNPCC, FAP, Li-Fraumeni syndrome, PeutzJeghers syndrome, Cowdens syndrome VI Classification • Lauren system – by morphology Intestinal (type 1) ♦ Retained glandular structure, morphologically similar to adenocarcinomas arising in the intestinal tract, sharp margins ♦ Associated with most environmental risk factors ♦ No familial tendencies ♦ Better prognosis Diffuse (type 2) ♦ Scattered cell clusters without formation of glands due to lack of intercellular adhesions ♦ Deceptive margins (appear clear to the surgeon and pathologist, but are often determined to be involved retrospectively) involving large areas of the stomach ♦ Cancers tend to be multifocal and located beneath an intact mucosal surface ♦ Linitus plastica – particularly aggressive form where the stomach appears as a “leather-flask” shape on barium swallow due to poor distensibility from extensive tumor infiltration ♦ Not recognizably influenced by most environmental factors ♦ No associated pre-malignant lesion ♦ More often in younger patients ♦ Associated strongly with genetic factors • The Paris Classification – by endoscopic appearance, typically used for T1 lesions (see below), may be beneficial as a guide to endoscopic therapy Type – superficial polypoid, flat/depressed, or excavated tumors Type – polypoid, usually attached on a wide base Type – ulcerated with sharply demarcated margins and raised margins Type – ulcerated, infiltrative, without clear margins Type – nonulcerated, diffusely infiltrating Type – unclassifiable • By Histology Intestinal type ♦ Tubular ♦ Papillary ♦ Mucinous Diffuse type = Signet-ring cell Undifferentiated • By Location Proximal – fundus/cardia ♦ Incidence is rising ♦ More aggressive, worse prognosis, more likely diffuse type Distal – antrum/body ♦ Most intestinal type cancers are in the incisura angularis Currently, 30% of gastric cancers are in the antrum, 30% in the body, 40% in the fundus/cardia VII Clinical Presentation • History à In the US, 25% present with localized disease, 31% with regional disease, 32% with metastatic disease Early gastric cancer is usually asymptomatic Advanced gastric cancer most frequently presents with weight loss (62% usually from insufficient caloric intake rather than catabolism) and persistent abdominal pain (52%) Other symptoms may include nausea (34%), dysphagia (26%), melena (20%), early satiety (18%), indigestion (17%) • Physical Exam – All physical signs are late events None are pathognomonic Palpable enlarged stomach with succession splash Hepatomegaly – liver metastases are usually multifocal or diffuse Sister Mary Joseph node – periumbilical node Virchow’s node – left supraclavicular lymph node Irish node – left axillary node Blumer shelf – shelf-like tumor of the anterior rectal wall Krukenberg tumor – metastatic tumor to the ovary • Paraneoplastic Syndromes – poor prognostic features Sign of Leser-Trelat – sudden appearance of diffuse seborrheic keratoses Dermatomyositis Acanthosis nigricans Circinate erythema • Other Associated Abnormalities Pseudoachalasia – from involvement of Auerbach’s plexus of tumors near the GE junction Trousseau’s syndrome – hypercoagulable state Microangiopathic hemolytic anemia Membranous nephropathy • Pattern of Metastasis Gastric cancer can spread by direct invasion, via lymphatics, or hematogenously Direct extension: most commonly omentum/peritoneum, pancreas, diaphragm, transverse colon, duodenum, esophagus Lymphatic drainage is through multiple pathways Hematogenous spread commonly results in liver metastases • Tumor markers – All have low sensitivity and specificity, and none are recommended ♦ CEA, CA 125 – elevated in 45-50% of cases ♦ CA 19-9 – elevated in 20% of cases • Imaging Studies à à à • EGD (white light, chromoendoscopy, magnification endoscopy, narrow band imaging) – Diagnostic study of choice ♦ Single biopsy of an ulcerated lesion has a 70% sensitivity, while biopsies increases the sensitivity to 98% ♦ Up to 5% of malignant ulcers appear benign grossly (benign ulcers have folds which extend to the base of the ulcer) Barium studies – Helpful when bulky proximal tumors prevent passage of EGD scope ♦ Sensitivity may be as low as 14% in early gastric cancer ♦ ~75% diagnostic accuracy for advanced cancers ♦ May be helpful in diagnosis of linitis plastica, which is more obvious on radiographic study than on endoscopy Chest X-Ray – Can be used to assess for metastases, though CT is preferred, especially for proximal cancers CT or MRI of the abdomen/pelvis/+chest – Assess for metastases ♦ CT accurately assesses the T stage (see below) in only 50-70% of cases ♦ Peritoneal metastases smaller than 5mm are frequently missed on CT and 20-30% of patients with negative CTs will have intraperitoneal disease on laparoscopy PET scan – Usually not helpful ♦ Gastric cancer, particularly the diffuse type, can have low metabolic activity ♦ Sensitivity for peritoneal carcinomatosis is 50% ♦ Medicare does not reimburse for PET for gastric cancer Endoscopic ultrasound ♦ Allows for more precise T staging when CT or MRI does not show metastatic disease (accuracy 77-93%) This is important when considering endoscopic mucosal resection ♦ Accuracy of N staging is only slightly higher than CT, but allows FNA of suspicious nodes ♦ Not a requisite part of the staging workup as EUS findings rarely affect the need for laparotomy EUS is not recommended by the NCCN (National Comprehensive Cancer Network) guidelines Exploratory and Staging Laparotomy – Usually done to look for peritoneal implants NCCN guidelines say to “consider” laparotomy in patients who appear to have locoregional disease (other than Tis, T1a, stage 4) Peritoneal washings for cytology is recommended for patients without visible implants as this predicts early relapse and some centers will give neoadjuvant therapy VIII Staging and Prognosis • TNM Staging System – used more extensively in the Western hemisphere, has prognostic significance 10 à Stage 1A 1B 3A 3B • Primary Tumor – T stage is depth, not size ♦ Tx Primary tumor can not be assessed ♦ T0 No evidence of primary tumo ♦ Tis Carcinoma in situ: no invasion of lamina propia ♦ T1 Tumor invades lamina propria or submucosa ♦ T2 Tumor invades muscularis propria or subserosa ◊ T2a Tumor invades muscularis propria ◊ T2b Tumor invades subserosa ♦ T3 Tumor penetrates serosa (visceral peritoneum) without I nvasion of adjacent structures ♦ T4 Tumor invades adjacent structures Nodes – N stage is number of positive nodes, not location; Staging is not reliable if fewer than 10 lymph nodes are examined ♦ Nx Regional lymph nodes can not be assessed ♦ N0 No regional lymph node metastasis ♦ N1 1-6 positive regional lymph nodes ♦ N2 7-15 positive regional lymph nodes ♦ N3 >15 positive regional lymph nodes Metastasis ♦ Mx Distant metastasis can not be assessed ♦ M0 No distant metastasis ♦ M1 Distant metastasis TNM Tis, N0, M0 T1, N0, M0 T1, N1, M0 T2a/b, N0, M0 T1, N2, M0 T2a/b, N1, M0 T3, N0, M0 T2a/b, N2, M0 T3, N1, M0 T4, N0, M0 T3, N2, M0 T4, N1-3, M0 T1-3, N3, M0 Tany, Nany, M1 year survival >90% 60-80% 50-60% 30-40% 20% 10% 90% after surgical resection, 65% without surgery) Median duration to progression without surgery is 37 months 50-70% are intestinal type Findings may be subtle on white light endoscopy, consider chromoendoscopy, magnification endoscopy, or narrow band imaging Treatment Standard is gastrectomy Patients with elevated lesions