Inflammatory Bowel Disease-Associated Neoplasia



Inflammatory Bowel Disease-Associated Neoplasia


Julianne K. Purdy, MD





Key Facts


Macroscopic Features



  • Polypoid dysplastic lesion/DALM



    • Adenoma-like: Endoscopically resectable, dome-shaped, sharp borders


    • Non-adenoma-like: Not endoscopically resectable, sessile/plaque-like, indistinct margins


Microscopic Pathology



  • Low-grade dysplasia



    • Nuclei uniformly enlarged and hyperchromatic; nuclear stratification in basal 1/2 of cells


    • Minor glandular crowding; no cribriform architecture


  • High-grade dysplasia



    • Ovoid hyperchromatic nuclei; high N:C ratio; complete loss of nuclear polarity


    • Crypt branching/budding; cribriform architecture


  • Polypoid dysplastic lesion/DALM



    • Cannot histologically distinguish sporadic adenoma and IBD-related polypoid dysplasia


    • Non-adenoma-like DALM: Adjacent flat dysplasia; more asymmetry/architectural variability


    • Diagnose as polypoid low- or high-grade dysplasia; endoscopist decides management


  • Confirm dysplasia with GI pathology expert


Top Differential Diagnoses



  • Regeneration within inflammation



    • Surface maturation (goblet cells), nuclear stratification only at bases of crypts


    • Vesicular nuclei, prominent nucleoli, abundant eosinophilic cytoplasm


    • No crypt budding/branching; no cribriform architecture







Hematoxylin & eosin shows a polypoid dysplastic lesion with a broad base. There is focal villiform architecture image, cystic change, and hypermucinous epithelium image.






Hematoxylin & eosin shows high-grade dysplasia in flat colonic mucosa. The nuclei are ovoid, enlarged, and hyperchromatic with loss of polarity. There are also mitoses image and a cribriform architecture.


TERMINOLOGY


Synonyms



  • Dysplasia


Definitions



  • Dysplasia or carcinoma associated with longstanding inflammatory bowel disease (IBD)


  • Dysplasia-associated lesion or mass (DALM) = polypoid dysplastic lesion



    • Term 1st used to describe sessile plaque-like lesions that were not endoscopically resectable


    • Term “adenoma-like” DALM used to describe discrete endoscopically resectable polyps identical to sporadic adenomas


ETIOLOGY/PATHOGENESIS


Genetic/Familial Link



  • Colorectal cancer (CRC) in 1st degree relative: ≥ 2x higher risk of CRC Inflammation → Genomic Instability


  • > 10 years of disease & pancolitis: Highest risk for CRC



    • Risk in Crohn disease (CD) similar to that for ulcerative colitis (UC) with comparable duration/extent


    • Left-sided UC: Increased CRC risk after 15-20 years of disease (˜ 10 years later than if pancolitis)


    • Ulcerative proctosigmoiditis: No increased risk


  • Response to inflammation overwhelmed → widespread genomic instability



    • Emergence of neoplastic clones → dysplasia/carcinoma



      • Silent genetic damage to mucosa before dysplasia


  • 70-85% of CRC in IBD: Chromosomal instability pathway



    • Widespread gains/losses of genomic material, inactivation of tumor suppressor genes


    • Shared genetic alterations with sporadic CRC; different timing/prevalence



      • Mutations/loss of p53 common and early in IBD (late in sporadic CRC)


      • Inactivation of APC gene (common/early in sporadic CRC) & KRAS mutations (common in adenomas) infrequent in IBD


  • 15-30% of CRC in IBD: Microsatellite instability (MSI) pathway



    • Leads to CRC with MSI, BRAF mutations, or widespread gene promoter hypermethylation


    • Higher prevalence of MSI in UC-associated CRC than in sporadic CRC (10-15%)


    • Dysfunction of mismatch repair genes


    • Activating BRAF mutations: Marker for serrated neoplasia pathway in inflammatory mucosa in IBD; precedes MSI in IBD-related oncogenesis


    • Methylation of CpG islands in genes in nonneoplastic epithelium of UC patients with high-grade dysplasia (HGD) or CRC


CLINICAL ISSUES


Epidemiology



  • Incidence



    • Dysplasia



      • UC: Prevalence up to 24%; more common than in CD (prevalence 2-16%)


      • Elevated > flat


      • In 83-100% of cases of IBD with carcinoma


      • Dysplasia found distant from carcinoma site in 23-70%


    • CRC in IBD



      • < 1-2% of all CRC in general population


      • UC: CRC prevalence 3.7% overall; 5.4% in patients with pan-UC


      • Mean cumulative incidence of CRC in UC: 2% after 10 years, 2.5-10% after 20 years, 8-20% after 30 years



      • Similar incidence for CD after adjusting for disease duration and extent


  • Age



    • Mean age of CRC in IBD patients 40-50 years (10-20 years earlier than CRC in general population)


    • Median age of IBD patients with polypoid dysplasia within colitis similar to UC patients with CRC


Site



  • Dysplasia



    • Distribution: Most often multifocal; can be isolated


    • UC patients with ileal pouch anal anastomosis (IPAA): Very small risk of dysplasia in ileal pouch; slightly greater risk in transition zone/rectal cuff


  • Carcinoma



    • Colon most common site



      • UC: Rectum and sigmoid colon


      • CD: 73% in colon (right and rectosigmoid colon)


      • Frequent synchronous tumors: 12% of IBD-related CRC (3-5% of sporadic CRC)


      • Synchronous tumor sites: Colon, rectum, anus, and external/internal fistulous tracts


      • Usually arises in pancolitis


    • Small intestine: 27% of CD-related adenocarcinoma


    • Anus (CD)


Presentation



  • Dysplasia usually asymptomatic


  • Carcinoma: Most are asymptomatic; rarely symptoms of obstruction


Natural History



  • Most UC patients do not develop dysplasia or CRC; most with dysplasia do not get CRC


  • CD patients with only small intestine involvement



    • Low risk for CRC; case reports in strictures/fistulae


    • Risk of small intestinal adenocarcinoma 10-12x > general population


  • Sporadic adenoma/adenoma-like DALM



    • With complete polypectomy and continued surveillance: Low risk of progression to CRC


    • IBD patients: Equal risk for sporadic adenomas as general population


  • Non-adenoma-like DALM: High risk for concurrent/subsequent CRC (> 40% risk of CRC at colectomy)


  • Flat low-grade dysplasia (LGD)



    • ˜ 20% risk of CRC if immediate colectomy; up to ˜ 1/2 of patients get HGD or CRC within 5 years


    • CRC risk 9x that of patients without dysplasia


    • Unifocal LGD as likely to progress to HGD or CRC as multifocal LGD


    • Associated with underlying low-grade tubuloglandular adenocarcinoma without HGD or DALM


  • Flat HGD: 20-50% of patients have CRC at colectomy


  • Indefinite for dysplasia



    • Risk for HGD or CRC intermediate between that of patients with no dysplasia and flat LGD (9% get HGD/CRC within 5 years)


  • Dysplasia may regress/be stable for long periods


  • May develop CRC with only prior LGD or without any prior dysplasia


Treatment



  • Options, risks, complications



    • Colonoscopic surveillance



      • Indefinite for dysplasia: Shorten surveillance interval


      • After proctocolectomy & IPAA: If chronic pouchitis or history of dysplasia/carcinoma, long-term surveillance


      • Flat LGD: Shorten surveillance interval or colectomy


      • Chromoendoscopy: Use dye to improve detection of dysplasia; increases sensitivity/specificity


    • Endoscopic removal



      • Polypoid dysplastic lesions: If completely resectable & no flat dysplasia elsewhere, continue surveillance (even if HGD in polyp)


    • Surgery (colectomy)



      • Flat HGD


      • Flat LGD: Most data favors colectomy but still controversial



      • “Non-adenoma-like” DALM (polypoid dysplastic lesion with suspicious gross features, i.e., broad, plaque-like)


  • Drugs



    • Prevention: No drug presently effective for primary prevention of CRC in IBD patients


Prognosis



  • Significantly increased risk for CRC (including synchronous malignancies)



    • 2-3x greater than that of general population


    • 50-60% newly diagnosed IBD-related CRC stage I-II


    • Stage for stage, prognosis of CRC in IBD patients similar to patients with sporadic CRC


    • CD patients: CRC has better prognosis than ileal carcinoma


MACROSCOPIC FEATURES


Dysplasia



  • Flat dysplasia: No endoscopic lesion


  • Raised: Polypoid dysplastic lesions



    • May be slight elevation above surrounding mucosa


    • Recent data suggest most adenoma-like


    • Adenoma-like DALM



      • Endoscopically resectable


      • Dome-shaped, sharp borders, smooth intact surface; no necrosis or fixation to colonic wall


      • Debate regarding whether IBD-related if within colitis with well-defined stalk (with nondysplastic stalk epithelium)


    • Non-adenoma-like DALM



      • Visible lesion within colitis, not endoscopically resectable


      • Sessile, irregular shape, indistinct margins


      • Ulceration, velvety patch/plaque, wart-like thickening, stricture, broad-based mass


Carcinoma



  • Usually flat; difficult to visualize endoscopically


  • May be minimally raised above surrounding mucosa with indistinct borders


  • Irregular plaque, villiform carpet-like growth, pedunculated/sessile polyp, stricture, ulcer


MICROSCOPIC PATHOLOGY


Key Descriptors

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Jul 6, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Inflammatory Bowel Disease-Associated Neoplasia

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