Small & large gut


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Small & large gut

  2. 2. Normal Small Intestine
  4. 4. Important features► Villous to crypt length ratio is 3:1, 5:1► One lymphocyte per five enterocytes► Paneth cells secrete defensins present up to ascending colon► Peyer patches , M cells► Small intestine 6 meters (25cm duodenum)► Large intestine 1.5 meters (20cm Rectum)► Anal canal 4cm► Enteritis(duodenitis, ileitis), Colitis(typhilitis, proctitis), Cryptitis
  5. 5. Major Causes of MalabsorptionDefective Intraluminal Digestion• Pancreatic insufficiency- pancreatitis or cystic fibrosis• Zollinger-Ellison syndrome- inactivation of pancreatic enzymes by excess gastric acid• Ileal dysfunction or resection, with decreased bile salt uptake• Cessation of bile flow from obstruction, hepatic dysfunctionPrimary Mucosal Cell AbnormalitiesDefective terminal digestion• Disaccharidase deficiency (lactose intolerance)• Bacterial overgrowth, with brush border damageDefective epithelial transport• Abetalipoproteinemia• Primary bile acid malabsorption owing to mutations in the ileal bile acid transporterReduced Small Intestinal Surface AreaGluten-sensitive enteropathy (celiac disease)Crohn diseaseLymphatic ObstructionLymphoma,Tuberculosis and tuberculous lymphadenitisInfectionAcute infectious enteritis or Parasitic infestationTropical sprue, Whipple disease (Tropheryma whippelii)IatrogenicSubtotal or total gastrectomyShort-gut syndrome, following extensive surgical resection or by pass
  6. 6. CELIAC DISEASE► Celiac disease (celiac sprue, gluten- sensitive enteropathy) a chronic disease, characteristic mucosal lesion of small intestine and impaired nutrient absorption, which improves on withdrawal of wheat gliadins and related grain proteins from diet► Celiac disease occurs largely in Caucasians and is rare or nonexistent among native Africans, Japanese, and Chinese► Infants, yet adults in 5 th decade of life may seek attention
  7. 7. Pathogenesis Sensitivity to gluten, alcohol-soluble, water-insoluble protein component gliadin (protein found in gluten fraction of wheat) and closely related grains (oat, barley, and rye) Interplay between genetic predisposing factors, host immune response, and environmental factors is central to disease pathogenesis► Exposure to gliadin results in T-cell mediated chronic inflammatory reaction with accumulation of intraepithelial CD8+ T cells and large numbers of lamina propria CD4+ T cells, which are sensitized to gliadin results in circulating antibodies against gliadin► Epithelial cells secrete large amount of IL5 that activate CD8+ T cells (increases risk of T cell lymphoma)► Family history important in celiac disease, almost all individuals with celiac disease share major histocompatibility complex class II HLA-DQ2 or HLA- DQ8 haplotype► Proposed that gliadin is deamidated by enzyme transglutaminase into peptides which binds to DQ2 and DQ8, recognition of these peptides by CD4+ T cells leads `to secretion of Gamma interferon which damages intestinal wall
  8. 8. CELIAC DISEASEGross:Duodenal folds are absent or reducedMicroscopy: Atrophic villi (Usually complete) Normal thickness of mucosa Villous crypt ratio decreased Crypt hyperplastic-elongated tortuous Increase mitoses Increase in no of lymphocytes, plasma cells, eosinophils, macrophages Intraepithelial leucocytes Vacuolar degeneration and loss of brush borders of surface epithelium
  9. 9. Out come of Celiac Disease► Intestinal Non Hodgkin T-cell lymphoma► Chronic nonspecific duodenojejunoileitis► Small intestine adenocarcinoma► Squamous cell carcinoma of esophagus► Dermatitis herpitiformis blistering skin lesion
  10. 10. Diagnosis of Celiac Disease► Clinical malabsorption (Diarrhea ,flatulence, wt loss, fatigue, failure to thrive in childern► Small bowel biopsy Villous atrophy► Responds to gluten with drawl from diet► Antigliaden or antiendomysial antibodies► Antitransglutiminase IgA, IgG► Antireticulin antibodies
  11. 11. Normal/Celiac sprue
  12. 12. Celiac
  13. 13. TROPICAL SPRUE► Definite geographic distribution► Bacterial etiology with or with out additive effects of fat.► Unaffected by gluten ingestion, responds to folic acid, vit B12, tetracycline.► There is partial villous atrophy
  14. 14. WHIPPLE’S DISEASE► Male to female ratio 10:1► Large macrophages in lamina propria, distorting the villi, alternating with empty spaces.► Histiocytes cytoplasm contains diastase-resistant PAS positive & gram positive abundant bacilli Tropheryma whippelii► Diagnosis by PCR, immuno, electron microscopy.► Biopsy of peripheral lymph nodes – presence of typical macrophages.
  15. 15. WHIPPLE
  16. 16. GIARDIA
  17. 17. AMEBIC COLITIS► Simulate ulcerative colitis or Crohn’s disease► Gross: ulceration covered by exudate, with normal intervening mucosa► Site: cecum and ascending colon► L/M: nonspecific► Flask shaped ulcer, relative paucity of inflammatory cells beneath ulcer► Trophozoites of E. histolytica► Erythrocytosis by trophozoites usually present► Can be detected by PAS stain► Stool R/E
  18. 18. Ameba
  19. 19. Cryptosporidosis
  20. 20. Major Causes of Bacterial EnterocolitisEscherichia coli• ETEC EHEC EPEC EIECSalmonellaShigellaCampylobacterYersinia enterocoliticaVibrio cholerae,Clostridium difficileClostridium perfringensMycobacterium tuberculosis ProtozoaAmebic colitis
  21. 21. Pseudo membranous colitis
  22. 22. Ulcers of Intestine► Oval- Salmonella typhi long axes along axes of ileum► Linear-Salmonella paratyphi► Flask shaped –amebic► Irregular –Shigella► Multiple superficial ulcers-Campylobacter jejuni► Ulcer along transverse axes- Tuberculosis► Early Aphthous & late long linear serpintine-Crohn► Extensive broad base – Ulcerative colitis► Solitary Rectal Ulcer► Malignant ulcers
  23. 23. Granulomatous lesions of Intestine► Tuberculosis caseating granulomas► Crohn disease non-caseating granulomas► Foreigen body granulomas► Necrotizing granulomas-Yersinia enterocolitica, Y. pseudetuberculosis► Oliogranuloma-against fat
  24. 24. SOLITARY RECTAL ULCER► Solitary ulcerated or polypoid lesion 4-18cm from anal margin► Associated with rectal prolapse► S/S: passage of blood and mucus , altered bowel habits and painL/M: superficial and irregular mucosal ulceration► Hyperplasia of crypts, villous configuration► Obliteration of lamina propria by fibroblasts, elastin and smooth muscles► Thickened muscularis mucosae► ↓ lymphocytes and plasma cells► Chronic form– similar to colitis cystica profunda
  25. 25. HIRSCHSPRUNG’S DISEASECause: lack of coordinated Sex: 80% ♂ movements of distal large ► Association with bowel due to loss of intrinsic inhibitory intestinal atresia and innervations anorectal malformation► Absent parasympathetic S/S: abdominal distention, ganglion cells in delayed meconium intramural and passage, tight anus submucosal plexus due to ► Proximal bowel dilatation failure of migration of & hypertrophy of muscle neural crest cells or ► Complications: acute immune mediated intestinal obstruction, neuronal necrosis enterocolitis, megacolon,► Age: 1st yr life perforation, sepsis
  27. 27. HIRSCHSPRUNG’S DISEASEL/M:► Aganglionosis in both plexus of segment of bowel► Hypertrophied nerves, altered distribution of interstitial cells of Cajal, fibromuscular dysplasia of arteries, hyperplasia of lymphoglandular complexBiopsy types:► Full thickness biopsy of rectum► Biopsy should be 2cm above anal valve in infant and 3cm in older children► Suction or mucosal rectal biopsy
  28. 28. TYPES1. Classic: aganglionic segment begins in distal colorectum and extend in adjacent proximal dilated bowel2. Short segment: involvement of rectum and rectosigmoid for few cm3. Ultra-short: involved segment very narrow, easily missed4. Long-segment: involves most or all of large bowel, may extend into small bowel5. Zonal colonic aganglionosis: only short segment involved, ganglion cells present below and above aganglionic segment
  29. 29. HIRSCHSPRUNG’S DISEASE► ↑Acetylcholinesterase activity in lamina propria and muscularis mucosae► NSE, neurofilaments, highlight hypertrophied nerves and absent ganglion cells► S-100—absent normal periganglionic satellite cellsAcquired Megacolon► IBD, Chagas disease, intestinal obstruction, psychosomatic disorders
  30. 30. Acquired MegacolonIBDChagas diseaseIntestinal obstruction,Psychosomatic disorders
  31. 31. Toxic Megacolon
  32. 32. Normal / Inflamed Appendix
  33. 33. Pathogenesis Acute Appendicitis Appendiceal inflammation is associated with obstructionin 50% to 80% of cases, usually in the form of a fecalithand, less commonly, a gallstone, tumor, or ball of worms(oxyuriasis vermicularis). Continued secretion of mucinous fluid inthe obstructed viscus presumably leads to a progressiveincrease in intraluminal pressure sufficient to causeeventual collapse of the draining veins. Ischemic injury then favors bacterialproliferation with additional inflammatory edema andexudation, further embarrassing the blood supply. Nevertheless, a significant minority of inflamedappendices have no demonstrable luminal obstruction,and the pathogenesis of the inflammation remainsunknown.
  34. 34. Acute AppendicitisMorphology:► Earliest stages, scant neutrophilic exudate in mucosa, submucosa, and muscularis propria. Subserosal vessels congested, and often perivascular neutrophilic infiltrate. Normal glistening serosa changes into dull, granular, red membrane► Later stage, a prominent neutrophilic exudate generates a fibrinopurulent reaction over the serosa , abscess formation within wall, along with ulcerations and foci of suppurative necrosis in mucosa acute suppurative appendicitis .► Large areas of hemorrhagic ulceration of mucosa and green-black gangrenous necrosis of wall, extending to serosa, creating acute gangrenous appendicitis , followed by rupture and suppurative peritonitis► The histologic criterion for the diagnosis of acute appendicitis is neutrophilic infiltration of the muscularis propria.
  35. 35. Acute AppendicitisACUTE APPENDICITISOBSTRUCTIVE► fecolith► foreign body► calculus-gall stone► Mucocoele► Tumor: primary secondary--- cecum► Diffuse lymphoid hyperplasia (10 to 19 yrs)► Oxyuris vermicularisNON OBSTRUCTIVE► Secondary to generalized infection (viral-Measles)
  36. 36. Fungal  candidiasis,  cryptosporidiosisOthers  crohn disease  ulcerative colitis  sarcoidosis  yersiniosis
  37. 37. Acute Appendicitis
  38. 38. ACUTE APPENDICITISD/D Mesenteric lymphadenitis Gynecologic lesions Acute diverticulitis Meckel’s diverticulitis Infarction of greater omentum Ureteric colic Chemotherapy induced typhilitis
  39. 39. Tumors of AppendixNon-neoplastic:MUCOSAL HYPERPLASIANeoplastic:MUCINOUS TUMORS Mucinous cystadenomas Mucinous cystadenocarcinomaADENOCARCINOMA Primary secondaryCARCINOID
  40. 40. CARCINOID► Most common tumor of appendix► One in 300 appendicectomies► Peak incidence in 3rd and 4th decades of life► Mostly incidental► Mostly occur at the tip► Mostly less than 1cm in diameter► GROSS► Firm, grayish white► Fairly well circumscribed► Not encapsulated► Characteristic yellow coloration after formalin fixation.
  41. 41. Histologic Pattern of Carcinoid► Classic insular type► Carcinoids with glandular differentiation► Tubular type► Goblet cell carcinoid
  42. 42. Carcinoid
  43. 43. CLASSIC TYPE► Solid nests of small monotonous cells with occasional acinar or rosette formation.► Mitoses rare► Peculiar retraction of tumor periphery from the stroma► Invasion of muscle and lymph vessels is the rule► Spread to the peritoneal surface not rare
  44. 44. IMMUNOHISTOCHEMISTRYTumor cells are positive for:► argentaffin► argyrophilUltrastructurally: filled with pleomorphic dense core secretory granulesImmunohistochemically reactive for:► neuron-specific enolase,► chromogranin► 5-HT
  45. 45. Major Causes of Intestinal Obstruction Mechanical Obstruction ► Adhesions ► Hernias, internal or external ► Volvulus ► Intussusception ► Tumors ► Inflammatory strictures ► Obstructive gallstones, fecaliths, foreign bodies ► Congenital strictures; atresias ► Congenital bands ► Meconium in mucoviscoidosis ► Parasites ► Imperforate anus Pseudo-obstruction ► Paralytic ileus (e.g., postoperative) ► Vascular—bowel infarction ► Myopathies and neuropathies (e.g., Hirschsprung)
  46. 46. Diverticulosis
  48. 48. Ischemic Bowel DiseaseAcute occlusion of Celiac, superior and inferior mesenteric arteriesTypes► Mucosal-hypoperfusion acute or chronic► Mural- “ “ “ “► Transmural- occlusion of major mesenteric blood vessels
  49. 49. Predisposing conditions for ischemia► Arterial Thrombosis- atherosclerosis, vasculitis► Arterial Embolism-cardiac vegetations► Venous Thrombosis-Oral contraceptives, postoperative state► Non occlusive ischemia- cardiac failure, shock, dehydration► Miscellaneous-radiation injury, volvulus, stricture, amyloidosis, Diabetes mellitus
  50. 50. Ischemic injury two phases► Initial hypoxic injury► Secondary reperfusion injury-generation of oxygen free radicals, neutrophils infiltration, production of inflammatory mediators
  51. 51. INFARCTION
  52. 52. INFARCTION
  53. 53. ISCHEMIC COLITISAge: >50yrs—arteriosclerosis, diabetes, vascular surgery► Younger pts—collagen-vascular diseases, Wegener’s granulomatosis, amyloidosis, oral contraceptives► S/S: sudden onset of bleeding, abdominal pain, bloody diarrhea, vomiting► Site: segmental disease, splenic flexure commonly involved► D/D: IBD
  54. 54. ISCHEMIC COLITISX-ray: gas within bowel wall, thumb printingGross: pseudopolyps, ulceration and fibrosisL/M: in chronic ischemia ulcer covered by granulation tissue extending into submucosa► Hemosiderin abundant, hyaline thrombi► Ischemic necrosis—full thickness mucosal necrosis, hyalinized lamina propria, hemorrhage and atrophic crypts in healed stage
  55. 55. Inflammatory Bowel DiseaseChronic relapsing inflammatory disorder-obscure origin► Crohn disease Autoimmune, affect any part of GIT► Ulcerative colitis Chronic inflammatory disease limited to colon & rectum Both exhibit extra-intestinal inflammatory manifestations
  56. 56. Etiology-PathogenesisIdiopathic-cause unknownTwo key pathogenic abnormalities► Strong immune response against normal microbial flora in genetic susceptible individuals► Defects in epithelial barrier function
  57. 57. Pathogenesis of IBDA-Genetic Susceptibility 1. Associated genes with CD are HLA- DR1/DQw5, NOD2 2. HLA-DR 2 increase in U. ColitisB-Intestinal Flora increase immune reaction by providing antigens and inducing co-stimulators and cytokines contribute to T-cell activation, defects in epithelial barrier allow luminal flora to gain access to mucosal lymphoid tissue –trigger immune responseC-Abnormal T-Cell response to much T-cell activation and/or too little control by regulatory T- lymphocytes results in damaging the mucosa
  58. 58. Diagnosis of IBD Clinical history Radiographic- string sign in CD, Lead pipe in UC Lab Findings (serum antibodies): pANCA positive in75%of UC & 11%in CD ASCA Elevated in CD Tissue Diagnosis
  59. 59. CROHN DISEASEEPIDEMIOLOGY► Both sexes female more than males► All ages peak age 2nd &3rd decade► Primarily disease of Western developed populations► Annual incidence in USA 3per 100,000Fully developed CD is pathologically characterized by;1. Sharply delimited, transmural inflammatory process with mucosal damage2. Non-caseating granulomas3. Fissures and fistulae
  60. 60. GROSS► Skip lesions► Cobblestone appearance► Transmural involvement, Creeping fat► Early- aphthous ulcers► Late-Ulcer linear, serpentine and discontinuous with intervening normal or edematous mucosa► Healing→ long rail-track scars► Pseudopolyps or mural bridging lesions may develop► Stricture, fissure, fistulas► Mesenteric lymphadenopathy
  61. 61. Crohn DiseaseMICROSCOPY► Tranmural inflammation► Fissures► Non caseating granulomas► Mucosa relatively normal, normal content of mucin► Glandular architecture maintained► submucosal lymph edema, lymphoid hyperplasia, patchy necrosis, atrophy or regenerative hyperplasia.COMPLICATIONS► Intramural abscess► Fistulas, perforation► Occasionally carcinoma.
  62. 62. CROHN DISEASE of COLON (GRANULOMATOUS COLITIS)►Involve large bowel in 40% cases, with or without ileal component►Ileum involved-50%►Anal lesions-75%Complications: Fistula, skin ulceration, toxic megacolon, colonic Ca (risk < UC)
  63. 63. Crohn- Cobble Stone & Sharp Demarcation
  66. 66. C/F of CD► Intermittent attacks of mild diarrhea, fever, and abdominal pain spaced by asymptomatic periods lasting for weeks to many months► Attacks precipitated by emotional stress► Colonic involvement can result in fecal blood loss► Sometime present as a case of acute appendicitis or acute bowel perforation► Extensive involvement of ileum result in marked loss of albumin- protein losing enteropathy► Malabsorption of vit B12 P.anemia► Malabsorption of bile salts –steatorrhea► Fistulae and Fissures with urinarry bladder, vagina, perianal skin► Extraintestinal manifesintations migratory polyarthritis, sacroilitis, ankylosing spondylitis, erythema nodusum clubbing of fingers, hepatic primary sclerosing cholangitis
  68. 68. ULCERATIVE COLITIS► Age: 20-30yrs► Sex: ♂=♀► Etiology: unknown► S/S: prolonged duration, many remissions and exacerbations► Site: left sided colon, begins in rectosigmoid► Ulcerative proctitis—disease localized to rectum► Pancolitis—involve entire colon
  69. 69. ULCERATIVE COLITISGross: varies with stage► Acute: mucosal surface wet and glare  Petechial hemorrhages  Ulcers undermining mucosa, mucosal bridges  Pseudopolyps► Advanced: bowel—fibrotic, narrowed and shortened  Atrophy of all components of wall  Increased pericolic fat► Quiescent: no ulceration, mucosa atrophic► Back wash ileitis
  70. 70. ULCERATIVE COLITISL/M: mucosal and submucosal disease► Acute: ↑ inflammatory cells in lamina propria► Inflammation remain above muscularis mucosae► Crypt abscess, cyrptitis► Marked ↓ cytoplasmic mucus, irregularly shaped glands, paneth cell metaplasia► Atrophic and regenerative changes in glands► Nuclear enlargement, ↑ mitosis► Dilated blood vessels, mucosal capillary thrombi► Ulcers covered by granulation tissue► Pseudopolyps= granulation tissue + inflammed mucosa
  71. 71. ULCERATIVE COLITIS► Submucosa—normal, inflammed, hyperemic, infiltrated by fat or fibrosed (depending on stage)► Submucosal endarteritis obliterans (10%)► Muscularis externa—hypertrophic/normal► Subserosal fibrosisQuiescent stage:Mucosa grossly normalMucin content restored, irregularly branched glands, paneth cells, neutrophils in lamina propria
  72. 72. ULCERATIVE COLITISExtraintestinal manifestations:liver disease, Arthritis, UvietisPyoderma gangreonosumComplications: perforation, peritonitis, abscess, toxic megacolon, venous thrombosis Increase risk of dysplasia/carcinoma
  73. 73. Clinical Manifestation Of UC► Relapsing disorder, asymptomatic interval of months to years► Attacks of bloody mucoid diarrhea persist for days, weeks to months► Initial attack may lead to serious bleeding with fluid and electrolyte imbalance► Toxic megacolon may lead to perforation
  74. 74. Ulcerative Colitis
  75. 75. Dysplasia in Ulcerative colitis
  76. 76. Features UC CDClinicalRectal bleeding Common InconspicuousAbdominal mass Never 10-15%Abdominal pain Left sided Right sidedSigmoidoscopy 95% abnormal <50% abnormalFree perforation 12% 4%Colon CA 5-10% V rareAnal Fissures Rare, minor 75%, fissures..Response to steroid 75% 25%Results of surgery Very good FairIleostomy dysfunction Rare Common
  77. 77. Feature Crohn Disease-SI Crohn Disease-Colon Ulcerative ColitisMacroscopic► Bowel region Ileum ± colon Colon ± ileum Colon only► Distribution Skip lesions Skip lesions Diffuse► Stricture Early Variable Late/rare► Wall appearance Thickened Thin Thin► Dilation No Yes YesMicroscopic► Inflammation Transmural Transmural Limited in mucosa► Pseudopolyps No to slight Marked Marked► Crypt Abscess Not seen Common► Ulcers Deep, linear Deep, linear Superficial► Lymphoid reaction Marked Marked Mild► Fibrosis Marked Moderate Mild► Serositis Marked Variable Mild to none► Granulomas Yes (50%) Yes (50%) No► Fistulae/sinuses Yes Yes No► Lymph node Granulomas Do ReactiveClinical► Fat/vit malabsorp Yes Yes, if ileum No► Malignant potential Rare +/- Yes► Resp to surgery Poor Fair Good
  78. 78. Tumors Small & Large IntestineNon-neoplastic (Benign) Polyps► Hyperplastic polyps► Hamartomatous polyps • Juvenile polyps • Peutz-Jeghers polyps► Inflammatory polyps► Lymphoid polypsNeoplastic Epithelial LesionsBenign • Adenoma *Malignant • Adenocarcinoma * • Carcinoid tumor • Anal zone carcinomaMesenchymal Lesions► Gastrointestinal stromal tumor (GIST)► Other benign lesions • Lipoma • Neuroma • Angioma► Kaposi sarcomaLymphomaMetastatic
  79. 79. Intestinal Polyps
  80. 80. Hyperplastic/ PJ polyp
  81. 81. Juvenile Rectal Polyp
  82. 82. Tubular adenoma
  83. 83. Adenomatous polyps
  84. 84. Villous adenoma
  85. 85. Villous adenoma
  86. 86. Familial polyposis
  87. 87. Gardenar syndrome
  88. 88. Adenocarcinoma colon
  89. 89. Adenocarcinoma Colon
  90. 90. BENIGN EPITHELIAL TUMORSBRUNNER’S GLAND ADENOMA► Nodular proliferation of histologically normal Brunner’s glands, accompanied by ducts and scattered stromal elements, cilliated cysts and adipose tissue.► Focal multifocal or diffuse► Located commonly at posterior wall of duodenum at junction of first and second parts.
  91. 91. BENIGN EPITHELIAL TUMORSADENOMAS► More often In duodenum and jejunum’ single or multiple, sessile or pedunculated► Microscopically can be villoglandular polyp, adenomatous polyp or villous adenoma.► Malignant transformation can occur mostly when lesion is large villous or multiple.HAMARTOMATOUS POLYP Benign juvenile Rectal polyp► Jejunoileum– (in Peutz Jeghers syndrome)► Glands supported by broad bands of smooth muscle fibers► Several types of epithelial cells are present.► Associated with adenocarcinima and adenoma malignum of uterine cervix, ovarian mucinous tumors, breast carcinoma.
  92. 92. ADENOCARCINOMA► Both sexes elderly population less common than counterpart in colon.► More common in upper portion of small bowel► Associated with hereditary nonpolyposis colorectal carcinoma syndrome, Peutz-Jeghers syndrome, Reckling- huasen’s disease, bowel duplication, Crohn’s disease, at ileostomy sites, jejunal limb of Roux-en-Y esophagojejunostomy.► GROSS- duodenal carcinoma; papillary configuration, distal lesions; napkin-ring, polypoid or fungating appearance► MICROSCOPY- moderately well differentiated adenocarcinoma. Mucin production, CEA reactivity is the rule► Commonly positive for chromogranin 5-HT► IMMUNO- COX-2, sPLA2 cPLA2.peptide hormones► ULTRASTRUCTURE- prominent development of microvilli.
  93. 93. SMALL CELL NEUROENDOCRINE CARCINOMA► Rare,► MICROSCOPY- Small round oval cells, scanty cytoplasm, hyperchromatic nucleus.► ULTRASTRUCTURE- dense-core granules of neurosecretory type► IMMUNORECTIVE for neuroendocrine markers► Deeply invasive, prone to metastasis, very poor prognosis.ANAPLASTIC CARCINOMA► Highly bizarre tumor cells, multinucleated with abundant cytoplasm, no glandular differentiation.► Aggressive
  94. 94. CARCINOID TUMORS► Low grade neoplasm originating from the diffuse neuroendocrine system outside of pancreas and thyroid C cells.► Adults,► Located in ileum mostly► GROSS- intact mucosa , tumor infiltrating the submucosa and extending to muscularis externa.► Buckling of bowel wall due to fibrosis► Brightly yellow color► MICROSCOPY- solid nests of monotonous population of cells having small round nuclei scant to moderate granular cytoplasm fine nucleoli.► Peripheral palisading common , scanty mitotic figures, lymphatic and neural invasion common.► Microscopic types from A to E : insular, trabecular, glandular, undifferentiated, mixed.
  95. 95. CARCINOID TUMORS► HISTOCHEMISTRY- argentafin argyrophilic positive, negative for mucin► ULTRASTRUCTURE- dense core pleomorphic secretory granules► IMMUNO- keratin CK7, CK 20 +ve, pan-endocrine markers +ve, 5-HT, substance P gastrin, somatostatin, glucagon , PP, bombesin, GRP +ve► MOLECULAR AND GENETIC FEATURES- aneuploidy common, MEN-1 Negative, p53 rare► SPREAD AND METASTASIS- low grade , slow growth rate, highly invasive, metastasis to regional lymph nodes and liver.► CARCINOID SYNDROME- cyanosis of face, chest, intermittent hypertension, palpitations, watery stools.
  96. 96. MALIGNANT LYMPHOMA AND RELATED DISORDERS► Most common site for extra nodal lymphomaT-CELL LYMPHOMA► Mostly a complication of celiac sprue and other malabsorption syndromes.► CD56 +ve, associated with EBV.► Intense eosinophilic infiltrate may obscure the diagnosisB-CELL LYMPHOMA► Arise from mucosa associated lymphoid tissue► Mostly solitary , common in ileum► Diffusely infiltrating bulky mass with garden hose appearance, extensive ulcerations.► Regional lymph nodes usually also involved.
  97. 97. MALIGNANT LYMPHOMA AND RELATED DISORDERSIMMUNOPROLIFERATIVE SMALL INTESTINAL DISEASE IPSID► Common among Arabs, Jews, blacks of South Africa.► Associated with diarrhea and malabsorption► Low grade form- heavy lymphoplasmacytic infiltration of cells of slightly immature appearance, monoclonal alpha heavy chains.► High grade form- highly pleomorphic large cell lymphoma with immunoblastic and plasmacellular features. Immunocytochemical positivety for alpha chains► Prominent starry sky appearance or follicular lymphoid hyperplasia my be present
  98. 98. MALIGNANT LYMPHOMA AND RELATED DISORDERSLOW GRADE B-CELL LYMPHOMA (MALT TYPE)► Predominance of small lymphoid cells, formation of lymphoepithelial lesions, reactive follicles.► Large cell lymphoma high grade form may be associated with low grade or present in absence of low grade component. Mostly plasmacytoid cellsFOLLICULAR LYMPHOMA► Predilection for terminal ileum, innumerable small polypoidal masses,► Translocation 14:18 typical► Arises from local antigen responsive B cells
  99. 99. MALTOMA
  100. 100. ► TABLE 17-13 -- Hereditary Syndromes Involving the Gastrointestinal Tract► Syndromes Altered Gene Pathology in GI Tract► Familial adenomatous polyposis (FAP) APC Multiple adenomatous polyps► • Classic FAP► • Attenuated FAP► • Gardner syndrome► • Turcot syndrome► Peutz-Jeghers syndrome STK11 Hamartomatous polyps► Juvenile polyposis syndrome SMAD4 Juvenile polyps► BMPRIA► Hereditary nonpolyposis colorectal carcinoma Defects in mismatch DNA repair genes Colon cancer► Tuberous sclerosis TSC1 Inflammatory polyps► TSC2► Cowden disease PTEN Hamartomatous polyps
  101. 101. ► Non-Neoplastic Polyps► The overwhelming majority of intestinal polyps occur on a sporadic basis, particularly in the colon, and increase in frequency with age. Non-neoplastic polyps include the hyperplastic► polyp, the hamartomatous polyp, the inflammatory polyp, and the lymphoid polyp. Hyperplastic polyps represent about 90% of all epithelial polyps in the large intestine. They may arise at► any age but usually are discovered incidentally in the sixth and seventh decades. They are found in more than half of all persons age 60 and older. It is believed that the hyperplastic polyp► results from decreased epithelial cell turnover and accumulation of mature cells on the surface. Harmatomatous polyps are malformations of the glands and the stroma. They can occur► sporadically or occur in the setting of genetic syndromes ( Table 17-13 ). Inflammatory polyps, also known as pseudopolyps, represent islands of inflamed regenerating mucosa surrounded► by ulceration. These are seen primarily in patients with severe, active IBD. Lymphoid polyps are an essentially normal variant of the mucosal bumps containing intramucosal lymphoid► tissue.► .hyperplastic polyp
  102. 102. ► Hamartomatous Polyps.► Juvenile polyps represent focal hamartomatous malformations of the mucosal epithelium and lamina propria. For the most part they are sporadic lesions, with the vast majority occurring► in children younger than age 5. Isolated hamartomatous polyps may be identified in the colon of adults; these incidental lesions are referred to as retention polyps . In both age groups,► nearly 80% of the polyps occur in the rectum, but they may be scattered throughout the colon. Juvenile polyps tend to be large (1 to 3 cm in diameter), rounded, smooth or slightly► lobulated lesions with stalks up to 2 cm in length; retention polyps tend to be smaller (<1 cm diameter). Histologically, lamina propria comprises the bulk of the polyp, enclosing abundant► cystically dilated glands. Inflammation is common, and the surface may be congested or ulcerated. In general they occur singly and being hamartomatous lesions have no malignant► potential. However, the rare autosomal dominant juvenile polyposis syndrome, in which there are multiple (50 to 100) juvenile polyps in the gastrointestinal tract, does carry a risk of► adenomas and hence adenocarcinoma. Mutations in the SMAD4/DPC4 gene (which encodes a TGF- b signaling intermediate) account for some cases of juvenile polyposis syndrome.[79]
  103. 103. ► Peutz-Jeghers polyps are hamartomatous polyps that involve the mucosal epithelium, lamina propria, and muscularis mucosa. These hamartomatous lesions may also occur singly or► multiply in the Peutz-Jeghers syndrome . This rare autosomal dominant syndrome is characterized by multiple hamartomatous polyps scattered throughout the entire gastrointestinal tract► and melanotic mucosal and cutaneous pigmentation around the lips, oral mucosa, face, genitalia, and palmar surfaces of the hands. Patients with this syndrome are at risk for► intussusception, which is a common cause of mortality. Peutz-Jeghers polyps tend to be large and pedunculated with a firm lobulated contour. Histologically, an arborizing network of► connective tissue and well-developed smooth muscle extends into the polyp and surrounds normal abundant
  104. 104. Adenoma- carcinoma sequence postulated that loss of one normal copy of tumorsuppressor gatekeeper gene APC occurs early. Indeed, individuals may be born withone mutant allele of APC, rendering them extremely likely to develop colon cancer.This is "first hit," according to Knudsons hypothesis loss of normal copy of APC genefollows ("second hit"). Mutations of oncogene K-RAS seem to occur next. Additionalmutations or losses of heterozygosity inactivate tumor suppressor gene p53 andSMAD2 and SMAD4 leading finally to emergence of carcinoma, in whichadditional mutations occur. .
  105. 105. ► TABLE 17-14 -- TNM Classification of Carcinoma of the Colon and Rectum► Tumor Stage Histologic Features of the Neoplasm► Tis Carcinoma in situ (high-grade dysplasia) or intramucosal carcinoma (lamina propria invasion)► T1 Tumor invades submucosa► T2 Extending into the muscularis propria but not penetrating through it► T3 Penetrating through the muscularis propria into subserosa► T4 Tumor directly invades other organs or structures► Nx Regional lymph nodes cannot be assessed► N0 No regional lymph node metastasis► N1 Metastasis in 1 to 3 lymph nodes► N2 Metastasis in 4 or more lymph nodes► Mx Distant metastasis cannot be assessed► M0 No distant metastasis► M1 Distant metastasis► 867► Figure 17-
  106. 106. ► TABLE 17-15 -- Clinical Features of the Carcinoid Syndrome► • Vasomotor distubances► ••Cutaneous flushes and apparent cyanosis (most patients)► • Intestinal hypermotility► ••Diarrhea, Cramps, nausea, vomiting (most patients)► • Asthmatic bronchoconstrictive attacks► ••Couth, wheezing, dyspnea (about one third of patients)► • Hepatomegaly► ••Nodular liver owing to hepatic metastases (some patients)► • Systemic fibrosis (some patients)► ••Cardiac involvement► ••••Pulmonic and tricuspid valve thickening and stenosis► ••••Endocardial fibrosis, principally in the right ventricle► ••••(Bronchial carcinoids affect the left side)► ••Retroperitoneal and pelvic fibrosis► ••Collagenous pleural and intimal aortic plaques► metastases are usually not required for the production of a carcinoid syndrome by extraintestinal carcinoids (such as those arising in the lungs or ovaries), because active substances
  107. 107. ► GASTROINTESTINAL LYMPHOMA► Any segment of the gastrointestinal tract may be secondarily involved by systemic dissemination of non-Hodgkin lymphomas. However, up to 40% of lymphomas arise in sites other than► lymph nodes, and the gut is the most common location. Conversely, about 1% to 4% of all gastrointestinal malignancies are lymphomas. By definition, primary gastrointestinal lymphomas► exhibit no evidence of liver, spleen, mediastinal lymph node, or bone marrow involvement at the time of diagnosis—regional lymph node involvement may be present. Primary► gastrointestinal lymphomas usually arise as sporadic neoplasms but also occur more frequently in certain patient populations: (1) Chronic gastritis caused by H. pylori, (2) chronic► spruelike syndromes, (3) natives of the Mediterranean region, (4) congenital immunodeficiency states, (5) infection with human immunodeficiency virus, and (6) following organ► transplantation with immunosuppression.► Intestinal tract lymphomas can be classified into B-cell and T-cell lymphomas. The B-cell lymphoma can be subdivided into MALT lymphoma, immunoproliferative small-intestinal► disease (IPSID), and Burkitt lymphoma.► 1. MALT lymphoma is a sporadic lymphoma, which arises from the B cells of MALT (mucosa- associated lymphoid tissue, described under gastric lymphoma). This type of lymphoma
  108. 108. ► 1. MALT lymphoma is a sporadic lymphoma, which arises from the B cells of MALT (mucosa- associated lymphoid tissue, described under gastric lymphoma). This type of lymphoma► is the most common form in the Western hemisphere. The biologic features of these lymphomas are different from node-based lymphomas in that (1) many behave as focal tumors► in their early stages and are amenable to surgical resection; (2) relapse may occur exclusively in the gastrointestinal tract; (3) genotypic changes are different than those observed in► nodal lymphomas: the t(11;18) translocation is relatively common in MALT lymphoma; and (4) the cells are usually CD5- and CD10-negative. This type of gastrointestinal► lymphoma usually affects adults, has no gender predilection, and may arise anywhere in the gut: stomach (55% to 60% of cases); small intestine (25% to 30%), proximal colon► (10% to 15%), and distal colon (up to 10%). The appendix and esophagus are only rarely involved.► The pathogenesis of these lymphomas is under intense scrutiny. The concept has been advanced that lymphomas of MALT origin arise in the setting of mucosal lymphoid► activation and that these lymphomas are the malignant counterparts of hypermutated, postgerminal- center memory B cells. As discussed earlier, Helicobacter-associated chronic► gastritis, in particular, has been proposed as a driving force for the development of gastric MALT lymphoma, the result of antigen-driven somatic mutation of► 869► gastric lymphoid tissue. However, the etiologic factors for intestinal lymphoma are still unknown, although history of IBD appears to increase the risk.► 2. IPSID is also referred to as Mediterranean lymphoma. It is an unusual intestinal B-cell lymphoma arising in patients with Mediterranean ancestry, having a background of chronic
  109. 109. ► 2. IPSID is also referred to as Mediterranean lymphoma. It is an unusual intestinal B-cell lymphoma arising in patients with Mediterranean ancestry, having a background of chronic► diffuse mucosal plasmacytosis. The plasma cells synthesize an abnormal Iga heavy chain, in which the variable portion has been deleted. A high proportion of patients have► malabsorption and weight loss preceding the development of the lymphoma. The diagnosis is made most commonly in children and young adults, and both sexes appear to be► affected equally. The exact etiology of this type of lymphoma is not known, although infection appears to play a role.[95]► 3. The intestinal T-cell lymphoma is usually associated with a long-standing malabsorption syndrome (such as celiac disease) that may not constitute a true gluten-sensitive► enteropathy. This lymphoma occurs in relatively young individuals (age 30 to 40), often following a 10- to 20-year history of symptomatic malabsorption. Alternatively, a diffuse► enteropathy with malabsorption may accompany the development of a lymphoma. Intestinal T- cell lymphoma arises most often in the proximal small bowel, and its overall► prognosis is poor (reported 11% five-year survival rate).► Morphology.► Gastrointestinal lymphomas can assume a variety of gross appearances. Since all the gut lymphoid tissue is mucosal and submucosal
  110. 110. ► Morphology.► Gastrointestinal lymphomas can assume a variety of gross appearances. Since all the gut lymphoid tissue is mucosal and submucosal, early lesions appear as plaque-like expansions of the► mucosa and submucosa. Diffusely infiltrating lesions may produce full-thickness mural thickening, with effacement of the overlying mucosal folds and focal ulceration. Others may be► polypoid, protruding into the lumen, or form large, fungating, ulcerated masses. Tumor infiltration into the muscularis propria splays the muscle fibers, gradually destroying them. Because► of this feature, advanced lesions frequently cause motility problems with secondary obstruction. Large tumors sometimes perforate because of lack of stromal support; reduction in tumor► bulk during chemotherapy also may lead to perforation.► In the earliest histologic lesions, atypical lymphoid cells may be seen infiltrating the mucosa, with effacement and loss of glands and massive expansion of lymphoid tissue. Extreme► numbers of atypical lymphoid cells may populate the superficial or glandular epithelium (lymphoepithelial lesion). With established lymphomas, the mucosa, submucosa, and even muscle► wall are replaced by a monotonous infiltrate of malignant cells, consisting of a mixture of small lymphocytes and immunoblasts in varying proportions. Lymphoid follicles are occasionally► formed. Most gut lymphomas are of B-cell type (over 95%) and are evenly split between low- and high-grade tumors. The small fraction of T-cell lymphomas occurring in the intestine are► commonly high-grade lesions.► Clinical Features.► With the exception of T-cell lymphomas, primary gastrointestinal lymphomas generally have a better prognosis than do those arising in other sites. Ten-year survival for patients with► localized mucosal or submucosal disease approaches 85%. Early discovery is key to survival; thus, gastric lymphomas generally have a better outcome than those of the small or large► bowel. In general, the depth of local invasion, size of the tumor, the histologic grade of the tumor, and extension into adjacent viscera are important determinants of prognosis
  111. 111. CA & DYSPLASIA IN UC► Incidence of colorectal Ca-- ↑ in pt with UC► 5-10% in older series, current rate—2%► Risk is ↑ when:► Entire colon involved, disease is continuous, unremitting, long standing and when disease begins in childhood► Gross: thick mucosa with nodular or velvety surface
  112. 112. CA & DYSPLASIA IN UCL/M: adenocarcinoma with varying degrees of differentiation► Mucinous and poorly differentiated Ca proportion relatively ↑► Frank Ca always preceded by dysplasia in flat atrophic mucosa► Multiple rectal biopsies recommended for detection of dysplasia► IHC: ↑ CEA, sialomucin ,↓ Ig, strong p53 & MIB-1 staining
  113. 113. DYSPLASIA IN UC
  114. 114. CLASSIFICATION OF DYSPLASIA1. Negative for dysplasia2. Indefinite for dysplasia, probably negative3. Indefinite for dysplasia, unknown4. Indefinite for dysplasia, probably positive5. Positive for dysplasia, low grade6. Positive for dysplasia, high grade
  115. 115. DYSPLASIA IN UC
  116. 116. FOLLOW UP► Category 1+2→ regular follow up► Category 3+4 → short-term follow up► Category 6 → colectomy► Category 5 → short term follow up or consider colectomy► Surveillance for pt with UC: started after 8- 10yrs of extensive colitis and 15 yrs of left sided colitis
  117. 117. ► COMPLICATIONS►perforation leading to  diffuse peritonitis  peri appendiceal abscess  fibrous induration► venous spread to liver---pylephlebitic abscess► peri appendicitis  primary from appendix  secondary inflammation in surrounding struct25
  118. 118. ► Morphology.► Hyperplastic Polyps.► These are small (usually <5 mm in diameter) epithelial polyps that appear as nipple-like, hemispheric, smooth, moist protrusions of the mucosa, usually positioned on the tops of mucosal► folds. They may occur singly but more often are multiple, and over half are found in the rectosigmoid colon. Histologically, they are composed of well-formed glands and crypts lined by► non-neoplastic epithelial cells, most of which show differentiation into mature goblet or absorptive cells. The delayed shedding of surface epithelial cells leads to infoldings of the crowded► epithelial cells and fission of the crypts, creating a serrated epithelial profile and an irregular crypt architecture ( Fig. 17-56A ). Although large hyperplastic polyps may rarely coexist with► foci of adenomatous change, the usual small, hyperplastic polyp is considered to have virtually no malignant potential . However, the hyperplastic polyps occurring in the setting of► the rare hyperplastic polyposis syndrome can harbor epithelial cell dysplasia (adenoma), and hence are considered at risk for carcinoma. The► 859► underlying genetic basis for this syndrome is not known.► Hamartomatous Polyps.
  119. 119. MALTOMA
  120. 120. MALIGNANT LYMPHOMA AND RELATED DISORDERSMANTEL CELL LYMPHOMA► Rare.► Multiple lymphoid polypsTRUE HISTIOCYTIC LYMPHOMAS► Cells positive for morphologic and histochemical markers of histiocytes and lacking reactivity for lymphoid markersOther lymphomas include► BURKITT’S LYMPHOMA► HODGKIN’S LYMPHOMA► ANAPLASTIC LARGE CELL LYMPHOMA► MULTIPLE MYELOMA► FOLLICULAR DENDRITIC CELL TUMOR
  122. 122. EPITHELIAL POLYPS1. Adenomatous polyps2. Familial polyposis3. Gardner’s syndrome4. Turcot’s syndrome5. Villous adenoma6. Hyperplastic polyps7. Juvenile (retention) polyp8. Peutz-Jeghers polyp9. Transitional polyp
  123. 123. ADENOMATOUS POLYP► Site: 40% rt colon, 40% left colon, 20% rectum► Familial, autosomal dominant► S/S: asymptomatic or bleeding, change in bowel habits or intussusception► Gross: mostly <1cm, sessile or pedunculated. Single or multipleL/M: ↑ in no. of glands and cells/unit area► Cells crowding, hyperchromatic nuclei, ↑mitosis► Mucin usually ↓
  124. 124. ADENOMATOUS POLYP► IHC: CEA, CK+► Genetics: aneuploidy, p53+, bcl-2+► E/M: nuclear and cytoplasmic alterations, abnormal secretory dropletss► Focal areas of villous type can be seen► Villous=glandular→ villoglandular polypsAtypia in polyp related to:► ↑ age, no. of polyps/pt, size of polyp, villous change► Atypia grading: mild, moderate, severe
  125. 125. ADENOMATOUS POLYP► Atypical glands maybe seen in polyp beneath muscularis mucosae. D/D: malignant transformation in polyp► Helpful differential features:1. Cytological features of glands same as surface2. Glands surrounded by loose inflammed stroma and scattered muscle bundles3. Hemosiderin granules around glands► Glands may become cystic and rupture→ mucin lakes► Squamous metaplasia, morula formation, clear cell change, endocrine cells—maybe seen in polyp
  127. 127. FAMILIAL POLYPOSIS► Autosomal dominant► Gene: APC localized to 5q21, k-ras mutation► Mechanism: persistence of DNA synthesis in epithelial cells► Age: 2nd decade of life► Gross: bowel studded with polyp ranging from slightly elevated to large masses, maybe flat or depressed► 100 polyps—familial polyposis► May involve other parts of GIT: stomach and small bowel► Untreated cases may develop Ca (20 yrs earlier than ordinary colorectal Ca)► Early colectomy recommended
  128. 128. GARDNER’S SYNDROME► Familial condition► S/S: Adenomatous polyp of large bowel and sometimes small bowel and stomach, osteoma of skull, mandible, multiple keratinous cysts of skin and soft tissue tumors especially intraabdominal fibromatosis► Gene: mutation of APC► Tendency for large bowel Ca is high► May also develop Ca of small bowel (periampullary)
  129. 129. TURCOT’S SYNDROME► S/S: colorectal adenomatous polyps and glioblastoma multiforme► Genetics: Autosomal recessive► Mutation of APC or mismatch-repair gene
  130. 130. VILLOUS ADENOMA► Age: older patients► Site: rectum or rectosigmoid► S/S: fluid and electrolyte depletion► Gross: single mass that may grow to encircle bowel completely► Papillary villous projection and attached by wide base, 10%--pedunculated► L/M: villous projections ramify through long, paillary growth► IHC: CEA+, mucin-ve► Complications: Ca -29-70%► Treatment: local excision or APR depending on size of tumor
  131. 131. HYPERPLASTIC (METAPLASTIC) POLYP► Sessile, small sized(5mm), rarely pedunculated and large sizedL/M: elongated glands with intraluminal foldings—saw toothed appearance► Mitotis ↑ at base► Abundant cytoplasm, inconspicuous basal nucleus► Thickened basement membrane► Surface epithelium has micropapillary appearance► IHC: CEA+, sialomucin↓
  132. 132. MIXED HYPERPLASTIC— ADENOMATOUS POLYP► Prominent sawtoothed appearance—serrated adenoma► Some malignant potentialINVERTED HYPERPLASTIC POLYP:► Site: right colon► L/M: endophytic growth, penetration of muscularis mucosaeMULTIPLE HYPERPLASTIC POLYPOSIS SYNDROME:► Large polyps, maybe associated with adenocarcinoma
  133. 133. JUVENILE POLYP► Age: common in children, 1/3rd –adults► Site: rectosigmoid► S/S: rectal bleeding, autoamputation common► Gross: granular, red surface and cystic, lattice like appearance on cut sectionL/M: ulceration covered by granulation tissue► Cystically dilated glands with mucus, no atypia► Stroma—inflammation and edema► MULTIPLE JUVENILE POLYPOSIS— multiple polyps of juvenile type► Ass with adenomatous polyp and adenoca of large bowel, duodenum, stomach or pancreas
  134. 134. PEUTZ-JEGHERS POLYPS► Similar to small bowel counterpart► Disorganized glands, several types of cells, no atypia, smooth muscle fibers from muscularis mucosae► Genetics: mutation of LKB1 gene
  135. 135. RELATIONSHIP WITH CA1. Malignant transformation of solitary hyperplastic polyps, retention polyps and polyps of Peutz-Jeghers in negligible2. Polyposis syndrome— risk ↑  Familial polyposis & Gardner’s syndrome—100% risk  Juvenile polyposis, hyperplastic polyposis and Peutz- Jegher syndrome—risk ↓ but definitely ↑ed  ↑ risk of duodenal and amupullary adenocarcinoma3. Villous adenoma→ malignant—29-70% cases4. Adenomatous polyp (flat, villoglandular)→ malignant5. Not all adenomas→ malignant – Larger and villous the polyp →↑ chance of focal Carcinoma6. Parallelism between adenomatous polyp and adenocarcinoma
  136. 136. ADENOMA-CARCINOMAChromosome SEQUENCEalteration 18q 17p 12pgene 5q DNA Loss loss Mutation mutation or hypomethylation DCC p53 K ras loss AFP Normal Hyper Early Intermedia Late epithelium proliferativ adenoma te adenoma epithelium adenoma Other alterations Carcinoma Metastasis
  137. 137. TREATMENT OF POLYPS► Solitary juvenile polyps—simple removal► Familial polyposis—colectomy even in young pts► Villous adenoma—removal in toto, determination of Ca in specimen—effect further surgery► Solitary adenomatous polyp:  under reach of rectosigmoidoscope removed endoscopically  High up polyp—fiberoptic scope removal► Proximally located polyp large—anterior resection of segment of bowel
  138. 138. PRESENCE OF CA IN POLYP► Carcinomatous glands may be present only in mucosa and lamina propria above muscularis mucosae— ca in situ  No lymph node mets  Require simply polypectomy► May extend beyond muscularis mucosae but not invading stalk —  Lymph node mets—1%  Simple polypectomy► May extend to base of stalk or beyond— focal Ca with stalk invasion  Lymph node mets— ↑  colectomy
  139. 139. CARCINOMA► Age: 62yrs—mean age► Sex: ♂=♀► Etiology: dietary fats and animal protein► Genetics—familial polyposis, hereditary nonpolyposis colorectal cancer sydrome (Lynch syndrome)► Torre-muir syndrome► Patients with IBD have↑ predisposition for Ca► Complication of irradiation for Ca Cx
  140. 140. CARCINOMA► S/S: change in bowel habit, rectal bleeding, anemia, vague abdominal pain► Intestinal obstruction—left sided tumor► Perforation► Serum CEA —detected in 72-97% cases of colorectal Ca, disappears after tumor resection, reappears after recurrence or mets► CEA used for monitoring therapy► Can be detected in tissues as well► Detection of mutations of ras and APC genes in stool
  141. 141. RAISED SERUM CEA► SEEN IN:► Colorectal Ca► Ca stomach► Ca pancreas► Ca breast► Ca prostate► CLD► Chronic renal disease► ↑ CEA never detected in normal individuals
  142. 142. CARCINOMASite: rectosigmoid—50%► Rt sided tumor—↑ common in elderly, blacks and with diverticular disease► Multicentric Ca—3-6% casesGross:► Polypoid—bulky mass with well defined rolled magins► Ulcerative/infiltrating—less elevated surface with central ulceration► Flat or depressed Ca—deep stromal and lymphovascular invasion► Wall invasion can be seen grossly► Mucinous Ca—gelatinous or glaring► Determine pericolic extension and vein invasion on gross► Determine appearance of rest of colon—polyp or Ca elsewhere
  143. 143. HISTOPATHOLOGY► Well to modeately differentiated adenocarcinoma with variable mucin► Cells—columnar, goblet and few endocrine► Inflammatory and desmoplastic reaction► Invasion of all layers of bowel► Pericolic extension, perineural and veinous invasion► Metaplastic bone formation—very rare► Residual polyp or hyperplastic glands seen at tumor edge
  146. 146. MICROSCOPIC TYPES1. Mucinous Ca2. Signet ring Ca3. Basaloid (cloacogenic Ca)4. Clear cell Ca5. Hepatoid adenoca6. Medullary (solid, poorly differentiated) adenocarcinoma7. Anaplastic (solid, giant cell, sarcomatoid) ca8. Squamous differentiation9. Trophoblastic differentiation10. Endocrine differentiation11. Rhabdoid differentiation
  148. 148. SIGNET RING CARCINOMA► Rare form► Age: young► Gross: diffuse infiltration of bowel wall, maybe seen in adenomatous polyp as wellL/M: diffuse growth, with few gland formation► Signet ring cells► Mets: lymph nodes, peritoneal surface and ovary rather than liver► Prognosis: very poorD/D: gastric signet ring ca or breast ca► Benign signet ring change seen in pseudomembranous colitis and inflammatory conditions► IHC: CK7-/CK20+
  149. 149. BASALOID CA: MEDULLARY CA:► Same as anal couterpart ► Site: cecum, rt colonCLEAR CELL CA: ► Sex: ♀► Not specific entity ► Genetics: microsatellite► Morphological variant of instability adenocarcinoma with ANAPLASTIC CA: glycogen accumulation in ► Aggressive behavior cells SQUAMOUSHEPATOIDADENOCA: DIFFERENTIATION:► Similar to gastric counterpart ► Site: cecum► RHABDOID FEATURES: ► Adenosquamous Ca► Site: cecum ► Squamous cell Ca► Aggressive behavior
  150. 150. TROPHOBLASTIC 2. In tumors with mixed DIFFRENTIATION: composition► Focal change in adenoca ► Typcial adenoca+clear cut► hCG+ enodcrine differentitation► Rarely—choriocarcinoma or 3. Neuroendocrine Ca glassy cell Ca form ► Organoid appearanceENDOCRINE ► Large cells DIFFERENTIATION: 4) Small cell1. As scttered endocrine cells (neuroendocrine) Ca in typical adenoca ► Similar to pulmonary► Seen in mucinous ca counterpart► ↑ seen after chemo or ► E/M: few dense core radiotherapy secretory granules ► IHC: NSE+ 5. Carcinoid tumor
  151. 151. HISTOCHEMISTRY:► Mucin+ (PAS)IHC:► MUC1 and MUC3+, MUC2-ve, MUC5AC-ve► CK20+/CK7- : helps to differentiate from Ca ovary and lung► CEA+: seen as a rule, -ivity means that tumor is not colorectal in origin► CDX2+► TAG-72+, LEA+► Loss of blood gp Ag, HLA A,B,C expression—poorly differentiated Ca► Abnormalities of lectin binding► Villin+, cathepsinB+► Calretenin+--undifferentiated► hCG—mucinous and poorly differentiated tumors► PLAP+ 10%► ER/PR -ve
  152. 152. MOLECULAR GENTICS► Somatic mutations of genes:► APC, mismatch repair genes, p53, k-ras and DCC► Microsatellite instability associated tumors—mucinous or poorly differentiated, right sided, prominent host response and with circumferential growth► Β catenin is associated with APC gene► E-cadherin and α-catenin correlates with local invasion and mets► p53 mutation► Mutation of ras oncogene► Deletion of von Hippel-Lindau gene► Enhanced expression of c-myc oncogene► Ki-67--↑ proliferative activity
  153. 153. COLORECTAL CARCINOMABIOPSY:► +ve biopsy should be obtained before definitive treatment► Larger lesion—multiple biopsies► Better differentiated tumors and signet ring Ca—difficult to identify► Rectal tumors—biopsy the submucosal invasive tumor frontCYTOLOGY:► Accurate via of diagnosing colorectal Ca► Brush cytology via fiberoptic scope► Rectal lesion can be sampled through cytology
  154. 154. GRADING & STAGING► Dukes staging system—1973 :  A: tumor involve wall of bowel only  B: tumor extend through the wall  C1: tumors with regional lypmh node mets  C2: tumors with +ve lymph nodes at point of mesenteric blood vessel ligature  D: distant mets► Astler and Coller—1954:  A: limited to mucosa  B1: involving muscularis externa but not penetrating it  B2: penetrating through muscularis externa  C1: confined to bowel wall but with nodal mets  C2: penetrating through wall and with nodal mets
  155. 155. GRADING & STAGING► TNM:► GRADING:  I Well differentiated  II Moderately differentiated  III Poorly differentiated  Grading should be determined by worst pattern rahter than the predominant one
  156. 156. SPREAD AND METASTASIS► Most common sites of colonic mets:► Regional lymph nodes and liver► Lymph nodes ↑ common—poorly differentiated areas and highly infiltrative pattern► Minimum number of nodes recovered from surgical specimen of colorectal Ca should be 14-15► Lymph nodes micromets req—serial H&E section, IHC for CK, PCR for CK19/20 or mutant k-ras► Pericolonic tumor deposits—tumor nodules in perineural, perivascular or intravascular location beyond muscularis propria► Other metastatic site: preitoneum, lung, ovaries► Rare– CNS, bone, testis, uterus and oral cavity
  157. 157. TREATMENT► Surgical resection:► Ca cecum or ascending colon—ileocolectomy► Tumors below peritoneal reflection—APR► Ca in other areas of bowel—anterior resection► Resectability rate for Ca colorectum—92%► Operative mortality—2%► Pre and postoperative radio and chemotherapy—variable results in different centers
  158. 158. PROGNOSIS► 5 yr survival rate after curative resection—40-60%► Local recurrence and regional lymph node mets90% of failure cases► AJCC divided prognostic factors into certain categories:► Category I: well supported by literature, generally used in pt management and of sufficient importance to modify TNM system► Category IIA: extensively studied biologically &/or clinically. Prognostic value for therapy, sufficient to be noted in pathology report► Category IIB: well studied but not sufficiently established for Category I or IIA► Category III: not yet established to meet criteria for Category I or II► Category IV: studied and shows no consistent prognostic significance
  159. 159. PROGNOSTIC FACTORS1. Age: very young and very old—poor prognosis – Young—advanced stage, UC, signet ring and mucinous tumors— bad prognosis  More important in rectal than colonic tumors2. Sex: ♀ better than ♂3. CEA serum levels: >5 ng/ml—adverse prognosis4. Tumor location: controversial, however left sided lesion better5. Tumor multiplicity: no difference6. Local extent: better for focal microscopic tumor and tumor restricted to mucosa or submucosa – Worse for tumors extending beyond wall7. Tumor size: not a reliable factor (category III)8. Tumor edge: non polypoid edge worse than polypoid (category III)
  160. 160. PROGNOSTIC FACTORS9. Obstruction: worse prognosis in some series10. Perforation: poor prognosis11. Tumor margins and inflammatory reaction: – Pushing margins and inflammatory infiltrate—better prognosis (IIA) – Tumor infiltration by eosinophils and S-100+ dendritic cells—better prognosis – ≥ 4 mast cells x 30 oil immersion fields—poor prognosis9. Vascular invasion: ↓ survival rate – Lymph vessel invasion less importance than venous invasion (IIA)9. Perineural invasion: sign of advanced disease (IIA)
  161. 161. PROGNOSTIC FACTORS14. Surgical margins: – involvement of radial margin—single most ciritical factor in determining recurrence (IIA) – Recurrence chance ↑--tumor <2m away from circumferential margin15. Tumor thickness: correlates with node and liver mets16. Microscopic type: – Mucinous, signet ring and anaplastic—worse prognosis – Medullary Ca—imporved outcome (IIB)15. Acinar morphology: microacinar growth—poor prognosis16. Neuroendocrine cells: controversial (III)17. Tumor angiogenesis: recurrence and ↓ survival (III)18. Mucin related Ag: MUC1 and sialyl-Lewis(x)—tumor progression (III)
  162. 162. PROGNOSTIC FACTORS21. HLA-DR: better prognosis22. hCG: not an adverse prognostic factor23. bcl-2: improved prognosis (IIB)24. DNA ploidy: prognostic value doubtful25. Cell proliferation: controversial26. Allelic loss of chromosome 18q: negative prognosis (IIB)27. TGF-β mutation: favorable prognosis28. Oncogene expression: – K-ras mutation—recurrent disease (IIB) – ras p21—recurrent disease – P53—independent prognostic factor (IIB) – c-myc—correlated with degree of differentiation – Microsatellite instability—improved survival – Thymidylate synthatase mRNA—poor prognosis – Lack of p27—poor prognosis (IIB)
  163. 163. PROGNOSTIC FACTORS29. Lymph node involement: poor prognosis (I) – Location and extent of node important – ↑ nodes involved→↑ worse the prognosis – Micromets in nodes—poor survival (III)29. Pattern of lymph node reaction: regional nodes showing cell mediated immune response—better survival30. Staging: correlates with prognosis (I)31. Microscopic grade: correlates with prognosis (IIA)
  164. 164. TNM CLASSIFICATION► PRIMARY TUMOR (t)► TX Primary tumor can’t be assessed► T0 No evidence of primary tumor► Tis Ca in situ: intraepithelial or invasion of lamina propria► T1 Tumor invades submucosa► T2 Tumor invades muscularis propria► T3 Tumor invades through muscularis propria into subsersosa or into nonperitonealized pericolic or perirectal tissue► T4 Tumor directly invades other organs or structures and / or perforates visceral peritoneum
  165. 165. TNM CLASSIFICATION► REGIONAL LYMPH NODES (N)► NX Regional lymph nodes can’t be assessed► N0 No regional lymph node metastasis► N1 Metastasis in 1 to 3 regional lymph nodes► N2 Metastasis in ≥ 4 regional lymph nodes► DISTANT METASTASIS (M)► MX Distant metastasis can’t be assessed► M0 No distant metastasis► M1 Distant metastasis
  166. 166. STAGE GROUPINGSTAGE T N M DUKES MAC 0 Tis N0 M0 — — I T1 N0 M0 A A T2 N0 M0 A B1 IIA T3 N0 M0 B B2 IIB T4 N0 M0 B B3 IIIA T1-2 N1 M0 C C1 IIIB T3-4 N1 M0 C C2/C3 IIIC Any T N2 M0 C C1/C2/C3 IV Any T Any N M1 — D
  167. 167. CARCINOID TUMORSite:► Rectum—more common, anterior or lateral wall, round shape, usually <0.5cm, nodal mets rare, maybe seen in ass with UC or CD, ovarian carcinoid and as collision tumor with adenomatous component► May occur in any part of large bowel► Colonic carcinoid— large, penetrate wall deeply with regional nodal mets► S/S: never ass with carcinoid syndromeGross:► flat or slightly depressed plaque or polypoid lesion► Yellow color after formalin fixation
  168. 168. CARCINOID TUMORL/M:► Ribbon and festoons, minor tubular and acinar component with mucin► Crypt cell proliferative micronests► Argyrophil+, argentaffin-veIHC:► Panendocrine markers+ (NSE, synaptophysin, crhromogranin)► Somatostatin, glucagon, substance P, peptide YY+► Gastrin/cholecystokinin, calcitonin, pancreatic polypeptide and motilin +► Rectal—CEA+, hCG+, prostatic acid phosphatase+Treatment: rectal carcinoid <2cm, limited to mucosa or submucosa by local excision► Large tumors/ invasion of muscularis propria—radical surgery
  169. 169. LYMPHOMA► Less frequently seen in large bowel compared to stomach and small bowel► Seen in HIV infected or transplant recipients or in pts with UCGross: prominent mucosal folds, ulceration, large mass or solitary/multiple polyps► Regional nodes involved—50% casesL/M: non hodgkin lymphoma► Low grade—MALToma—plasmacytoid differentiation► Mantle cell lymphoma► Anaplastic large cell lymphoma► AILD like lymphoma► Hodgkin’s lymphoma
  170. 170. METASTATIC TUMORS► Disk like areas with central ulceration► Primary: Melanoma, Ca lung► Prostatic Ca mets may simulate primary rectal Ca► Mesothelioma as multiple colonic polyps