RCSI Pathology Lecture: Tumours of the Large Bowel 2024 PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Tumours of the Large Bowel Class Year 2 Course Pathology Lecturer Prof Muna Sabah Dat...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Tumours of the Large Bowel Class Year 2 Course Pathology Lecturer Prof Muna Sabah Date 2nd October 2024 LEARNING OUTCOMES Describe types of Polyps List risk factors for colon carcinoma Describe clinical presentation and diagnosis of colorectal carcinoma Define the factors that influence the prognosis of colorectal carcinoma Describe other intestinal tumours TUMOURS OF SMALL & LARGE BOWEL Primary tumours Non-neoplastic polyps Epithelial neoplasms  Benign adenomatous polyps  Malignant – Adenocarcinoma – Carcinoid Mesenchymal neoplasms Lymphoma Secondary tumours (rare) Tumours of large bowel are more common than tumours of the small bowel POLYPS Mass arising from the mucosal epithelium or from the submucosal connective tissue protruding into the lumen of the gut  Non-neoplastic polyps  Neoplastic polyps= Adenomas Pedunculated (with a stalk) or sessile (flat) NON-NEOPLASTIC POLYPS Hyperplastic (metaplastic) polyps Hamartomatous polyps  Juvenile  Peutz-Jeghers Inflammatory polyps Lymphoid polyps HYPERPLASTIC POLYPS Common lesions >50% of people over 60 years Often found in the recto-sigmoid Less than 5 mm Single or multiple Asymptomatic Composed of non-neoplastic glands with goblet cell differentiation and serrated appearance Results from delayed shedding of surface epithelial cells Virtually no malignant potential JUVENILE POLYPS Hamartomatous malformations of bowel mucosa Children < 5 years but can be encountered in adults Rectum Can be large (1-3 cm) Cystically dilated glands in an inflamed stroma No malignant potential Juvenile polyposis (multiple juvenile polyps + adenomas)  PEUTZ-JEGHER POLYPS Hamartomatous polyps of small intestine & colon Single or multiple (Peutz-Jeghers syndrome)  Glands and connective tissue with smooth muscle Peutz-Jeghers syndrome  Autosomal dominant syndrome  Mucocutaneous pigmentation (around lips, oral mucosa, genitalia and palmar surfaces of the hand)  Multiple hamartomatous polyps throughout GI tract - No malignant potential but the patients have increased risk of developing GI and non-GI cancers (pancreas, breast, lung, ovary and uterus) HAMARTOMATOUS SYNDROMES Cowden syndrome  Autosomal dominant syndrome (PTEN)  Multiple hamartomatous polyps and trichoepitheliomas  No malignant potential but the patients have increased risk of developing thyroid and breast cancer Cronkhite-Canada syndrome  Hamartomatous polyps, nail atrophy, skin pigmentation INFLAMMATORY AND LYMPHOID POLYPS Inflammatory (pseudo) polyps  Inflamed regenerative mucosa surrounded by ulcerated tissue  Seen in patients with longstanding inflammatory bowel disease Lymphoid polyp  Intramucosal lymphoid tissue ADENOMATOUS POLYPS=NEOPLASTIC POLYPS Common lesions (prevalence 50% at age of 60) Proliferation of dysplastic epithelium (range from mild to severe) Precursors of carcinoma  Benign but may progress to adenocarcinoma via the adenoma-carcinoma sequence ADENOMATOUS POLYPS Three types  Tubular (tubular glands)  Villous (villous projection)  Tubulovillous (mixture of the previous two) Can be pedunculated (most typical of tubular adenoma) or sessile (most typical of villous adenoma) ADENOMATOUS POLYPS All adenomatous polyps are covered by dysplastic epithelium Risk of malignancy correlates with  Size (>2cm)  Histologic type (villous component)  Degree of dysplasia Since they are considered pre-malignant all should be removed ADENOMATOUS POLYPS May be asymptomatic May present with occult bleeding, anaemia, protein loss and obstruction Treatment- complete excision SESSILE SERRATED LESIONS Overlap with hyperplastic polyps, but serrated architecture in the crypt base Lack cytologic features of dysplasia Right colon May be asymptomatic May present with occult bleeding, anaemia, protein loss and obstruction Treatment- complete excision FAMILIAL ADENOMATOUS POLYPOSIS (FAP) Autosomal dominant inheritance Mutations of APC gene on 5q21 Numerous adenomatous polyps throughout GI tract (esp. large bowel)  Minimum 100, may be >2000 Average age of onset of polyps is the teens to twenties (bleeding & anaemia) Virtually 100% risk of carcinoma (within 10 to 15 years)- indication for prophylactic total colectomy) GARDNER’S SYNDROME A variation of FAP Mutations of APC gene Autosomal dominant Multiple adenomas, epidermoid cyst (skin), fibromatosis (soft tissue), osteomas (bone) and abnormal dentition (teeth) Increased risk of duodenal cancer and thyroid cancer TURCOT’S SYNDROME A variation of FAP Mutations of APC gene Autosomal dominant Colorectal adenomatous polyps and brain tumours (gliomas, medulloblastoma) ADENOMA-CARCINOMA SEQUENCE The development of carcinoma from adenomatous lesion Populations that have high prevalence of adenomas have a high prevalence of colorectal cancer The distribution of adenomas is comparable to that of colorectal cancer The peak incidence of adenomatous polyps antedate by some years the peak for cancer The risk of cancer is related to the number of adenomas Adenomatous lesions are often seen in association with invasive carcinoma ADENOMA-CARCINOMA SEQUENCE APC mutations (FAP-germline, Adenoma-sporadic) Inactivation/mutation of other allele of APC Activation of K-ras (12p) Loss of DCC gene (18q) Loss of p53 (17p) Increase expression of COX Activation of telomerase BOWEL SCREEN Target population- 59 to 69 years Target individuals offered screening every 2 years Screening conducted using home test kit  (Faecal Immunochemical Test- FIT) (Faecal Immunochemical Test- FIT)  Polyps are usually clinically silent, but can bleed  Aim to remove adenomatous polyps before progression to carcinoma (colonoscopy)  All polyps are removed and examined microscopically COLON ADENOCARCINOMA Disease of western world Peak incidence is in 7th decade  Carcinoma in a young person is associated with genetic predisposition or UC RISK FACTORS Increasing age Adenomatous polyps Hereditary syndromes Inflammatory bowel disease (esp. UC) Diet (low fibre, high fat, high carbohydrates, high intake of red meat and decreased intake of micronutrients, vitamins A,C & E) Obesity Physical inactivity HEREDITARY COLON CANCER SYNDROMES Familial adenomatous polyposis Hereditary nonpolyposis colorectal cancer (HNPCC) COLON ADENOCARCINOMA-CUMULATIVE GENETIC ALTERATIONS OR “MULTI-HIT” HYPOTHESIS Two pathways:  Adenoma-carcinoma sequence: APC mutations (FAP- germline, Adenoma-sporadic)  Microsatellite instability (HNPCC, serrated lesions) LYNCH SYNDROME HNPCC (Lynch syndrome)  Autosomal dominant familial syndrome  Colonic cancer is not associated with pre-existing adenomas and is usually right sided  Lower number of polyps than FAP  Lynch syndrome 1- Increased risk of colon cancer  Lynch syndrome 2- Increased risk of colon cancer and non-GI cancers (endometrial, ovarian) Defect in the mismatch DNA repair genes  MSH2  MLH1  MLH6  PMS1  COLORECTAL CARCINOMA Tumours in the proximal colon tend to grow as polypoid lesions “cauliflower”, may ulcerate  occult bleeding  Iron deficiency anaemia in an adult (especially a male) = colon cancer until proven otherwise In the distal colon tend to be annular, encircling lesions “Napkin-ring”  constriction with symptoms and signs of obstruction (rectal bleeding and changing bowel habits) WHY DO TUMOURS OF THE LEFT SIDE PRESENT WITH OBSTRUCTION? Annular tumours Lumen is narrower than the right side Solid faecal material SYMPTOMS OF COLORECTAL CANCER Change in bowel habits Blood in stool Iron deficiency anaemia Abdominal discomfort/pain Note: Colonic carcinoma is associated with an increased risk of Streptococcus bovis endocarditis Left-sided carcinoma Decreased stool calibre, left lower quadrant pain, blood- streaked stool Right-sided carcinoma Iron deficiency anaemia and vague pain MICROSCOPIC FEATURES Adenocarcinoma Well, moderately or poorly differentiated May produce mucin Invade through the bowel wall Metastasise to lymph nodes and then to liver and lungs DIAGNOSIS Colonoscopy and biopsy Barium enema Occult blood Digital rectal examination CEA (carcinoembryonic antigen- tumour marker) - Low sensitivity and specificity  To assess the adequacy of resection and detect early recurrence Radiology-staging PROGNOSIS Stage of the tumour Tumour grade (degree of differentiation) Tumour location – Left sided lesions have a poorer prognosis because they tend to be more invasive Adequacy of excision (margins) Genetic mutations and MSI STAGING MOST IMPORTANT PROGNOSTIC FACTOR-TNM T- Depth of invasion; tumours limited to the mucosa generally do not spread due to lack of lymphatics in the mucosa N- Spread to regional nots M- Distant spread; most commonly involves the liver ANCILLARY TESTS Immunohistochemistry for mismatch repair proteins  MSH2  MLH1  PMS1  MPS2 MSI by PCR Gene mutation testing: KRAS, NRAS, BRAF – BRAF testing (if IHC deficient or MSI-High) – MLH1 promoter methylation (if MSI high or deficient MLH1) MONOCLONAL ANTIBODIES APPROVED TO TREAT METASTATIC COLON CANCER Erbitux® (cetuximab) and Vectibix® (panitumumab) by blocking the EGFR signalling pathway – Effectiveness of EGFR inhibition depends on downstream mutations – KRAS, BRAF, NRAS mutations are associated with resistance to anti-EGFR therapy Avastin® (bevacizumab) blocks the growth of blood vessels to the tumour NEUROENDOCRINE TUMOURS (CARCINOID) Tumours of neuroendocrine cells Present throughout GI tract  Most common sites: appendix, small bowel, rectum, stomach, colon May secrete numerous bioactive hormones (esp. serotonin) Low grade malignant tumours Behaviour correlates with size, location and depth of penetration NEUROENDOCRINE TUMOURS (CARCINOID)- PATHOLOGY Solitary or multicentric firm, yellow-tan nodules Usually submucosal masses, sometimes with ulceration Cause striking desmoplastic response Form islands, trabeculae, glands or sheets Monotonous, speckled nuclei and abundant pink cytoplasm Contain cytoplasmic secretory dense-core granules IMMUNOHISTOCHEMISTRY CARCINOID TUMOURS Chromogranin Synaptophysin CD56 Proliferation index Ki67 GRADE CARCINOID TUMOURS (NEUROENDOCRINE TUMOURS) Grade 1, 2, 3 – depending on number of mitoses and Ki67 % CLINICAL FEATURES Asymptomatic Obstruction Bleeding May release their products into circulation  Zollinger-Ellison syndrome (Gastrin)  Cushing syndrome (adrenocorticotropic hormone)  Hypoglycemia (insulin) Carcinoid syndrome- production of serotonin  CARCINOID SYNDROME Seen only with massive liver metastases  5-HT is degraded in the liver  Hepatic metastasis not required for extra GI carcinoids Excess elaboration of serotonin detected in blood and urine 1. Vasomotor disturbances (skin flushing) 2. Intestinal hypermotility (diarrhoea/cramps) 3. Bronchospasm (wheezing, cough) 4. Systemic fibrosis (with cardiac involvement right ventricular subendocardial fibrosis, pulmonary and tricuspid valve) 5. Hepatomegaly (metastasis) Symptoms can be triggered by alcohol or emotional stress MESENCHYMAL TUMOURS Benign lipoma, leiomyoma, schwannoma Gastrointestinal stromal tumours (GISTs) GASTROINTESTINAL STROMAL TUMOURS (GISTS) Mesenchymal neoplasms of the GI tract Arise from the pacemaker cells of the GIT (ICC) 2/3 in stomach 25% small intestine