Neoplasms of Large Bowel PDF

# Neoplasms of Large Bowel ## 18th September 2024 ### Prof. G Callagy ## Outline * Definitions * Common colonic polyps * Hereditary cancer syndromes * Colorectal carcinoma * Risk factors * Molecular pathways * Presentation, diagnosis/staging, Mx, * Other: Diverticular disease ## De...

# Neoplasms of Large Bowel ## 18th September 2024 ### Prof. G Callagy ## Outline * Definitions * Common colonic polyps * Hereditary cancer syndromes * Colorectal carcinoma * Risk factors * Molecular pathways * Presentation, diagnosis/staging, Mx, * Other: Diverticular disease ## Definitions * Polyp * A mass protruding into lumen * Neoplasm * A proliferation of cells that results from autonomous, excessive, uncoordinated growth of tissue * Dysplasia * Abnormal cells that have some malignant features but do not have invasive or metastatic potential (e.g. intra-epithelial neoplasia, in situ) * Adenocarcinoma * Invasive carcinoma showing glandular differentiation i.e. has metastatic potential * Hamartoma * An abnormal arrangement of tissue that is native to the site. Can be neoplastic or non-neoplastic ## Normal Colon The image shows a normal colon, with the following parts labelled: * Mucosa * Subserosa * Muscularis propria * Serosa * Crypt * Lamina propria * Muscular mucosa ## Types of Polyps in Colon * **Epithelial (commonest)** * Hyperplastic (Inc. Sessile serrated lesions) * Adenomas * Carcinomas * Neuroendocrine tumours * **Non-epithelial** * Neoplastic * Lipomas * Gastrointestinal stromal tumours (GIST) * Neural, vascular tumours * Lymphoma * Inflammatory * e.g. chronic inflammatory bowel disease; rectal prolapse * Hamartomas ## Symptoms of a polyp * Asymptomatic * Frank bleeding * Especially if large or on left side * Occult bleeding * Right side > left * Picked up by screening * Anaemia * Metabolic changes (i.e. hypokalemia) with VA * If large * Altered bowel habit * Obstruction * Rarely, intussusception ## Intussusception * Can occur with any type of mass * Fixes one part of the colon * Telescopes an adjacent portion of the colon * Causes obstruction The image shows a description of intussusception of the small intestine with the following parts labelled: * Small intestine with intussusception * Intussusception (cross section view) ## Hyperplastic Polyp * Common * Mostly in recto-sigmoid region * Usually <0.5 cm * Asymptomatic * Hyperplastic mucosa * Malignant potential rare * Sampled/removed at colonoscopy Several images show hyperplastic polyps, comparing them to a normal polyp. ## Sessile Serrated Lesion * Type of hyperplastic polyp * Usually in right side of colon * Serrated crypts with asymmetric architecture at base of crypt (boot shaped; inverted T) * No dysplasia * Possible precursor for MSI-high sporadic carcinomas * Removed at colonoscopy; no need for clear margins Several images show sessile serrated lesions, comparing them to hyperplastic polyps and a normal polyp. ## Adenomas * Common * Middle-aged adults * Left > right side * Contain dysplastic epithelium by definition * Growth pattern is usually pedunculated or sessile ## Tubular Adenomas (TA) The image shows a pedunculated tubular adenoma. ## Villous (Sessile) Adenomas The image shows a broad-based, sessile villous adenoma. ## Villous Adenomas (VA) The image shows a villous adenoma with finger-like projections. ## Risk of Adenoma Progressing to Malignancy Associated with: * Increasing size * Cancer rare in adenoma < 10 mm * 40% adenomas > 40 mm associated with malignancy * Presence of high-grade dysplasia * Higher proportion of villous growth * Number of adenomas * Molecular profile is likely to be important in the future The image shows an adenoma with high-grade dysplasia. ## Management of Adenomas * Generally removed at colonoscopy * Complete excision at colonoscopy is often possible for TAs but not always necessary in the absence of high-grade dysplasia (HGD) * HGD in an adenoma necessitates 'complete' excision with clear margins * Large VAs may require surgery to obtain clear margins because it can be difficult to excise a VA * Surveillance * Depending on risk profile (e.g. number of adenomas, type, size) ## Hamartoma * Uncommon * Occurs anywhere in GIT * Disorganised arrangement of structures normal to the site * Most are solitary * Removed at colonoscopy * Can occur as part of a syndrome, especially if multiple * e.g. Peutz Jeghers, Cowden, Cronkite Canada Syndrome, Tuberous sclerosis ## Colorectal Carcinoma: Epidemiology Colorectal carcinoma is the 3rd most common cancer and cause of cancer mortality. Peak age of diagnosis is 60-70s. A table shows the number of cases, rates and deaths for colorectal carcinoma between 2018-2020 in Ireland, broken down by gender. A graph shows average annual case count for both males and females in Ireland, broken down by age group. This graph also shows the rate per 100,000 population for both males and females in Ireland, broken down by age group. ## Colorectal Carcinoma: Risk factors * Diet: High caloric diet, high fat and refined carbohydrate intake and low vegetable and fibre intake; low intake of vitamin A, E, C * Smoking * Sedentary lifestyle * Aspirin shown to be protective * Sporadic adenomas/Hx of removal of adenoma * History of adenomas in 1st degree relatives * Family History of CRC * Risk x 2-3 in 1st degree relatives of CRC patients * Risk x 3-4 if > 1 family member affected * Risk x 4 if cancer at young age (e.g. 45-59yrs) ## Carcinoma and CIBD * Risk in long-standing UC with pancolitis * Overall incidence is low * Symptoms masked by underlying disease * Multiple carcinomas without obvious mass * Mechanism not entirely clear (?oxidative stress) CIBD: Chronic Inflammatory Bowel Disease ## Colon Cancer Cases Arising in Various Family Risk Settings This image shows a pie chart illustrating the percentages of colon cancer cases: * Sporadic cases ( majority): * Cases with familial risk (10% to 30%): * Lynch Syndrome (hereditary nonpolyposis colorectal cancer): (2% to 3%) * Hamartomatous polyposis syndromes: (<0.1%) * Familial adenomatous polyposis: (<1%) ## Common Polyposis Syndromes A Venn Diagram shows the Polyposis Syndromes: On the left side labelled Adenomas: * APC gene-related * FAP * Attenuated FAP * Gardner * Turcot * MYH-associated Polyposis (MAP) * MYH (BER gene) On the right side labelled Hamatomas: * Peutz-Jeghers (STK11) * Juvenile Polyposis * (SMAD TGFb pathway) FAP: Familial adenomatous polyposis; BER Base excision repair ## Polyposis Syndromes: FAP * AD inheritance * Inactivating germline mutation in APC (adenomatous polyposis coli) ch 5, * APC is a TSG * >>100 adenomas in large bowel * Adenomas and ca in small bowel, stomach * 100% risk of progression to colorectal carcinoma * Extra-GI manifestations are also present (neoplastic and non-neoplastic) * fibromatosis, cysts, CHRPE, carcinoma of thyroid adrenal, pancreas, bile duct etc ## Lynch Family Syndrome (HNPCC) * AD * Mutations in DNA MMR genes * 80% lifetime risk of CRC * Onset at 45 years * Rapid growth * Right side, multiple tumours, mucinous subtype, dense lymphocytic infiltrate) * Carcinoma of small bowel & endometrium HNPCC, hereditary non-polyposis colorectal cancer ## Molecular basis of CRC: Pathways that Drive Colonic Neoplasia This image shows 2 circles: On the left, labelled Chromosomal Instability (CIN) in blue: * Sporadic: * Hereditary (e.g. FAP) On the right, labelled Microsatellite Instability (MSI) in green: * Sporadic Methylation: * Lynch Family /HNPHCC ## Chromosomal Instability (CIN) pathway * Mechanism for cancers arising in FAP and 80% sporadic carcinomas * Stepwise accumulation of genetic aberrations that correlate with a morphological progression from normal mucosa to adenomas to carcinomas (adenoma-carcinoma sequence) * Number of mutations is more important than the sequence * 4-5 molecular events in key pathways necessary ## CIN (APC) pathway The image illustrates the CIN (APC) pathway, showing the progression of cancer from normal colonic epithelium to small adenoma, large adenoma, and carcinoma. The pathway is labelled with the key genes involved, including: * APC * RAS * PI3K * Cell Cycle/Apoptosis * TGF-β * Tumours show aneuploidy and chromosomal losses * CIN is an effective way of causing loss of a wild type allele of tumour suppressor genes ## Microsatellite instability (MSI) pathway * 10-15% sporadic cancers and tumours arising in HNPCC/Lynch Family Syndrome * Loss of mismatch repair (MMR) protein function * Morphological sequence not as well understood as for CIN pathway ## Microsatellite instability (MSI) pathway Role of Mismatch Repair Proteins The image illustrates the role of mismatch repair proteins in the microsatellite instability (MSI) pathway. It shows a DNA double helix, with a mismatch between the strands, and the location of the MMR proteins, which are labelled as follows: * MLH1 * PMS2 * MSH2 * MSH6 The image also shows the chemical structure of adenine and ribose. * MMR proteins proof-read DNA during replication and correct errors * 4 major proteins * Form heterodimer pairs ## Role of Mismatch Repair Proteins in CRC This image outlines the role of mismatch repair proteins in colorectal cancer, illustrating the pathway from epigenetic changes (hypermethylation) or germline mutations in MMR proteins to colorectal cancer. * Epigenetic i.e. hypermethylation in sporadic cases * Defect in genes coding for MMR proteins * Reduced capacity to repair specific types of DNA damage in certain cells * Germline mutation in MMR gene (Lynch Syndrome/HNPCC) * Increased rate of mutation in microsatellite DNA (mutation rate 1000 fold higher than normal) * Microsatellites in key regulatory genes * Colorectal Carcinoma ## Microsatellite Instability (MSI) Pathway This image shows the progression of microsatellite instability (MSI) from germline or somatic mutations of mismatch repair genes to accumulated mutations in genes that regulate growth, differentiation, and/or apoptosis. * Germline (inherited) or somatic (acquired) mutations of mismatch repair genes * Alteration of second allele by LOH, mutation, or promoter methylation * Microsatellite instability/ "mutator phenotype" * Accumulated mutations in genes that regulate growth, differentiation, and/or apoptosis * Loss of expression of MMR proteins and alterations in DNA microsatellites (MSI) * Chromosome complement largely intact in contrast to CIN pathway * TGFbR and BAX, BRAF (usually not p53, KRAS) ## Classic Presentation: Right-Sided carcinoma * Sx related to occult blood loss * Fatigue * Pallor, pale conjunctivae i.e. Iron def anaemia * Vague mass in RIF * ± Altered bowel habit * FOB positive DDx * Other causes of IDA * Appendiceal mass; adenoma other tumour * Ovarian mass ## Classic Presentation: left-sided tumour * Altered bowel habit * Constipation/diarrhoea * PR bleeding * ± abdominal pain * + LIF mass DDx * Adenoma * Colitis e.g. CIBD * Diverticular disease; rectal prolapse; * Other tumour e.g. Spread of tumour to bowel ## Diagnosis of CRC requires tissue obtained at colonoscopy This image shows 2 microscopic images of colonic tissue, with a yellow circle highlighting a section that has been biopsied. It also shows 2 macroscopic images of colon that have been colonoscoped. * >90% Adenocarcinomas * Often with intra-gland necrosis * Characteristic cytokeratin profile (CK20+; CK7-, CDX2 +) ## Mucinous adenocarcinoma is more common in MSI-positive CRC This image shows 2 microscopic images of colonic adenocarcinoma, with the following parts labelled: * Pools of extra-cellular mucin * Intra-cellular mucin (signet ring cells) ## Staging * CRC spread is direct, by lymphatics and by blood * Staging is performed by Radiology (e.g. CT/MRI abdomen + thorax; bone scans) and Pathology (examination of resection) * TNM stage * Level of invasion through wall (T) * Lymph node involvement (N) * Metastasis to other organs (M) The image shows a CT scan showing a cancerous tumour in the colon. ## T_IS, T₁ , T₂ , T₃ This image shows a diagram of how the depth of tumor invasion is measured in the TNM system for staging. ## 5 year survival related to stage This image shows the 5-year survival rate related to stage at diagnosis, with a pie chart to the left and bar chart to the right. * Stage I (NN, T1 T2) 95% * Stage II (NN, T3 T4) 80% * Stage III (NP, any T) 65% * Stage IV (M1) 5% * Limited to submucosa 95% * Node-positive 75% * Metastasis 4% The bar chart shows the 5-year net survival for colorectal cancer in Ireland, broken down by diagnosis year. ## Treatment * Surgery with clear margins * + radiotherapy for tumours below the peritoneal reflection to ensure clearance at circumferential margin * Chemotherapy (5FU + others) * Neoadjuvant or adjuvant * For disease with high risk features * Stage II, NO disease with adverse features * Stage III, NP disease * Stage IV, Metastatic disease ## Molecular Diagnostics in CRC * Evaluation of MSI Status to determine * Hereditary Status (Lynch Family Syndrome) * Usually by IHC evaluation of MMR proteins * Can do MSI testing or sequencing of satellites * Also aids decision re chemotherapy * RAS mutation screen by NGS/gene assays and HER2 testing (IHC/ISH) in metastatic disease to guide use of targeted therapeutics IHC, Immunohistochemistry; ISH, in situ hybridisation; NGC, Next generation sequencing ## Targeted Therapeutics This image shows a flowchart of targeted therapeutics: * MSI positive (MMR protein loss) * MSI positive tumours do worse with some agents e.g. 5FU * HRAS/NRAS mutation * Mutant RAS tumours do not respond to anti-EGFR TKIs * HER2 overexpression/amplification * Respond to anti-HER2 therapy (e.g. Trastuzumab) TKI, Tyrosine Kinase Inhibitors ## Take Home * Hyperplastic polyps and adenomas are the commonest polyps in the colon * Adenomas are assessed for risk of malignancy (no., size, HGD, villosity) * Hereditary CRC arises with Polyposis syndromes (FAP, MAP) and non-polyposis syndrome (HNPCC) * CRC arises by two main pathways: CIN and MSI * Tumour stage predicts outcome and includes assessment of level of invasion through wall (T) * Targeted therapies have emerged based on RAS, HER2 ## Neuroendocrine tumours * Tumours arising from neuroendocrine cells along GIT * Well-differentiated neuroendocrine tumours (i.e. carcinoids) regarded as low/intermediate grade risk with indolent behaviour * More common in small intestine, stomach than in appendix or large bowel * Appendiceal tumours are often identified as an incidental submucosal mass at the tip * Carcinoid syndrome is uncommon with intestinal carcinoids ## Diverticular Disease The image on the left shows the outpouching of mucosa in the colon. The image on the right shows a microscopic view of the outpouching. * Complications * Diverticulitis (Inflammation) * Abscess * Perforation * Fistula * Haemorrhage * Stricture (obstruction) * Colonoscopy/imaging studies to ax * Management depends on complication ## Images * Webpath * Robbins and Cotran, Pathologic basis of disease * NCI * Boland 2010 Gastroenterology ## Thank you