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GI 2 Pathology--Chapt 16 and 17 > Chapter 17 part 9--Polyps, cancer > Flashcards

Chapter 17 part 9--Polyps, cancer Flashcards

1
Q

FAP (Fmilial adenomatous polyposis)

A
  • autosomal dominant disorder caused by mutations of adenomatous polyposis coli (APC) gene
  • 75% cases are inherited; rest is de novo mutations
  • teens develop >100 colonic adenomatous polyps and if untreated colorectal carcinoma will develop in 100% by age 30
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2
Q

Prophoylaxis for colon cancer from FAP

A
  • colectomy eliminates risk of colon cancer

- these patients also develop adenomas in stomach and ampulla of Vater

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3
Q

Variants of FAP

A
  • Gardner syndrome

- Turcot syndrome

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4
Q

Gardner syndrome

A

-multiple osteomas (mandible, skull, long bones), epidermal cysts, fibromatous (desmoid tumors), abnormal dentition (impacted teeth), and increased incidence of duodenal and thyroid cancers

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5
Q

Turcot syndrome

A
  • rarer

- besides adenomas, patients develop medulloblastomas

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6
Q

FAP patients WITHOUT APC loss have mutations of

A
  • the base excision repair gene MUTYH
  • some APC and MUTYH mutations give rise to attenuated forms of FAP, characterized by delayed polyp development and appearance of colon carcinoma after age 50
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7
Q

Hereditary Nonpolyposis Colorectal Cancer

A
  • Also known as Lynch syndrome
  • caused by mutations in genes encoding proteins responsible for detection, excision and repair of DNA replication errors
  • accounts for 2-4% of colon cancers
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8
Q

Specific genes associated with HNPCC

A
  • MSH2 and MLH1
  • patients inherit one defective copy and when second is lost by mutations or epigenetic silencing, mutations accrue at rates up to 1000 times normal, mostly in regions of micro satellite repeats–leading to micro satellite instability
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9
Q

Adenocarcinoma

A
  • most common GI malignancy and constitutes 15% of all cancer-related deaths in US
  • major cause of morbidity and mortality worldwide
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10
Q

Epidemiology of Adenocarcinoma

A
  • Dietary factors influence risk
  • increased rates seen with reduced veggie fiber intake and increased levels of refined carbs and fat
  • may influence composition of GI flora as well as synthesis of carcinogenic by-products that remain in prolonged contact with intestinal mucosa due to diminished stool bulk
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11
Q

Antioxidants and adenocarcinoma

A

-Diminished antioxidants (vitamins A, C, and E) can also influence malignant potential

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12
Q

NSAIDS and adenocarcinoma

A

-have protective effect–related to inhibition of formation of PGE2 that promotes epithelial proliferation

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13
Q

Pathogenesis of adenocarcinoma

A
  • multiple genetic and epigenetic events
  • classic adenoma-carcinoma sequence
  • no single event or sequence of events is requisite but multiunit genetic mechanism involved
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14
Q

Adenocarcinoma pathogenesis–APC/B-catenin pathway

A
  • associated with Wnt and the classic adenoma-carcinoma sequence
  • APC is key negative regulator of B-catenin!!
  • APC protein normally binds to and promotes B-catenin degradation
  • With loss of APC, B-catenin accumulates and translocates to nucleus, where it activates a cassette of genes that promote proliferation
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15
Q

Adenocarcinoma pathogenesis–DNA mismatch repair deficiency

A
  • mutations accumulate in microsatellite repeats, a condition referred to as micro satellite instability (MSI)
  • Some microsatellite sequences are located in coding or promoter regions of genes involved in regulation of cell growth, such as those encoding type II TGF-B receptor and proapoptotic protein BAX
  • Since TGF-B inhibits colonic epithelial cell proliferation, mutation of type II TGF-B receptor contributes to uncontrolled cell growth whereas loss of BAX enhance survival of genetically abnormal clones
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16
Q

Adenocarcinoma pathogenesis–microsatellite unstable colon cancers WITHOUT mutations in DNA mismatch repair enzymes

A
  • Have CpG island hypermethylation
  • MLH1 promoter region is typically hypermethylated, reducing MLH1 expression and its repair function
  • Activating mutations in oncogene BRAF are common in these cancers
  • combo of microsatellite instability, BRAF activating mutations and methylation of specific targets like MLH1 =hallmark!
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17
Q

Late KRAS and p53 mutations in Adenocarcinoma pathogenesis

A

-promote growth and prevent apoptosis

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18
Q

Adenocarcinoma pathogenesis–SMAD mutations

A

-reduce TGF-B signaling and promote cell cycle progression

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19
Q

Adenocarcinoma pathogenesis–telomerase

A

-reactivation prevents cellular senescence

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20
Q

Where are adenocarcinoma tumors located in the colon?

A

-equally distributed along colon

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21
Q

Gross morphology of adenocarcinoma

A
  • Polypoid, exophytic masses
  • characteristic in cecum and right colon
  • annular masses with “napkin-ring” obstruction are characteristic of distal colon
  • Both forms penetrate bowel wall over many years
22
Q

Microscopic morphology of adenocarcinoma

A
  • typically made of tall, columnar cells resembling adenomatous neoplastic epithelium but with invasion into submucosa, muscular propria or beyond
  • minority produce copious extracellular mucin
23
Q

Molecular changes in the adenoma-carcinoma sequence

A
  • Loss of one normal copy of tumor suppressor gene APC occurs early
  • ppl with one mutant allele are at increased risk
  • Also inactivation of APC in colonic epithelium may occur later–first hit according to Knudson hypothesis
  • loss of intact second copy of APC follows (second hit)
  • Other changes: KRAS mutation, losses at 18q21 with SMAD2 and SMAD4 and inactivation of tumor suppressor gene TP53 lead to carcinoma in which more mutations occur
  • temporal sequence of changes but accumulation of mutations rather than their occurrence is most critical
24
Q

Morphologic and molecular changes in the mismatch repair pathway of colon carcinogenesis

A
  • Defects in mismatch repair genes result in MSI and permit accumulation of mutations in numerous genes
  • If these mutations affect genes involved in cell survival and proliferation, cancer may develop
25
Q

Other features of carcinomas

A
  • can also be poorly differentiated, solid tumors without gland formation
  • Less commonly, foci of neuroendocrine differentiation, signet-ring features or squamous differentiation occur
26
Q

Invasive tumors

A

-strong desmoplastic response

27
Q

Clinical features of colorectal carcinoma

A
  • insiduous–may go undetected for long periods
  • fatigue, weakness, iron deficiency anemia, abdominal discomfort, progressive bowel obstruction and liver enlargement (metastases)
28
Q

Colorectal carcinoma prognosis

A
  • differs with stage of disease at diagnosis
  • 5-year survival rates related to depth of tumor penetration and lymph node involvement and range from almost 100% for lesions limited to mucosa to 40% for extensively invasive tumors
  • distal metastasis reduces 5-year survival significantly
  • Overall U.S. 5-year survival is 65%
  • Only surgery is curative
29
Q

Hemorrhoids

A
  • variceal dilations of anal and perianal submucosal venous plexi
  • associated with constipation (straining at stool), venous stasis during pregnancy and cirrhosis (portal hypertension)
30
Q

External hemorrhoids

A

-occur with ectasia of inferior hemorrhoidal plexus below the anorectal line

31
Q

internal hemorrhoids

A

-due to ectasia of superior hemorrhoidal plexus above the anorectal line;

32
Q

Complications of hemorrhoids

A

-secondary thrombosis (with recanalization), strangulation, or ulceration with fissure formation can occur

33
Q

Acute appendicitis

A
  • most common acute abdominal condition requiring surgery

- lifetime risk is 7%

34
Q

Pathogenesis of appendicitis

A
  • 50-80% associated with obstruction of appendices lumen by fecalith, tumor or worms (Oxyuriasis vermicularis) causing increased intraluminal pressure
  • followed by ischemia–exacerbated by edema and exudate–and bacterial invasion
35
Q

Appendicitis morphology–Earcly acute appendicitis

A
  • exhibits scant appendiceal neutrophil exudate with subserosal confession and perivascular neutrophil emigration
  • serosa is dull, granular and red
36
Q

Advanced acute appendicitis morphology

A
  • acute suppurative appendicitis
  • involves more severe neutrophilic infiltration with fibrinopurulent serosal exudate, luminal abscess formation, ulceration and suppurative necrosis
  • can progress to ACUTE GANGRENOUS APPENDICITIS followed by perforation
37
Q

Clinical features of appendicitis

A
  • occur at any age but mainly affects adolescents and young adults
  • Classically–periumbilical pain migrating to right lower quadrant, nausea or vomiting, abdominal tenderness, mild fever, and leukocytosis
38
Q

Other mimics for appendicitis

A

-enterocolitis, mesenteric lymphadenitis, systemic viral infection, acute salpingitis, ectopic pregnancy, mittelschmerz, and Meckel diverticulitis

39
Q

Complications of Appendicitis

A

-pyelophlebitis, portal vein thrombosis, liver abscess and bacteremia

40
Q

Tumors of the appendix

A
  • Carcinoid
  • Mucocele
  • Mucinous cystadenocarcinoma
41
Q

Carcinoid

A

-most common tumor in the appendix

42
Q

Mucocele

A

-reflects dilation of the appendiceal lumen by mutinous secretions; can be due to innocuous obstruction with inspissated mucus, to mucin-secreting adenomas or to adenocarcinoma

43
Q

Mutinous cystadenocarcinoma

A
  • indistinguishable from cystadenomas except for appendiceal wall invasion by neoplastic cells and peritoneal implants
  • peritoneum becomes distended with tenacious, semisolid, mucin producing anapestic adenocarcinoma cells, designated pseudomyxoma peritonei!!!–>Fatal!!
44
Q

Peritoneal Cavity–Inflammatory disease

A

-Peritonitis from bacterial infection or chemical irritation

45
Q

Chemical irritation leading to peritonitis can be caused by:

A

leakage of bile or pancreatic enzymes (sterile peritonitis)

  • Perforation of the biliary system or abdominal viscera complicated by superinfection
  • Acute hemorrhagic pancreatitis; bowel wall damage can lead to secondary bacterial peritonitis
  • Foriegn material, inducing granulomas and scarring
  • Endometriosis (ectopic endometrial implants) or ruptured dermoid cysts that release keratins and induce an intense granulomatous reaction
  • Perforation of abdominal viscera
46
Q

Peritoneal infection–Bacterial peritonitis

A

-results when GI tract bacteria are released into abdominal cavity–usually after bowel perforation (e.g., due to appendicitis, peptic ulcer, cholecystitis, diverticulitis, and intestinal ischemia); acute salpingitis, abdominal trauma, or peritoneal dialysis are other bacterial sources

47
Q

Spontaneous bacterial peritonitis

A
  • develops without an obvious source of contamination

- occurs in the setting of ascites (e.g., nephrotic syndrome or cirrhosis)

48
Q

Morphology of peritoneal infection

A

-Peritoneal membranes become dull and gray, followed by exudation and frank suppuration; localized abscesses can develop although inflammation tends to remain superficial

49
Q

Sclerosing Retroperitonitis

A
  • aka Ormond disease

- dense fibrosis of retroperitoneal tissues; likely a primary inflammatory process

50
Q

Peritoneal tumors

A

-may be primary or secondary; all are malignant!!

51
Q

Primary peritoneal tumors

A
  • rare
  • include mesothelioma (similar to pleural or pericardial mesotheliomas) and desmoplastic small round cell tumor
  • characteristic t(11;22) translocation yielding a fusion of genes associated with Ewig sarcoma and Wilms tumor (EWS-WT1); morphologically resembles Ewig sarcoma
52
Q

Secondary tumors

A
  • common and derived from any cancer

- ovarian and pancreatic adenocarcinomas

GI 2 Pathology--Chapt 16 and 17 (14 decks)

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