Small Intestine & Large Intestines PDF

Small & large intestines  Outline: Small intestine & Colon Intestinal obstruction: mechanical, paralytic (ileus) Vascular disorders Diarrheal diseases: malabsorptive diarrhea Enterocolitis: diarrhea, infectious, others Inflammatory bowel disease (IBD) Diverticular d...

Small & large intestines  Outline: Small intestine & Colon Intestinal obstruction: mechanical, paralytic (ileus) Vascular disorders Diarrheal diseases: malabsorptive diarrhea Enterocolitis: diarrhea, infectious, others Inflammatory bowel disease (IBD) Diverticular disease Colonic polyps Neoplastic diseases Tumors of the anal canal Acute appendicitis & tumors of the Appendix  Intestinal obstruction At any level, but small intestine is most often involved b/c of its relatively narrow lumen Mechanical or functional Hernias, intestinal adhesions, intussusception, & volvulus account for 80% mechanical obstruction Functional: ileus (esp. postsurgical), infarction, etc Clinical manifestations: abdominal pain & distention, vomiting, & constipation  Intestinal obstruction The four major mechanical causes of intestinal obstruction are (1) herniation of a segment in the umbilical or inguinal regions, (2) adhesion between loops of intestine, (3) volvulus, & (4) intussusception.  Abdominal Hernia Any weakness or defect in the wall of the peritoneal cavity may permit protrusion of a serosa-lined pouch of peritoneum called a hernia sac Acquired hernias most commonly occur anteriorly, through the inguinal & femoral canals or umbilicus, or at sites of surgical scars Risk of visceral protrusion (external herniation); most occur in inguinal hernias (narrow orifices & large sacs) Small bowel loops herniate most often, but portions of omentum or large bowel may also herniate & become entrapped  Abdominal Hernia Pressure at the neck of the outpouching bowel may impair venous drainage, leading to stasis & edema These changes ↑ the bulk of the herniated loop, leading to permanent entrapment (incarceration) &, over time, arterial & venous compromise (strangulation) => infarction Incarcerated umbilical hernia  Incarcerated hernia Strangulated hernia with infarction Portion of bowel incarcerated within an inguinal hernia. Note dusky areas of serosa & associated hemorrhage that indicate ischemic damage.  Adhesions Surgical procedures, infection, or peritoneal inflammation (endometriosis) => adhesions b/n bowel segments, the abdominal wall, or operative sites Fibrous bridges can create closed loops through which other viscera may slide & become entrapped => internal This is an adhesion (arrow) between herniation => obstruction & loops of small intestine strangulation  Adhesions from previous surgery The dark red infarcted small intestine contrasts with the light pink viable bowel. The forceps extend through an internal hernia in which a loop of bowel & mesentery has been caught. The trapped bowel has lost its blood supply.  Intussusception A segment of the intestine, constricted by a wave of peristalsis, telescopes into the immediately distal segment Once trapped, the invaginated segment is propelled by peristalsis & pulls the mesentery along Most common cause of intestinal obstruction in children younger than 2 yrs of age Untreated => intestinal obstruction, compression of mesenteric vessels, & infarction  Intussusception Jujeno-jujenal intussusception B, A tumor mass (right, labelled tumor) is A. The intussusceptum present at the leading edge of the B. The intussuscipiens (arrow) intussusception  Volvulus When a loop of bowel twists about its mesenteric point of attachment => luminal & vascular compromise Presents with features of both obstruction & infarction Most often in sigmoid colon, followed in frequency by the cecum, small bowel, stomach, or, rarely, transverse colon  Sigmoid volvulus Operative findings showing large sigmoid volvulus.  Ischemic bowel disease Acute compromise of any major vessel, caused by thrombosis or embolism=> infarction of intestine Pathogenesis: Ø Severity determined by severity of vascular compromise, the time frame of its development, & the vessels that are affected Ø Two phases: hypoxic injury & greatest damage initiated by restoration of the blood supply (reperfusion injury) Ø Distribution of ischemic damage: Watershed zone (splenic flexure) & patterns of intestinal microvessels (hairpin turn) => surface epithelium particularly vulnerable  Ischemic bowel disease Mural infarction is mucosal & submucosal infarction Acute or chronic hypoperfusion => mucosal or mural infarctions Acute vascular obstruction => transmural infarction => purulent serositis and perforation Morphology: Ischemic bowel disease (A) Jejunal resection with dusky serosa of acute ischemia (mesenteric thrombosis). (B) Mucosa is dark colored because of hemorrhage Transmural hemorrhagic small bowel infarction Disappearance of the normal folding pattern & a dusky black mucosa  Mucosal infarct The villi of the small intestine are necrotic with sloughing & loss of the epithelium. The lamina propria has a hemorrhagic appearance Morphology: Ischemic bowel disease (A) Characteristic attenuated and partially detached villous epithelium in acute jejunal ischemia. Note the hyperchromatic nuclei of proliferating crypt cells. (B) Chronic colonic ischemia with atrophic surface epithelium and fibrotic lamina propria  Clinical Features: ischemic bowel disease Acute transmural infarction: sudden, severe abdominal pain & tenderness, s/t accompanied by nausea, vomiting, & bloody diarrhea or grossly melanotic stool => shock and vascular collapse Dx of intestinal infarction may be delayed or missed b/c physical signs overlap with other abdominal emergencies Mucosal barrier breaks down, bacteria enter the circulation & sepsis Mortality rate in cases complicated by sepsis exceeds 50%  Hemorrhoids Greek "haimorrhoides phlebes" - bleeding veins Dilated anal & perianal collateral vessels 5% of general population, rare greatest wall tension) Presents after 6th decade Lower intestinal bleeding maroon or bright red Twisted dilated submucosal veins & venules (arrows)  Diarrheal disease Diarrhea is defined as the passage of loose or watery stools, typically of amounts greater than 200 grams per day Worldwide, diarrheal diseases are estimated to cause the deaths of 1.5 -2 million children under 5 yrs of age annually Secretory, Osmotic, Malabsorptive & Exudative diarrhea  Malabsorptive diarrhea Chronic diarrhea and is characterized by defective absorption of fats, fat- & water soluble vitamins, proteins, carbohydrates, electrolytes, minerals, & water A hallmark of malabsorption is steatorrhea, characterized by excessive fecal fat & bulky, frothy, greasy, yellow or clay- colored stools Malabsorption results from a disturbance in intraluminal digestion, terminal digestion, transepithelial transport & lymphatic transport of absorbed lipids Diarrhea (from nutrient malabsorption & excessive intestinal secretion), flatus, abdominal pain, & weight loss Steatorrhea Defects in Malabsorptive & Diarrheal Disease  Celiac disease AKA Celiac sprue or gluten-sensitive enteropathy Immune-mediated enteropathy triggered by the ingestion of gluten-containing cereals, such as wheat, rye, or barley, in genetically predisposed individuals (class II HLA-DQ2 or HLA- DQ8) Dx: histology (2nd portion of the duodenum or proximal jejunum), & serology (antibodies against tissue transglutaminase, endomysial & gliadin) An ↑ risk of enteropathy associated T-cell lymphoma, & small intestinal adenocarcinoma  Celiac disease A model for the pathogenesis of celiac disease (left). CD4+ T cells are stimulated by antigen presenting cells displaying deamidated gliadin peptides to produce a variety of cytokines that stimulate antibody production from B cells. The source of the epithelial damage (denoted by dotted lines) is less certain. Cytokines such as interferon-ƴ produced by the CD4+ T cells may directly damage epithelial cells. Alternatively, deamidated gliadin may induce epithelial cells to produce IL-15, stimulating intraepithelial CD8+ T cells expressing the NKG2D receptor to recognize and kill epithelial cells expressing the molecule MIC-A (MHC class I polypeptide-related sequence A). The resulting morphologic alterations (right) include varying degrees of villous atrophy, increased numbers of intraepithelial lymphocytes, and epithelial proliferation with crypt elongation Normal small intestinal Celiac disease: blunting & mucosa. flattening of villi & crypt elongation  Celiac disease This high power view shows numerous Advanced cases of celiac disease intraepithelial lymphocytes show complete loss of villi, or total villous atrophy. Note the dense plasma cell infiltrates in the lamina propria and intraepithelial lymphocytes  Infectious enterocolitis More than 1 million deaths annually and greater than 10% of deaths in children younger than 5 years of age Present with diarrhea, abdominal pain, urgency, perianal discomfort, incontinence, & hemorrhage Specific pathogens vary widely Ø Viral: Norovirus (AKA Norwalk virus), rotavirus Ø Bacteria: Cholera, Shigellosis, Enteric (typhoid) fever, E. coli, Pseudomembranous colitis (C. difficile), etc Ø Parasitic: Ascaris lumbricoides, Strongyloides, Giardia lamblia, Cryptosporidium, Entamoeba histolytica, etc  Infectious enteritis A) Histologic features of viral enteritis include increased numbers of intraepithelial & lamina propria lymphocytes & crypt hypertrophy. (B) Diffuse eosinophilic infiltrates in parasitic infection. This case was caused by Ascaris (upper inset), but a similar tissue reaction could be caused by Strongyloides (lower inset). (C) Schistosomiasis can induce an inflammatory reaction to eggs trapped within the lamina propria.  Infectious enteritis cont. D) Entamoeba histolytica in a colon biopsy specimen. Note some organisms ingesting red blood cells (arrow). (E) Giardia lamblia, which are present in the luminal space over nearly normal-appearing villi, are easily overlooked. (F) Cryptosporidium organisms are seen as small blue spheres that appear to lie on top of the brush border but are actually enveloped by a thin layer of host cell cytoplasm.  Amebic colitis: affects the cecum & ascending colon Multiple ulcers Classic flask-shaped (with a narrow neck & broad base) ulcer  Amebic liver abscess: ~ 40% of patients with amebic dysentery Thick brown paste like material: “Anchovy paste” like pus aspirated from percutaneous liver abscesses drainage.  Pseudomembranous colitis Antibiotic-associated colitis or diarrhea Caused by Clostridioides (formerly Clostridium) difficile Causes pseudomembrane formation Disruption of the normal colonic microbiota by antibiotics allows C. difficile overgrowth => toxin Frequency of antibiotic use & its effect on colonic microbiota Risk factors: antibiotic treatment, > 65 yrs, use of proton pump inhibitors, hospitalization, & immunosuppression Watery diarrhea & abdominal cramping; dehydration, fever, and leukocytosis are seen in more severe cases Dx: positive nucleic acid amplification test & a positive stool test for C. difficile toxin  Clostridioides difficile colitis Pseudomembranous colitis (A) The colon is coated by tan pseudomembranes composed of neutrophils, dead epithelial cells, and inflammatory debris (endoscopic view). (B) Typical pattern of neutrophils emanating from a crypt is reminiscent of a volcanic eruption  Inflammatory Bowel Disease (IBD) Is a chronic inflammatory condition triggered by the host immune response to intestinal microbes in genetically predisposed individual Ulcerative colitis & Crohn disease (regional enteritis) Distinction b/n Crohn disease & ulcerative colitis is primarily based on distribution of affected sites & the morphologic expression of disease at those sites “Indeterminate Colitis” in 10% of IBD Features of Crohn Disease & Ulcerative Colitis Features of Crohn Disease & Ulcerative Colitis Features of Crohn Disease & Ulcerative Colitis Distribution & types of lesions in IBD  Ulcerative colitis Crohn's disease Note the continuous involvement of the right Ulcers that are separated from half of the specimen & abrupt transition to each other by mucosa that normal mucosa. The affected mucosa is appears close to normal (skip hyperemic & shows numerous pseudopolyps lesions)  Epidemiology: IBD Frequently present in adolescents or in young adults Increasing incidence: hygiene hypothesis: ?reduced frequency of enteric infections early in life due to improved hygiene results in inadequate development of regulatory processes that limit mucosal immune responses Preservatives & other materials added to processed foods induce low-grade mucosal damage  Pathogenesis: IBD Result from the combined effects of alterations in host interactions with intestinal microbiota, intestinal epithelial dysfunction, & aberrant mucosal immune responses Genetic factors: – Family history, concordance rate for monozygotic twins, NOD (nucleotide oligomerization binding domain 2) in Crohns disease Abnormal mucosal immune responses Epithelial defects Changes in the microbiota A model of pathogenesis of inflammatory bowel disease (IBD) IFN-g, Interferon gamma; TNF, tumor necrosis factor  Gross: Crohn disease (A) Small-intestinal stricture. (B) Linear mucosal ulcers and thickened intestinal wall. (C) Creeping fat.  Gross: Crohn disease CS Cobblestone (CS) appearance of the mucosa Perforation & associated serositis  Microscopy: Crohn disease (A) Haphazard crypt organization results from repeated injury & regeneration. (B) Noncaseating granuloma. (C) Transmural Crohn disease with markedly thickened wall and submucosal and serosal granulomas (arrows).  Clinical Features: Crohn disease Variable; mild diarrhea, fever, & abdominal Pain Aasymptomatic intervals (remissions) & disease reactivation associated with physical or emotional stress, specific dietary items, NSAID use, & cigarette smoking Iron deficiency anemia, malabsorption, fibrosing strictures, recur, fistulas Extra-intestinal manifestations: uveitis, migratory polyarthritis, sacroiliitis, ankylosing spondylitis, erythema nodosum, and clubbing of the fingertips,  Ulcerative colitis (UC) (A) Endoscopic view of severe ulcerative colitis with ulceration & adherent mucopurulent material. (B) Total colectomy with pancolitis showing active disease, with red, granular mucosa in the cecum (left) and smooth, atrophic mucosa distally (right). (C) Sharp demarcation between active ulcerative colitis (bottom) and normal (top). (D) This full-thickness histologic section shows that disease is limited to the mucosa  Gross pathology of ulcerative colitis (C) Inflammatory polyps. (D) Mucosal bridges can join inflammatory polyps.  Ulcerative colitis (UC) Limited to the colon & rectum Extraintestinal manifestations overlap with those of Crohn disease: Ø Migratory polyarthritis, sacroiliitis, ankylosing spondylitis, uveitis, & skin lesions 2.5-7.5% have primary sclerosing cholangitis Always involves the rectum & extends proximally in a continuous fashion Backwash ileitis: mild mucosal inflammation of the distal ileum, may be present in pancolitis Histopathology of ulcerative colitis A) Crypt abscess. (B) Pseudopyloric metaplasia (right). (C) Disease is limited to the mucosa (above the arrow).  Toxic megacolon: ulcerative colitis Uncommonly, Inflammation & inflammatory mediators may damage the muscularis propria & disturb neuromuscular function, leading to colonic dilation & toxic megacolon Significant risk of perforation (most common cause of UC- related mortality)  Clinical Features: ulcerative colitis Relapsing disorder characterized by attacks of bloody, stringy, often mucoid diarrhea associated with lower abdominal pain and cramps that are temporarily relieved by defecation => subside Relapse Extraintestinal manifestations of ulcerative colitis overlap with those of Crohn disease, including migratory polyarthritis, sacroiliitis, ankylosing spondylitis, uveitis, skin lesions, pericholangitis, and primary sclerosing cholangitis  Indeterminate Colitis Due to genetic, pathologic, & clinical overlap between ulcerative colitis and Crohn disease Definitive Dx is not possible in ~10% of IBD patients Do not involve the small bowel & have colonic disease in a continuous pattern typical of UC but also have features suggestive of Crohn disease  Colitis associated neoplasia Long-term complications of UC & colonic Crohn disease is the development of adenocarcinoma Begins as dysplasia => carcinoma Risk of for development of dysplasia related to: Duration of disease: Risk increases beginning 8 to 10 years after disease initiation Extent of involvement: Patients with involvement of the entire colon are at greater risk than those with only partial involvement Inflammation: Greater frequency & severity of active inflammation (characterized by the presence of neutrophils) may ↑ risk  Early detection of neoplasia Patients are typically enrolled in colonoscopic surveillance programs approximately 8 years after diagnosis of IBD An important exception to this approach is in patients with primary sclerosing cholangitis, who are at markedly greater risk for development of dysplasia; in this instance, surveillance is generally initiated at the time of diagnosis Early detection of neoplasia by endoscopic surveillance programs ~ 8 yrs after Dx of IBD Regular and extensive mucosal biopsy & histological examination to identify dysplastic epithelium  Colitis-associated dysplasia (A) Dysplasia with extensive nuclear stratification & marked nuclear hyperchromasia. (B) Cribriform glandular arrangement in high-grade dysplasia. (C) Colectomy specimen with high-grade dysplasia on the surface & underlying invasive adenocarcinoma. A large cystic, neutrophil-filled space lined by invasive adenocarcinoma is apparent (arrow) beneath the muscularis mucosae. Also seen are small invasive glands (arrowhead).  Diverticular disease Acquired pseudo- diverticular rather not true diverticula Outpouchings (flask- like) of the colonic mucosa & submucosa 50% western adults >60yrs Multiple => Protruding from the sigmoid colon are multiple rounded bluish-gray diverticula diverticulosis (red arrow)  Pathogenesis: diverticular disease Develop due to elevated intraluminal pressure ↑ pressure leads to mucosa & submucosa to herniate through structural weakness (@ sites where nerves & arterial vasa recta & their connective tissue sheaths penetrate the inner circular muscle coat to create discontinuities) Most diverticula occur in the narrowest part of the colon, the sigmoid, which experiences the highest pressures during peristaltic contractions Abnormal contractions due to ?high in red meat & low in fiber  Sigmoid diverticular disease (A) Endoscopic view of two sigmoid diverticulae. (B) regularly spaced stool- filled diverticulae. (C) Cross-section showing the outpouching of mucosa beneath the muscularis propria. (D) protrusion of the mucosa through the muscularis propria.  Clinical Features: diverticulosis Most asymptomatic, ~20%: intermittent cramping, continuous lower abdominal discomfort, constipation, & diarrhea Complications: Obstruction of diverticula & stasis of contents => diverticulitis & peridiverticulitis Perforation abscess, sinus tract & occasionally peritonitis Recurrent diverticulitis => fibrotic thickening or stricture formation Bleeding (silently, even fatally)  Stalk Colonic polyps Any discrete mass of tissue protruding into the lumen Most common in colorectum Pedunculated (with stalk) polyp Pedunculated polyp or sessile (without stalk) Classified: Ø Non-neoplastic: inflammatory, hamartomatous, or hyperplastic Ø Neoplastic: adenoma, has potential to progress to cancer Endoscopy appearance of polyp Pedunculated polyp Sessile polyp  Hamartomatous Polyps Sporadically or as components of genetically determined or acquired syndromes Many hamartomatous polyp syndromes are caused by germline mutations in tumor suppressor genes or proto- oncogenes Some of these syndromes are associated with increased cancer risk => premalignant, neoplastic lesions  Juvenile Polyps Most common type of hamartomatous polyp Sporadic or syndromic Sporadic juvenile polyps are usually solitary Juvenile polyposis: autosomal dominant syndrome, dozens of polyps, ↑ risk for adenocarcinoma of the colon & other sites; germline mutation in genes that encode components of the TGFb/BMP signaling pathway (e.g., SMAD4) Most occur “pileup” of goblet cells No malignant potential (A) Polyp surface with irregular tufting Most in the left colon & < 5 of epithelial cells. (B) Tufting results from mm epithelial overcrowding. (C) Epithelial crowding produces a serrated architecture when crypts are cut in cross section.  Adenomas: neoplastic Polyps Most common & clinically important neoplastic polyps are colonic adenomas which are precursor lesions of colorectal colorectal adenocarcinomas No sex predilection Present in 50% of adults living in the Western world > 50 yrs of age Screening colonoscopy starting at 45 years of age Individuals with a family history are screened at least 10 yrs before the youngest age at which a relative was diagnosed  Morphology: adenomas 0.3 to 10 cm, pedunculated or sessile Histologically, the cytologic hallmark is epithelial dysplasia, marked by nuclear hyperchromasia, elongation, and stratification Classified as tubular (75% tubular), tubulovillous (25% villous), or Villous (75% villous) based on their architecture Risk of malignancy (presence of cancer in a polyp) – Size (most important) 40% of lesions >4 cm in diameter contain foci of invasive cancer – High-grade dysplasia is a 2nd, less important risk factor Most are clinically silent  Colonic adenomas (A) Pedunculated adenoma (endoscopic view). (B) Adenoma with a velvety surface. (C) Low-magnification photomicrograph of a pedunculated tubular adenoma Histologic appearance of colonic adenomas (A) Tubular adenoma with a smooth surface and rounded glands. In this case, crypt dilation and rupture, with associated reactive inflammation, can be seen at the bottom of the field. (B) Villous adenoma with long, slender projections that are reminiscent of small-intestinal villi. (C) Dysplastic epithelial cells (top) with an increased nuclear-to-cytoplasmic ratio, hyperchromatic and elongated nuclei, and nuclear pseudostratification. Compare with the nondysplastic epithelium (bottom) Tubulovillous adenoma with Focal high grade dysplasia Note the prominent nuclear stratification with pleomorphism and intraluminal papillary tufting (right gland), significantly different from conventional low grade dysplasia (left gland) Familial Colonic Neoplasia Syndromes  Familial adenomatous polyposis (FAP) Autosomal dominant disorder marked by the appearance of numerous colorectal adenomas by the teenage years that is caused by mutation of the adenomatous polyposis coli (APC) gene Dx of classic FAP: a count of ~ 100 polyps 75% inherited Colorectal adenocarcinoma develops in 100% of patients with untreated FAP, often before 30 years of age Prophylactic colectomy is standard therapy for individuals carrying APC mutations  FAP cont. Specific APC mutations are also associated with the development of other manifestations of FAP such as Gardner syndrome and Turcot syndrome  FAP Multiple small polyps are present throughout this colon  FAP (A) Hundreds of small colonic polyps are present along with a dominant polyp (right). (B) Three tubular adenomas are present in this single microscopic field.  Hereditary Nonpolyposis Colorectal Cancer (HNPCC) AKA, Lynch syndrome: autosomal dominant condition marked by an increased risk for cancers of the colorectum, endometrium, stomach, ovary, ureters, brain, small bowel, hepatobiliary tract, and skin Occur at younger ages than do sporadic colon cancers Are often located in the right colon Precursors tend to be sessile serrated adenomas => adenocarcinomas with abundant mucin Caused by inherited germline mutations in mismatch repair genes e.g., MSH2 or MLH1 => microsatellite (short repeating DNA sequences) instability  Colorectal adenocarcinoma Most common malignancy of the GI tract Major contributor to morbidity & mortality WW Peaks at 60-70 yrs of age but younger age in Ethiopia Most prevalent in higher income countries Diets with low intake of unabsorbable vegetable fiber (? ↓ed stool bulk & altered intestinal microbiota => oxidative byproducts of bacterial metabolism) & high intake of refined carbohydrates & fat (hepatic synthesis of cholesterol & bile acids => carcinogens by intestinal bacteria) Aspirin/NSAIDs have a protective effect (inhibition of cyclooxygenase-2 => promote epithelial proliferation  Pathogenesis: colorectal adenocarcinoma APC/β-catenin & microsatellite instability (MSI) pathways APC/β-catenin activated in the classic adenoma-carcinoma sequence => increased WNT signaling MSI associated with defects in DNA mismatch repair & accumulation of mutations in microsatellite repeat regions of the genome Both pathways involve the stepwise accumulation of multiple mutations but differ in the genes involved & the mechanisms by which mutations occur  Morphologic and molecular changes in the adenoma-carcinoma sequence It is postulated that loss of one normal copy of the tumor suppressor gene APC occurs early. Individuals with FAP are born with one mutant allele, making them extremely prone to the development of colon cancer. Other mutations involving KRAS, SMAD2, and SMAD4, and the tumor suppressor gene TP53, as well as activation of telomerase, lead to the emergence of a full-blown cancer. Although there may be a preferred temporal sequence for these changes, it is the aggregate effect of the mutations, rather than their order of occurrence, that appears most critical. APC, Adenomatous polyposis coli; COX-2, cyclooxygenase-2; LOH, loss of heterozygosity  Morphologic and molecular changes in the mismatch repair pathway of colon carcinogenesis Defects in mismatch repair genes (most commonly MLH1 or MSH2) result in microsatellite instability & permit accumulation of mutations in numerous genes. If these mutations affect genes involved in cell survival & proliferation, cancer may develop. IGF2R, Insulin-like growth factor 2 receptor; LOH, loss of heterozygosity; TCF-4, transcription factor-4; TGFbRII, transforming growth factor beta receptor II. Invasive colorectal carcinoma & two adenomatous polyps  Morphology: colorectal adenocarcinoma Proximal right colon (cecum & ascending Distal left colon tumors tend to be colon) tumors grow as polypoid, exophytic annular lesions that produce “napkin mass with rolled edges, rarely cause ring” constrictions & luminal obstruction narrowing => s/t obstruction  Histologic appearance of colorectal carcinoma (A) Well-differentiated adenocarcinoma. Note the elongated, hyperchromatic nuclei. Necrotic debris, present in the gland lumen, is typical. (B) Poorly differentiated adenocarcinoma forms a few glands but is largely composed of infiltrating nests of tumor cells. (C) Mucinous adenocarcinoma with signet-ring cells and extracellular mucin pools  Clinical Features: colorectal adenocarcinoma Develop insidiously & may therefore go undetected for long periods Cecal & right sided colon cancers present with fatigue & weakness due to iron-deficiency anemia v “The underlying cause of iron-deficiency anemia in an older man or postmenopausal woman is GI cancer until proven otherwise” Left-sided colorectal cancer => occult bleeding, changes in bowel habits (smaller caliber stool), or cramping, left lower- quadrant discomfort, s/t obstruction  Metastatic colorectal carcinoma (A) Lymph node metastasis. Note the glandular structures within the subcapsular sinus. (B) Solitary subpleural nodule of colorectal carcinoma metastatic to the lung. (C) Liver containing two large & many smaller metastases. Note the central necrosis within metastases.  Prognostic factors: colorectal adenocarcinoma Most important prognostic factors Ø Depth of invasion & the presence of lymph node metastases Invasion into the muscularis propria significantly reduces the probability of survival, which is decreased further by the presence of lymph node metastases The TNM (tumor-nodes-metastases) classification is used to define tumor stage Five-year survival rates vary widely worldwide Ø Overall 5yr survival in US is 65% (ranges 90% to 40% depending on stage) American Joint Committee on Cancer (AJCC) TNM Classification of Colorectal Carcinoma AJCC, TNM Classification of Colorectal Carcinoma Colorectal cancer staging system  Tumors of the anal canal Squamous cell carcinoma (SCC) – Most common; high-risk HPV 16 & 18 associated Basaloid or cloacogenic carcinoma Condyloma acuminatum (low-risk HPV related) Anal SCC: ulcerating, fungating mass keratinizing SCC protruding from the anal verge  Anal condyloma acuminatum Cauliflower like warty perianal skin Hyperplastic epidermis hyperkeratosis lesions with verrucous architecture & perinuclear halos  Acute appendicitis Most common in adolescents & young adults Lifetime risk of 7%; slightly M>F Preoperative Dx can be difficult & may be confused with mesenteric lymphadenitis, acute salpingitis, ectopic pregnancy, mittelschmerz (pain associated with ovulation), & Meckel diverticulitis  Pathogenesis: acute appendicitis Initiated by a progressive ↑ in intraluminal pressure that compromise venous outflow In 50-80% associated with luminal obstruction usually by stone-like mass of stool (fecalith) or, less commonly, a gallstone, tumor, or mass of worms Ischemic injury & stasis of luminal contents => bacterial proliferation, trigger inflammatory responses including tissue edema & neutrophilic infiltration of the lumen, muscular wall, & periappendiceal soft tissues Acute appendicitis: congested erythematous fibrino-purulent coating on the serosal surface & fecalith (arrow)  Acute appendicitis cont. Dx: neutrophilic infiltration of the muscularis propria Complications: Ø Acute gangrenous appendicitis => perforation or rupture => suppurative peritonitis Ø Pyelophlebitis, portal venous thrombosis, liver abscess, & Neutrophilic infiltration of the muscularis propria bacteremia  Clinical Features: Acute appendicitis Periumbilical pain that then moves to the right lower quadrant, followed by nausea, vomiting, low-grade fever, & a mildly elevated peripheral WBC count McBurney’s sign, deep tenderness noted at a location two- thirds of the distance from the umbilicus to the right anterior superior iliac spine Classic signs & symptoms of acute appendicitis are often absent, creating difficulty in clinical diagnosis 20% false positive rate of appendectomy (remove normal appendices) due to preoperative diagnostic challenges CT scanning are helpful in narrowing the differential diagnosis  Tumors of the appendix Carcinoid tumor or well-differentiated neuroendocrine tumor ü Most common ü Discovered incidentally at the time of surgery or pathologic examination of a resected appendix ü Is almost always benign ü Solid bulbous swelling at the distal tip, 2-3 cm  Mucinous neoplasms of the appendix Most in 6th decade, mucinous epithelial proliferation, extracellular mucin, & pushing tumor margins; an infiltrating invasive pattern => mucin-producing adenocarcinoma Mucin can dissect through the wall to the peritoneal surface, causing appendiceal rupture Classified as low-grade or high-grade appendiceal mucinous neoplasms (LAMN, HAMN) Peritoneal spread of LAMN, HAMN, or mucin producing adenocarcinomas (of the appendix or colon) can lead to pseudomyxoma peritonei, in which tenacious, semisolid mucin fills the abdomen  Pseudomyxoma peritonei (Jelly Belly) Mucinous ascites Mucinous ascites results from Numerous gelatinous globules of rupture or extension from a mucin (arrow) in the intraoperative mucinous appendiceal neoplasm  Pseudomyxoma Peritonei mucin mucin Bluish gelatinous mucin globules which Pools of extracellular mucin associated were widely disseminated in the with fibrosis and rare glands lined by peritoneal cavity simple mucinous epithelium lacking cytologic atypia.