Intestinal Disorders Flashcards

Question

Giardia Lamblia

Answer 1

* **Most common pathogenic parasitic infection** * _Transmission:_ **fecal contaminated water or food** * Present in unfiltered public water supplies, rural streams * Worse in immunocompromised * **Pear shape trophozoite** on duodenal biopsy * No obvious invasion ⇒ **nl** **intestinal morphology by LM** * _Mechanism_: organisms adhere to surface, ↓ expression of brush-border enzymes (including lactase) and damage microvilli * _Clinical_: **acute or chronic diarrhea, malabsorption, and wt loss** * Dx infection by finding cysts in stool samples * Oral abx effective but _recurrence is common_

Answer 2

* Parasitic causes of enterocolitis * Etiologic agent of **amebiasis** * _Transmission_: **Fecal-oral** * **Cyst form**: * Infectious form * Form identified in colon and feces * _Pathogenesis_: * Penetrates mucosa * ± **Deep ulceration** * ± Portal system spread w/ **systemic** **dissemination** and formation of **liver, lung, and brain abscesses**

Answer 3

* Drug Induced * Treatment related: chemotherapy, radiation * Neutropenic colitis (typhlitis) * Obstruction related * Diversion colitis * Diverticular disease related * Graft vs Host disease

Answer 4

* Hernia * Adhesions * Intussusception * Volvulus * Tumors and strictures (some due to Crohn Disease)

Answer 5

**Protrusion of a portion of the peritoneal sac through a defect in the wall of the peritoneal cavity** * #1 cause of intestinal obstruction world-wide; #3 cause US * **Incarcerated**: Hernia contains entrapped bowel * **Strangulated**: Infarction of trapped bowel due to compromise of blood flow

Answer 6

**Fibrosis between bowel loops or bowel to other structure** * **#1 cause of intestinal obstruction in US** * _Etiology_: surgery, inflammatory bowel disease, endometriosis, peritonitis (common denominator) * _Complication_: ‘internal herniation’, obstruction, infarction

Answer 7

**Segment of small intestine becomes ‘telescoped’ into the more distal intestine**, peristalsis propels the segment distally Children: w/ or without lesion Adult: w/ lesion (intraluminal mass as ‘lead point’)

Answer 8

Twisting of a loop of bowel about its mesenteric base of attachment

Answer 9

* **↓** **Blood supply** **⇒** **hypoxia, accumulation of metabolic byproducts, bacterial overgrowth** **⇒** **necrosis** * _Extent_: * **Mucosal**: mucosa only * **Mural**: mucosa and submucosa (may be due to non-occlusive flow problem) * **Transmural**: necrosis of all layers (vessel is often mechanically obstructed) * **Sharply defined border** w/ normal * Infarcted bowel **intensely congested** (dusky to purple red) * **Wall edema** w/ **coagulative necrosis** of muscularis propria 1-4 days after onset * Chronic ischemic colitis may mimic Idiopathic IBD

Answer 10

* _Arterial occlusion_ (30-50%) * **Thrombus**: Usually proximal and w/ plaque * **Embolus**: Cardiac vegetations, procedures, aortic plaque * **Dissecting aortic aneurysm** * Other: **iatrogenic, vasculitis, hypercoagulable states** * _Nonocclusive Ischemia_ (30-50%) * **Splanchnic vasoconstriction**: associated w/ myocardial infarction, congestive failure, shock, trauma, hypovolemia, drugs * _Mesenteric venous thrombosis_ (10-15%) * **Hypercoagulable states**: oral contraceptives, invasive neoplasms * **Cirrhosis** * **Sepsis** * _Miscellaneous_ * **Radiation injury** * **Mechanical causes of obstruction**

Answer 11

* _Intestinal response to ischemia has 2 phases:_ * **Hypoxic injury** * At onset of vascular compromise * Epithelial cells are relatively resistant to transient hypoxia * **Reperfusion injury** * More damaging * May trigger multiorgan failure * May be due to leakage of gut lumen bacterial products into systemic circulation, free radical production, neutrophil infiltration * _Variables_: * Severity of vascular compromise * Time frame of development * Vessels affected

Answer 12

* GI tract = _most common site_ of **extranodal lymphoma** * 1-4% of GI malignancies * \> 95% are **B cell type** * _Sites_: **stomach** (55-60%) \> **small intestine** (25-30%) \> **colon** (10-15%) * _Prognosis is dependent on_: **stage, lymphoma type** * If disease limited to mucosa or submucosa, 10 yr survival ~ 85%

Answer 13

* _B Cell_ * **MALT** (Mucosal Associated Lymphoid Tissue) type * Low grade and High grade * **Mediterranean Lymphoma** * Pts have _underlying chronic diffuse mucosal plasmacytosis_ * Cells make **abnormal IgA**, often preceded by malabsorption * **Mantle Cell Lymphoma** * **Burkitt and Burkitt-like Lymphoma** * **EBV-Associated Lymphoproliferative Disease** * Other types as seen in lymph nodes * _T Cell_ * **EATL** (Enteropathy Associated T-cell Lymphoma) * Other

Answer 14

* **Helicobacter gastritis** * **Natives of Mediterranean region** * **Immunodeficiencies** * Congenital * HIV * Immunosuppressed * EBV related * **Celiac sprue**

Answer 15

* **Etiology unknown** * Must exclude known causes first * _Idiopathic inflammatory bowel disease (IIBD)_ * **Ulcerative Colitis (UC)** * **Crohn Disease (CD)** * **Indeterminate Colitis** (~10% of IBD pts) * _Microscopic colitis_ * **Collagenous colitis** * **Lymphocytic colitis**

Answer 16

* Initially individuals may have a dx of **chronic colitis, etiology unknown** * _Idiopathic inflammatory bowel disease (IIBD)_ * **Ulcerative Colitis (UC)** * **Crohn Disease (CD)** * **Indeterminate Colitis** * ~10% of IBD pts

Answer 17

* Consider other possibilities when pts present w/ 1^st episode suspicious for IBD * _Must r/o other causes:_ * **Parasitic disease** * **Bacterial pathogens** (C. difficile, Salmonella, Shigella, E. coli, Campylobacter) * **Diverticulitis** * **Ischemia** and other potential causes for bleeding, diarrhea, fever, and/or abd pain

Answer 18

* **↑** **Worldwide incidence** * Areas adopting a more “Western” lifestyle * More common in **Jewish individuals** * Less common in **African-Americans** * Anyone can develop IBD regardless of race/ethnicity * **M=F incidence**

Answer 19

* **Genetics / Fhx** * ~10-15% of lBD pts have an affected 1° family member * MZ twins: CD ~60% concordance, UC concordance ~15% * _Pathogenesis_ * Genetic susceptibility, environmental factors, and immune response * “Trigger” in susceptible host ⇒ abnormal immune response ⇒ inflammation ⇒ tissue injury

Answer 20

**Susceptibility locus for IBD** * NOD2 activates down-stream inflammatory cell signaling * Ass. w/: aggressive disease, fibrostenotic disease, and recurrence post-op * Common in Caucasian population * Up to 20% carry one mutation, 1% carry two * Chance of NOD-2 homozygotes developing CD no greater than 4%

Answer 21

* _Location:_ * Limited to the ileum (**ileitis**) (~40%) * Terminal ileum and colon (**ileocolitis**) (~40%) * Only the **colon** (20%) * Predominant sx: **crampy pain, diarrhea, fever, weight loss** * Physical exam findings vary w/ location and severity of disease * **±** **Aphthous mouth ulcers** * **± TTP** **over involved bowel** (usu. RLQ TTP & thickening) * **±** **Perianal disease** (fistulas or tender induration) * **±** **Anemia** from chronic disease or blood loss * **CRP or ESR** may be used to monitor inflammation

Answer 22

* Disease is _regional_ ⇒ **skip lesions** * Earliest lesion is the **aphthous ulcer** * Multiple lesions can coalesce into **linear ulcers** * Some mucosa is spared ⇒ **cobblestone appearance** * _Diseased tissue_ is **depressed** * Can develop **fissures** between mucosal folds * These can _extend_ _transmurally_ to become **fistula tract or perforation site** * Bowel wall thickens ⇒ **fibrotic** * Mesenteric fat can extend to cover the serositis ⇒ **‘creeping fat’**

Answer 23

* _Active Crohn’s disease:_ * **Cryptitis** * Neutrophils infiltrate ⇒ damage crypt epithelium * **Crypt abscess** * Cluster of neutrophils w/in a crypt * Often associated w/ **crypt destruction** * **Ulceration** * _Repeated cycles of crypt destruction and regeneration lead to:_ * **Distortion of mucosal architecture** * Crypts w/ bizarre branching shapes and unusual orientations to one another * Epithelial metaplasia w/ gastric antral-appearing glands (**Pseudo-pyloric metaplasia**) * **Paneth cell metaplasia** * **Mucosal atrophy** w/ loss of crypts * **Noncaseating granulomas** (~35%) * Any layer of intestinal wall or in mesenteric lymph nodes

Answer 24

6x ↑risk of **carcinoma** ↑ Risk of **EBV-Associated Lymphoma** related to therapy

Answer 25

* _Location:_ * May involve rectum only (**ulcerative proctitis**) * Varying degrees of sigmoid and descending colon (**left sided colitis**) * Disease proximal to the splenic flexure (**pancolitis**) * Dominant feature of UC is **bloody diarrhea** * **Bowel urgency, rectal discomfort, and abdominal cramping** * **±** Systemic complications (ex. **fever** and **weight loss**) * Depends on the extent of colonic involvement * **Episodic \> continuous disease** * Abdominal TTP common (often over left colon) * _Labs:_ * Anemia from blood loss * ↑ WBC * ↑ ESR or CRP

Answer 26

* **Continuous involvement** * **Friable surface w/ easy bleeding** * Broad-based **ulceration** * **Pseudopolyps** * **Isolated islands of regenerating mucosa** * Can fuse to create ‘**mucosal bridges**’ * **Leather strap** appearance * **Mucosal atrophy** * Smooth surface w/o folds * **Backwash ileitis** (10%) * Mild mucosal inflammation of the distal ileum in severe cases w/ pancolitis * Inflammation may _disturb neuromuscular function_ ⇒ **colonic dilation and toxic megacolon** ⇒ ± **perforation**

Answer 27

* _Active UC_ (similar to Crohn’s) * **Inflammatory infiltrates** * **Crypt abscesses** * **Architectural crypt distortion** * **Epithelial metaplasia** * But inflammatory process is **diffuse** **&** **limited to mucosa and superficial submucosa** * _Healed disease:_ * **Submucosal fibrosis** * **Mucosal atrophy** * **Distorted mucosal architecture** * May also revert to near normal after prolonged remission * **Granulomas are not present** in UC

Answer 28

* **20-30x** **↑ risk** **for neoplastic transformation** of colonic mucosa * _Highest risk of dysplasia:_ * **Disease \>10 years duration** * **Pancolitis** * Inactive disease is not protective * Absolute risk of 35% at 30 yrs of disease

Answer 29

* **Aphthous ulcers** in the mouth * **Sclerosing cholangitis** in UC * Does not improve w/ tx of the UC * **Ankylosing spondylitis** * Is not influenced by tx * **Migrating large joint arthritis** * Usually asymmetric * May precede the onset of IBD * Usually responds to IBD treatment * **Pyoderma gangrenosum** * Ulcerating and undermining skin lesion * May respond to aggressive IBD therapy * **Erythema nodosum** * Painful and hyperemic nodules on the anterior leg * Usually responds well to IBD therapy * **Ocular complications** include episcleritis, scleritis, and uveitis

Answer 30

* Fibrostenosis ⇒ **Stricture** * Stricture ⇒ proximal dilation and pressure ⇒ **abscess** and fistula * Penetrating Disease ⇒ **Fistula** * Fistulas can form between: Entero-Enteric, Entero-Colonic, Entero-Vesicular, Entero-Vaginal, Entero-Cutaneous * **Perianal Disease w/ abscess** * **Superinfection** * C. difficile is a common offender * **Toxic Megacolon** * Leads to i**ntestinal perforation** * **Short Bowel Syndrome** * Severe malabsorption due to loss of small bowel surface area * **Colorectal Neoplasm** * ↑ Colon cancer risk w/ duration of illness and extent of disease * Guidelines for screening vary on the location / extent of disease * Pts w/ **primary sclerosis cholangitis** at risk for **cholangiocarcinoma**

Answer 31

* _Potential pharm IBD treatments:_ * **Mesalamine** * **Steroids** * **Immunomodulators** * **Antibiotics** * **Anti-TNF agents** * _Surgical:_ * **Severe and unresponsive UC** may require a **colectomy** * **Surgery for CD** is usually for **obstruction and/or abscess** in the _small bowel_ and for **chronicity** in _large bowel disease_ * **Resections** performed w/ aim of preserving as much small bowel as possible * Newer treatment options ⇒ ↓ need for surgery in IBD

Answer 32

* Unknown Etiology * **No gross abnormality seen** * **Chronic watery diarrhea** * _Two forms:_ * **Collagenous Colitis** * **Lymphocytic Colitis**

Answer 33

* Type of microscopic colitis * **Women 40-70 y/o** * **Focal thickening of subepithelial collagen** * ↑ intraepithelial lymphocytes * ↑ mixed inflammatory cells in lamina propria

Answer 34

* Type of microscopic colitis * F=M * **Marked** **↑** **intraepithelial lymphocytes** * Associations: **Celiac sprue, other autoimmune diseases**

Answer 35

* 1° in **sigmoid colon** (\> 95%) * **Pseudodiverticulum**: mucosa and submucosa herniate through wall in area of muscle interruption * _Epidemiology:_ * **Affects 50% of those \> 60 y/o in US** * Rare under age 30 * **80% are clinically silent** * _Pathogenesis:_ * **Colonic structure issue** * Weak areas in muscularis propria where the nerves, arterial vasa recta, and connective tissue sheaths penetrate inner circular muscle coat * Colonic external longitudinal layer of muscularis propria gathered into 3 bands (taeniae coli) * ↑ Intraluminal pressure from exaggerated peristaltic contractions, w/ spasmodic sequestration of bowel segments * Inner layers prolapse through muscle gaps (pseudodiverticula) * Enhanced by diets low in fiber (↓ stool bulk)

Answer 36

* _Clinician dx_: **presence of diverticula** * _Pathological dx_: **presence of uninflamed diverticula** * Pt may experience **crampy discomfort, constipation, diarrhea, but most have no sx**

Answer 37

* Diverticulum becomes **obstructed** ⇒ **inflammation** ⇒ **diverticulitis** * Clinical sx: **fever,** **↑** **WBC count, peritoneal signs** * Pathologist sees **inflamed diverticula** * If perforation occurs ⇒ **pericolonic abscesses, sinus tracts, peritonitis** * Pt can present w/ **acute abdomen** * Even without perforation, can be left w/ chronic issues ⇒ **fibrosis, stricture,** etc.

Answer 38

* Bleeding * Abscess * Fistula * Stenosis * Rupture * Impaction

Answer 39

* **Variceal dilations of anal and perianal venous plexus due to** **↑** **venous pressure** * Affects 5% of population * _Risks include:_ * **Straining at stool** * **Pregnant woman** * **Portal HTN** * _Complications:_ * **Thrombosis** * **Infarction** * **Fissure** * **Ulceration**

Answer 40

* **Malformed mucosal and submucosal vessels** * Most often in **cecum** and **right colon**, usu. **after age 60** * _Pathogenesis_: interference w/ submucosal venous drainage ⇒ retrograde distension, ? loss of vascular integrity * Seen in 1% of adults but **accounts for 20% of significant lower GI bleeding** * Chronic, intermittent * Acute, massive

Answer 41

* Worm-like structure: 7 cm length, 1 cm diameter * **Lined by colonic type mucosa**, rich in **lymphoid follicles** * Fibrous obliteration w/ ↑ age * Function unknown * _Disorders:_ * **Acute appendicitis** * **Mucocele** * **Tumors** (Carcinoid is most common)

Answer 42

* _Clinical features:_ * Relatively common * Lifetime risk is 7%, M\>F * Primarily **young adults** * **RLQ/periumbilical pain, N/V, fever** * _Pathogenesis:_ * **Luminal obstruction** by fecalith or other object (worms, gallstone, tumor, etc) seen in _50-80% of cases_ * **Compromises venous outflow** * Tissue undergoes **ischemic injury** * **Stasis of lumen contents** ⇒ bacterial proliferation ⇒ **inflammatory response** (edema, PMN infiltration) * Can result in **perforation** and **peritonitis** if not detected and removed

Answer 43

* Most common is **carcinoid** * May also see **adenomas** or **non-mucin-producing adenocarcinomas** * **Mucocele** * **Dilated appendix filled w/ mucin** * _Multiple etiologies:_ * Obstructed appendix filled w/ mucin * **Mucinous cystadenoma** * **Mucinous cystadenocarcinoma** * May result in **pseudomyxoma peritonei:** implantation of mucinous carcinoma cells on peritoneum * Can do repeated debulking’s but is usu. fatal

Answer 44

* Arise from **neuroendocrine cell** of GIT * Neuroendocrine cell differentiates from gut stem cell * **Endocrine and paracrine functions** * Can also arise in the lung * Peaks in **6^th decade** * _Location:_ * **Appendix \> small intestine \> rectum \> stomach \> colon** * May present w/ syndrome related to **hormone production** * **Prognosis of GI carcinoids determined by location** * _Foregut carcinoids_: rare metz, includes stomach * _Midgut carcinoids_: often aggressive, in jejunum and ileum, can invade and metastasize * _Hindgut carcinoids_: in appendix and colorectum, usually discovered incidentally, worse behavior in prox. colon than in rectum, rarely metastasize * For individual tumors, also consider: * **Depth of penetration** * **Size** * \< 1 cm rarely metastasize * \> 2 cm usually have metz * Overall survival: 90% exclusive of appendiceal

Answer 45

* **Intramural or submucosal lesion** w/ overlying mucosa that can **ulcerate** * Tumors are yellow or tan, and firm * _Histology_ * **Islands or strands of tumor cells** w/ **‘salt and pepper’ chromatin** * _Stain for NE markers_: **chromogranin, synaptophysin**, NE granules on EM * Histologic examination cannot distinguish benign from malignant tumors

Answer 46

* Due to **excessive serotonin** * _Can test blood and urine for:_ * **5-hydroxy-tryptamine [5HT]** * **5-HIAA** (5-hydroxyindoleacetic acid) * Occurs in _1% of carcinoid pts_ and in _20% of those w/ metastases_ * **Requires bypass of portal circulation** * Metastases w/ GI tumors * Lung tumors, ovary tumors * _Clinical features:_ * **Vasomotor disturbances**: cutaneous flushing, cyanosis * **Intestinal hypermotility**: diarrhea, cramps, nausea and vomiting * **Asthmatic bronchoconstrictive attacks**: cough, wheezing, dyspnea * **Hepatomegaly**: nodular liver * **Systemic fibrosis**: endocardial, valvular, retroperitoneal, pelvic

Answer 47

* Most common in the **colon**, can see elsewhere * Begin as **small mucosal elevations** * **Sessile**: grow directly from surface w/o stalk * **Pedunculated**: have a stalk

Answer 48

* **Non-neoplastic polyps** * Hyperplastic polyps * Inflammatory polyps * Hamartomatous polyps (sporadic/syndromatic) * Juvenile polyps * Peutz Jegher polyps * **Neoplastic polyps** * Adenoma (see dysplasia)

Answer 49

* Non-neoplastic polyp * Due to **delayed shedding of surface epithelial cells** * Most common in **rectosigmoid** * Typically small (\< 0.5 cm) * Usually seen in pts in **50s-60s** * **No known neoplastic potential**

Answer 50

Ex. **solitary rectal ulcer syndrome** * Presents w/ **rectal bleeding, mucus discharge, inflammatory lesion** of _anterior rectal wall_ * Due to **impaired relaxation of anorectal sphincter** * Creates sharp angle @ anterior rectal shelf ⇒ recurrent abrasions ⇒ ulceration of rectal mucosa ⇒ **polyp &** **±** **mucosal prolapse**

Answer 51

_Examples:_ * Juvenile Polyps * Peutz Jeghers Syndrome * Cowden Syndrome and Bannayan-Ruvalcaba-Riley Syndrome * Cronkhite-Canada Syndrome

Answer 52

* Majority present as **sporadic lesion** in _rectum_ * Most common in **children \< 5 yrs** * _In adults_, sporadic lesion can be present ⇒ **retention polyp** * Pedunculated, dilated glands filled w/ mucin and inflammatory debris

Answer 53

* Autosomal dominant * 3-100 polyps throughout GI tract, most in _colorectum_ * Can **hemorrhage** when **ulcerated** * **Dysplasia** in up to 20% of these polyps ⇒ **↑** **risk of colon CA** * _Associated congenital defects_: **pulmonary AVMs**

Answer 54

* _Genetic defect:_ **LOF mutation in LKB1/STK11** in 50% w/ familial syndrome * Encodes a kinase regulating cell growth and metabolism * Autosomal dominant * **Presents near age 11** * _Clinical characteristics:_ * **Melanotic mucosal and cutaneous pigmentation** * Lips, buccal mucosa, genitalia, palmar surfaces * **Hamartomatous polyps** throughout GI tract * Most common in small intestine * _Associations:_ * **↑** **Risk of carcinoma** * Colon, pancreas, breast, lung, ovary, uterus, testes * In women: **ovarian sex cord tumor w/ annular tubules**

Answer 55

* **Hamartomatous polyp syndromes** * **LOF** mutation in **PTEN** * Tumor suppressor gene * Autosomal dominant * **_Cowden_** * **Microcephaly, hamartomatous polyps in intestine, benign skin tumors**, **subcutaneous hemangiomas** * **↑ R****isk of breast, follicular thyroid and endometrial CA** * **_BRR_** * Also **mental deficiency, developmental delay** * Less neoplasia than Cowden

Answer 56

a. Trichilemmomas on the nape of the neck b. Palmar keratoses c. Perioral papillomatous papules and nasal polyposis d. Gastric hamartomas

Answer 57

* Not hereditary * Usually seen **over age 50** * Clinical: * **Diarrhea, wt loss, abd pain, weakness, nail atrophy and splitting, hair loss, skin hyperpigmentation/hypopigmentation** * **Hamartomatous polyps** in _stomach, small intestine and colorectum_ * Resemble juvenile polyps but **non-polyp mucosa shows similar changes** * Cause unknown, no specific therapy, 50% fatal

Answer 58

* **Neoplastic epithelium** that _remains confined w/in the basement membrane_ * Can develop in flat areas that look normal * **Nuclear hyperchromasia (dark nuclei), elongation, and stratification** * ± **Large nucleoli** and **fewer goblet cells** * Epithelial cells **fail to mature** as they move toward surface * Show **genetic characteristics of neoplastic transformation** * _Colonoscopic appearance of dysplasia:_ * Flat mucosa w/ appearance of colitis/normal (**sessile**) * **DALM**: Dysplasia associated lesion or mass * **Adenoma-like**: polypoid projection w/ stalk (peduculated) * Graded as: Low grade, High grade * Precursor lesion to **adenocarcinoma**

Answer 59

* **Benign pedunculated or sessile polypoid lesion composed of dysplastic tissue** * **Incidence is age related** * 50% of adults in West have by age 50 * Precursor lesion to **adenocarcinoma** * Recommend surveillance exam by age 50 * Earlier for those w/ family hx * 10 yrs before youngest affected relative was dx * 4x risk for family members * **Most adenomas won’t progress to adenocarcinoma**, but don’t know which ones * No gender predominance * Often **asymptomatic**, can cause **bleeding**

Answer 60

* **Tubular**: \> 75% pit architecture * Most common adenoma (90%) * Usually **small, pedunculated** * **Tubulovillous**: 25-50% villous architecture * 5-10% of adenomas * **Villous**: \> 50% villous * 1% of adenomas * Usually **large and sessile** * **Sessile serrated:** * Looks like hyperplastic polyps but are **premalignant** * _Carcinoma risk_ * Consider **size of adenoma**, **tubular vs villous,** **pedunculated vs sessile**, and **amount of dysplasia** * ~40% risk of CA in sessile polyps \> 4 cm

Answer 61

* Dysplastic epithelial cells **breach BM** → lamina propria or muscularis mucosa * Adenoma → **intramucosal carcinoma** * Does not metastasize * **_Polypectomy_** _is adequate therapy unless:_ * Cannot be performed d/t location and/or size * Lesion on tissue margin * Intramucosal carcinoma poorly differentiated * Angiolymphatic invasion present * Next step would be **invasion beyond muscularis mucosa** * Now **invasive adenoCA** ⇒ can spread

Answer 62

* **Most common GI cancer** * **Preventable cancer** * High impact disease (incidence and death) * At-risk population (family hx, genetics, elderly etc.) * Precursor lesions (polyps or adenomas) * Tests to detect precursor lesions (colonoscopy ⇒ highly sensitive)

Answer 63

* _USA_ * **Most common GI malignancy**, peak age 60-70 * 2nd most common cause of CA death after lung * 130k new cases/yr; 55k deaths/yr * _Worldwide_ * 30x difference in incidence rate in developed countries vs India, South America, Africa * **Migration changes risk status** * Lifestyle and diet changes * Low fiber, high carbs and fats associated w/ ↑ risk * NSAIDs may have protective effect * ⊗ COX -2 * Highly expressed in colon CA

Answer 64

* _⊕_ _Risk Factors_ * **Age** * ≥ 50 y/o * **Hereditary syndromes** * Present as early as 10-15 y/o * FAP (APC Pathway) * HNPCC (Microsatellite instability) * **Family Hx** ⇒ even w/o genetic syndromes * **Diet** * Low dietary fiber, High animal fat, High sugar * **Red meat and smoking** * Nitrosamines and heterocyclic amines * ? APC mutations * ? K-ras mutation * **Alcohol** * Acetaldehyde-DNA damage * **Obesity** * Insulin Resistance and high Insulin growth factors * **Smoking** * **IBD** * Crohn’s colitis * Ulcerative Colitis * _⊖_ _Risk Factors_ * **Vegetables** * Antioxidants ⇒ ↓ DNA damage * Folate ⇒ ↑ DNA integrity * ↓ Growth stimulus * ↓ Transit time * **Physical activity/low body mass**

Answer 65

**Typical progression up to 10 yrs** Multifactorial etiology: * **Hereditary susceptibility** * **Diet & environmental factors** * **Somatic genetic change** * _Two distinct genetic pathways_ * Both involve stepwise accumulation of multiple mutations * Epigenetic events, e.g. methylation-induced gene silencing, may enhance progression along both * **Genetic syndromes** ⇒ can accelerate progression to \< 3 yrs

Answer 66

* **Adenomatous Polyposis Coli (APC) / B-catenin Pathway** * 80% of sporadic colon CA * Associated w/ _WNT and classic adenoma-carcinoma sequence_ * Mutation in **KRAS, p53, SMAD 2 and 4** play a role * **Microsatellite Instability Pathway** * Associated w/ defects in **DNA mismatch repair** * Mutation in **MSH2, MLH1, and BRAF** play a role * Common in _SSA, mucinous CA, right colon site_

Answer 67

* _FAP and variants_ (mutation in APC gene) * **Familial adenomatous polyposis (FAP)** * **Attenuated FAP** * Delay in polyps, \< 100, delayed colon CA * **Gardner syndrome** * Soft tissue and bone tumors, epidermal cysts, dental issues * **Turcot syndrome** (CNS tumors) * ⅔ have APC gene mutation ⇒ **medulloblastomas** * ⅓ have DNA repair gene mutation ⇒ **glioblastomas** * **Hereditary nonpolyposis colorectal cancer** (HNPCC, Lynch syndrome)

Answer 68

* Autosomal dominant * _Germline genetic defect:_ * **Chromosome 5q21** * **Adenomatous polyposis coli (APC) gene** * _APC function:_ * Regulation of **ß catenin induced signaling** * Regulation of **cell adhesion** via _ß-catenin_ and _E-cadherin_ * Regulation of **cell migration** via _microtubule interaction_ * **Cell cycle block** ⇒ ? inhibits _cell cycle components_

Answer 69

* **Multiple adenomas** * In colorectum: min 100, max \> 2k * Look like sporadic ones * **Flat or depressed adenomas and microscopic ones** * _In upper GI tract_, most commonly _around ampulla_ * _In stomach_, may develop **adenomas**, more commonly see **fundic gland polyp** * _Extra-intestinal signs and symptoms_ * **Congenital hypertrophy of retinal pigment epithelium** * Can detect at birth * Virtually all pts develop **colorectal carcinoma** * Usually **before age 30** * _Treatment:_ * **Colectomy** * Still need to monitor other GI sites

Answer 70

**“Lynch Syndrome”** * Most common type of familial colorectal CA syndrome * **Accounts for 1-5% of cases of colorectal cancer** * **Do not see extensive polyposis but polyps present** * Difficult to distinguish from “sporadic” cases * **Early onset of colon CA** (usually _right colon_) * And other cancers * Esp. those in **endometrium, urinary tract, stomach and biliary system**

Answer 71

* Germline mutation in a **DNA mismatch-repair gene** * MSH2, MLH1, PMS1, PMS2, MSH6 * Encode proteins that **repair mismatches of nucleotides** * Occur when DNA polymerase inserts the wrong bases in newly made DNA * W/o repair, **mistakes persist as unstable tandemly repeated DNA sequences** ⇒ **microsatellite instability** * Also seen in **15% of sporadic cancers**

Answer 72

* **Molecular testing** * Demonstrate tumor has _microsatellite instability_ * Test for _germline mutation in DNA mismatch repair gene_ * **Amsterdam Criteria** * ≥ 3 members in at least 2 successive generations must have colorectal CA * At least one case dx before age of 50 yrs * One of the affected members should be a first degree relative of the other two * **Bethesda Criteria** * Amsterdam criteria individuals * Individuals w/ two HNPCC- related cancers * Individuals w/ colorectal CA and 1^st degree relative w/ ≥ 1 of the following: * Colorectal CA dx’d under 45 yrs * HNPCC-related CA dx'ed under 45 yrs * Adenoma dx’ed under 40 yrs * Individuals \< 45 yrs w/ colorectal or endometrial CA * Individuals w/ proximal cancer of undifferentiated type * Individuals \< 45 yrs w/ signet-ring CA * Individuals \< 40 yrs w/ adenomas

Answer 73

* **Screen everyone** between _50-75 y/o_ * FHx, genetic syndromes start at lower age * _76-85 y/o_ ⇒ **screen if not done before and if relatively healthy** * _\> 85 y/o_ ⇒ **do not screen**

Answer 74

* _Precursor lesions_ (polyps) ⇒ **many asymptomatic** * Remains silent for years * _Invasive component_ elicits a **strong desmoplastic response** ⇒ **firm consistency** * _Clinical presentation:_ **Symptoms insidious** * **Right colon** (38%) * **Fatigue, weakness, iron deficiency anemia** (d/t occult blood loss) * Exophytic, polypoid lesions * Protrudes into lumen * **Transverse colon** (18%) * **Descending (left) colon** (8%) * **Occult bleeding, change in bowel habit, LLQ discomfort** * Annular, encircling lesions * Constricting, ‘napkin ring’ **prone to obstruction** * Colonic obstruction ⇒ **abd pain, vomiting, inability to eat** * **Sigmoid colon** (35%) * _In the rectum, sigmoid colon, villous adenoma_ ⇒ **diarrhea** * **Multiple sites** 1% * _Advanced stages_ * **Grossly visible rectal bleeding** * _Spread:_ * **Direct extension** * **Metastasizes** through _blood vessels and lymphatics_ * Preferred sites ⇒ **LN, liver, lungs, bones** * When cancer _metastatic_ ⇒ **weight loss** * _Prognosis:_ most influenced by **depth of invasion** and **whether LN’s are positive**

Answer 75

* **T staging:** * Rectal CA: Endoscopic US (EUS) and MRI are equivocal * Colon CA: EUS can be used, but usu. not needed * **N staging:** * Rectal CA: EUS has the best sensitivity, can biopsy, CT * Colon CA: CT, often better-established post-op (histology) * **M staging:** * CT, esp. combo w/ PET * Brain ⇒ MRI * Liver ⇒ Dynamic MRI/CT

Answer 76

* _For carcinoma in situ (Tis), intramucosal carcinoma, or high-grade dysplasia_ * **Polypectomy** or **endoscopic mucosal resection via colonoscopy** * _For all other stages_ * Tx options depend on disease specifics * Ex. depth of tumor invasion in the colon and presence of metastasis * Includes: * **Surgery** * **Chemotherapy** * **Radiation therapy**

Answer 77

* _Upper ⅓_: lined by columnar rectal epithelium * _Middle ⅓_: transition to stratified squamous * _Lower ⅓_: stratified squamous

Answer 78

* **1.5% of digestive system CA** * In US: 3,400 new cases per year * Can be **glandular, squamous, or basaloid** (cloacogenic CA) * **Pure squamous cell CA** often ass. w/ _HPV infection_ * Also causes precursor lesions: **Anal Intraepithelial Neoplasia (AIN), condyloma**

Answer 79

* **Rectal bleeding**: 45% * May be mistaken as hemorrhoid * **Pain/rectal mass sensation**: 30% * **No rectal symptoms**: 20% * **Size of tumor most important prognosticator** * ≤ 2cm: cure 80% * ≥ 5cm: cure \< 50%

Answer 80

* _Strong evidence_ * HPV infection * Receptive anal intercourse * STI * \> 10 sexual partners * Hx of cervical, vulvar or vaginal CA * Immunosuppression after solid organ transplantation * _Moderately strong evidence_ * HIV infection * Long-term use of corticosteroids * Cigarette smoking