BMS 150 Pathology 5.09 GI Cancers PDF

Pathology 5.09 GI cancers Dr. Hurnik BMS 150 Week 14 Outline PATHOLOGY 5.09 Esophageal carcinomas Esophageal adenocarcinoma Squamous cell carcinoma Stomach Gastric polyps Gastric adenoma Gastric adenocarcinoma Gastric lymphoma I...

Pathology 5.09 GI cancers Dr. Hurnik BMS 150 Week 14 Outline PATHOLOGY 5.09 Esophageal carcinomas Esophageal adenocarcinoma Squamous cell carcinoma Stomach Gastric polyps Gastric adenoma Gastric adenocarcinoma Gastric lymphoma Intestines Colonic adenoma Adenocarcinoma of the colon Liver Hepatic adenoma Hepatic carcinoma Pancreas Ductal adenocarcinoma Learning outcomes Coming soon… Esophageal carcinomas - intro Two main variants: § Adenocarcinoma § Squamous cell carcinoma Relatively common, but deadly § FYI - 15,560 Americans diagnosed in 2007, 13,940 deaths that same year (number of deaths/year almost the same as number of new diagnoses!) Risk factors: § Squamous carcinoma: alcohol and tobacco use, poverty, caustic esophageal injury, achalasia, tylosis, Plummer-Vinson syndrome, and frequent consumption of very hot beverages § Adenocarcinoma: long-standing GERD and Barrett’s esophagus as well as tobacco use Diets rich in fruits and vegetables are protective Esophageal adenocarcinoma – etiology & pathogenesis Epithelial clones identified in nondysplastic Barrett metaplasia persist and accumulate mutations during progression to dysplasia and invasive carcinoma § Mutation or overexpression of p53 are present at early stages of esophageal adenocarcinoma § Additional genetic changes include amplification of c- ERB-B2, cyclin D1, and cyclin E genes, mutation of RB  Esophageal adenocarcinoma - pathology Usually occurs in the distal third of the esophagus and may invade the adjacent gastric cardia § Initially appears as flat or raised patches in otherwise intact mucosa § Large masses of 5 cm or more in diameter may develop, can infiltrate diffusely or ulcerate and invade deeply Microscopically, Barrett esophagus is frequently present adjacent to the tumor Tumors resemble intestinal cells and most Figure 17.10 Esophageal cancer. (A) Adenocarcinoma usually commonly produce mucin and form glands occurs distally and, as in this case, often involves the gastric cardia. Squamous cell carcinoma of the esophagus – etiology and pathology Etiology: § Loss of several tumor suppressor genes, including p53 and p16/INK4a Pathology: § In contrast to adenocarcinoma, half of squamous cell carcinomas occur in the middle third of the esophagus § Early lesions appear as small, gray-white, plaque-like thickenings § Progress over months to years to grow into tumor masses that may be polypoid or exophytic Can protrude into and obstruct the lumen or ulcerate and infiltrate § May invade surrounding structures including the respiratory tree, causing pneumonia; Figure 17.10 Esophageal cancer. aorta, causing catastrophic exsanguination; (B) Squamous cell carcinoma is mediastinum and pericardium most frequently found in the mid-esophagus, where it commonly causes strictures. Esophageal carcinomas – clinical features & prognosis Clinical features: § Dysphagia, odynophagia, obstruction First dysphagia to solid food is prominent, eventually leading to liquid dysphagia Weight loss and debilitation result from both impaired nutrition and effects of the tumor itself Hemorrhage and sepsis may accompany tumor ulceration Prognosis is exceptionally poor – 5 year survival is 10% - 25% (slightly better for adenocarcinoma) § Due to the frequency of metastases at diagnosis Stomach – Gastric Polyps 75% of all gastric polyps are either inflammatory or hyperplastic polyps § Are common between 50 and 60 years of age Usually develop in association with chronic gastritis, which initiates the injury and reactive hyperplasia that leads to polyp growth § The larger the polyp, the increased likelihood for presence of malignancy (polyps > 1.5 cm must be investigated) § Usually a smooth, ovoid growth that can exhibit superficial erosions and variable degrees of inflammation in the lamina propria Figure 17.17 Gastric polyps. (A) Hyperplastic polyp containing They look pretty normal, histologically corkscrew-shaped foveolar glands. Stomach – Gastric adenoma - intro Gastric adenoma make up 10% of all gastric polyps § Incidence increases progressively with age - males affected 3X more Usually 50-60 years of age § Gastric adenomas have a greater risk of cancer than colonic adenomas Etiology: § Adenomas in chronic gastritis are associated with gastric atrophy and intestinal metaplasia Stomach – Gastric adenoma Pathology § Usually solitary lesions < 2 cm in diameter Most commonly located in the stomach antrum (higher malignant potential if in fundus) § Risk of progression to adenocarcinoma is related to size of lesion (higher risk in lesions greater than 2 cm in diameter) Carcinoma in up to 30% of gastric adenomas when larger than 2 cm § Majority of adenomas composed of intestinal-type columnar epithelium Stomach – Gastric adenocarcinoma Intro § Classified based on their location and morphology Types: § Diffuse – diffuse infiltrative growth patterns § Intestinal - composed of glandular structures Epidemiology § Adenocarcinoma comprises 90% of all gastric cancers Highest incidence in Japan, Chile, Costa Rica, and Eastern Europe § 20-fold higher than in North America, Northern Europe, Africa, and Southeast Asia § Incidence in North America has dropped by 85% since 1930 Thought to be related to reduced rates of H. pylori infections & environmental factors Reduced consumption of of N-nitroso compounds and benzo[a]pyrene Gastric adenocarcinoma - pathophysiology Pathophysiology: § Tends to develop in the setting of chronic inflammation § Genes of interest: p53 mutations are common Diffuse - Loss of function of E-cadherin FYI – could be due to germline mutation of tumour suppressor gene CDH1 which encodes E-cadherin OR hypermethylation & silencing of CHD1 promotor § Review - What was the role of E-cadherin? Intestinal – mutations that increase signaling via the Wnt pathway  Gastric adenocarcinoma - pathology Pathology: § Advanced cancers are those that penetrate below the submucosa into the muscular wall § Described as either intestinal or diffuse variants Intestinal: § composed of malignant cells forming neoplastic intestinal glands resembling those of colonic adenocarcinoma Diffuse: § composed of gastric-type mucous cells that generally do not form glands but rather permeate the mucosa and wall as Figure 17.18 Gastric adenocarcinoma. (A) Intestinal-type adenocarcinoma consisting of scattered individual "signet-ring" cells an elevated mass with heaped-up borders or small clusters in an "infiltrative" and central ulceration. Compare to the peptic ulcer in Fig. 17.15A. (B) Infiltrative type growth pattern (linitis plastica) gastric cancer. The gastric wall is markedly thickened, and rugal folds are partially lost, but there is no dominant mass. Gastric adenocarcinoma – Clinical features Clinical features: § Symptomatically similar to PUD or chronic gastritis until it’s turned into advanced lesion What were these symptoms? § Advanced lesions: weight loss, anorexia, altered bowel habits, anemia, and hemorrhage Prognosis & progression: § If caught early, surgical resection results in 90% 5- year survival If advanced, 5-year survival is 20% § Common metastasis include the following locations: supraclavicular sentinel lymph node, ovaries Stomach – Gastric lymphoma - intro Most common site for lymphoma outside of lymph nodes § Arise at sites of chronic inflammation Most common cause of “pro-lymphomatous” inflammation in stomach is chronic H. pylori infection Gastric lymphoma – pathogenesis and pathology Originate in GI tract at sites of preexisting MALT, such as the Peyer's patches of the small intestine § More commonly within tissues normally devoid of organized lymphoid tissue Tend to be B-cell lymphomas § Dense lymphocytic infiltrate in lamina propria § Neoplastic lymphocytes infiltrate gastric glands focally to create diagnostic lymphoepithelial lesions § Reactive-appearing B-cell follicles present - some have plasmacytic differentiation Gastric Lymphoma - Prognosis Clinical Features: § Clinical findings are those of underlying B12 deficiency Why? § Fatigue, low-grade fevers, nausea, constipation, tarry stool, epigastric pain, weight loss, anemia, and SOB Prognosis: § Generally good – 90% 5-year survival if caught at an early stage, and 30-40% if discovered at more advanced stages Intestine – Colonic adenoma - intro Most common (and clinically important) neoplastic polyps are colonic adenomas Adenomas = intraepithelial neoplasms that range from small, often pedunculated polyps to large sessile lesions § Benign polyps that are precursors to colorectal adenocarcinoma § FYI - Other neoplastic polyps include carcinoid tumors, stromal tumors, lymphomas, and metastatic cancer (rare) Risk factors: § Present in nearly 50% of adults living in the Figure 17.45 Colonic Western world by age 50 - No gender preference adenomas. (A) Pedunculated adenoma § Precursors to colorectal cancer - recommended (endoscopic view). that all adults in the US undergo surveillance colonoscopy by age 50 Typically screened at least 10 years before youngest age at which a relative was dx Colonic adenoma – pathology & progression Pathology: § Adenomas exhibit epithelial dysplasia, but the majority of adenomas do not progress to adenocarcinoma Dysplasia = nuclear hyperchromasia, elongation, and stratification - accompanied by reduction in number of goblet cells § Epithelium fails to mature as cells migrate from crypt to surface § Range from 0.3 to 10 cm in diameter and can be sessile or pedunculated Progression to colorectal adenocarcinoma: § Size is the most important characteristic that correlates with risk of malignancy 40% of lesions > 4 cm in diameter contain foci of cancer Intestine – Adenocarcinoma of the colon Epidemiology: § Most common malignancy of GI tract and major cause of morbidity and mortality worldwide Small intestine is a relatively uncommon site for benign and malignant tumors 130,000 new cases and 55,000 deaths from colorectal adenocarcinoma - 15% of all cancer-related deaths Peak incidence: 60 to 70 years of age § < 20% of cases occur before age 50 Colorectal carcinoma most prevalent in United States, Canada, Australia, New Zealand, Denmark, Sweden, and other developed countries Adenocarcinoma of the colon - Etiology Etiology: § Dietary factors most closely associated with increased colorectal cancer rates Low intake of unabsorbable vegetable fiber and high intake of refined carbohydrates and fat § Reduced fiber content leads to decreased stool bulk and altered composition of intestinal microbiota § Deficiencies of vitamins A, C, and E (free-radical scavengers) compound damage caused by oxidants § High fat intake enhances hepatic synthesis of cholesterol and bile acids - converted into carcinogens by intestinal bacteria § COX-2 inhibitors may be protective  Adenocarcinoma of the colon - Etiology Etiology continued § Genes: FYI Adenocarcinoma of the colon - Pathogenesis Pathogenesis § Two distinct genetic pathways described: 1. APC/β-catenin pathway associated with WNT and the classic adenoma-carcinoma sequence 2. Microsatellite instability pathway associated with defects in DNA mismatch repair § Both pathways involve stepwise accumulation of multiple mutations - genes and mechanisms of mutation differ § BRAF mutations also common (proto-oncogene) Adenocarcinoma of the colon - Pathogenesis APC/β-catenin pathway 80% of sporadic colon tumors, typically includes mutation of APC early in the neoplastic process Both copies of the APC gene must be inactivated § APC is a key negative regulator of β-catenin, a component of the WNT signaling pathway The APC normally promotes degradation of β- catenin. With loss of APC function, β-catenin accumulates and translocates to the nucleus B-catenin activates MYC and cyclin D1, which promote proliferation additional mutations follow, including activating mutations in KRAS (which also promote growth and prevent apoptosis) & p53 loss of function (often due to chromosomal instability) late event Adenocarcinoma of the colon - Pathogenesis Microsatellite instability pathway: § Due to loss of mismatch repair genes, mutations accumulate in microsatellite repeats, a condition referred to as microsatellite instability § Usually silent because microsatellites are typically in noncoding regions § Some microsatellite sequences are located in the coding or promoter region of genes involved in regulation of cell growth: Type II TGF-β receptor Pro-apoptotic protein BAX  Figure 17.51 Adenocarcinoma of the Colorectal carcinoma. (B) Cancer of the colon - Pathology sigmoid colon that has invaded through the muscularis propria and is Pathology present within subserosal adipose tissue (left).Areas of § Distributed equally over entire chalky necrosis are length of colon present within the colon wall (arrow). § Can be palpable as firm masses § Tumors in proximal colon grow as polypoid, exophytic masses that Figure 17.51 extend along one wall of the viscus Colorectal carcinoma. (A) - rarely causing obstruction Circumferential, ulcerated rectal § Carcinomas in distal colon tend to cancer. Note the be annular lesions that produce anal mucosa at the bottom of the “napkin-ring” constrictions and image. luminal narrowing – can cause obstruction Adenocarcinoma of the colon – Clinical Features Clinical Features: § Insidious development Cecal and other right-sided colon cancers à bleeding leading to iron deficiency anemia, fatigue, & weakness Left-sided colorectal adenocarcinomas may cause occult bleeding, changes in bowel habits, or cramping left lower quadrant discomfort Prognosis: § most important prognostic factors are depth of invasion and the presence or absence of lymph node metastases § Liver is most common site of metastatic lesions - result of portal drainage of colon § Metastases may also involve regional lymph nodes, lungs and bones Liver – Hepatic adenomas Intro: Hepatic adenomas have clinical significance for three reasons: 1. When they present as an intrahepatic mass they may be mistaken for the more ominous hepatocellular carcinomas 2. Subcapsular adenomas have a tendency to rupture, particularly during pregnancy, causing life-threatening intraperitoneal hemorrhage 3. Rarely, they may transform into carcinomas § Usually they are well-differentiated and are almost always benign Epidemiology Hepatic adenomas tend to occur in young women who have used oral contraceptives; tumors generally regress if contraceptive use is terminated Although hormonal stimulation seems to be involved in causation, etiology is not clear Incidence of adenoma is approximately 1 in 100,000 Liver – Hepatic carcinoma Primary carcinomas of the liver: hepatocellular carcinoma (HCC) Epidemiology: § represent 20% to 40% of cancers in many other countries 82% of hepatocellular carcinoma cases occur in countries with high rates of chronic HBV infection § More common in southeast Asian and African countries - 52% of all HCC cases occur in China § relatively uncommon in North America and western Europe (0.5% to 2% of all cancers) § Liver is the most common site of metastasis for colon cancer In North America and in most of Europe malignancies in the liver are usually due to metastases, not primary hepatocellular carcinomas Hepatic carcinoma - Etiology Risk factors & etiology: Major risk factor is long-standing cirrhosis Chronic viral infection (HBV, HCV), chronic alcoholism, non- alcoholic steatohepatitis (NASH), and food contaminants (primarily aflatoxins) are common world-wide causes Aflatoxin is produced by the fungus Aspergillus flavus, which contaminates peanuts and grains Binds covalently with cellular DNA, mutates p53 Less commonly: alpha-1 antitrypsin deficiency & hemochromatosis Common driver mutations: Activating mutations in Beta-catenin genes TERT mutations – upregulated telomerase Inactivating mutations to p53 Hepatic carcinoma – Pathophysiology & Pathology Pathophysiology § Most HCC occur in setting of chronic liver disease with cirrhosis Repeated cycles of cell death and regeneration Thought that the accumulation of mutations during continuous cycles of cell division may damage DNA repair mechanisms and eventually transform hepatocytes § 15-20% arise in noncirrhotic livers Pathology § Relatively well-differentiated malignant tumour that can secrete bile Invades vascular structures early, with snakelike masses that can migrate along the portal vein or vena cava Tend to be less dependent on lymph Figure 18.52 Hepatocellular carcinoma. (A) Liver removed at autopsy showing a node infiltration for metastasis unifocal neoplasm replacing most of the right hepatic lobe. Hepatic carcinoma – Clinical Features Clinical features: § Ill-defined upper abdominal pain, malaise, fatigue, weight loss, and sometimes awareness of an abdominal mass or abdominal fullness § In many cases the enlarged liver can be felt on palpation Prognosis: § 5-year survival of large tumors is dismal, with the majority of patients dying within the first 2 years. § Screening procedures and advances in imaging can detect HCCs less than 2 cm in diameter, much better prognosis Pancreas – Neoplastic cysts A variety of cysts can arise the the pancreas § Majority are non-neoplastic pseudocysts § 5 – 15% are neoplastic cysts § (also have non-neoplastic congenital cysts) Neoplastic cysts can range from harmless benign cysts to pre-cancerous lesions Pancreatic cancer – Ductal adenocarcinoma Pancreatic cancer – also known as ductal adeno- carcinoma § Epidemiology 4th leading cause of cancer deaths § What three surpass it? Estimated that in 2008 approximately 37,000 Americans were diagnosed with pancreatic cancer, and that virtually all of them will die from their disease § Primarily a disease in the elderly, 80% of cases occurring between the ages of 60 and 80 Main risk factor is smoking Others: chronic pancreatitis and diabetes Pancreatic Cancer - pathophysiology 90% begin as pancreatic intraepithelial neoplasia § KRAS gene is the most frequently altered oncogene in pancreatic cancer Result in constitutively activation of Ras § Inactivation of CDKN2A, which encodes p16 § Inactivation of p53 gene Pancreatic Cancer - Pathology Pathology: § 60% arise in the head of the gland, 15% in the body, and 5% in the tail; in 20% the neoplasm diffusely involves the entire gland § Ductal adenocarcinomas that form glandular structures and secrete mucin Have two characteristic features § It is highly invasive § elicits an intense non-neoplastic host reaction composed of fibroblasts, lymphocytes, and extracellular matrix (aka “desmoplastic response”). As a result à Usually hard, stellate, Figure 19.13 Carcinoma of the pancreas. (A) Cross-section through gray-white, poorly defined masses the tail of the pancreas showing normal pancreatic parenchyma and a normal pancreatic duct (left) and a pale mass centered on the duct (right). Pancreatic Cancer - Progression Clinical features: § Typically silent until tumour causes obstruction or invades adjacent structures § Jaundice from obstruction of common bile duct which type of jaundice is this? Courvoisier sign – palpably enlarged, non-tender gallbladder + painless jaundice § Weight loss, anorexia, and generalized malaise and weakness tend to be signs of advanced disease Prognosis: § Poor - 5-year survival rate is less than 5% § Highest mortality rate of any cancer References Coming soon…