Geographic Distribution Highest rates (over 40 per 100,000 in males) are reported from Japan, China, the former USSR, and certain countries in Latin America. The lowest rates (< 15 per 100,000) are seen in North America (specifically, its white population), India, the Philippines, most African countries, some countries in Western Europe, and Australia.
Change In Histology Pattern Intestinal gastric cancer common in males older age more prevalent in high-risk areas linked to environmental factors The diffuse or infiltrative type frequent in both sexes common in younger age groups worse prognosis
Change In Histology Pattern Worldwide decline in the incidence of the intestinal type. By contrast, the decline in the diffuse type has been more gradual (now accounts for approximately 30 percent of gastric carcinoma) Despite the decline in gastric cancer overall, there has been an explosive increase in incidence of cancer of the gastric cardia.
Lymphoma GIT is the predominant site of extranodal non-Hodgkin lymphomas. Primary NHLs of the GI tract are rare, accounting for only 1 to 4 percent of malignancies arising in the stomach, small intestine, or colon. Secondary GI involvement is relatively common, occurring in approximately 10 percent of patients with limited stage NHL at the time of diagnosis, and up to 60 percent of those dying from advanced NHL. In the United States (US), gastric lymphoma is the most common extranodal site of lymphoma.
CarcinoidTumour The overall age-adjusted incidence rates were 2.0 for men and 2.4/100,000 for women in 1983-1998.
GIST The most common nonepithelial benign neoplasm involving the GI tract. Constitute only 1 percent of primary GI cancers. The annual incidence of GIST in the United States is at least 4000 to 6000 new cases (roughly 7 to 20 cases per million population per year).
Etiology Amr Mohamed Samir 735 Amr Mohamed Dawood 737
Gastric cancer is more common in patients with pernicious anemia, blood group A, or a family history of gastric cancer. Environmental factors appear to be more related etiologically to the intestinal form than the diffuse form.
Factors increasing the risk of gastric cancer: Family history Diet (high in nitrates, salt, fat) Familial polyposis Gastric adenomas Hereditary nonpolyposis colorectal cancer Helicobacter pylori infection Atrophic gastritis, intestinal metaplasia, dysplasia Previous gastrectomy or gastrojejunostomy (>10 y ago) Tobacco smoking Ménétrier's disease
Factors decreasing the risk of gastric cancer: Aspirin Diet (high fresh fruit and vegetable intake) Vitamin C
Helicobacter Pylori:Chronic helicobacter pylori infection increases the risk of gastric cancer about threefold when compared to uninfected patients.
Patients with history of gastric ulcer are more likely to develop gastric cancer, and patients with a history of duodenal ulcer are at decreased risk for gastric cancer.
Premalignant conditions of the stomach 1. Polyps Hyperplastic polyps can be associated with carcinoma. Patients with familial adenomatouspolyposis have a high prevalence of gastric adenocarcinoma.
2. Atrophic gastritis Chronic atrophic gastritis is the most common precursor for gastric cancer particularly the intestinal subtype and is usually associated with H. Pylori infection.
3. Intestinal metaplasia Gastric carcinoma often occurs in an area of intestinal metaplasia. Type III intestinal metaplasia is most commonly associated with gastric cancer, usually of the intestinal subtype. Eradication of helicobacter pylori infection leads to significant regression of intestinal metaplasia and improvement in atrophic gastritis.
4. Gastric remnant cancer stomach cancer can develop, usually years following distal gastrectomy or gastroenterostomy. 5. Other premalignant states: Patients with hereditary, non polyposis colorectal cancer have a 10% risk of developing gastric cancer. Ménétrier's disease: gastric mucosal hypertrophy.
Gross Pathology Amr Maher Basiony 733 Amr Mohamed Helmy 734
Premalignant Conditions of the StomachPolyps Hyperplastic Polyps
Microscopic picture of adenocarcinoma Amr Mohamed Mosa 735 Amr Mohamed Halawa 738
There are a number of classifications proposed for gastric adenocarcinoma.
Lauren classification Intestinal type Glandular cells . (large , abundant cytoplasm , hyperchromic nuclei) Intracellular mucin polarized to surface . Pushed margins , presence of lymphocytes . Metastasizes to nodes, liver Diffuse type Small clamps or single . (small . less cytoplasm , hypochromic nuclei) No polarized mucin . Diffuse and infiltrative . Mixtures of above two types
WHO classification Tubular Tubules and acini Becomes solid if poorly differentiated Papillary Fibrovascular stalks Mucinous >50% of tumor is mucin Signet ring >50% of carcinoma is composed of signet ring cells
Special types Clear cell variant described as having clear to pale eosinophilic cytoplasm Tubulo-papillary architecture Dysplasia ranges from minimal to severe Round basal or mid-level nuclei in lower grades Location in cardia and pylorus
Hepatoid Closely resembles hepatocellular carcinoma Frequently associated with intestinal type / tubulo-papillary gastric adenocarcinoma Eosinophilic to clear cytoplasm Round to oval nuclei with prominent nucleoli Frequent vascular invasion and liver metastasis
Adenosquamous Mixture of two patterns, more than just focal
Grading WHO (applies only to tubular pattern in WHO classification) Well differentiated – well formed glands Moderately differentiated - may be combined as well (low grade) Poorly differentiated (high grade) Highly irregular glandsor Single cells and clusters
Dyspepsia Highly suspicion for any elderly man above 40 complaining of dyspepsia which does not clear completely under simple medical treatment to stop medication and be investigated for gastric carcinoma .
Pain: it differs from that of peptic ulcer that it is not usually induced after meals but more to be induced after meat and protein meals . it is not responsive to medical treatment , vomiting or alkali . it is usually due to high tone of the stomach wall or involving of nerve or peritoneum. It is visceral type of pain , vague , located in upper abdomen specially in epigastric region . N.B In gross picture type 2 and 3 (non infiltrating – infiltrating ulcer) there is peptic ulcer like pain and even relieved by antacid and this is dangerous cause it delay the diagnosis but usually there is achlorhydra .
Vomiting: Feature of organic stomach diseases like peptic ulcer or gastric carcinoma, it occurs in the moment of highest pain ,induced by tension and hyper tonicity of the stomach . it is a good sign if there is relief after vomiting which exclude out the malignancy potential
Nausea: Sickness sensation without actual vomit + sweating + feeling to faint . It happen due to hypotonia of gastric musculature , It is usually psychic in origin but as well in organic diseases like carcinoma or chronic gastritis . Nausea usually precede vomiting
Flatulence: Distention of stomach with gas which usually tend to be belshed but it is more in functional stomach disease more than organic ones .
Disturbance of appetite: Anorexia specially to protein meals also anorexia due to other diseases like gastritis ,TB , Anaemia , psychogenic .
Others: Heart burn , waterbrash ( water and mucus in mouth) and erucation (acidic gastric contents in mouth)
2- Anemia and Cachexia: Progressive anaemia , loss of weight , dehydration and general weakness and this can be the only presenting picture .
3- Mass: Mass in epigastrium or left hypochondrium , it may be the only presentation and it indicate a late inoperable tumor . It is irregular , tender , mobile or fixed.
Complication: Haematemesis , may be few in amount or copious associated with food particles , in peptic ulcer the amount is always higher than that of gastric carcinoma. Secondaries to the liver , pyloric obstruction …..
Spread:- Direct : It extends to seroperitonium then to the near by organs (pancreas , spleen , liver , transverse colon ) . Tumor in cardia : spread to esophagus Tumor in pylorus : to duodenum . Lymphatic : (very aggressive ) to lymphnodes in greater and lesser curvature . celiac and para aortic mediastinal (for tumors of the cardia) virschaw lymph nodes
Spread Blood : from portal vein to liver and maybe lung or bone . transperitoneal : 1-krunkenburg syndrome (or maybe by blood) . 2-sister mary Josef nodules . 3-malignant ascites . 4-Blumer’s shelf (mass during rectal examination) .
Paraneoplastic manifestations:- rarely seen at initial presentation. Dermatologic findings may include the sudden appearance of diffuse seborrheic keratoses or acanthosis nigricans which is characterized by velvety and darkly pigmented patches on skin folds. Neither finding is specific for gastric cancer. Other paraneoplastic abnormalities that can occur in gastric cancer include a microangiopathic hemolytic anemia , membranous nephropathy , and hypercoagulable states (Trousseau's syndrome) . Polyarteritis nodosa has been reported as the single manifestation of an early and surgically curable gastric cancer
I. Laboratory Studies CBC : reveals anemia, due to bleeding, liver dysfunction, or poor nutrition. Serum electrolytes. Coagulation studies. Liver and Kidney function tests. Tumor markers: Carcinoembryonic antigen (CEA) Cancer antigen (CA) 19-9
II. Endoscopy Room set-up and patient positioning for endoscopy
Upper GI endoscopy is the diagnostic procedure of choice in the work-up of gastric carcinoma.
Multiple biopsy specimens (7 or more) should be obtained from any visually suspicious areas.
Repeated sampling at the same tissue site, reaching deeper into the gastric wall.
Multiple samples should be obtained around the ulcer crater.
Involvement of intraabdominal nodal groups (e.g. retropancreatic, portal, mesenteric, and paraaortic)
is classified as distant metastases.
The 2002 AJCCTNM staging of gastric carcinoma
Primary tumor (T)
TX - Primary tumor (T) cannot be assessed T0 - No evidence of primary tumor Tis - Carcinoma in situ, intraepithelial tumor without invasion of lamina propria T1 - Tumor invades lamina propria or submucosa T2 - Tumor invades muscularispropria or subserosa T3 - Tumor penetrates serosa (ie, visceral peritoneum) without invasion of adjacent structures T4 - Tumor invades adjacent structures
Patients with incurable disease should not be subjected to radical surgery that cannot help them.
Incurable patients are those with: Haematogenous metastases Involvement of the distant peritoneum N4 nodal disease and disease beyond the N4 nodes Fixation to structures that cannot be removed. Involvement of another organ does not indicate incurability, provided that it can be removed.
Controversies with respect to operability include patients with:
N3 nodal involvement Involvement of the adjacent peritoneum
Remaining patients are considered operable and should undergo curative resection. Most of the patients should have neoadjuvant chemotherapy as it improves survival.
Total gastrectomy The operation is best performed through a long upper midline incision. The stomach is removed en bloc, including the tissues of the entire greater omentum and lesser omentum. The transverse colon is completely separated from the greater omentum.
The subpyloric nodes are dissected and the first part of the duodenum is divided, usually with a surgical stapler. The hepatic nodes are dissected down to clear the hepatic artery. This dissection also includes the suprapyloric lymph nodes. The lymph node dissection is continued to the origin of the left gastric artery.
The dissection is then continued along the splenic artery taking all of the nodes at the superior aspect of the pancreas and in the splenichilum. The access to the nodal tissues around the upper stomach and oesophagogastric junction is achieved by separation of the stomach from the spleen, if the spleen is not going to be removed.
The oesophegus is divided at an appropriate point using a combination of stay sutures and a soft non crushing clamp, usually of the right angled variety.
It is important that the proximal and distal resection margins are well clear of the tumour as their involvement carries an appalling prognosis. If in doubt, a frozen section should be performed. Gastrointestinal continuity is reconstituted by means of a Roux loop.
A purse-string is placed in the cut end of the oesophagus. The side of the oesophagus is stapled onto the side of the Roux loop by means of a circular stapler. The anastomosis can also be fashioned end to end.
The blind open end of the Roux loop may then be closed either with sutures or with a linear stapler. The Roux loop may be placed in either, an anticolic or retrocolic position. The jejunojejunostomy is undertaken in the usual fashion(end to side).
Extent of lymphadenectomy There remains some controversy about the extent of the lymphadenectomy required for the optimal treatment of curable gastric cancers. In Japan, at least a D2 gastrectomy (removal of second tier of lymph nodes) is performed on all operable gastric cancers. They usually preserve the spleen and pancreas.
The Japanese research society for gastric cancer has numbered the lymph node stations that potentially drain the stomach. Generally, these are grouped into level D1 nodes which are perigastric, D2 nodes which are along the hepatic and splenic arteries, and D3 nodes which are the most distant.
Overall, it seems that the oncological outcome may be better following a D2 gastrectomy. The traditional radical gastrectomy removes the spleen and the distal pancreas en bloc with the stomach which is adequate for the clearance of the lymph nodes around the splenicartery. However, there now seems doubt that this substantially increases the complication rates. Therefore, it’s no longer routinely done as part of the D2 gatrectomy.
The difference between D1 and D2 operations depend upon the tiers of lymph node removed. In general, D1 resection involves the removal of perigastricnodes while D2 resection involves removal of the lymph nodes along the major arterial trunks along with the perigastric nodes.
Subtotal gastrectomy For tumours distally placed in the stomach it seems unnecessary to remove the whole stomach. The operation is very similar to total gastrectomy except that the most proximal part of the stomach is preserved, the blood supply being derived from the short gastric arteries.
After the resection the gastrointestinal continuity is restored by: The simplest form of reconstruction is to close the stomach from the lesser curve, near the oesophagogastric junction with staples or sutures and then perform an anastomosis of the greater curve to the jejunum as in Billroth II/ polya type gastrectomy. Reconstruction using a Roux loop to avoid marked enterogastric reflux and bile reflux oesophagitis that occurs with Billroth II/ polya type gastrectomy.
In inoperable patients with resectabletumours having significant symptoms of, either obstruction or bleeding, palliative resection is appropriate. A palliative gastrectomy need not be radical and it is sufficient to remove the tumour and reconstruct the gastrointestinal tract.
In inoperable patients with non resectabletumours obstructing the distal stomach, other palliative procedures need to be considered. Palliative procedures include:
High gastroenterostomy which is a poor operation that very frequently doesn’t allow the stomach to empty adequately and may produce the additional problem of bile reflux. A Roux loop with wide anastomosis between the stomach and the jejunum may be a better option, even though this may not allow the stomach to empty well.
3. Gastric exclusion and oesophagojejunostomy is practiced by some surgeons.
In inoperable patients with non resectabletumours situated in the cardia, either palliative intubation, stenting or another form of recanalisation can be used.
Endoscopic resection: In has been demonstrated in some centers that some patients with early gastric cancer can be adequately treated by an endoscopic mucosal resection. The addition of laparoscopic lymph node sampling may be considered in selected patients. This procedure should be limited to patients with: Tumors less than 2 cm in size Negative lymph node sampling Confined to the mucosa on endoscopic ultrasonogrophy Absence of other gastric lesions
If the resected specimen shows no ulceration, no penetration of the muscularis mucosa, no lymphatic invasion, and size less than 3 cm, then the risk of lymph node metastases is less than 1%.
Other treatment modalities In patients with advanced gastric cancer where radical surgery is not curative, radiotherapy and chemotherapy may be used.
Its use is controversial as there are a number of radiosensitive tissues in the region of the gastric bed, which limits the dose that can be given. However, it may have a role in the palliative treatment of painful bony metastases.
Gastric cancer may respond well to combination cytotoxic chemotherapy and neoadjuvant chemotherapy improves outcome following surgery. In operable tumours, patients should receive chemotherapy before surgery. The best results are obtained using a regimen of a combination of epirubicin, cis platinum, and infusional 5-fluorouracil or an oral analogue such as capicitabine.
In inoperable tumors or patients with advanced disease chemotherapy is considered palliative. The patients receive a first line chemotherapy including the same regimen as in operable tumors, although oxaliplatin is being substituted for cis-platinum as it has fewer side effects. Second line treatment using combinations that include taxotere are increasingly being used.
Outlook after surgical treatment The difference in staging and a higher standard of surgery in Japan probably accounts for these results.
The most common site of relapse following radical gastrectomy is the gastric bed, due to inadequate extirpation of the primary tumor. Widespread nodal metastases, distant nodal metastases and liver metastases are all common. Dissemination to the lung and bones only occurs after liver metastases are already established.
Low grade MALT lymphoma is not a surgical lesion. Remarkably, when helicobacter pylori is eradicated and the gastritis improves the low grade MALT lymphoma often disappears.
If low grade MALT lymphoma persists after helicobacter pylori eradication, radiation should be considered for disease clinically confined to the stomach, while chemotherapy with or without radiation is used for more advanced lesions.
In High grade gastric lymphoma most patients are currently treated with chemotherapy and radiation, without surgical resection.
For disease limited to the stomach and regional nodes, radical subtotal D2 gastrectomy may be performed, especially for bulky tumors with bleeding and/ or obstruction. Palliative gastrectomy may have a role in the treatment of tumor complications.
Gastrointestinal stromaltumor Wedge resection with clear margins is adequate surgical treatment. Sometimes adjacent structures are invaded by the primary tumor. If safe, en bloc resection of the involved surrounding organs is appropriate to remove all tumor when the primary is large and invasive.
Imatinib (gleevec) a chemotherapeutic agent yields excellent results in patients with metastatic or unresectable gastrointestinal stromal tumors. However, 50% of patients develop resistance to imatinib within two years. Five year survival for patients with low grade lesions is about 80%, while those with high grade lesions have a five year survival of about 30%.
Gastric carcinoid tumor Gastric carcinoids should be resected when diagnosed. In patients with small lesions confined to the mucosa resection may be done endoscopicallyusing endoscopic mucosal resection given that there are only few lesions and the margins are histologically negative. Larger lesions may be removed by D1 or D2 gastrectomy.
Surgical debulking may be useful in certain patients with metastatic disease. Somatostatin analogue is useful in controlling the symptoms of carcinoid syndrome but apparently does not prolong the survival in patients with metastatic gastric carcinoid.
Increased heart rate or elevated blood pressure.
Waking during surgery or being awake throughout the surgery (very rare).
Malignant hyperthermia, a reaction that causes the patient’s temperature to rise rapidly, is life threatening.
Complications of any surgery: Wounds Bleeding Delayed Healing After Surgery Blood Clots Caused by Surgery Infections Peritonitis Cardiovascular Risks Pulmonary Risks Death
Complications of gastrectomy Dumping syndrome Afferent loop syndrome Bilious vomiting Blind loop syndrome Weight loss Reactive hypoglycemia Anemia Softening and bending of the bones
Dumping syndrome Food is rapidly dumped into the small intestine from the stomach. Some patients experience : Lightheadedness Heart palpitations Sweating Nausea and vomiting after a meal Treated by adjusting the diet (eating smaller, more frequent meals and limiting liquids).
Bile reflux gastritis Patients may complain of: Early satiety (feeling of fullness after eating), Abdominal discomfort Vomiting of pure bile It may follow any operation in which the pylorus has been removed or bypassed but is most common following gastroenterostomy.
Blind loop syndrome Patients may suffer from: Sudden onset of diahrrea Malabsorption features low vitamin B12 and normal or raised folate due to decreased acidity and increased bacterial overgrowth in the blind ended loop
Reactive hypoglycemia Blood sugar levels become too high after a meal stimulating the release of insulin, occurring about two hours after eating. A high protein diet and smaller meals are advised.
Pernicious anemia loss of the intrinsic factor (IF) secreting parietal cells in the stomach lining. IF is essential for the uptake of vitamin B12. patient will suffer from a vitamin B12 deficiency. This can lead to pernicious anemia which severely reduces erythropoiesis. Treated by giving the patient direct injections of vit B12
Softening and bending of the bones Deficiency of Vitamin D and calcium. Softening and bending of the bones can produce pain and osteoporosis. According to one study, the risk for spinal fractures may be as high as 50% after gastrectomy.
The American Cancer Society estimates that in 2007 there were an estimated one million new cases, nearly 70% of them in developing countries, and about 800,000 deaths
Recent advances in Pathophysiology: Recent Understanding the vascular supply of the stomach allows understanding of the routes of hematogenous spread. Recent Understanding the lymphatic drainage can clarify the areas at risk for nodal involvement by cancer. Recent studies suggest that the disease is multi factorial -> that leads to discovery of many factors that may cause gastric cancer like Helicobacter pylori infection, radiation exposure.
Recent advances in Diagnosis : 1-History: Understanding that Early disease that has no specific symptoms; some patients with incidental complaints are diagnosed with early gastric cancer. Patients may complain of indigestion, nausea or vomiting, dysphagia, postprandial fullness, loss of appetite, melena, hematemesis, and weight loss.
Recent advances in Diagnosis : 2-Physical examination: Signs may include enlarged lymph nodes such as Irish node (anterior axillary). Blumer shelf (ie, shelflike tumor of the anterior rectal wall) may also be present. Paraneoplastic syndromes such as dermatomyositis, acanthosis nigricans, and circinate erythemas are poor prognostic features.
Recent advances in Diagnosis : 3-Investigation: 1)Laboratory Studies: Electrolyte panels Carcinoembryonic antigen (CEA) is increased in 45-50% of cases. Cancer antigen (CA) 19-9 is elevated in about 20% of cases. 2)Imaging Studies: Esophagogastroduodenoscopy has a diagnostic accuracy of 95%.. Biopsy of any ulcerated lesion Endoscopic ultrasound 3)Culture. 4)Genetic studies: As in The endemic-type tumor which invades large areas of the stomach.
Recent advances in Treatment : Treatment modality of gastric cancer has been improved in the last 40 years The 5-year survival rate for curative surgical resection ranges from 30-50% for patients with stage II disease and from 10-25% for patients with stage III disease.
Recent advances in Treatment : Early Operable Tumour: A)In surgical treatment: 1-EMR&ESD EMD (endoscopic mucosal resection) ESR (endoscopic submucosal dissection) *These are the method to remove the tumor using endoscopic technique that has developed over 20 years ago 2-Sentinal Lymph Node First LN to which the cancer spread (1st station of metastasis ) that should be taken as Biopsy It can be diagnosed by intraoperative mythelene blue dye trace or by radio isotope and using gamma camera
Recent advances in Treatment : Early Operable Tumour: B) In adjuvant chemotherapy: The taxanes represent a new class of drugs with considerable activity in a number of tumor types. Early-phase trials of paclitaxel and docetaxel, alone or in combination, have shown encouraging results in the treatment of patients with advanced gastric cancer. In the recently reported interim analysis of the phase III V325 trial, docetaxel, when combined with cisplatin and 5-FU, proved to be superior to the standard cisplatin plus 5-FU regimen in terms of response rate, time to tumor progression, and overall survival.. Recent trials suggest that adjuvent chemotherapy act as radio sensitizer Recent trials suggest that neoadjuvent chemotherapy can result in down staging of the tumour Choice of preoperative and postoperative chemotherapy versus postoperative chemotherapy and radiation remains controversial
Recent advances in Treatment : Early Operable Tumour: C)In adjuvant radiotherapy: Intraoperative radiotherapy Some studies suggest that intraoperative radiotherapy (IORT) shows promising results. This alternative method of delivering radiotherapy allows for a high dose to be given in a single fraction while in the operating room so that other critical structures can be avoided.
Recent advances in Treatment : Early Operable Tumour: D)Adjuvant chemoradiotherapy: A recent studies performed in the United States demonstrated a survival benefit associated with postoperative chemoradiotherapy compared with surgery alone. In this study, patients underwent an en bloc resection. Patients with T3 and/or N+ adenocarcinoma of the stomach or gastroesophageal junction were randomized to receive a bolus of 5-fluorouracil (5-FU) and leucovorin (LV) and radiotherapy or observation. Patients who received the adjuvant chemoradiotherapy demonstrated improved disease-free survival (from 32% to 49%) and improved overall survival rates (from 41% to 52%) compared to those who were merely observed. This regimen is considered the standard of care in the United States.
Recent advances in Treatment : Advanced Inoperable (unresectable) Tumour: Many patients present with distant metastases,that cannot be resected completely Early results reported in 2007 by Japanese clinicians suggest some improvement in both response rates and survival with the oral fluoropyrimidine used alone or in combination with cisplatin. Recent results combines 3 investigational drugs: Tegafur (a prodrug of 5-FU), Gimeracil (an inhibitor of fluorouracil degradation) and Oteracil (Potassium oxanate) a GI tract adverse-effect modulator. These results remain to be confirmed by ongoing studies in Europe and North America. .
Recent advances in Treatment : Advanced Inoperable (unresectable) Tumour: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF). future treatment strategies may be guided by the use of gene signatures. Some studies reveals that in patients receiving chemotherapy after gastrectomy for advanced gastric cancer, intratumoral mRNA expression of thymidylate synthase (TS) is an independent prognostic factor for response to chemotheray have improve recurrence-free survival and overall survival Overexpression of human epidermal growth factor receptor 2 (HER2) is a significant negative prognostic factor for gastric cancer. trial of usage of trastuzumab with chemotherapy in HER2-positive advanced gastric cancerimprove the prognosis of advanced gastric cancer