Gastric Cancer 2024-2025 PDF

uplogo UNIVERSITY OF PERUGIA DEPARTMENT OF MEDICINE Master’s Degree in Medical, Veterinary and Forensic Biotechnological Science Academic Year 2024-2025 Digestive System Diseases Gastric C...

uplogo UNIVERSITY OF PERUGIA DEPARTMENT OF MEDICINE Master’s Degree in Medical, Veterinary and Forensic Biotechnological Science Academic Year 2024-2025 Digestive System Diseases Gastric Cancer Monia Baldoni  Gastric Tumours ▪ Epithelial Polyps Benign ▪ Non-Epithelial Intramural Tumours ▪ Epithelial Adenocarcinoma Malignant Lymphomas GIST (Gastro-Intestinal Stromal Tumours) ▪ Non-Epithelial Neuroendocrine tumours Leiomyosarcomas  Gastric Tumours Malignant gastric tumours can originate from all the different histological components of the stomach, but in most cases, they are adenocarcinomas. Adenocarcinoma (>90%) Lymphoma (3 - 5%) Neuroendocrine tumour - NET (1%) Leiomyosarcoma ( USA, Australia and New Zealand) Although stomach cancer incidence rates have declined in East Asian countries following the global trend, stomach cancer is still the second most common cancer in East Asia, accounting for approximately 50% of all cases of stomach cancer worldwide Among the East Asian countries, the Republic of Korea has the highest incidence of stomach cancer in the world, and the incidence of stomach cancer in China accounts for more than 40% of all new cases Adenocarcinoma: Epidemiology Demographic trends differ by tumor location and histology. While there has been a marked decline in distal, intestinal-type gastric cancers, the incidence of proximal, diffuse-type adenocarcinomas of gastric cardia has been increasing, particularly in Western countries.  Adenocarcinoma: Epidemiology Gastric cancer (GC) and esophageal adenocarcinoma (EAC) are linked by almost inverse epidemiology. Whereas GC incidence rates have been declining rapidly, EAC has been one of the most rapidly increasing cancers in the United States, with increases in EAC incidence of more than 450% over the past 40 years. GC is now most prevalent in developing countries, where the most predominant types are intestinal-type tumors of the gastric corpus and antrum. Barrett esophagus (BE) and EAC have been uncommon in Asian countries but are now very frequent in Western countries. The incidence of gastric cardia cancer has been increasing. Helicobacter pylori infection could be a risk factor for cardia cancer, especially in countries with a high prevalence of H. pylori infection, and it is associated with atrophy in the cardia. In contrast, H. pylori-negative gastric cardia cancer occurs in patients without gastric atrophy, mostly in the United States and Western Europe, and seems to be strongly associated with gastro-esophageal reflux disease (GERD) or obesity, suggesting the presence of two forms of cardia cancer. BE and EAC are negatively associated with H. pylori infection. Multiple studies have confirmed that infection with H. pylori, particularly cytotoxin-associated gene A (cagA)+ strains, is protective against BE and EAC, and thus many have speculated that the rising incidence of EAC can be partly attributed to the falling rates of H. pylori infection.  Environmental Risk Factors There are geographic and ethnic differences in the incidence of gastric cancer around the world, as well as trends in each population over time. Emigrants from high-incidence to low-incidence countries often experience a decreased risk of developing gastric carcinoma. Such findings strongly suggest that environmental factors have an important role in the etiology of gastric cancer and that exposure to risk factors occurs early in life.  Environmental Risk Factors Helicobacter pylori infection. The World Health Organization's IARC classified H. pylori as a group 1, or definite, carcinogen. Four sources of evidence support an association between H. pylori infection and gastric cancer: epidemiologic studies comparing prevalence rates of gastric cancer and H. pylori infection, cross-sectional studies evaluating H. pylori infection in patients with gastric cancer, prospective studies associating H. pylori infection with gastric cancer, and clinical trials demonstrating a significantly reduced incidence of gastric cancer after eradication of H. pylori. H. pylori infection has been associated with an approximately six-fold increase in the risk of adenocarcinomas distal to the cardia, including both the intestinal and diffuse types  Environmental Risk Factors Low socioeconomic status. The risk of distal gastric cancer is increased by approximately twofold in populations with low socioeconomic status. By contrast, proximal gastric cancers have been associated with higher socioeconomic class. High intakes of salt and salt-preserved and smoked foods Exposure to N-nitroso compounds (compounds containing an -NO group) from the diet, tobacco smoke, and other environmental sources, as well as from endogenous synthesis which contributes to 40 to 75 percent of total exposure. N-nitroso compounds are generated after the consumption of nitrates, which are natural components of foods like vegetables and potatoes but are also used as a food additive in some cheeses and cured meats. Dietary nitrates are absorbed in the stomach and secreted in saliva in a concentrated form, where they are reduced to nitrites by oral bacteria. Nitrites can also react with nitrosatable compounds, such as amines, amides, and amino acids, to form N-nitroso compounds.  Environmental Risk Factors Diets that are high in fried food, processed meat, fish, and alcohol and low in consumption of vegetables, fruits, milk and vitamins (A, C, E and β-carotene) In 2015, the World Health Organization's International Agency for Research on Cancer (IARC) reviewed the evidence linking the intake of processed meat with a variety of cancer sites and concluded that there was a positive association between the consumption of processed meat and stomach cancer. Processed meats (e.g., sausages, bacon, ham, beef jerky, corned beef, and other smoked, salted, fermented, or cured meats) were classified as group 1 carcinogens, placing these foods in the same risk category for cancer as asbestos, cigarettes, and alcohol.  Environmental Risk Factors Tobacco smoking and alcohol abuse, obesity EBV infection (5-10%). EBV-associated gastric cancers are characterized by DNA methylation of the promoter region of various cancer-associated genes, which silences the expression of these genes. How this leads to gastric cancer is unclear but silencing the expression of certain genes may modulate the latent-lytic switch of EBV infection, allowing the virus to escape immune detection and remain dormant within the host cells. EBV-associated gastric cancers have distinct clinicopathologic characteristics, including male predominance, preferential location in the gastric cardia or postsurgical gastric stump, lymphocytic infiltration, a lower frequency of lymph node metastasis, perhaps a more favorable prognosis, and a diffuse type of histology.  Risk factors Gastric surgery. The Billroth II procedure (gastrojejunostomy) carries a higher risk than the Billroth I procedure (gastroduodenostomy). It is thought to be due to the regurgitation of alkaline bile and pancreatic juice (which is greater after a Billroth II procedure compared with a Billroth I procedure) Cancer survivors who received abdominal irradiation. An elevated risk of gastric cancer has been reported in adult survivors of testicular cancer and Hodgkin lymphoma and in childhood cancer survivors who received abdominal radiation therapy. An especially high risk has been noted in Hodgkin lymphoma survivors who received both subdiaphragmatic radiation therapy and high-dose of procarbazine.  Host-related Risk Factors Blood group Individuals of blood group A have been known for decades to show an approximately 20 percent excess of gastric cancer compared with those of groups O, B, or AB. They also show a similar increase in the rate of pernicious anemia. Some data suggest that group A may be particularly associated with diffuse-type gastric cancer. It is possible that the observed associations are not due to the blood group antigens themselves but to the effects of genes closely associated with them. Family history of gastric cancer (risk ↑ 6-7 times): genetic susceptibility and same environmental exposure factors (clustering of H. pylori infection within families)  Host-related Risk Factors Truly hereditary (familial) gastric cancer accounts for 1 to 3% of the global burden of gastric cancer and comprises at least three major syndromes: hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), and familial intestinal gastric cancer (FIGC). The risk of developing gastric cancer is high in these families, but only HDGC is genetically explained. Hereditary diffuse gastric cancer: Germline truncating mutation in the CDH1 gene, which encodes the cell adhesion protein E-cadherin. These mutations are not concentrated in a single hotspot, but rather they are evenly distributed along the CDH1 gene in several different exons. The trigger and molecular mechanism by which the second allele of E-cadherin is inactivated appear to be diverse and include promoter hypermethylation, mutation, and loss of heterozygosity. The result is the loss of expression of the cell adhesion molecule E-cadherin. Gastric Adenocarcinoma Classification Heterogeneous histological appearance in the same patient and between different patients Gastric cancers can be classified in several ways, according to both histologic and macroscopic findings. Numerous classification systems In the last few years are relevant the molecular characteristics. Molecular markers may help better define the classification of these tumors, and precision medicine could influence treatment choices and better delineate a patient’s prognosis  Gastric Adenocarcinoma: Classification The Lauren Histological (1965) classification is the oldest and, at the same time the most commonly used – Intestinal type (well-differentiated) – Diffuse type (poorly differentiated) Gastric Adenocarcinoma: Classification Intestinal type (by Lauren, 1965) Expanding growth pattern (by Ming, 1977) Diffuse type (by Lauren, 1965) Infiltrating growth pattern (by Ming, 1977) Early gastric cancer  Gastric Adenocarcinoma Intestinal type Adenocarcinoma Cell morphology Epidemiology Pathogenesis Genetic pattern ≠ Diffuse type Adenocarcinoma Intestinal type Adenocarcinoma Clinical presentation Gastric localization Treatment response Prognosis ≠ Diffuse type Adenocarcinoma  Lauren classification Intestinal Type Diffuse Type 1. Well differentiated (gland 1. Poorly differentiated cell with or formation) without signet-ring cell 2. Expansive growth pattern 2. Infiltrating growth pattern 3. Environmental risk factors 3. Genetic aetiology 4. Mean age 55 4. Patients < 50 5. Prevalent in the distal stomach 5. No prevalent localization 6. M:F = 2:1 6. M=F 7. H.p. +++ 7. H.p. +-, not sequence atrophy, 8. Decreased incidence in western IM, cancer countries 8. Not changed incidence 9. Better prognosis 9. Poor prognosis  HELICOBACTER PYLORI “It has been clearly demonstrated that the development of Gastric Adenocarcinoma, as well as few other malignancies, is related to a specific infection, so...... in Gastric Adenocarcinoma pathogenesis the H.P. plays a principal role ”  HELICOBACTER PYLORI AND GASTRIC ADENOCARCINOMA Chronic active gastritis/ atrophic gastritis Intestinal metaplasia/Dysplasia/ Adenocarcinoma High incidence of intestinal-type adenocarcinoma in areas with high prevalence of H.P. infection. H.P. infection in > 90% of patients with intestinal-type adenocarcinoma. HELICOBACTER PYLORI AND GASTRIC ADENOCARCINOMA  HELICOBACTER PYLORI AND GASTRIC ADENOCARCINOMA Gastric cancer is a result of a complex interplay between bacterial virulence factors, host inflammatory responses, and environmental influences. H. pylori virulence factors including BabA, OipA, CagA, and VacA influence the outcome of H. pylori infection, with CagA and VacAs1m1 types associated with increased disease severity. Helicobacter pylori damages the apical-junctional complex at the level of the tight junction (TJ) and adherens junction (AJ) and it destroys cell polarity. Disruption of the adherens junction results in the translocation of β-catenin and p120 to the nucleus, altering the transcription of genes that promote disease progression. Host genetic diversity also contributes to gastric cancer, including polymorphisms within IL-1β, TNFα, IL-10 and IL-23. Host iron (Fe) levels and salt (NaCl) concentrations also impact the virulence of H. pylori. High salt increases CagA production while the low-iron levels increase the assembly of T4SS pili, CagA translocation and, IL-8 secretion.  Bacterial virulence factors Genes within the cag island encode proteins that form a bacterial type IV secretion system (T4SS) that translocates proteins across the bacterial membrane into host gastric epithelial cells. The terminal gene product of the cag island is CagA, and this is one of the substrates that is translocated into host cells by the T4SS Once phosphorylated by members of the Abl and Src family kinases, phospho- CagA targets and interacts with numerous intracellular effectors to lower the threshold for carcinogenesis. Phospho-CagA activates a eukaryotic tyrosine phosphatase (SHP-2), leading to sustained activation of extracellular signal- regulated kinase 1 and 2 (ERK1/2), Crk adaptor, and C-terminal Src kinase, and induces morphological transformations similar to changes induced by growth factor stimulation.  Bacterial virulence factors The amount of phospho-CagA is tightly self-regulated; however, non- phosphorylated CagA also exerts effects within the cell that contribute to pathogenesis. Non-phosphorylated CagA interacts with the cell adhesion protein E-cadherin, the hepatocyte growth factor receptor c-Met, the phospholipase PLC-γ, the adaptor protein Grb2, and the kinase PAR1b/MARK2, and activates ß-catenin which culminate in pro-inflammatory and mitogenic responses, disruption of cell-cell junctions, and loss of cell polarity, all of which promote neoplastic progression.  Host inflammatory responses CagA stimulates gastric epithelial cells to express and release excessive amounts of pro- inflammatory Cytokines, such as secretion of IL-8 Glandular damage Hypochlorhydria/Achlorh ydria Atrophic gastritis (PG1/PG2 sensitivity >98% GASTRIC CANCER: DIAGNOSIS It is mandatory to take numerous biopsies, always!!!  GASTRIC CANCER: BORRMANN CLASSIFICATION Type I – polypoid Type II – ulcerating Type III – ulcerating/infiltrating Type IV – diffuse infiltrating (linitis plastica)  Gastric Cancer Type I Borrmann Polypoid  Gastric Cancer Type II Borrmann Ulcerating  Gastric Cancer Type III Borrmann Ulcerating/infiltrating  Gastric Cancer Type IV Borrmann Diffuse infiltrating  EARLY GASTRIC CANCER  Adenocarcinoma confined to the gastric mucosa and/or submucosa regardless of the lymph node status offering an excellent (>90%) chance of cure based on surgical resection  Most early gastric carcinomas are small and often are in the lesser curvature around the angulus.  If left untreated, early gastric cancer proceeds to the advanced stage over a period of a few years  Histologically, the most common forms of early gastric adenocarcinoma are well differentiated, mostly with tubular and papillary architecture, >70%.  Early Gastric Cancer Protruded Elevated Superficial II (80%) Flat Depressed Excavated Early Gastric Cancer  EARLY GASTRIC CANCER Depth of Lymph node 5-year invasion metastasis survival rate Mucosa 0-7% about 100% Submucosa 8-25% 80-90% Early Gastric Cancer  E.G.C. type II superficial (depressed)  Gastric Cancer Prognostic factors Local invasion Lymph nodes and distant metastasis involvement Histology (intestinal/diffuse) Genetic mutation ??? GASTRIC CANCER: SPREAD Through lymphatic vessels: ✓ Locoregional lymph nodes ✓ Liver hilum ✓ Splenic ✓ Along the curvature ✓ Other abdominal lymph nodes ✓ Next to the pancreas ✓ Para aortic group ✓ Esophageal  GASTRIC CANCER: SPREAD ❖ Lymphatic spread Subclavia Supraclavicular lymph nodes ❖ Haematogenous spread or (troisier) dissemination: liver, pulmonary, Lungs liver and bone metastasis ❖ Direct spread: to liver, esophagus pancreas, transverse colon Celiac tripod and colon mesentery Portal system ❖ In women, spreading to serosa allows peritoneal seeding (peritoneal carcinomatosis) and ovarian metastasis Peritoneal seeding (Krukenberg tumor) Peritoneal Krukenberg carcinomatosis tumor  STAGING OF GASTRIC CANCER  Two systems:  Japanese classification (more elaborate and anatomic based)  Western: developed by American Joint Committee on Cancer (AJCC) and International Union Against Cancer (UICC) - more widely used - (TNM staging system) STAGING OF GASTRIC CANCER: TNM  STAGING WORKUP  Biopsy  Imaging  CT-scan evaluates for metastases (M stage)  20-30% patients with negative CT have intraperitoneal disease at laparotomy  Accuracy of 50-70% for T stage  Slightly worse accuracy for N stage compared to EUS  The EUS is the most reliable nonsurgical method to evaluate the depth of invasion  More accurate than CT for T stage  65-90% accurate for N stage  STAGING WORKUP  PET  More sensitive than CT for detection of distant metastases.  Also useful for detecting LNs  Negative PET is not helpful - even advanced tumors can be falsely negative if the metabolic activity is low.  Most diffuse gastric cancers (signet ring) are not FDG avid GASTRIC CANCER STAGING: COMPUTERIZED TOMOGRAPHY  GASTRIC CANCER STAGING: ENDOSCOPIC ULTRASOUND T1sm: tumour invades submucosa  GASTRIC CANCER STAGING: ENDOSCOPIC ULTRASOUND T2: tumour invades muscolaris propria  GASTRIC CANCER STAGING: ENDOSCOPIC ULTRASOUND T3: tumour penetrates serosa connective tissue without invasion of visceral peritoneum  GASTRIC CANCER STAGING: ENDOSCOPIC ULTRASOUND T4 N1: tumour invades adjacent structure with metastasis in two regional lymph nodes  GASTRIC CANCER: SEROLOGIC MARKERS  CEA, CA-125, CA 19-9 may be elevated but have low sensitivity/specificity  None are diagnostic  Preoperative elevation in markers usually pretends high risk of adverse outcome  No serologic finding should exclude surgical consideration GASTRIC CANCER: TREATMENT  Locoregional (stage I-III) disease  Potentially curable  Refer for multidisciplinary evaluation and consideration of surgery  Advanced (stage IV) disease  Palliative therapy  Studies indicate longer survival and better quality of life with systemic treatment  GASTRIC CANCER: TREATMENT  Complete surgical resection with removal of LNs (only chance of cure)  Possible in < 1/3 of cases  Subtotal gastrectomy for distal carcinomas, total or near-total for proximal masses  Reduction of tumor bulk (palliative)  Chemotherapy (cisplatin + 5-FU or irinotecan)  Partial response in 30-50% of patients  Radiation (for pain control, no mortality benefit with XRT alone) GASTRIC ADENOCARCINOMA: TREATMANT Gastric Adenocarcinoma Early diagnosis Advanced (early gastric cancer) stage SURGERY ? Combined treatment EMR Endoscopic Mucosal Resection (chemotherapy and ESD Endoscopic Submucosal Dissection surgery) 5 years survival rate ~ 80-90% 5 years survival rate ~ 10-15 % GASTRIC CANCER: TREATMENT  GASTRIC CANCER: Molecular Targeted therapy Epidermal Growth Factor Receptor (EGF-R) overexpression occurs in 50-63% of gastric adenocarcinomas (immunohistochemistry or FISH). It is positively correlated with the depth of tumor invasion and negatively correlated with the degree of tumor differentiation and survival Type 2 EGF-R, HER2-neu (c-erbB2), is overexpressed in 10-25% of cases. HER- 2/neu proto-oncogene, located on chromosome 17 (q12-21), is a transmembrane glycoprotein consisting of 125 amino acids and weighing 185Kd. HER-2/neu codes an intrinsic tyrosine kinase activity, which is one of a four-member family of the EGF receptor. Normally, HER-2/neu is expressed in a number of cells and tissues and plays important roles in intracellular signaling, growth, differentiation, survival, and cell adhesion pathways  GASTRIC CANCER: Molecular Targeted therapy Trastuzumab is a recombinant, humanized IgG1 monoclonal antibody that targets the extracellular domain IV of the HER-2 protein. As HER2 is overexpressed in gastric cancer and associated with poor prognosis, Trastuzumab with its mechanism of interacting with HER2 protein and causing cell apoptosis and interfering with downstream signals is a relevant target. Trastuzumab use is approved in advanced gastric cancer.  GASTRIC CANCER: Molecular Targeted therapy Multiple clinical studies have confirmed that molecular targeted therapy acts on various mechanisms of gastric cancer, such as the regulation of epidermal growth factor, angiogenesis, immuno-checkpoint blockade, the cell cycle, cell apoptosis, key enzymes, c- Met, mTOR signalling, and insulin-like growth factor receptors, to exert a stronger anti- tumor effect. Recent advances in chemotherapy, targeted therapy, and immunotherapy offer promising treatments. Perioperative chemotherapy is now the standard for resectable gastric cancer. Progress has also been made in treating metastatic disease using targeted immunotherapies. Molecular biomarkers such as PD-L1, MSI, and HER2 guide personalized treatment approaches. Histological and Molecular Classification in Gastric Cancer  GASTRIC CANCER: Molecular Targeted therapy The Cancer Genome Atlas (TCGA) proposed a classification that identifies dysregulated pathways and potential gene mutations in four distinct molecular subtype groups: - The first subtype comprises Epstein–Barr virus (EBV)-positive tumors (9%) characterized by high levels of DNA hypermethylation. - The second subtype includes microsatellite instability (MSI) tumors (22%) with a hypermutated genome, DNA hypermethylation, and MLH1 silencing. - The third subtype consists of genomically stable (GS) tumors (20%) exhibiting a low mutation burden and displaying more aggressive disease traits. Over 70% of these tumors demonstrate diffuse histology and harbor somatic CDH1 mutations and Claudin 18.2 rearrangements. - The final subtype is chromosomal instability (CIN) tumors (50%) which are associated with intestinal histology and exhibit high somatic copy number aberrations, common TP53 mutations, and amplifications of the RAS receptor tyrosine kinase pathway. In the CIN subtype, most affected genes are vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) (10%), Human epidermal growth factor receptor (ERBB2) (24%), ERBB3 (8%), FGFR2 (8%), and c-Met (8%) GASTRIC CANCER: Molecular Targeted therapy Molecular mechanisms and signaling pathways in gastric cancer. The figure illustrates the main molecular pathways and key factors involved in GC development and progression, including MAPK, HER2, PI3K/AKT/mTOR, HGF/c-Met, p53, Wnt/β- catenin, NF-κB and PD-1/PD-L1 and CTL4.  GASTRIC CANCER: Molecular Targeted therapy Although an increasing number of clinical studies have explored the effect of targeted therapy alone or in combination with chemotherapy in the field of gastric cancer, its application in gastric cancer remains in its infancy compared with its successful use in colon, lung, and breast cancers. Targeted therapy for gastric cancer continues to face enormous challenges. Numerous phase II clinical trials have been performed; however, precise Phase III clinical trials are lacking. Additional in-depth Phase III clinical studies must be pursued to obtain sufficient evidence to support the use of targeted therapy for gastric cancer.  GASTRIC CANCER: Molecular Targeted therapy Targeting a single molecule has limited use for the treatment of gastric cancer because of the complex pathogenesis of the disease. Consequently, drugs that target a single molecule will be susceptible to a loss of efficacy soon after compensatory mechanism activation. Furthermore, it is difficult to target the entire tumor because subclones of gastric cancer cells exhibit different biological behaviors. This is only one of the primary reasons for the failure of single agents as a broad treatment for gastric cancer. Therefore, the development of multi-target drugs or the combination of targeted drugs with surgery, radiotherapy, and chemotherapy may result in new opportunities for cancer treatment. GASTRIC CANCER: Molecular Targeted therapy Immunotherapy and target therapy in metastatic gastric cancer. Currently, available immunotherapy and targeted therapy based on different biomarkers  GASTRIC CANCER: palliative therapy Laser Stent  PRIMARY GASTRIC LYMPHOMA MALT-LYMPHOMA (MALToma) is a form of lymphoma involving the mucosa-associated lymphoid tissue (MALT) of the stomach It is cancer originating from B cells in the marginal zone of the MALT and is also called extranodal marginal zone B cell lymphoma. PRIMARY GASTRIC LYMPHOMA Lymphoma Hodgkin’s Non-Hodgkin’s Extranodal Nodal MALT Splenic GI Tract Others PRIMARY GASTRIC LYMPHOMA MALT lymphoma MALT (mucosa associated lymphoid tissue) lymphoma First described in 1983 Extra-nodal marginal zone B-cell lymphoma Indolent (low grade) is the most common extra-nodal site of non-Hodgkin lymphoma and represents 30% to 40% of all extra-nodal lymphomas Most common in GI tract (50%) Stomach mostly involved (60-70% of GI MALT-lymphomas)  PRIMARY GASTRIC LYMPHOMA Primary gastric lymphoma represents approximately 5% of all gastric malignancies. It also represents 4% to 20% of all non-Hodgkin lymphomas (NHL) 65-75% of all gastrointestinal lymphomas developed in the stomach Max incidence between 50-60 years of age M:F=2-3:1 Incidence: 1/100000 inhabitants in western countries Higher incidence in immunosuppressed MALT: Mucosa Associated Lymphoid Tissues Congenital MALT: Acquired MALT: Peyer’s Patches – Gut skin – salivary gland – Stomach – lungs associated lymphoid tissue -Thyroid Helicobacter Pylori Chronic inflammation ✓ Acquired MALT, infection promotes MALT formation through chronic antigen stimulation ✓ Non-Hodgkin extra-nodal marginal zone B-cell lymphoma ▪ H. Pylori is present in> 90% of MALT Lymphomas ▪ H. Pylori eradication can treat low grade MALT Lymphomas PRIMARY GASTRIC LYMPHOMA Chronic HP infection is the only known risk factor for MALT gastric lymphoma “…There is little doubt that, at least one type of tumor, gastric lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is causally related to Hp infection as it is acquired in gastric mucosa almost in 100% in association with Hp infection. Clinical studies have shown that the eradication of bacterium, at least from early lesions, results in tumor regression in 60 to 92%...” Gastric MALT lymphomas are strongly associated with Helicobacter pylori infection. This pathogen is the most common infectious agent related to worldwide cancers (5.5% of total cancers)  PRIMARY GASTRIC LYMPHOMA: SYMPTOMS The most common presenting symptoms of a gastric MALT lymphoma are non-specific upper gastrointestinal complaints that often lead to an endoscopy, usually revealing non-specific gastritis or peptic ulcer with mass lesions being unusual. Stomach-ache and dyspepsia (about 90 %) Anorexia (50%) e weight loss(25%) Nausea and vomiting (18%) Melena, hematemesis, faecal occult blood (20%) Early satiety Back pain, low grade fever PRIMARY GASTRIC LYMPHOMA: DIAGNOSIS EGDS with biopsies: Mucosal erythema Mass or polyp that can be ulcerated Gastric ulcer Mucosal nodularity Thickened folds Gastric MALT lymphoma can involve any part of the organ, but more frequently it affects the antrum. GASTRIC LYMPHOMA DIAGNOSIS Primary gastric lymphoma (PGL) represents a rare pathology, which can be easily misdiagnosed because of unspecific symptoms of the digestive tract. Histologically, PGL can vary from indolent marginal zone B-cell lymphoma of the mucosa- associated lymphoid tissue (MALT) to aggressive diffuse large B-cell lymphoma (DLBCL). Diagnosis is based on the histopathological evaluation of the gastric biopsies, principally on B-cells lymphocytes analysis through immunochemistry. The MALT lymphomas (marginal zone B-cell lymphoma of the mucosa- associated lymphoid tissue) are positive for surface immunoglobulins (Igs), for pan-B antigens (CD19, CD20, and CD79a), and for marginal zone typical antigens (CD35 and CD21). Meanwhile, the aggressive Diffuse Large B-cell Lymphoma (DLBCL) immunophenotype is different with CD45, CD5, and CD10 expression, which can be used as a prognostic indicator. MALT lymphoma and DLBCL have in common bcl-2 rearrangement in the 30% of cases; c-myc rearrangement is less frequent. GASTRIC LYMPHOMA DIAGNOSIS It is important to mention that MALT lymphomas are low-grade lesions and DLBCL gastric lymphomas are high-grade and more common than the first one. Treatment is different for these two pathologies. Microscopic features are a present diffuse polymorphous population of B-cells expanding the lamina propria, numerous plasma cells some of these may have Dutcher bodies (intranuclear inclusion made up of immunoglobulin), small or medium sized irregular (centrocyte-like) cells forming lymphoepithelial lesions and reactive lymphoid follicles. The difference between low-grade and high-grade lymphoma lies in the blast's percentage ( >20% = high-grade) It was discovered that MALT lymphoma expresses high levels of a ligand (APRIL), a novel cytokine which is crucial in sustaining B-cell proliferation Also, H. pylori and H. pylori-specific T cells stimulate the macrophages to produce APRIL. H. pylori can translocate the CagA protein directly into B-cells resulting in extracellular signal-regulated kinase activation and Bcl-2 expression up-regulation, leading to apoptosis inhibition GASTRIC LYMPHOMA DIAGNOSIS During HP infection, normal B cells are transformed into malignant clone via three chromosomal translocations – t(11;18) (q21;q21), t(1;14)(p22;q32), and t(14;18)(q32;q21), which produces activation of nuclear factor kappa B (NF-κB), which plays a role in immunity, inflammation, and apoptosis. Studies show that t(11;18)(q21;q21) was found to be more prevalent in patients with CagA-positive H. pylori strains which determine MALT lymphoma. PRIMARY GASTRIC LYMPHOMA: TREATMENT H.p. eradication Several studies confirm the effectiveness of antibiotic therapy with long- term remissions in 70% to 100% of patients with localized, H. pylori- positive, MALT lymphomas. (non-bulky mass, no metastasis) Almost 10% of MALT lymphomas are unrelated to H pylori infection, and the pathogenesis remains unclear, so treatment is based on: Surgery Radiation therapy Chemotherapy and immunotherapy (Rituximab: anti CD20) GIST: GastroIntestinal Stromal Tumour ❖ Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumours in GI tract. ❖ Gastrointestinal stromal tumors (GISTs) may be malignant (cancer) or benign (not cancer). ❖ They are most common in the stomach and small intestine but may be found anywhere in or near the GI tract. ❖ GISTs arise in smooth muscle pacemaker interstitial cells of Cajal (ICC), in the wall of the GI tract. GIST: GastroIntestinal Stromal Tumors History ❖ GISTs originally thought to derive from smooth muscle (since they arise within the gut wall, from the muscle layer), but only rarely do these cells show clear-cut features of complete muscle differentiation. ❖ In the 80s immunohistochemistry showed GIST produce markers related to muscle tissue and nervous tissue ❖ The term “GIST” was first used in 1983 ❖ In the 1990s some tumours classified as GIST were truly myogenic, some neural, others bidirectional and some had the ‘null’ phenotype ❖ Up to two-thirds were CD34 positive, the possibility that GIST might be related to the interstitial cells of Cajal was raised by investigators ❖ Unfortunately, Schwannomas and a proportion of true smooth muscle tumours were also CD 34 positive GIST: GastroIntestinal Stromal Tumors ❖ In 1998 Hirota and colleagues discovered a specific mutation in the intracellular domain of the c-kit receptor, which is a product of the c-kit or KIT proto-oncogene, in GISTs; and he showed GISTs shared striking ultrastructural and immunophenotypic similarities with interstitial cells of Cajal: Hirota S, Isozaki K, Moriyama Y et al. “Gain-of-function mutations of c-kit in human GIST” c-KIT (CD117), a type III receptor tyrosine kinase (RTK) that is involved in the development and maintenance of RBC, mast cells, melanocytes, germ cells and interstitial cells of Cajal (ICC). Loss of function KIT mutations result in anaemia, loss of mast cells, white coat ‘spotting’ due to failure of migration of dermal melanocytes, sterility due to a block in gametogenesis and gastrointestinal abnormalities due to loss of ICC.  GIST AND C-KIT  The c-kit receptor is one of many membrane tyrosine kinase receptors involved in cellular signalling pathways.  CD117 molecule (or antigen) is part of the c-kit receptor.  The c-kit tyrosine kinase receptor is encoded by the proto- oncogene (KIT, c-kit) located on the long arm of chromosome 4 (4q11-q12) and this gene consists of 21 exons  The CD117 antigen is expressed by almost all GISTs in contrast to other spindle-cell tumours of the GI tract GIST: GastroIntestinal Stromal Tumors In 1998, Hirota e coll. have documented not only the increased expression of KIT in GIST, but also the presence of mutations at the level of the juxta-membrane domain (exon 11) of the KIT gene in five of six patients (83%) affected by these tumors. The KIT mutation implied a gain-of-function linked to the activation of the kinase even in the absence of the binding of the ligand. UNCONTROLLED KINASE ACTIVATION THE MOLECULAR ETIOLOGY  In normal cells activation of the c-kit tyrosine kinase requires the presence of an endogenous ligand (KIT ligand, c-kit ligand, or stem cell factor)  Approx 80 % of GISTs have KIT protooncogene mutations that lead to activation of the c-kit receptor resulting in spontaneous receptor activation not requiring a ligand.  Observed both in sporadic and hereditary cases  A subset of GISTs lacking c-kit mutations have activating mutations in the PGFRα gene (platelet derived growth factor receptor alpha), another tyrosine kinase receptor GISTS ARE IDENTIFIED BY:  either c-kit immunoreactivity (detection of the CD117 antigen) or  the presence of activating mutations in KIT or PDGFRα  ARE GISTS DERIVED FROM ICC?  Interstitial cells of Cajal (ICC) form the interface between the autonomic innervation of the bowel wall and the smooth muscle itself.  The KIT RTK plays essential roles in the development and maintenance of normal ICCs.  Ultrastructural and immunophenotypic features of both neuronal and smooth muscle differentiation (just like GISTs)  It is postulated that GISTs originate from CD34 positive stem cells within the wall of the gut and differentiate toward the pacemaker cell phenotype (ICC)  Malignant GISTs may represent dedifferentiated ICCs that maintain a CD34-positive stem cell phenotype  Attractive hypothesis but still open to question GIST: GastroIntestinal Stromal Tumors ❖ Incidence: 1,5/2 cases every 100.000 inhabitants/year. ❖ 1-3% of all GI tract tumours ❖ Mean age of onset: 55-65 years. GISTs are uncommonly seen in patients younger than 40, however, cases in children and young adults have been reported. Sporadic GISTs are the most common while familial GISTs, with germline mutation of the KIT gene, are rare but have been well described. Paediatric GISTs account for about 1-2% of GISTs ❖ 10-30% of GISTs are Malignant with no clear gender predilection GIST: GastroIntestinal Stromal Tumors ❖The majority of GISTs (60%) are seen in the stomach, usually in the fundus. The percentages of GISTs found in other portions of the GI tract are reported as 30% in the jejunum and ileum, 5% in the duodenum, 5% in the colorectum, and rarely in the esophagus and appendix. ❖ The most common metastatic sites of gastrointestinal stromal tumors are the liver (65%) and peritoneum (21%); GISTs rarely metastasize to lymph nodes (6%), bone (6%), lung (2%), and soft tissue (less than 1%) GIST: GastroIntestinal Stromal Tumors size: < 1 cm to >35 cm GIST: GastroIntestinal Stromal Tumors GIST: GastroIntestinal Stromal Tumors FREQUENCE SITE COMMENT (%) ESOPHAGUS 2 STOMACH 50-60 1-2% of gastric Tumours 15-20 % of small bowel SMALL BOWEL 20-30 Tumours COLORECTAL 5-10 0,1% of colorectal cancer RETROPERITONEUM, OMENTUM, OTHER SITE 5 GALLBLADDER, APPENDIX, PANCREAS. GIST: GastroIntestinal Stromal Tumors clinical presentation is related to localization and tumor size; most patients generally present with nonspecific symptoms like abdominal pain. SITE SIGNS AND SYMTOMPS ESOPHAGUS dysphagia, odynophagia, weight loss, heart burn, hematemesis STOMACH bleeding, pain, anorexia, dyspepsia SMALL BOWEL pain, intestinal obstruction/blockage COLORECTAL Bleeding, changes in the frequency of bowel movements GIST: GastroIntestinal Stromal Tumors ❖ GIST’s diagnosis usually is accidental, e.g. during an endoscopic examination due to no specific symptoms, and only rarely as the consequence of specific symptoms such as abdominal pain, early satiety, GI BLEEDING, or GI obstruction. GIST: GastroIntestinal Stromal Tumors ENDOSCOPY  Usually, GISTs show up as fixed protrusion in the GI tract (submucosal tumours)  GISTs in most of the cases are covered by normal mucosa.  Instrumental diagnosis:  Endoscopic ultrasound,  Computerized Tomography (CT scan),  Magnetic Resonance Imaging (MRI),  Positron emission tomography (PET). GIST: GastroIntestinal Stromal Tumors ENDOSCOPY  Endoscopic UltraSound (EUS) 1 EGDS: identification of submucosal mass 3 EUS: fine needle aspiration is necessary for 2 diagnosis EUS: the mass takes origin from the muscular layer. GIST: GastroIntestinal Stromal Tumors Immunohistochemistry ❖ GISTs have specific morphology and an immunohistochemical pattern. ❖ 95 % of GISTs are positive for KIT (CD117), KIT positivity is a major defining feature for the diagnosis of GIST for a tumour that has morphological features compatible with GIST, although KIT positivity alone is not sufficient for the diagnosis. This receptor is composed of an extracellular ligand-binding region, a transmembrane sequence, a juxta-membrane domain, and two cytoplasmic kinase domains. The uncontrolled kinase activity results in constitutive oncogenic signalling. ❖When there is KIT negativity, as in approximately 5 % of GISTs,, another tyrosine kinase receptor is mutated: the PDGFRα (Platelet Derived Growth Factor Receptor Alpha). GIST: GastroIntestinal Stromal Tumors Prognosis Independent prognostic factors for GIST include the mitotic index (more than 10% nuclei positive for Ki-67 is related to high risk of metastasis) and tumour size. These prognostic factors allow risk stratification for GISTs (high, moderate, low, and very low). The latest studies identified other two prognostic factors: tumor location (gastric vs. no-gastric), CD34, and layer invasion. GIST: GastroIntestinal Stromal Tumors Therapy ❖ Imatinib is a first-line standard therapy for inoperable, metastatic, or recurrent GISTs. It is a tyrosine kinase receptor inhibitor, such as c- kit or PDGF-alfa. Response to target therapy reaches 80%. ❖ When GIST patients have progressive disease under imatinib treatment or are unable to tolerate imatinib because of adverse events, sunitinib is recommended. ❖ The third-line therapy for GISTs progressing under sunitinib treatment is regorafenib.