Small & large gut

SMALL & LARGE SMALL & LARGE INTESTINEINTESTINE

PATHOLOGYPATHOLOGY

Normal Small IntestineNormal Small Intestine

NORMAL COLONNORMAL COLON

Important featuresImportant features

► Villous to crypt length ratio is 3:1, 5:1Villous to crypt length ratio is 3:1, 5:1► One lymphocyte per five enterocytesOne lymphocyte per five enterocytes► Paneth cells secrete defensins present up to Paneth cells secrete defensins present up to

ascending colonascending colon► Peyer patches , M cellsPeyer patches , M cells► Small intestine 6 meters (25cm duodenum)Small intestine 6 meters (25cm duodenum)► Large intestine 1.5 meters (20cm Rectum)Large intestine 1.5 meters (20cm Rectum)► Anal canal 4cm Anal canal 4cm ► Enteritis(duodenitis, ileitis), Colitis(typhilitis, Enteritis(duodenitis, ileitis), Colitis(typhilitis,

proctitis), Cryptitisproctitis), Cryptitis

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

CELIAC DISEASECELIAC DISEASE

►Celiac disease (celiac sprue, gluten-Celiac disease (celiac sprue, gluten-sensitive enteropathy) a chronic sensitive enteropathy) a chronic disease, characteristic mucosal lesion disease, characteristic mucosal lesion of small intestine and impaired nutrient of small intestine and impaired nutrient absorption, which improves on absorption, which improves on withdrawal of wheat gliadins and related withdrawal of wheat gliadins and related grain proteins from dietgrain proteins from diet

►Celiac disease occurs largely in Celiac disease occurs largely in Caucasians and is rare or nonexistent Caucasians and is rare or nonexistent among native Africans, Japanese, and among native Africans, Japanese, and ChineseChinese

► Infants, yet adults in 5Infants, yet adults in 5thth decade of life decade of life may seek attentionmay seek attention

PathogenesisPathogenesis Sensitivity to gluten, alcohol-soluble, water-insoluble protein Sensitivity to gluten, alcohol-soluble, water-insoluble protein

component gliadin (protein found in gluten fraction of wheat) and component gliadin (protein found in gluten fraction of wheat) and closely related grains (oat, barley, and rye) closely related grains (oat, barley, and rye)

Interplay between genetic predisposing factors, host immune Interplay between genetic predisposing factors, host immune response, and environmental factors is central to disease response, and environmental factors is central to disease pathogenesis pathogenesis

► Exposure to gliadin results in T-cell mediated chronic inflammatory Exposure to gliadin results in T-cell mediated chronic inflammatory reaction with accumulation of intraepithelial CD8+ T cells and large reaction with accumulation of intraepithelial CD8+ T cells and large numbers of lamina propria CD4+ T cells, which are sensitized to numbers of lamina propria CD4+ T cells, which are sensitized to gliadin results in circulating antibodies against gliadin gliadin results in circulating antibodies against gliadin

► Epithelial cells secrete large amount of IL5 that activate CD8+ T Epithelial cells secrete large amount of IL5 that activate CD8+ T cells (increases risk of T cell lymphoma) cells (increases risk of T cell lymphoma)

► Family history important in celiac disease, almost all individuals with Family history important in celiac disease, almost all individuals with celiac disease share major histocompatibility complex class II HLA-celiac disease share major histocompatibility complex class II HLA-DQ2 or HLA-DQ8 haplotypeDQ2 or HLA-DQ8 haplotype

► Proposed that gliadin is deamidated by enzyme transglutaminase Proposed that gliadin is deamidated by enzyme transglutaminase

into peptides which binds to DQ2 and DQ8, recognition of these into peptides which binds to DQ2 and DQ8, recognition of these peptides by CD4+ T cells leads `to secretion of Gamma interferon peptides by CD4+ T cells leads `to secretion of Gamma interferon which damages intestinal wallwhich damages intestinal wall

CELIAC DISEASECELIAC DISEASEGross:Gross:Duodenal folds are absent or reducedDuodenal folds are absent or reducedMicroscopy:Microscopy: Atrophic villi (Usually complete)Atrophic villi (Usually complete) Normal thickness of mucosaNormal thickness of mucosa Villous crypt ratio decreasedVillous crypt ratio decreased Crypt hyperplastic-elongated tortuousCrypt hyperplastic-elongated tortuous Increase mitosesIncrease mitoses Increase in no of lymphocytes, plasma cells, Increase in no of lymphocytes, plasma cells,

eosinophils, macrophageseosinophils, macrophages Intraepithelial leucocytes Intraepithelial leucocytes Vacuolar degeneration and loss of brush Vacuolar degeneration and loss of brush

borders of surface epitheliumborders of surface epithelium

Out come of Celiac DiseaseOut come of Celiac Disease

► Intestinal Non Hodgkin T-cell lymphomaIntestinal Non Hodgkin T-cell lymphoma►Chronic nonspecific duodenojejunoileitisChronic nonspecific duodenojejunoileitis►Small intestine adenocarcinomaSmall intestine adenocarcinoma►Squamous cell carcinoma of esophagusSquamous cell carcinoma of esophagus►Dermatitis herpitiformis blistering skin Dermatitis herpitiformis blistering skin

lesionlesion

Diagnosis of Celiac DiseaseDiagnosis of Celiac Disease

►Clinical malabsorption Clinical malabsorption (Diarrhea ,flatulence, wt loss, fatigue, (Diarrhea ,flatulence, wt loss, fatigue, failure to thrive in childernfailure to thrive in childern

►Small bowel biopsy Villous atrophySmall bowel biopsy Villous atrophy►Responds to gluten with drawl from dietResponds to gluten with drawl from diet►Antigliaden or antiendomysial antibodiesAntigliaden or antiendomysial antibodies►Antitransglutiminase IgA, IgGAntitransglutiminase IgA, IgG►Antireticulin antibodiesAntireticulin antibodies

Normal/Celiac sprueNormal/Celiac sprue

CeliacCeliac

TROPICAL SPRUETROPICAL SPRUE

► Definite geographic distributionDefinite geographic distribution► Bacterial etiology with or with out additive Bacterial etiology with or with out additive

effects of fat.effects of fat.► Unaffected by gluten ingestion, responds to Unaffected by gluten ingestion, responds to

folic acid, vit B12, tetracycline.folic acid, vit B12, tetracycline.► There is partial villous atrophyThere is partial villous atrophy

WHIPPLE’S DISEASEWHIPPLE’S DISEASE

► Male to female ratio 10:1Male to female ratio 10:1► Large macrophages in lamina propria, Large macrophages in lamina propria,

distorting the villi, alternating with empty distorting the villi, alternating with empty spaces.spaces.

► Histiocytes cytoplasm contains diastase-Histiocytes cytoplasm contains diastase-resistant PAS positive & gram positive resistant PAS positive & gram positive abundant bacilli abundant bacilli Tropheryma whippeliiTropheryma whippelii

► Diagnosis by PCR, immuno, electron Diagnosis by PCR, immuno, electron microscopy.microscopy.

► Biopsy of peripheral lymph nodes – presence Biopsy of peripheral lymph nodes – presence of typical macrophages.of typical macrophages.

WHIPPLEWHIPPLE

GIARDIAGIARDIA

AMEBIC COLITISAMEBIC COLITIS

► Simulate ulcerative colitis or Crohn’s diseaseSimulate ulcerative colitis or Crohn’s disease► Gross:Gross: ulceration covered by exudate, with normal ulceration covered by exudate, with normal

intervening mucosaintervening mucosa► Site:Site: cecum and ascending colon cecum and ascending colon► L/M:L/M: nonspecific nonspecific► Flask shaped ulcer, relative paucity of inflammatory Flask shaped ulcer, relative paucity of inflammatory

cells beneath ulcercells beneath ulcer► Trophozoites of E. histolyticaTrophozoites of E. histolytica► Erythrocytosis by trophozoites usually presentErythrocytosis by trophozoites usually present► Can be detected by PAS stainCan be detected by PAS stain► Stool R/EStool R/E

AmebaAmeba

CryptosporidosisCryptosporidosis

Major Causes of Bacterial Enterocolitis

Escherichia coli • ETEC EHEC EPEC EIEC SalmonellaShigella Campylobacter Yersinia enterocoliticaVibrio cholerae,Clostridium difficile Clostridium perfringensMycobacterium tuberculosis ProtozoaAmebic colitis

Pseudo membranous colitisPseudo membranous colitis

Ulcers of IntestineUlcers of Intestine► Oval- Salmonella typhi long axes along axes of Oval- Salmonella typhi long axes along axes of

ileumileum► Linear-Salmonella paratyphiLinear-Salmonella paratyphi► Flask shaped –amebicFlask shaped –amebic► Irregular –ShigellaIrregular –Shigella► Multiple superficial ulcers-Campylobacter jejuniMultiple superficial ulcers-Campylobacter jejuni► Ulcer along transverse axes- TuberculosisUlcer along transverse axes- Tuberculosis► Early Aphthous & late long linear serpintine-Early Aphthous & late long linear serpintine-

CrohnCrohn► Extensive broad base – Ulcerative colitisExtensive broad base – Ulcerative colitis► Solitary Rectal UlcerSolitary Rectal Ulcer► Malignant ulcersMalignant ulcers

Granulomatous lesions of Granulomatous lesions of IntestineIntestine

►Tuberculosis caseating granulomasTuberculosis caseating granulomas►Crohn disease non-caseating Crohn disease non-caseating

granulomasgranulomas►Foreigen body granulomasForeigen body granulomas►Necrotizing granulomas-Yersinia Necrotizing granulomas-Yersinia

enterocolitica, Y. pseudetuberculosisenterocolitica, Y. pseudetuberculosis►Oliogranuloma-against fatOliogranuloma-against fat

► Solitary ulcerated or polypoid lesion 4-18cm from anal Solitary ulcerated or polypoid lesion 4-18cm from anal marginmargin

► Associated with rectal prolapseAssociated with rectal prolapse► S/S:S/S: passage of blood and mucus , altered bowel habits passage of blood and mucus , altered bowel habits

and painand pain

L/M:L/M: superficial and irregular mucosal ulceration superficial and irregular mucosal ulceration► Hyperplasia of crypts, villous configurationHyperplasia of crypts, villous configuration► Obliteration of lamina propria by fibroblasts, elastin and Obliteration of lamina propria by fibroblasts, elastin and

smooth musclessmooth muscles► Thickened muscularis mucosaeThickened muscularis mucosae► ↓ ↓ lymphocytes and plasma cellslymphocytes and plasma cells► Chronic form– similar to colitis cystica profundaChronic form– similar to colitis cystica profunda

SOLITARY RECTAL ULCERSOLITARY RECTAL ULCER

Sex:Sex: 80% ♂ 80% ♂► Association with Association with

intestinal atresia and intestinal atresia and anorectal malformationanorectal malformation

S/S:S/S: abdominal distention, abdominal distention, delayed meconium delayed meconium passage, tight anuspassage, tight anus

► Proximal bowel dilatation Proximal bowel dilatation & hypertrophy of muscle& hypertrophy of muscle

► Complications:Complications: acute acute intestinal obstruction, intestinal obstruction, enterocolitis, megacolon, enterocolitis, megacolon, perforation, sepsisperforation, sepsis

Cause:Cause: lack of coordinated lack of coordinated movements of distal large movements of distal large bowel due to loss of bowel due to loss of intrinsic inhibitory intrinsic inhibitory innervationsinnervations

► Absent parasympathetic Absent parasympathetic ganglion cells in ganglion cells in intramural and intramural and submucosal plexus due to submucosal plexus due to failure of migration of failure of migration of neural crest cells or neural crest cells or immune mediated immune mediated neuronal necrosisneuronal necrosis

► Age: 1st yr lifeAge: 1st yr life

HIRSCHSPRUNG’S DISEASEHIRSCHSPRUNG’S DISEASE

HIRSCHSPRUNG’S DISEASEHIRSCHSPRUNG’S DISEASE

HIRSCHSPRUNG’S DISEASEHIRSCHSPRUNG’S DISEASEL/M:L/M: ► Aganglionosis in both plexus of segment of bowelAganglionosis in both plexus of segment of bowel► Hypertrophied nerves, altered distribution of Hypertrophied nerves, altered distribution of

interstitial cells of Cajal, fibromuscular dysplasia interstitial cells of Cajal, fibromuscular dysplasia of arteries, hyperplasia of lymphoglandular of arteries, hyperplasia of lymphoglandular complexcomplex

Biopsy types:Biopsy types:► Full thickness biopsy of rectumFull thickness biopsy of rectum► Biopsy should be 2cm above anal valve in infant Biopsy should be 2cm above anal valve in infant

and 3cm in older childrenand 3cm in older children► Suction or mucosal rectal biopsySuction or mucosal rectal biopsy

TYPESTYPES1.1. Classic: aganglionic segment begins in distal Classic: aganglionic segment begins in distal

colorectum and extend in adjacent proximal colorectum and extend in adjacent proximal dilated boweldilated bowel

2.2. Short segment: involvement of rectum and Short segment: involvement of rectum and rectosigmoid for few cmrectosigmoid for few cm

3.3. Ultra-short: involved segment very narrow, Ultra-short: involved segment very narrow, easily missedeasily missed

4.4. Long-segment: involves most or all of large Long-segment: involves most or all of large bowel, may extend into small bowelbowel, may extend into small bowel

5.5. Zonal colonic aganglionosis: only short segment Zonal colonic aganglionosis: only short segment involved, ganglion cells present below and involved, ganglion cells present below and above aganglionic segmentabove aganglionic segment

HIRSCHSPRUNG’S DISEASEHIRSCHSPRUNG’S DISEASE► ↑↑Acetylcholinesterase activity in lamina Acetylcholinesterase activity in lamina

propria and muscularis mucosaepropria and muscularis mucosae► NSE, neurofilaments, highlight hypertrophied NSE, neurofilaments, highlight hypertrophied

nerves and absent ganglion cellsnerves and absent ganglion cells► S-100—absent normal periganglionic satellite S-100—absent normal periganglionic satellite

cellscellsAcquired MegacolonAcquired Megacolon► IBD, Chagas disease, intestinal obstruction, IBD, Chagas disease, intestinal obstruction,

psychosomatic disorderspsychosomatic disorders

Acquired MegacolonAcquired Megacolon

IBDIBD

Chagas diseaseChagas disease

Intestinal obstruction, Intestinal obstruction,

Psychosomatic disordersPsychosomatic disorders

Toxic MegacolonToxic Megacolon

Normal / Inflamed AppendixNormal / Inflamed Appendix

Pathogenesis Pathogenesis Acute Acute AppendicitisAppendicitis

Appendiceal inflammation is associated with Appendiceal inflammation is associated with obstruction in 50% to 80% of cases, usually in the obstruction in 50% to 80% of cases, usually in the form of a fecalith and, less commonly, a form of a fecalith and, less commonly, a gallstone, tumor, or ball of worms gallstone, tumor, or ball of worms (oxyuriasis(oxyuriasis

vermicularis)vermicularis). Continued secretion of mucinous . Continued secretion of mucinous fluid in the obstructed viscus presumably leads to fluid in the obstructed viscus presumably leads to a progressive increase in intraluminal pressure a progressive increase in intraluminal pressure sufficient to cause eventual collapse of thesufficient to cause eventual collapse of the

draining veins. Ischemic injury then favors draining veins. Ischemic injury then favors bacterial proliferation with additional bacterial proliferation with additional inflammatory edema and exudation, further inflammatory edema and exudation, further embarrassing the blood supply.embarrassing the blood supply.

Nevertheless, a significant minority of inflamed Nevertheless, a significant minority of inflamed appendices have no demonstrable luminal appendices have no demonstrable luminal obstruction, and the pathogenesis of the obstruction, and the pathogenesis of the inflammation remains unknown.inflammation remains unknown.

Acute AppendicitisAcute AppendicitisMorphology:Morphology:► Earliest stagesEarliest stages, scant neutrophilic exudate in mucosa, , scant neutrophilic exudate in mucosa,

submucosa, and muscularis propria. Subserosal vessels submucosa, and muscularis propria. Subserosal vessels congested, and often perivascular neutrophilic infiltrate. congested, and often perivascular neutrophilic infiltrate. Normal glistening serosa changes into dull, granular, red Normal glistening serosa changes into dull, granular, red membrane membrane

► Later stageLater stage, a prominent neutrophilic exudate generates a , a prominent neutrophilic exudate generates a fibrinopurulent reaction over the serosa , abscess formation fibrinopurulent reaction over the serosa , abscess formation within wall, along with ulcerations and foci of suppurative within wall, along with ulcerations and foci of suppurative necrosis in mucosa necrosis in mucosa aacute suppurative appendicitiscute suppurative appendicitis. .

► Large areas of hemorrhagic ulceration of mucosa and green-Large areas of hemorrhagic ulceration of mucosa and green-black gangrenous necrosis of wall, extending to serosa, black gangrenous necrosis of wall, extending to serosa, creating creating acuteacute

gangrenous appendicitisgangrenous appendicitis, , followed by rupture and followed by rupture and suppurative peritonitissuppurative peritonitis

► The histologic criterion for the diagnosis of acute appendicitis The histologic criterion for the diagnosis of acute appendicitis is neutrophilic infiltration of the muscularis propria.is neutrophilic infiltration of the muscularis propria.

Acute AppendicitisAcute Appendicitis

ACUTE APPENDICITISACUTE APPENDICITISOBSTRUCTIVEOBSTRUCTIVE► fecolithfecolith► foreign bodyforeign body► calculus-gall stonecalculus-gall stone► MucocoeleMucocoele► Tumor: primary secondary--- cecumTumor: primary secondary--- cecum► Diffuse lymphoid hyperplasia (10 to 19 yrs)Diffuse lymphoid hyperplasia (10 to 19 yrs)► Oxyuris vermicularisOxyuris vermicularisNON OBSTRUCTIVENON OBSTRUCTIVE► Secondary to generalized infection (viral-Secondary to generalized infection (viral-

Measles)Measles)

FungalFungal candidiasis, candidiasis, cryptosporidiosiscryptosporidiosis

OthersOthers crohn diseasecrohn disease ulcerative colitisulcerative colitis sarcoidosissarcoidosis yersiniosisyersiniosis

Acute AppendicitisAcute Appendicitis

ACUTE APPENDICITISACUTE APPENDICITIS

D/DD/D Mesenteric lymphadenitisMesenteric lymphadenitis Gynecologic lesionsGynecologic lesions Acute diverticulitisAcute diverticulitis Meckel’s diverticulitisMeckel’s diverticulitis Infarction of greater omentumInfarction of greater omentum Ureteric colicUreteric colic Chemotherapy induced typhilitisChemotherapy induced typhilitis

Tumors of AppendixTumors of Appendix

Non-neoplastic: Non-neoplastic: MUCOSAL HYPERPLASIAMUCOSAL HYPERPLASIANeoplastic:Neoplastic:MUCINOUS TUMORSMUCINOUS TUMORS Mucinous cystadenomasMucinous cystadenomas Mucinous cystadenocarcinomaMucinous cystadenocarcinomaADENOCARCINOMAADENOCARCINOMA PrimaryPrimary secondarysecondaryCARCINOIDCARCINOID

CARCINOIDCARCINOID► Most common tumor of appendixMost common tumor of appendix► One in 300 appendicectomiesOne in 300 appendicectomies► Peak incidence in 3Peak incidence in 3rdrd and 4 and 4thth decades of decades of

lifelife► Mostly incidentalMostly incidental► Mostly occur at the tipMostly occur at the tip► Mostly less than 1cm in diameterMostly less than 1cm in diameter► GROSSGROSS► Firm, grayish whiteFirm, grayish white► Fairly well circumscribedFairly well circumscribed► Not encapsulatedNot encapsulated► Characteristic yellow coloration Characteristic yellow coloration

afterafter formalin fixation.formalin fixation.

Histologic Pattern of CarcinoidHistologic Pattern of Carcinoid

►Classic insular typeClassic insular type►Carcinoids with glandular Carcinoids with glandular

differentiationdifferentiation►Tubular type Tubular type ►Goblet cell carcinoidGoblet cell carcinoid

CarcinoidCarcinoid

CLASSIC TYPECLASSIC TYPE

► Solid nests of small monotonous cells with Solid nests of small monotonous cells with occasional acinar or rosette formation.occasional acinar or rosette formation.

► Mitoses rareMitoses rare► Peculiar retraction of tumor periphery from Peculiar retraction of tumor periphery from

the stromathe stroma► Invasion of muscle and lymph vessels is the Invasion of muscle and lymph vessels is the

rulerule► Spread to the peritoneal surface not rareSpread to the peritoneal surface not rare

IMMUNOHISTOCHEMISTRYIMMUNOHISTOCHEMISTRYTumor cells are positive for:Tumor cells are positive for:► argentaffinargentaffin► argyrophilargyrophil Ultrastructurally: filled with pleomorphic dense Ultrastructurally: filled with pleomorphic dense

core secretory granulescore secretory granulesImmunohistochemically reactive for:Immunohistochemically reactive for:► neuron-specific enolase,neuron-specific enolase,► chromograninchromogranin► 5-HT5-HT

Major Causes of Intestinal Major Causes of Intestinal ObstructionObstruction

Mechanical ObstructionMechanical Obstruction► AdhesionsAdhesions► Hernias, internal or externalHernias, internal or external► VolvulusVolvulus► IntussusceptionIntussusception► TumorsTumors► Inflammatory stricturesInflammatory strictures► Obstructive gallstones, fecaliths, foreign bodiesObstructive gallstones, fecaliths, foreign bodies► Congenital strictures; atresiasCongenital strictures; atresias► Congenital bandsCongenital bands► Meconium in mucoviscoidosisMeconium in mucoviscoidosis► ParasitesParasites► Imperforate anusImperforate anusPseudo-obstructionPseudo-obstruction► Paralytic ileus (e.g., postoperative)Paralytic ileus (e.g., postoperative)► Vascular—bowel infarctionVascular—bowel infarction► Myopathies and neuropathies (e.g., Hirschsprung)Myopathies and neuropathies (e.g., Hirschsprung)

DiverticulosisDiverticulosis

MECKEL’S DIVERTICULUMMECKEL’S DIVERTICULUM

Ischemic Bowel DiseaseIschemic Bowel Disease

Acute occlusion of Celiac, superior and Acute occlusion of Celiac, superior and inferior mesenteric arteriesinferior mesenteric arteries

Types Types ►Mucosal-hypoperfusion acute or Mucosal-hypoperfusion acute or

chronicchronic► Mural- “ “ “ “Mural- “ “ “ “►Transmural- occlusion of major Transmural- occlusion of major

mesenteric blood vesselsmesenteric blood vessels

Predisposing conditions for Predisposing conditions for ischemiaischemia

►Arterial Thrombosis- atherosclerosis, Arterial Thrombosis- atherosclerosis, vasculitisvasculitis

►Arterial Embolism-cardiac vegetationsArterial Embolism-cardiac vegetations►Venous Thrombosis-Oral contraceptives, Venous Thrombosis-Oral contraceptives,

postoperative statepostoperative state►Non occlusive ischemia- cardiac failure, Non occlusive ischemia- cardiac failure,

shock, dehydrationshock, dehydration►Miscellaneous-radiation injury, volvulus, Miscellaneous-radiation injury, volvulus,

stricture, amyloidosis, Diabetes mellitusstricture, amyloidosis, Diabetes mellitus

Ischemic injury two phasesIschemic injury two phases► Initial hypoxic injuryInitial hypoxic injury►Secondary reperfusion injury-Secondary reperfusion injury-

generation of oxygen free radicals, generation of oxygen free radicals, neutrophils infiltration, production of neutrophils infiltration, production of inflammatory mediatorsinflammatory mediators

INFARCTIONINFARCTION

INFARCTIONINFARCTION

ISCHEMIC COLITISISCHEMIC COLITIS

Age:Age: >50yrs—arteriosclerosis, diabetes, vascular surgery >50yrs—arteriosclerosis, diabetes, vascular surgery► Younger pts—collagen-vascular diseases, Wegener’s Younger pts—collagen-vascular diseases, Wegener’s

granulomatosis, amyloidosis, oral contraceptivesgranulomatosis, amyloidosis, oral contraceptives► S/S:S/S: sudden onset of bleeding, abdominal pain, bloody sudden onset of bleeding, abdominal pain, bloody

diarrhea, vomitingdiarrhea, vomiting► Site:Site: segmental disease, splenic flexure commonly segmental disease, splenic flexure commonly

involvedinvolved► D/D: IBDD/D: IBD

ISCHEMIC COLITISISCHEMIC COLITISX-ray:X-ray: gas within bowel wall, thumb printing gas within bowel wall, thumb printing

Gross:Gross: pseudopolyps, ulceration and fibrosis pseudopolyps, ulceration and fibrosis

L/M:L/M: in chronic ischemia ulcer covered by in chronic ischemia ulcer covered by granulation tissue extending into submucosagranulation tissue extending into submucosa

►Hemosiderin abundant, hyaline thrombiHemosiderin abundant, hyaline thrombi►Ischemic necrosis—full thickness mucosal Ischemic necrosis—full thickness mucosal

necrosis, hyalinized lamina propria, necrosis, hyalinized lamina propria, hemorrhage and atrophic crypts in healed stagehemorrhage and atrophic crypts in healed stage

Inflammatory Bowel DiseaseInflammatory Bowel Disease

Chronic relapsing inflammatory disorder-obscure Chronic relapsing inflammatory disorder-obscure originorigin

► Crohn diseaseCrohn disease

Autoimmune, affect any part of GITAutoimmune, affect any part of GIT► Ulcerative colitisUlcerative colitis

Chronic inflammatory disease limited to colon & Chronic inflammatory disease limited to colon & rectumrectum

Both exhibit extra-intestinal inflammatory Both exhibit extra-intestinal inflammatory manifestationsmanifestations

Etiology-PathogenesisEtiology-Pathogenesis

Idiopathic-cause unknownIdiopathic-cause unknown

Two key pathogenic abnormalitiesTwo key pathogenic abnormalities►Strong Strong immuneimmune response against response against

normal microbial normal microbial floraflora in in geneticgenetic susceptible individualssusceptible individuals

►Defects in epithelial barrier functionDefects in epithelial barrier function

Pathogenesis of IBDPathogenesis of IBD

A-Genetic SusceptibilityA-Genetic Susceptibility 1. Associated genes with CD are HLA-1. Associated genes with CD are HLA- DR1/DQw5, NOD2DR1/DQw5, NOD2 2. HLA-DR 2 increase in U. Colitis2. HLA-DR 2 increase in U. ColitisB-Intestinal Flora increase immune reaction by providing B-Intestinal Flora increase immune reaction by providing

antigens and inducing co-stimulators and cytokines antigens and inducing co-stimulators and cytokines contribute to T-cell activation, defects in epithelial contribute to T-cell activation, defects in epithelial barrier allow luminal flora to gain access to mucosal barrier allow luminal flora to gain access to mucosal lymphoid tissue –trigger immune response lymphoid tissue –trigger immune response

C-Abnormal T-Cell response to much T-cell activation C-Abnormal T-Cell response to much T-cell activation and/or too little control by regulatory T- lymphocytes and/or too little control by regulatory T- lymphocytes results in damaging the mucosaresults in damaging the mucosa

Diagnosis of IBDDiagnosis of IBD

Clinical historyClinical history Radiographic- string sign in CD, Lead pipe Radiographic- string sign in CD, Lead pipe

in UCin UC Lab Findings (serum antibodies): Lab Findings (serum antibodies): pANCA positive in75%of UC & 11%in CDpANCA positive in75%of UC & 11%in CD ASCA Elevated in CDASCA Elevated in CD Tissue DiagnosisTissue Diagnosis

CROHN DISEASE CROHN DISEASE

EPIDEMIOLOGYEPIDEMIOLOGY► Both sexes female more than malesBoth sexes female more than males► All ages peak age 2All ages peak age 2ndnd &3 &3rdrd decade decade► Primarily disease of Western developed populationsPrimarily disease of Western developed populations► Annual incidence in USA 3per 100,000Annual incidence in USA 3per 100,000Fully developed CD is pathologically Fully developed CD is pathologically

characterized by;characterized by;1. Sharply delimited, transmural inflammatory process 1. Sharply delimited, transmural inflammatory process

withwith mucosal damagemucosal damage2. Non-caseating granulomas2. Non-caseating granulomas3. Fissures and fistulae3. Fissures and fistulae

GROSSGROSS

► Skip lesionsSkip lesions► Cobblestone appearanceCobblestone appearance► Transmural involvement, Creeping fat Transmural involvement, Creeping fat ► Early- aphthous ulcersEarly- aphthous ulcers► Late-Ulcer linear, serpentine and discontinuous Late-Ulcer linear, serpentine and discontinuous

with intervening normal or edematous mucosawith intervening normal or edematous mucosa► HealingHealing→ long rail-track scars→ long rail-track scars► Pseudopolyps or mural bridging lesions may Pseudopolyps or mural bridging lesions may

develop develop ► Stricture, fissure, fistulasStricture, fissure, fistulas► Mesenteric lymphadenopathyMesenteric lymphadenopathy

Crohn DiseaseCrohn Disease

MICROSCOPYMICROSCOPY► Tranmural inflammationTranmural inflammation► FissuresFissures► Non caseating granulomasNon caseating granulomas► Mucosa relatively normal, normal content of mucinMucosa relatively normal, normal content of mucin► Glandular architecture maintainedGlandular architecture maintained► submucosal lymph edema, lymphoid hyperplasia, submucosal lymph edema, lymphoid hyperplasia,

patchy necrosis, atrophy or regenerative patchy necrosis, atrophy or regenerative hyperplasia. hyperplasia.

COMPLICATIONSCOMPLICATIONS► Intramural abscessIntramural abscess► Fistulas, perforationFistulas, perforation► Occasionally carcinoma.Occasionally carcinoma.

CROHN DISEASE of COLON CROHN DISEASE of COLON (GRANULOMATOUS COLITIS)(GRANULOMATOUS COLITIS)

►Involve large bowel in 40% cases, with or Involve large bowel in 40% cases, with or without ileal componentwithout ileal component

►Ileum involved-50%Ileum involved-50%►Anal lesions-75%Anal lesions-75%

Complications:Complications: Fistula, skin ulceration, toxic megacolon, Fistula, skin ulceration, toxic megacolon,

colonic Ca (risk < UC)colonic Ca (risk < UC)

Crohn- Cobble Stone &Crohn- Cobble Stone &Sharp DemarcationSharp Demarcation

CROHN DISEASECROHN DISEASE

CROHN FISSURECROHN FISSURE

C/F of CDC/F of CD► Intermittent attacks of mild diarrhea, fever, and Intermittent attacks of mild diarrhea, fever, and

abdominal pain spaced by asymptomatic periods abdominal pain spaced by asymptomatic periods lasting for weeks to many monthslasting for weeks to many months

► Attacks precipitated by emotional stressAttacks precipitated by emotional stress► Colonic involvement can result in fecal blood lossColonic involvement can result in fecal blood loss► Sometime present as a case of acute appendicitis or Sometime present as a case of acute appendicitis or

acute bowel perforationacute bowel perforation► Extensive involvement of ileum result in marked loss Extensive involvement of ileum result in marked loss

of albumin- protein losing enteropathyof albumin- protein losing enteropathy► Malabsorption of vit B12 P.anemiaMalabsorption of vit B12 P.anemia► Malabsorption of bile salts –steatorrheaMalabsorption of bile salts –steatorrhea► Fistulae and Fissures with urinarry bladder, vagina, Fistulae and Fissures with urinarry bladder, vagina,

perianal skinperianal skin► Extraintestinal manifesintations migratory Extraintestinal manifesintations migratory

polyarthritis, sacroilitis, ankylosing spondylitis, polyarthritis, sacroilitis, ankylosing spondylitis, erythema nodusum clubbing of fingers, hepatic erythema nodusum clubbing of fingers, hepatic primary sclerosing cholangitisprimary sclerosing cholangitis

ULCERATIVE COLITISULCERATIVE COLITIS


► Age:Age: 20-30yrs 20-30yrs► Sex:Sex: ♂=♀♂=♀► Etiology:Etiology: unknown unknown► S/S:S/S: prolonged duration, many remissions and prolonged duration, many remissions and

exacerbationsexacerbations► Site:Site: left sided colon, begins in rectosigmoid left sided colon, begins in rectosigmoid► Ulcerative proctitis—disease localized to rectumUlcerative proctitis—disease localized to rectum► Pancolitis—involve entire colonPancolitis—involve entire colon


Gross: Gross: varies with stagevaries with stage► Acute:Acute: mucosal surface wet and glare mucosal surface wet and glare

Petechial hemorrhagesPetechial hemorrhages Ulcers undermining mucosa, mucosal bridgesUlcers undermining mucosa, mucosal bridges PseudopolypsPseudopolyps

► Advanced:Advanced: bowel—fibrotic, narrowed and shortened bowel—fibrotic, narrowed and shortened Atrophy of all components of wallAtrophy of all components of wall Increased pericolic fatIncreased pericolic fat

► Quiescent:Quiescent: no ulceration, mucosa atrophic no ulceration, mucosa atrophic► Back wash ileitisBack wash ileitis


L/M: L/M: mucosal and submucosal diseasemucosal and submucosal disease► Acute:Acute: ↑ inflammatory cells in lamina propria ↑ inflammatory cells in lamina propria► Inflammation remain above muscularis mucosaeInflammation remain above muscularis mucosae► Crypt abscess, cyrptitisCrypt abscess, cyrptitis► Marked ↓ cytoplasmic mucus, irregularly shaped glands, Marked ↓ cytoplasmic mucus, irregularly shaped glands,

paneth cell metaplasiapaneth cell metaplasia► Atrophic and regenerative changes in glandsAtrophic and regenerative changes in glands► Nuclear enlargement, ↑ mitosisNuclear enlargement, ↑ mitosis► Dilated blood vessels, mucosal capillary thrombiDilated blood vessels, mucosal capillary thrombi► Ulcers covered by granulation tissueUlcers covered by granulation tissue► Pseudopolyps= granulation tissue + inflammed mucosaPseudopolyps= granulation tissue + inflammed mucosa


► Submucosa—normal, inflammed, hyperemic, Submucosa—normal, inflammed, hyperemic, infiltrated by fat or fibrosed (depending on stage)infiltrated by fat or fibrosed (depending on stage)

► Submucosal endarteritis obliterans (10%)Submucosal endarteritis obliterans (10%)► Muscularis externa—hypertrophic/normalMuscularis externa—hypertrophic/normal► Subserosal fibrosisSubserosal fibrosisQuiescent stage:Quiescent stage: Mucosa grossly normalMucosa grossly normalMucin content restored, irregularly branched glands, Mucin content restored, irregularly branched glands,

paneth cells, neutrophils in lamina propriapaneth cells, neutrophils in lamina propria


Extraintestinal manifestations:Extraintestinal manifestations:

liver disease, Arthritis, Uvietisliver disease, Arthritis, Uvietis

Pyoderma gangreonosumPyoderma gangreonosum

Complications:Complications:

perforation, peritonitis, abscess, toxic megacolon,perforation, peritonitis, abscess, toxic megacolon,

venous thrombosisvenous thrombosis

Increase risk of dysplasia/carcinomaIncrease risk of dysplasia/carcinoma

Clinical Manifestation Of UCClinical Manifestation Of UC

►Relapsing disorder, asymptomatic Relapsing disorder, asymptomatic interval of months to yearsinterval of months to years

►Attacks of bloody mucoid diarrhea Attacks of bloody mucoid diarrhea persist for days, weeks to monthspersist for days, weeks to months

► Initial attack may lead to serious Initial attack may lead to serious bleeding with fluid and electrolyte bleeding with fluid and electrolyte imbalanceimbalance

►Toxic megacolon may lead to Toxic megacolon may lead to perforationperforation

Ulcerative ColitisUlcerative Colitis

Dysplasia in Ulcerative colitisDysplasia in Ulcerative colitis

Features UC CD

Clinical

Rectal bleeding Common Inconspicuous

Abdominal mass Never 10-15%

Abdominal pain Left sided Right sided

Sigmoidoscopy 95% abnormal <50% abnormal

Free perforation 12% 4%

Colon CA 5-10% V rare

Anal Fissures Rare, minor 75%, fissures..

Response to steroid 75% 25%

Results of surgery Very good Fair

Ileostomy dysfunction Rare Common

Feature Crohn Disease-SI Crohn Disease-Colon Feature Crohn Disease-SI Crohn Disease-Colon Ulcerative ColitisUlcerative Colitis

MacroscopicMacroscopic► Bowel region Ileum ± colon Colon ± ileum Colon onlyBowel region Ileum ± colon Colon ± ileum Colon only► Distribution Skip lesions Skip lesions DiffuseDistribution Skip lesions Skip lesions Diffuse► Stricture Early Variable Late/rareStricture Early Variable Late/rare► Wall appearance Thickened Thin ThinWall appearance Thickened Thin Thin► Dilation No Yes YesDilation No Yes Yes

MicroscopicMicroscopic► Inflammation Transmural Transmural Limited in Inflammation Transmural Transmural Limited in

mucosamucosa► Pseudopolyps No to slight Marked MarkedPseudopolyps No to slight Marked Marked► Crypt Abscess Not seen CommonCrypt Abscess Not seen Common► Ulcers Deep, linear Deep, linear SuperficialUlcers Deep, linear Deep, linear Superficial► Lymphoid reaction Marked Marked MildLymphoid reaction Marked Marked Mild► Fibrosis Marked Moderate MildFibrosis Marked Moderate Mild► Serositis Marked Variable Mild to Serositis Marked Variable Mild to

nonenone► Granulomas Yes (50%) Yes (50%) NoGranulomas Yes (50%) Yes (50%) No► Fistulae/sinuses Yes Yes NoFistulae/sinuses Yes Yes No► Lymph node Granulomas Do ReactiveLymph node Granulomas Do Reactive

ClinicalClinical► Fat/vit malabsorp Yes Yes, if ileum NoFat/vit malabsorp Yes Yes, if ileum No► Malignant potential Rare +/- YesMalignant potential Rare +/- Yes► Resp to surgery Poor Fair GoodResp to surgery Poor Fair Good

Tumors Small & Large Tumors Small & Large IntestineIntestineNon-neoplastic (Benign) PolypsNon-neoplastic (Benign) Polyps

► Hyperplastic polypsHyperplastic polyps► Hamartomatous polypsHamartomatous polyps • • Juvenile polypsJuvenile polyps • • Peutz-Jeghers polypsPeutz-Jeghers polyps► Inflammatory polypsInflammatory polyps► Lymphoid polypsLymphoid polyps

Neoplastic Epithelial LesionsNeoplastic Epithelial LesionsBenignBenign • • Adenoma *Adenoma *MalignantMalignant • • Adenocarcinoma *Adenocarcinoma * • • Carcinoid tumorCarcinoid tumor • • Anal zone carcinomaAnal zone carcinomaMesenchymal LesionsMesenchymal Lesions► Gastrointestinal stromal tumor (GIST) Gastrointestinal stromal tumor (GIST) ► Other benign lesions • Lipoma • Neuroma • AngiomaOther benign lesions • Lipoma • Neuroma • Angioma► Kaposi sarcomaKaposi sarcomaLymphomaLymphomaMetastaticMetastatic

Intestinal PolypsIntestinal Polyps

Hyperplastic/ PJ polypHyperplastic/ PJ polyp

Juvenile Rectal PolypJuvenile Rectal Polyp

Tubular adenomaTubular adenoma

Adenomatous polypsAdenomatous polyps

Villous adenomaVillous adenoma

Villous adenomaVillous adenoma

Familial polyposisFamilial polyposis

Gardenar syndromeGardenar syndrome

Adenocarcinoma colonAdenocarcinoma colon

Adenocarcinoma ColonAdenocarcinoma Colon

BENIGN EPITHELIAL TUMORSBENIGN EPITHELIAL TUMORS

BRUNNER’S GLAND ADENOMABRUNNER’S GLAND ADENOMA►Nodular proliferation of histologically Nodular proliferation of histologically

normal Brunner’s glands, accompanied normal Brunner’s glands, accompanied by ducts and scattered stromal by ducts and scattered stromal elements, cilliated cysts and adipose elements, cilliated cysts and adipose tissue.tissue.

►Focal multifocal or diffuseFocal multifocal or diffuse►Located commonly at posterior wall of Located commonly at posterior wall of

duodenum at junction of first and duodenum at junction of first and second parts. second parts.

BENIGN EPITHELIAL TUMORSBENIGN EPITHELIAL TUMORS

ADENOMASADENOMAS ► More often In duodenum and jejunum’ single or multiple, More often In duodenum and jejunum’ single or multiple,

sessile or pedunculatedsessile or pedunculated► Microscopically can be villoglandular polyp, adenomatous Microscopically can be villoglandular polyp, adenomatous

polyp or villous adenoma.polyp or villous adenoma.► Malignant transformation can occur mostly when lesion is Malignant transformation can occur mostly when lesion is

large villous or multiple.large villous or multiple.HAMARTOMATOUS POLYPHAMARTOMATOUS POLYP Benign juvenile Rectal polypBenign juvenile Rectal polyp► Jejunoileum– (in Peutz Jeghers syndrome) Jejunoileum– (in Peutz Jeghers syndrome) ► Glands supported by broad bands of smooth muscle fibersGlands supported by broad bands of smooth muscle fibers► Several types of epithelial cells are present.Several types of epithelial cells are present.► Associated with adenocarcinima and adenoma malignum of Associated with adenocarcinima and adenoma malignum of

uterine cervix, ovarian mucinous tumors, breast carcinoma.uterine cervix, ovarian mucinous tumors, breast carcinoma.

ADENOCARCINOMA ADENOCARCINOMA ► Both sexes elderly population less common than Both sexes elderly population less common than

counterpart in colon.counterpart in colon.► More common in upper portion of small bowelMore common in upper portion of small bowel► Associated with hereditary nonpolyposis colorectal Associated with hereditary nonpolyposis colorectal

carcinoma syndrome, Peutz-Jeghers syndrome, carcinoma syndrome, Peutz-Jeghers syndrome, Reckling-huasen’s disease, bowel duplication, Reckling-huasen’s disease, bowel duplication, Crohn’s disease, at ileostomy sites, jejunal limb of Crohn’s disease, at ileostomy sites, jejunal limb of Roux-en-Y esophagojejunostomy.Roux-en-Y esophagojejunostomy.

► GROSS-GROSS- duodenal carcinoma; papillary duodenal carcinoma; papillary configuration, distal lesions; napkin-ring, polypoid or configuration, distal lesions; napkin-ring, polypoid or fungating appearancefungating appearance

► MICROSCOPY- MICROSCOPY- moderately well differentiated moderately well differentiated adenocarcinoma. Mucin production, CEA reactivity is adenocarcinoma. Mucin production, CEA reactivity is the rule the rule

► Commonly positive for chromogranin 5-HTCommonly positive for chromogranin 5-HT► IMMUNO- IMMUNO- COX-2, sPLA2 cPLA2.peptide hormonesCOX-2, sPLA2 cPLA2.peptide hormones► ULTRASTRUCTURE- ULTRASTRUCTURE- prominent development of prominent development of

microvilli.microvilli.

SMALL CELL NEUROENDOCRINE SMALL CELL NEUROENDOCRINE CARCINOMACARCINOMA

► Rare, Rare, ► MICROSCOPY-MICROSCOPY- Small round oval cells, scanty Small round oval cells, scanty

cytoplasm, hyperchromatic nucleus.cytoplasm, hyperchromatic nucleus.► ULTRASTRUCTURE- ULTRASTRUCTURE- dense-core granules of dense-core granules of

neurosecretory type neurosecretory type ► IMMUNORECTIVEIMMUNORECTIVE for neuroendocrine markers for neuroendocrine markers► Deeply invasive, prone to metastasis, very poor Deeply invasive, prone to metastasis, very poor

prognosis.prognosis.

ANAPLASTIC CARCINOMAANAPLASTIC CARCINOMA► Highly bizarre tumor cells, multinucleated with Highly bizarre tumor cells, multinucleated with

abundant cytoplasm, no glandular differentiation.abundant cytoplasm, no glandular differentiation.► Aggressive Aggressive

CARCINOID TUMORSCARCINOID TUMORS► Low grade neoplasm originating from the diffuse Low grade neoplasm originating from the diffuse

neuroendocrine system outside of pancreas and neuroendocrine system outside of pancreas and thyroid C cells.thyroid C cells.

► Adults, Adults, ► Located in ileum mostly Located in ileum mostly ► GROSS-GROSS- intact mucosa , tumor infiltrating the intact mucosa , tumor infiltrating the

submucosa and extending to muscularis externa.submucosa and extending to muscularis externa.► Buckling of bowel wall due to fibrosisBuckling of bowel wall due to fibrosis► Brightly yellow color Brightly yellow color ► MICROSCOPY-MICROSCOPY- solid nests of monotonous solid nests of monotonous

population of cells having small round nuclei scant population of cells having small round nuclei scant to moderate granular cytoplasm fine nucleoli.to moderate granular cytoplasm fine nucleoli.

► Peripheral palisading common , scanty mitotic Peripheral palisading common , scanty mitotic figures, lymphatic and neural invasion common.figures, lymphatic and neural invasion common.

► Microscopic types from A to E :Microscopic types from A to E : insular, insular, trabecular, glandular, undifferentiated, mixed.trabecular, glandular, undifferentiated, mixed.

CARCINOID TUMORSCARCINOID TUMORS► HISTOCHEMISTRY- HISTOCHEMISTRY- argentafin argyrophilic argentafin argyrophilic

positive, negative for mucin positive, negative for mucin ► ULTRASTRUCTURE-ULTRASTRUCTURE- dense core pleomorphic dense core pleomorphic

secretory granulessecretory granules► IMMUNO- IMMUNO- keratin CK7, CK 20 +ve, pan-endocrine keratin CK7, CK 20 +ve, pan-endocrine

markers +ve, 5-HT, substance P gastrin, markers +ve, 5-HT, substance P gastrin, somatostatin, glucagon , PP, bombesin, GRP +vesomatostatin, glucagon , PP, bombesin, GRP +ve

► MOLECULAR AND GENETIC FEATURES-MOLECULAR AND GENETIC FEATURES- aneuploidy common, MEN-1 Negative, p53 rare aneuploidy common, MEN-1 Negative, p53 rare

► SPREAD AND METASTASIS-SPREAD AND METASTASIS- low grade , slow low grade , slow growth rate, highly invasive, metastasis to growth rate, highly invasive, metastasis to regional lymph nodes and liver.regional lymph nodes and liver.

► CARCINOID SYNDROME-CARCINOID SYNDROME- cyanosis of face, cyanosis of face, chest, intermittent hypertension, palpitations, chest, intermittent hypertension, palpitations, watery stools.watery stools.

MALIGNANT LYMPHOMA AND RELATED MALIGNANT LYMPHOMA AND RELATED DISORDERSDISORDERS

► Most common site for extra nodal lymphoma Most common site for extra nodal lymphoma T-CELL LYMPHOMAT-CELL LYMPHOMA► Mostly a complication of celiac sprue and other Mostly a complication of celiac sprue and other

malabsorption syndromes.malabsorption syndromes.► CD56 +ve, associated with EBV.CD56 +ve, associated with EBV.► Intense eosinophilic infiltrate may obscure the Intense eosinophilic infiltrate may obscure the

diagnosisdiagnosisB-CELL LYMPHOMAB-CELL LYMPHOMA► Arise from mucosa associated lymphoid tissue Arise from mucosa associated lymphoid tissue ► Mostly solitary , common in ileumMostly solitary , common in ileum► Diffusely infiltrating bulky mass with garden hose Diffusely infiltrating bulky mass with garden hose

appearance, extensive ulcerations.appearance, extensive ulcerations.► Regional lymph nodes usually also involved.Regional lymph nodes usually also involved.


IMMUNOPROLIFERATIVE SMALL INTESTINAL IMMUNOPROLIFERATIVE SMALL INTESTINAL DISEASE IPSIDDISEASE IPSID

► Common among Arabs, Jews, blacks of South Africa.Common among Arabs, Jews, blacks of South Africa.► Associated with diarrhea and malabsorptionAssociated with diarrhea and malabsorption► Low grade form-Low grade form- heavy lymphoplasmacytic heavy lymphoplasmacytic

infiltration of cells of slightly immature appearance, infiltration of cells of slightly immature appearance, monoclonal alpha heavy chains.monoclonal alpha heavy chains.

► High grade form-High grade form- highly pleomorphic large cell highly pleomorphic large cell lymphoma with immunoblastic and plasmacellular lymphoma with immunoblastic and plasmacellular features. Immunocytochemical positivety for alpha features. Immunocytochemical positivety for alpha chainschains

► Prominent starry sky appearance or follicular Prominent starry sky appearance or follicular lymphoid hyperplasia my be presentlymphoid hyperplasia my be present


LOW GRADE B-CELL LYMPHOMA (MALT TYPE)LOW GRADE B-CELL LYMPHOMA (MALT TYPE)► Predominance of small lymphoid cells, formation of Predominance of small lymphoid cells, formation of

lymphoepithelial lesions, reactive follicles.lymphoepithelial lesions, reactive follicles.► Large cell lymphoma high grade form may be Large cell lymphoma high grade form may be

associated with low grade or present in absence of associated with low grade or present in absence of low grade component. Mostly plasmacytoid cells low grade component. Mostly plasmacytoid cells

FOLLICULAR LYMPHOMAFOLLICULAR LYMPHOMA► Predilection for terminal ileum, innumerable small Predilection for terminal ileum, innumerable small

polypoidal masses, polypoidal masses, ► Translocation 14:18 typical Translocation 14:18 typical ► Arises from local antigen responsive B cellsArises from local antigen responsive B cells

MALTOMAMALTOMA

► TABLE 17-13 TABLE 17-13 -- Hereditary Syndromes Involving the Gastrointestinal -- Hereditary Syndromes Involving the Gastrointestinal TractTract

► Syndromes Altered Gene Pathology in GI TractSyndromes Altered Gene Pathology in GI Tract► Familial adenomatous polyposis (FAP) Familial adenomatous polyposis (FAP) APC APC Multiple adenomatous Multiple adenomatous

polypspolyps► • • Classic FAPClassic FAP► • • Attenuated FAPAttenuated FAP► • • Gardner syndromeGardner syndrome► • • Turcot syndromeTurcot syndrome► Peutz-Jeghers syndrome Peutz-Jeghers syndrome STK11 STK11 Hamartomatous polypsHamartomatous polyps► Juvenile polyposis syndrome Juvenile polyposis syndrome SMAD4 SMAD4 Juvenile polypsJuvenile polyps► BMPRIABMPRIA► Hereditary nonpolyposis colorectal carcinoma Defects in mismatch Hereditary nonpolyposis colorectal carcinoma Defects in mismatch

DNA repair genes Colon cancerDNA repair genes Colon cancer► Tuberous sclerosis Tuberous sclerosis TSC1 TSC1 Inflammatory polypsInflammatory polyps► TSC2TSC2► Cowden disease Cowden disease PTEN PTEN Hamartomatous polypsHamartomatous polyps

► Non-Neoplastic PolypsNon-Neoplastic Polyps► The overwhelming majority of intestinal polyps occur on a sporadic basis, particularly in 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 the colon, and increase in frequency with age. Non-neoplastic polyps include the hyperplastichyperplastic

► polyp, the hamartomatous polyp, the inflammatory polyp, and the lymphoid polyp. polyp, the hamartomatous polyp, the inflammatory polyp, and the lymphoid polyp. Hyperplastic polyps represent about 90% of all epithelial polyps in the large intestine. Hyperplastic polyps represent about 90% of all epithelial polyps in the large intestine. They may arise atThey may arise at

► any age but usually are discovered incidentally in the sixth and seventh decades. They 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 are found in more than half of all persons age 60 and older. It is believed that the hyperplastic polyphyperplastic polyp

► results from decreased epithelial cell turnover and accumulation of mature cells on the 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 surface. Harmatomatous polyps are malformations of the glands and the stroma. They can occurcan occur

► sporadically or occur in the setting of genetic syndromes ( Table 17-13 ). Inflammatory sporadically or occur in the setting of genetic syndromes ( Table 17-13 ). Inflammatory polyps, also known as polyps, also known as pseudopolyps, pseudopolyps, represent islands of inflamed regenerating mucosa represent islands of inflamed regenerating mucosa surroundedsurrounded

► by ulceration. These are seen primarily in patients with severe, active IBD. Lymphoid 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 polyps are an essentially normal variant of the mucosal bumps containing intramucosal lymphoidlymphoid

► tissue.tissue.► .hyperplastic polyp.hyperplastic polyp

► Hamartomatous Polyps.Hamartomatous Polyps.► Juvenile polyps Juvenile polyps represent focal hamartomatous malformations of the mucosal represent focal hamartomatous malformations of the mucosal

epithelium and lamina propria. For the most part they are sporadic lesions, with the vast epithelium and lamina propria. For the most part they are sporadic lesions, with the vast majority occurringmajority occurring

► in children younger than age 5. Isolated hamartomatous polyps may be identified in the in children younger than age 5. Isolated hamartomatous polyps may be identified in the colon of adults; these incidental lesions are referred to as colon of adults; these incidental lesions are referred to as retention polypsretention polyps. In both age . In both age groups,groups,

► nearly 80% of the polyps occur in the rectum, but they may be scattered throughout the 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 colon. Juvenile polyps tend to be large (1 to 3 cm in diameter), rounded, smooth or slightlyslightly

► lobulated lesions with stalks up to 2 cm in length; retention polyps tend to be smaller 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, (<1 cm diameter). Histologically, lamina propria comprises the bulk of the polyp, enclosing abundantenclosing abundant

► cystically dilated glands. Inflammation is common, and the surface may be congested or 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 ulcerated. In general they occur singly and being hamartomatous lesions have no malignantmalignant

► potential. However, the rare autosomal dominant potential. However, the rare autosomal dominant juvenile polyposis syndrome, juvenile polyposis syndrome, in in which there are multiple (50 to 100) juvenile polyps in the gastrointestinal tract, does which there are multiple (50 to 100) juvenile polyps in the gastrointestinal tract, does carry a risk ofcarry a risk of

► adenomas and hence adenocarcinoma. Mutations in the adenomas and hence adenocarcinoma. Mutations in the SMAD4/DPC4 SMAD4/DPC4 gene (which gene (which encodes a TGF-b signaling intermediate) account for some cases of juvenile polyposis encodes a TGF-b signaling intermediate) account for some cases of juvenile polyposis syndrome.[79]syndrome.[79]

► Peutz-Jeghers polyps Peutz-Jeghers polyps are hamartomatous polyps that are hamartomatous polyps that involve the mucosal epithelium, lamina propria, and involve the mucosal epithelium, lamina propria, and muscularis mucosa. These hamartomatous lesions may also muscularis mucosa. These hamartomatous lesions may also occur singly oroccur singly or

► multiply in the multiply in the Peutz-Jeghers syndromePeutz-Jeghers syndrome. This rare . This rare autosomal dominant syndrome is characterized by multiple autosomal dominant syndrome is characterized by multiple hamartomatous polyps scattered throughout the entire hamartomatous polyps scattered throughout the entire gastrointestinal tractgastrointestinal tract

► and melanotic mucosal and cutaneous pigmentation around and melanotic mucosal and cutaneous pigmentation around the lips, oral mucosa, face, genitalia, and palmar surfaces of the lips, oral mucosa, face, genitalia, and palmar surfaces of the hands. Patients with this syndrome are at risk forthe hands. Patients with this syndrome are at risk for

► intussusception, which is a common cause of mortality. Peutz-intussusception, which is a common cause of mortality. Peutz-Jeghers polyps tend to be large and pedunculated with a firm Jeghers polyps tend to be large and pedunculated with a firm lobulated contour. Histologically, an arborizing network oflobulated contour. Histologically, an arborizing network of

► connective tissue and well-developed smooth muscle extends connective tissue and well-developed smooth muscle extends into the polyp and surrounds normal abundantinto the polyp and surrounds normal abundant

Adenoma- carcinoma sequence postulated that loss of one normal copy of tumor suppressor gatekeeper gene APC occurs early. Indeed, individuals may be born with one mutant allele of APC, rendering them extremely likely to develop colon cancer. This is "first hit," according to Knudson's hypothesis loss of normal copy of APC gene follows ("second hit"). Mutations of oncogene K-RAS seem to occur next. Additional mutations or losses of heterozygosity inactivate tumor suppressor gene p53 and SMAD2 and SMAD4 leading finally to emergence of carcinoma, in whichadditional mutations occur. .

► TABLE 17-14 TABLE 17-14 -- TNM Classification of Carcinoma of the Colon and Rectum-- TNM Classification of Carcinoma of the Colon and Rectum► Tumor Stage Histologic Features of the NeoplasmTumor Stage Histologic Features of the Neoplasm► Tis Carcinoma in situ (high-grade dysplasia) or intramucosal carcinoma Tis Carcinoma in situ (high-grade dysplasia) or intramucosal carcinoma

(lamina propria invasion)(lamina propria invasion)► T1 Tumor invades submucosaT1 Tumor invades submucosa► T2 Extending into the muscularis propria but not penetrating through itT2 Extending into the muscularis propria but not penetrating through it► T3 Penetrating through the muscularis propria into subserosaT3 Penetrating through the muscularis propria into subserosa► T4 Tumor directly invades other organs or structuresT4 Tumor directly invades other organs or structures► Nx Regional lymph nodes cannot be assessedNx Regional lymph nodes cannot be assessed► N0 No regional lymph node metastasisN0 No regional lymph node metastasis► N1 Metastasis in 1 to 3 lymph nodesN1 Metastasis in 1 to 3 lymph nodes► N2 Metastasis in 4 or more lymph nodesN2 Metastasis in 4 or more lymph nodes► Mx Distant metastasis cannot be assessedMx Distant metastasis cannot be assessed► M0 No distant metastasisM0 No distant metastasis► M1 Distant metastasisM1 Distant metastasis► 867867► Figure 17-Figure 17-

► TABLE 17-15 TABLE 17-15 -- Clinical Features of the Carcinoid Syndrome-- Clinical Features of the Carcinoid Syndrome► • • Vasomotor distubancesVasomotor distubances► ••••Cutaneous flushes and apparent cyanosis (most patients)Cutaneous flushes and apparent cyanosis (most patients)► • • Intestinal hypermotilityIntestinal hypermotility► ••••Diarrhea, Cramps, nausea, vomiting (most patients)Diarrhea, Cramps, nausea, vomiting (most patients)► • • Asthmatic bronchoconstrictive attacksAsthmatic bronchoconstrictive attacks► ••••Couth, wheezing, dyspnea (about one third of patients)Couth, wheezing, dyspnea (about one third of patients)► • • HepatomegalyHepatomegaly► ••••Nodular liver owing to hepatic metastases (some patients)Nodular liver owing to hepatic metastases (some patients)► • • Systemic fibrosis (some patients)Systemic fibrosis (some patients)► ••••Cardiac involvementCardiac involvement► ••••••••Pulmonic and tricuspid valve thickening and stenosisPulmonic and tricuspid valve thickening and stenosis► ••••••••Endocardial fibrosis, principally in the right ventricleEndocardial fibrosis, principally in the right ventricle► ••••••••(Bronchial carcinoids affect the left side)(Bronchial carcinoids affect the left side)► ••••Retroperitoneal and pelvic fibrosisRetroperitoneal and pelvic fibrosis► ••••Collagenous pleural and intimal aortic plaquesCollagenous pleural and intimal aortic plaques► metastases are usually not required for the production of a carcinoid syndrome by 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 extraintestinal carcinoids (such as those arising in the lungs or ovaries), because active substancessubstances

► GASTROINTESTINAL LYMPHOMAGASTROINTESTINAL LYMPHOMA► Any segment of the gastrointestinal tract may be secondarily involved by systemic 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 dissemination of non-Hodgkin lymphomas. However, up to 40% of lymphomas arise in sites other thansites other than

► lymph nodes, and the gut is the most common location. Conversely, about 1% to 4% of lymph nodes, and the gut is the most common location. Conversely, about 1% to 4% of all gastrointestinal malignancies are lymphomas. all gastrointestinal malignancies are lymphomas. By definition, primary gastrointestinal By definition, primary gastrointestinal lymphomaslymphomas

► exhibit no evidence of liver, spleen, mediastinal lymph node, or bone marrow exhibit no evidence of liver, spleen, mediastinal lymph node, or bone marrow involvement at the time of diagnosisinvolvement at the time of diagnosis—regional lymph node involvement may be present. —regional lymph node involvement may be present. PrimaryPrimary

► gastrointestinal lymphomas usually arise as sporadic neoplasms but also occur more gastrointestinal lymphomas usually arise as sporadic neoplasms but also occur more frequently in certain patient populations: (1) Chronic gastritis caused by H. pylori, (2) frequently in certain patient populations: (1) Chronic gastritis caused by H. pylori, (2) chronicchronic

► spruelike syndromes, (3) natives of the Mediterranean region, (4) congenital spruelike syndromes, (3) natives of the Mediterranean region, (4) congenital immunodeficiency states, (5) infection with human immunodeficiency virus, and (6) immunodeficiency states, (5) infection with human immunodeficiency virus, and (6) following organfollowing organ

► transplantation with immunosuppression.transplantation with immunosuppression.► Intestinal tract lymphomas can be classified into B-cell and T-cell lymphomas. The B-cell 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-intestinallymphoma can be subdivided into MALT lymphoma, immunoproliferative small-intestinal► disease (IPSID), and Burkitt lymphoma.disease (IPSID), and Burkitt lymphoma.► 1. 1. MALT lymphoma is a sporadic lymphoma, which MALT lymphoma is a sporadic lymphoma, which arises from the B cells of MALT arises from the B cells of MALT

(mucosa-associated lymphoid tissue, described under gastric lymphoma). (mucosa-associated lymphoid tissue, described under gastric lymphoma). This type of This type of lymphomalymphoma

► 1. 1. MALT lymphoma is a sporadic lymphoma, which MALT lymphoma is a sporadic lymphoma, which arises from the B cells of MALT (mucosa-arises from the B cells of MALT (mucosa-associated lymphoid tissue, described under gastric lymphoma). associated lymphoid tissue, described under gastric lymphoma). This type of lymphomaThis type of lymphoma

► is the most common form in the Western hemisphere. is the most common form in the Western hemisphere. The biologic features of these The biologic features of these lymphomas are different from node-based lymphomas in that (1) many behave as focal lymphomas are different from node-based lymphomas in that (1) many behave as focal tumorstumors

► in their early stages and are amenable to surgical resection; (2) relapse may occur 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 exclusively in the gastrointestinal tract; (3) genotypic changes are different than those observed inobserved in

► nodal lymphomas: the t(11;18) translocation is relatively common in MALT lymphoma; and 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(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 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 colongut: 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 (10% to 15%), and distal colon (up to 10%). The appendix and esophagus are only rarely involved.involved.

► The pathogenesis of these lymphomas is under intense scrutiny. The concept has been 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 lymphoidadvanced that lymphomas of MALT origin arise in the setting of mucosal lymphoid

► activation and that these lymphomas are the malignant counterparts of hypermutated, activation and that these lymphomas are the malignant counterparts of hypermutated, postgerminal-center memory B cells. As discussed earlier, postgerminal-center memory B cells. As discussed earlier, HelicobacterHelicobacter-associated chronic-associated chronic

► gastritis, in particular, has been proposed as a driving force for the development of gastric gastritis, in particular, has been proposed as a driving force for the development of gastric MALT lymphoma, the result of antigen-driven somatic mutation ofMALT lymphoma, the result of antigen-driven somatic mutation of

► 869869► gastric lymphoid tissue. However, the etiologic factors for intestinal lymphoma are still gastric lymphoid tissue. However, the etiologic factors for intestinal lymphoma are still

unknown, although history of IBD appears to increase the risk.unknown, although history of IBD appears to increase the risk.► 2. 2. IPSID is also referred to as Mediterranean lymphoma. IPSID is also referred to as Mediterranean lymphoma. It is an unusual intestinal B-cell It is an unusual intestinal B-cell

lymphoma arising in patients with Mediterranean ancestry, having a background of chroniclymphoma arising in patients with Mediterranean ancestry, having a background of chronic

► 2. 2. IPSID is also referred to as Mediterranean lymphoma. IPSID is also referred to as Mediterranean lymphoma. It is an unusual intestinal B-It is an unusual intestinal B-cell lymphoma arising in patients with Mediterranean ancestry, having a background cell lymphoma arising in patients with Mediterranean ancestry, having a background of chronicof chronic

► diffuse mucosal plasmacytosis. The plasma cells synthesize an abnormal Iga heavy 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 chain, in which the variable portion has been deleted. A high proportion of patients havehave

► malabsorption and weight loss preceding the development of the lymphoma. The malabsorption and weight loss preceding the development of the lymphoma. The diagnosis is made most commonly in children and young adults, and both sexes diagnosis is made most commonly in children and young adults, and both sexes appear to beappear to be

► affected equally. The exact etiology of this type of lymphoma is not known, although affected equally. The exact etiology of this type of lymphoma is not known, although infection appears to play a role.[95]infection appears to play a role.[95]

► 3. 3. The intestinal T-cell lymphoma The intestinal T-cell lymphoma is usually associated with a long-standing is usually associated with a long-standing malabsorption syndrome (such as celiac disease) that may not constitute a true malabsorption syndrome (such as celiac disease) that may not constitute a true gluten-sensitivegluten-sensitive

► enteropathy. This lymphoma occurs in relatively young individuals (age 30 to 40), enteropathy. This lymphoma occurs in relatively young individuals (age 30 to 40), often following a 10- to 20-year history of symptomatic malabsorption. Alternatively, often following a 10- to 20-year history of symptomatic malabsorption. Alternatively, a diffusea diffuse

► enteropathy with malabsorption may accompany the development of a lymphoma. enteropathy with malabsorption may accompany the development of a lymphoma. Intestinal T-cell lymphoma arises most often in the proximal small bowel, and its Intestinal T-cell lymphoma arises most often in the proximal small bowel, and its overalloverall

► prognosis is poor (reported 11% five-year survival rate).prognosis is poor (reported 11% five-year survival rate).► Morphology.Morphology.► Gastrointestinal lymphomas can assume a variety of gross appearances. Since all the Gastrointestinal lymphomas can assume a variety of gross appearances. Since all the

gut lymphoid tissue is mucosal and submucosalgut lymphoid tissue is mucosal and submucosal

► Morphology.Morphology.► Gastrointestinal lymphomas can assume a variety of gross appearances. Since all the gut lymphoid 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 thetissue 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 mucosa and submucosa. Diffusely infiltrating lesions may produce full-thickness mural thickening, with

effacement of the overlying mucosal folds and focal ulceration. Others may beeffacement 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 polypoid, protruding into the lumen, or form large, fungating, ulcerated masses. Tumor infiltration into

the muscularis propria splays the muscle fibers, gradually destroying them. Becausethe muscularis propria splays the muscle fibers, gradually destroying them. Because► of this feature, advanced lesions frequently cause motility problems with secondary obstruction. Large of this feature, advanced lesions frequently cause motility problems with secondary obstruction. Large

tumors sometimes perforate because of lack of stromal support; reduction in tumortumors sometimes perforate because of lack of stromal support; reduction in tumor► bulk during chemotherapy also may lead to perforation.bulk during chemotherapy also may lead to perforation.► In the earliest histologic lesions, atypical lymphoid cells may be seen infiltrating the mucosa, with 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. Extremeeffacement and loss of glands and massive expansion of lymphoid tissue. Extreme► numbers of atypical lymphoid cells may populate the superficial or glandular epithelium numbers of atypical lymphoid cells may populate the superficial or glandular epithelium

(lymphoepithelial lesion). With established lymphomas, the mucosa, submucosa, and even muscle(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 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 occasionallylymphocytes 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-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 aregrade tumors. The small fraction of T-cell lymphomas occurring in the intestine are► commonly high-grade lesions.commonly high-grade lesions.► Clinical Features.Clinical Features.► With the exception of T-cell lymphomas, primary gastrointestinal lymphomas generally have a better 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 withprognosis 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, 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 largegastric 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 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 prognosisextension into adjacent viscera are important determinants of prognosis

CA & DYSPLASIA IN UCCA & DYSPLASIA IN UC►Incidence of colorectal Ca--Incidence of colorectal Ca--↑ in pt with UC↑ in pt with UC►5-10% in older series, current rate—2%5-10% in older series, current rate—2%►Risk is ↑ when:Risk is ↑ when:►Entire colon involved, disease is continuous, Entire colon involved, disease is continuous,

unremitting, long standing and when disease unremitting, long standing and when disease begins in childhoodbegins in childhood

►Gross: thick mucosa with nodular or velvety Gross: thick mucosa with nodular or velvety surfacesurface

CA & DYSPLASIA IN UCCA & DYSPLASIA IN UC

L/M:L/M: adenocarcinoma with varying degrees of adenocarcinoma with varying degrees of differentiationdifferentiation

► Mucinous and poorly differentiated Ca proportion Mucinous and poorly differentiated Ca proportion relatively relatively ↑↑

► Frank Ca always preceded by dysplasia in flat Frank Ca always preceded by dysplasia in flat atrophic mucosaatrophic mucosa

► Multiple rectal biopsies recommended for detection Multiple rectal biopsies recommended for detection of dysplasiaof dysplasia

► IHC:IHC: ↑ CEA, sialomucin ,↓ Ig, strong p53 & MIB-1 ↑ CEA, sialomucin ,↓ Ig, strong p53 & MIB-1 stainingstaining

DYSPLASIA IN UCDYSPLASIA IN UC

CLASSIFICATION OF DYSPLASIACLASSIFICATION OF DYSPLASIA

1.1. Negative for dysplasiaNegative for dysplasia

2.2. Indefinite for dysplasia, probably negativeIndefinite for dysplasia, probably negative

3.3. Indefinite for dysplasia, unknownIndefinite for dysplasia, unknown

4.4. Indefinite for dysplasia, probably positiveIndefinite for dysplasia, probably positive

5.5. Positive for dysplasia, low gradePositive for dysplasia, low grade

6.6. Positive for dysplasia, high gradePositive for dysplasia, high grade

DYSPLASIA IN UCDYSPLASIA IN UC

FOLLOW UPFOLLOW UP

►Category 1+2Category 1+2→ regular follow up→ regular follow up►Category 3+4 → short-term follow upCategory 3+4 → short-term follow up►Category 6 → colectomyCategory 6 → colectomy►Category 5 → short term follow up or Category 5 → short term follow up or

consider colectomyconsider colectomy►Surveillance for pt with UC: started after 8-Surveillance for pt with UC: started after 8-

10yrs of extensive colitis and 15 yrs of left sided 10yrs of extensive colitis and 15 yrs of left sided colitiscolitis

► COMPLICATIONSCOMPLICATIONS

► perforation leading toperforation leading to diffuse peritonitisdiffuse peritonitis peri appendiceal abscessperi appendiceal abscess fibrous indurationfibrous induration

► venous spread to liver---pylephlebitic abscessvenous spread to liver---pylephlebitic abscess► peri appendicitisperi appendicitis

primary from appendixprimary from appendix secondary inflammation in surrounding struct25secondary inflammation in surrounding struct25

► Morphology.Morphology.► Hyperplastic Polyps.Hyperplastic Polyps.► These are small (usually <5 mm in diameter) epithelial polyps that appear as nipple-like, 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 hemispheric, smooth, moist protrusions of the mucosa, usually positioned on the tops of mucosalmucosal

► folds. They may occur singly but more often are multiple, and over half are found in the 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 rectosigmoid colon. Histologically, they are composed of well-formed glands and crypts lined bylined by

► non-neoplastic epithelial cells, most of which show differentiation into mature goblet or 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 absorptive cells. The delayed shedding of surface epithelial cells leads to infoldings of the crowdedthe crowded

► epithelial cells and fission of the crypts, creating a serrated epithelial profile and an epithelial cells and fission of the crypts, creating a serrated epithelial profile and an irregular crypt architecture ( Fig. 17-56irregular crypt architecture ( Fig. 17-56A A ). Although large hyperplastic polyps may rarely ). Although large hyperplastic polyps may rarely coexist withcoexist with

► foci of adenomatous change, foci of adenomatous change, the usual small, hyperplastic polyp is considered to the usual small, hyperplastic polyp is considered to have virtually no malignant potentialhave virtually no malignant potential. However, the hyperplastic polyps occurring in . However, the hyperplastic polyps occurring in the setting ofthe setting of

► the rare hyperplastic polyposis syndrome can harbor epithelial cell dysplasia (adenoma), the rare hyperplastic polyposis syndrome can harbor epithelial cell dysplasia (adenoma), and hence are considered at risk for carcinoma. Theand hence are considered at risk for carcinoma. The

► 859859► underlying genetic basis for this syndrome is not known.underlying genetic basis for this syndrome is not known.► Hamartomatous Polyps.Hamartomatous Polyps.

MALTOMAMALTOMA


MANTEL CELL LYMPHOMAMANTEL CELL LYMPHOMA► Rare.Rare.► Multiple lymphoid polypsMultiple lymphoid polypsTRUE HISTIOCYTIC LYMPHOMASTRUE HISTIOCYTIC LYMPHOMAS► Cells positive for morphologic and histochemical Cells positive for morphologic and histochemical

markers of histiocytes and lacking reactivity for markers of histiocytes and lacking reactivity for lymphoid markerslymphoid markers

Other lymphomas includeOther lymphomas include► BURKITT’S LYMPHOMABURKITT’S LYMPHOMA► HODGKIN’S LYMPHOMAHODGKIN’S LYMPHOMA► ANAPLASTIC LARGE CELL LYMPHOMAANAPLASTIC LARGE CELL LYMPHOMA► MULTIPLE MYELOMAMULTIPLE MYELOMA► FOLLICULAR DENDRITIC CELL TUMORFOLLICULAR DENDRITIC CELL TUMOR

BURKITT’S LYMPHOMABURKITT’S LYMPHOMA

EPITHELIAL POLYPSEPITHELIAL POLYPS

1.1. Adenomatous polypsAdenomatous polyps2.2. Familial polyposisFamilial polyposis3.3. Gardner’s syndromeGardner’s syndrome4.4. Turcot’s syndromeTurcot’s syndrome5.5. Villous adenomaVillous adenoma6.6. Hyperplastic polypsHyperplastic polyps7.7. Juvenile (retention) polypJuvenile (retention) polyp8.8. Peutz-Jeghers polypPeutz-Jeghers polyp9.9. Transitional polypTransitional polyp

ADENOMATOUS POLYPADENOMATOUS POLYP

► Site:Site: 40% rt colon, 40% left colon, 20% rectum 40% rt colon, 40% left colon, 20% rectum► Familial, autosomal dominantFamilial, autosomal dominant► S/S:S/S: asymptomatic or bleeding, change in bowel asymptomatic or bleeding, change in bowel

habits or intussusceptionhabits or intussusception► Gross:Gross: mostly <1cm, sessile or pedunculated. mostly <1cm, sessile or pedunculated.

Single or multipleSingle or multiple

L/M:L/M: ↑ in no. of glands and cells/unit area↑ in no. of glands and cells/unit area► Cells crowding, hyperchromatic nuclei, ↑mitosisCells crowding, hyperchromatic nuclei, ↑mitosis► Mucin usually ↓Mucin usually ↓


► IHC: IHC: CEA, CK+CEA, CK+► Genetics:Genetics: aneuploidy, p53+, bcl-2+ aneuploidy, p53+, bcl-2+► E/M:E/M: nuclear and cytoplasmic alterations, abnormal nuclear and cytoplasmic alterations, abnormal

secretory dropletsssecretory dropletss► Focal areas of villous type can be seenFocal areas of villous type can be seen► Villous=glandularVillous=glandular→ villoglandular polyps→ villoglandular polyps

Atypia in polyp related to:Atypia in polyp related to:► ↑ ↑ age, no. of polyps/pt, size of polyp, villous changeage, no. of polyps/pt, size of polyp, villous change► Atypia gradingAtypia grading: mild, moderate, severe: mild, moderate, severe


► Atypical glands maybe seen in polyp beneath Atypical glands maybe seen in polyp beneath muscularis mucosae. D/D: malignant transformation in muscularis mucosae. D/D: malignant transformation in polyppolyp

► Helpful differential features: Helpful differential features:

1.1. Cytological features of glands same as surfaceCytological features of glands same as surface

2.2. Glands surrounded by loose inflammed stroma and Glands surrounded by loose inflammed stroma and scattered muscle bundlesscattered muscle bundles

3.3. Hemosiderin granules around glandsHemosiderin granules around glands► Glands may become cystic and ruptureGlands may become cystic and rupture→ mucin lakes→ mucin lakes► Squamous metaplasia, morula formation, clear cell Squamous metaplasia, morula formation, clear cell

change, endocrine cells—maybe seen in polypchange, endocrine cells—maybe seen in polyp

TUBULAR ADENOMATUBULAR ADENOMA

FAMILIAL POLYPOSISFAMILIAL POLYPOSIS

► Autosomal dominantAutosomal dominant► Gene:Gene: APC localized to 5q21, k-ras mutation APC localized to 5q21, k-ras mutation► Mechanism:Mechanism: persistence of DNA synthesis in epithelial cells persistence of DNA synthesis in epithelial cells► Age:Age: 2 2ndnd decade of life decade of life► Gross:Gross: bowel studded with polyp ranging from slightly bowel studded with polyp ranging from slightly

elevated to large masses, maybe flat or depressedelevated to large masses, maybe flat or depressed► 100 polyps—familial polyposis100 polyps—familial polyposis► May involve other parts of GIT: stomach and small bowelMay involve other parts of GIT: stomach and small bowel► Untreated cases may develop Ca (20 yrs earlier than ordinary Untreated cases may develop Ca (20 yrs earlier than ordinary

colorectal Ca)colorectal Ca)► Early colectomy recommendedEarly colectomy recommended

GARDNER’S SYNDROMEGARDNER’S SYNDROME

► Familial conditionFamilial condition► S/S:S/S: Adenomatous polyp of large bowel and sometimes Adenomatous polyp of large bowel and sometimes

small bowel and stomach, osteoma of skull, mandible, small bowel and stomach, osteoma of skull, mandible, multiple keratinous cysts of skin and soft tissue tumors multiple keratinous cysts of skin and soft tissue tumors especially intraabdominal fibromatosisespecially intraabdominal fibromatosis

► Gene:Gene: mutation of APC mutation of APC► Tendency for large bowel Ca is highTendency for large bowel Ca is high► May also develop Ca of small bowel (periampullary)May also develop Ca of small bowel (periampullary)

TURCOT’S SYNDROMETURCOT’S SYNDROME

►S/S:S/S: colorectal adenomatous polyps and colorectal adenomatous polyps and glioblastoma multiformeglioblastoma multiforme

►Genetics: Autosomal recessiveGenetics: Autosomal recessive►Mutation of APC or mismatch-repair geneMutation of APC or mismatch-repair gene

VILLOUS ADENOMAVILLOUS ADENOMA► Age: Age: older patientsolder patients► Site:Site: rectum or rectosigmoid rectum or rectosigmoid► S/S:S/S: fluid and electrolyte depletion fluid and electrolyte depletion► Gross:Gross: single mass that may grow to encircle bowel single mass that may grow to encircle bowel

completelycompletely► Papillary villous projection and attached by wide base, 10%--Papillary villous projection and attached by wide base, 10%--

pedunculated pedunculated ► L/M:L/M: villous projections ramify through long, paillary growth villous projections ramify through long, paillary growth► IHC:IHC: CEA+, mucin-ve CEA+, mucin-ve► Complications:Complications: Ca -29-70% Ca -29-70%► Treatment:Treatment: local excision or APR depending on size of local excision or APR depending on size of

tumortumor►

HYPERPLASTIC (METAPLASTIC) HYPERPLASTIC (METAPLASTIC) POLYPPOLYP

► Sessile, small sized(5mm), rarely pedunculated and Sessile, small sized(5mm), rarely pedunculated and large sizedlarge sized

L/M:L/M: elongated glands with intraluminal foldings—saw elongated glands with intraluminal foldings—saw toothed appearancetoothed appearance

► Mitotis Mitotis ↑ ↑ at baseat base► Abundant cytoplasm, inconspicuous basal nucleusAbundant cytoplasm, inconspicuous basal nucleus► Thickened basement membraneThickened basement membrane► Surface epithelium has micropapillary appearanceSurface epithelium has micropapillary appearance► IHC:IHC: CEA+, sialomucin CEA+, sialomucin↓↓

MIXED HYPERPLASTIC—MIXED HYPERPLASTIC—ADENOMATOUS POLYPADENOMATOUS POLYP

► Prominent sawtoothed appearance—serrated adenomaProminent sawtoothed appearance—serrated adenoma► Some malignant potentialSome malignant potentialINVERTED HYPERPLASTIC POLYP:INVERTED HYPERPLASTIC POLYP:► Site:Site: right colon right colon► L/M:L/M: endophytic growth, penetration of muscularis endophytic growth, penetration of muscularis

mucosaemucosaeMULTIPLE HYPERPLASTIC POLYPOSIS MULTIPLE HYPERPLASTIC POLYPOSIS

SYNDROME: SYNDROME: ► Large polyps, maybe associated with adenocarcinomaLarge polyps, maybe associated with adenocarcinoma

JUVENILE POLYPJUVENILE POLYP

► Age:Age: common in children, 1/3 common in children, 1/3rdrd –adults –adults► Site:Site: rectosigmoid rectosigmoid► S/S:S/S: rectal bleeding, autoamputation common rectal bleeding, autoamputation common► Gross:Gross: granular, red surface and cystic, lattice like granular, red surface and cystic, lattice like

appearance on cut sectionappearance on cut sectionL/M:L/M: ulceration covered by granulation tissue ulceration covered by granulation tissue► Cystically dilated glands with mucus, no atypiaCystically dilated glands with mucus, no atypia► Stroma—inflammation and edemaStroma—inflammation and edema► MULTIPLE JUVENILE POLYPOSISMULTIPLE JUVENILE POLYPOSIS— multiple polyps — multiple polyps

of juvenile typeof juvenile type► Ass Ass with adenomatous polyp and adenoca of large bowel, with adenomatous polyp and adenoca of large bowel,

duodenum, stomach or pancreasduodenum, stomach or pancreas

PEUTZ-JEGHERS POLYPSPEUTZ-JEGHERS POLYPS

►Similar to small bowel counterpartSimilar to small bowel counterpart►Disorganized glands, several types of cells, no Disorganized glands, several types of cells, no

atypia, smooth muscle fibers from muscularis atypia, smooth muscle fibers from muscularis mucosaemucosae

►Genetics: mutation of LKB1 gene Genetics: mutation of LKB1 gene

RELATIONSHIP WITH CARELATIONSHIP WITH CA1.1. Malignant transformation of solitary hyperplastic polyps, Malignant transformation of solitary hyperplastic polyps,

retention polyps and polyps of Peutz-Jeghers in retention polyps and polyps of Peutz-Jeghers in negligiblenegligible2.2. Polyposis syndrome— Polyposis syndrome— risk risk ↑↑

Familial polyposis & Gardner’s syndrome—100% riskFamilial polyposis & Gardner’s syndrome—100% risk Juvenile polyposis, hyperplastic polyposis and Peutz-Juvenile polyposis, hyperplastic polyposis and Peutz-

Jegher syndrome—risk ↓ but definitely ↑edJegher syndrome—risk ↓ but definitely ↑ed ↑ ↑ risk of duodenal and amupullary adenocarcinomarisk of duodenal and amupullary adenocarcinoma

3.3. Villous adenoma→ Villous adenoma→ malignantmalignant—29-70% cases—29-70% cases4.4. Adenomatous polyp (flat, villoglandular)→ malignantAdenomatous polyp (flat, villoglandular)→ malignant5.5. Not all adenomas→ malignantNot all adenomas→ malignant

– Larger and villous the polyp →↑ chance of focal Larger and villous the polyp →↑ chance of focal CarcinomaCarcinoma

6.6. Parallelism between adenomatous polyp and adenocarcinoma Parallelism between adenomatous polyp and adenocarcinoma

ADENOMA-CARCINOMA ADENOMA-CARCINOMA SEQUENCESEQUENCE

17p loss p53

Other alterations

Chromosome alteration gene 5q

mutation or loss AFP

DNA hypomethylation

12p Mutation

K ras

18q LossDCC

Normal epithelium

Hyper proliferativepithelium

Early adenoma

Intermediate adenoma

Late adenoma

Carcinoma Metastasis

TREATMENT OF POLYPSTREATMENT OF POLYPS

► Solitary juvenile polyps—simple removalSolitary juvenile polyps—simple removal► Familial polyposis—colectomy even in young ptsFamilial polyposis—colectomy even in young pts► Villous adenoma—removal in toto, determination of Ca in Villous adenoma—removal in toto, determination of Ca in

specimen—effect further surgeryspecimen—effect further surgery► Solitary adenomatous polyp:Solitary adenomatous polyp:

under reach of rectosigmoidoscope removed under reach of rectosigmoidoscope removed endoscopicallyendoscopically

High up polyp—fiberoptic scope removalHigh up polyp—fiberoptic scope removal► Proximally located polyp large—anterior resection of segment Proximally located polyp large—anterior resection of segment

of bowelof bowel

PRESENCE OF CA IN POLYPPRESENCE OF CA IN POLYP► Carcinomatous glands may be present only in mucosa and Carcinomatous glands may be present only in mucosa and

lamina propria above muscularis mucosae— lamina propria above muscularis mucosae— ca in situca in situ No lymph node metsNo lymph node mets Require simply polypectomyRequire simply polypectomy

► May extend beyond muscularis mucosae but not invading stalkMay extend beyond muscularis mucosae but not invading stalk— — Lymph node mets—1%Lymph node mets—1% Simple polypectomySimple polypectomy

► May extend to base of stalk or beyond— May extend to base of stalk or beyond— focal Ca with stalk focal Ca with stalk invasioninvasion Lymph node mets— Lymph node mets— ↑ ↑ colectomycolectomy

CARCINOMACARCINOMA

► AgeAge: 62yrs—mean age: 62yrs—mean age► Sex:Sex: ♂=♀♂=♀► Etiology:Etiology: dietary fats and animal protein dietary fats and animal protein► Genetics—familial polyposis, hereditary Genetics—familial polyposis, hereditary

nonpolyposis colorectal cancer sydrome (Lynch nonpolyposis colorectal cancer sydrome (Lynch syndrome)syndrome)

► Torre-muir syndromeTorre-muir syndrome► Patients with IBD have↑ predisposition for CaPatients with IBD have↑ predisposition for Ca► Complication of irradiation for Ca CxComplication of irradiation for Ca Cx

CARCINOMACARCINOMA

► S/S:S/S: change in bowel habit, rectal bleeding, anemia, change in bowel habit, rectal bleeding, anemia, vague abdominal painvague abdominal pain

► Intestinal obstruction—left sided tumorIntestinal obstruction—left sided tumor► PerforationPerforation► Serum CEASerum CEA —detected in 72-97% cases of —detected in 72-97% cases of

colorectal Ca, disappears after tumor resection, colorectal Ca, disappears after tumor resection, reappears after recurrence or metsreappears after recurrence or mets

► CEA used for monitoring therapyCEA used for monitoring therapy► Can be detected in tissues as wellCan be detected in tissues as well► Detection of mutations of ras and APC genes in stoolDetection of mutations of ras and APC genes in stool

RAISED SERUM CEARAISED SERUM CEA

► SEEN IN:SEEN IN:► Colorectal CaColorectal Ca► Ca stomachCa stomach► Ca pancreasCa pancreas► Ca breastCa breast► Ca prostateCa prostate► CLDCLD► Chronic renal diseaseChronic renal disease► ↑ ↑ CEA never detected in normal individualsCEA never detected in normal individuals

CARCINOMACARCINOMA

Site: Site: rectosigmoid—50% rectosigmoid—50% ► Rt sided tumor—Rt sided tumor—↑ ↑ common in elderly, blacks and with common in elderly, blacks and with

diverticular diseasediverticular disease► Multicentric Ca—3-6% casesMulticentric Ca—3-6% casesGross:Gross:► Polypoid—bulky mass with well defined rolled maginsPolypoid—bulky mass with well defined rolled magins► Ulcerative/infiltrating—less elevated surface with central Ulcerative/infiltrating—less elevated surface with central

ulcerationulceration► Flat or depressed Ca—deep stromal and lymphovascular Flat or depressed Ca—deep stromal and lymphovascular

invasioninvasion► Wall invasion can be seen grosslyWall invasion can be seen grossly► Mucinous Ca—gelatinous or glaringMucinous Ca—gelatinous or glaring► Determine pericolic extension and vein invasion on grossDetermine pericolic extension and vein invasion on gross► Determine appearance of rest of colon—polyp or Ca elsewhereDetermine appearance of rest of colon—polyp or Ca elsewhere

HISTOPATHOLOGYHISTOPATHOLOGY

► Well to modeately differentiated adenocarcinoma Well to modeately differentiated adenocarcinoma with variable mucinwith variable mucin

► Cells—columnar, goblet and few endocrine Cells—columnar, goblet and few endocrine ► Inflammatory and desmoplastic reaction Inflammatory and desmoplastic reaction ► Invasion of all layers of bowelInvasion of all layers of bowel► Pericolic extension, perineural and veinous Pericolic extension, perineural and veinous

invasioninvasion► Metaplastic bone formation—very rareMetaplastic bone formation—very rare► Residual polyp or hyperplastic glands seen at Residual polyp or hyperplastic glands seen at

tumor edgetumor edge

ADENOCARCINOMA COLONADENOCARCINOMA COLON

ADENOCARCINOMA COLONADENOCARCINOMA COLON

MICROSCOPIC TYPESMICROSCOPIC TYPES

1.1. Mucinous CaMucinous Ca2.2. Signet ring CaSignet ring Ca3.3. Basaloid (cloacogenic Ca)Basaloid (cloacogenic Ca)4.4. Clear cell CaClear cell Ca5.5. Hepatoid adenocaHepatoid adenoca6.6. Medullary (solid, poorly differentiated) adenocarcinomaMedullary (solid, poorly differentiated) adenocarcinoma7.7. Anaplastic (solid, giant cell, sarcomatoid) caAnaplastic (solid, giant cell, sarcomatoid) ca8.8. Squamous differentiationSquamous differentiation9.9. Trophoblastic differentiationTrophoblastic differentiation10.10. Endocrine differentiationEndocrine differentiation11.11. Rhabdoid differentiationRhabdoid differentiation

MUCINOUS CARCINOMAMUCINOUS CARCINOMA

SIGNET RING CARCINOMASIGNET RING CARCINOMA

► Rare formRare form► Age:Age: young young ► Gross:Gross: diffuse infiltration of bowel wall, maybe seen in diffuse infiltration of bowel wall, maybe seen in

adenomatous polyp as welladenomatous polyp as wellL/M:L/M: diffuse growth, with few gland formation diffuse growth, with few gland formation► Signet ring cellsSignet ring cells► Mets:Mets: lymph nodes, peritoneal surface and ovary rather lymph nodes, peritoneal surface and ovary rather

than liverthan liver► Prognosis: very poorPrognosis: very poorD/D:D/D: gastric signet ring ca or breast ca gastric signet ring ca or breast ca► Benign signet ring change seen in pseudomembranous Benign signet ring change seen in pseudomembranous

colitis and inflammatory conditionscolitis and inflammatory conditions► IHC:IHC: CK7-/CK20+ CK7-/CK20+

BASALOID CA:BASALOID CA:► Same as anal couterpartSame as anal couterpart

CLEAR CELL CA:CLEAR CELL CA:► Not specific entityNot specific entity► Morphological variant of Morphological variant of

adenocarcinoma with adenocarcinoma with glycogen accumulation in glycogen accumulation in cellscells

HEPATOIDADENOCA:HEPATOIDADENOCA:► Similar to gastric counterpartSimilar to gastric counterpart► RHABDOID FEATURES:RHABDOID FEATURES:► Site: cecumSite: cecum► Aggressive behaviorAggressive behavior

MEDULLARY CA:MEDULLARY CA:► Site: cecum, rt colonSite: cecum, rt colon► Sex: Sex: ♀♀► Genetics: microsatellite Genetics: microsatellite

instabilityinstability

ANAPLASTIC CA:ANAPLASTIC CA:► Aggressive behaviorAggressive behavior

SQUAMOUS SQUAMOUS DIFFERENTIATION:DIFFERENTIATION:

► Site: cecumSite: cecum► Adenosquamous CaAdenosquamous Ca► Squamous cell CaSquamous cell Ca

TROPHOBLASTIC TROPHOBLASTIC DIFFRENTIATION:DIFFRENTIATION:

► Focal change in adenocaFocal change in adenoca► hCG+hCG+► Rarely—choriocarcinoma or Rarely—choriocarcinoma or

glassy cell Ca formglassy cell Ca formENDOCRINE ENDOCRINE

DIFFERENTIATION:DIFFERENTIATION:1.1. As scttered endocrine cells As scttered endocrine cells

in typical adenocain typical adenoca► Seen in mucinous caSeen in mucinous ca► ↑ ↑ seen after chemo or seen after chemo or

radiotherapyradiotherapy

2.2. In tumors with mixed In tumors with mixed compositioncomposition

► Typcial adenoca+clear cut Typcial adenoca+clear cut enodcrine differentitationenodcrine differentitation

3.3. Neuroendocrine CaNeuroendocrine Ca► Organoid appearanceOrganoid appearance► Large cellsLarge cells4)4) Small cell Small cell

(neuroendocrine) Ca(neuroendocrine) Ca► Similar to pulmonary Similar to pulmonary

counterpartcounterpart► E/M: few dense core E/M: few dense core

secretory granulessecretory granules► IHC: NSE+IHC: NSE+5.5. Carcinoid tumorCarcinoid tumor

HISTOCHEMISTRY:HISTOCHEMISTRY:► Mucin+ (PAS)Mucin+ (PAS)IHC:IHC:► MUC1 and MUC3+, MUC2-ve, MUC5AC-veMUC1 and MUC3+, MUC2-ve, MUC5AC-ve► CK20+/CK7- : helps to differentiate from Ca ovary and lungCK20+/CK7- : helps to differentiate from Ca ovary and lung► CEA+: seen as a rule, -ivity means that tumor is not colorectal CEA+: seen as a rule, -ivity means that tumor is not colorectal

in originin origin► CDX2+CDX2+► TAG-72+, LEA+TAG-72+, LEA+► Loss of blood gp Ag, HLA A,B,C expression—poorly Loss of blood gp Ag, HLA A,B,C expression—poorly

differentiated Cadifferentiated Ca► Abnormalities of lectin bindingAbnormalities of lectin binding► Villin+, cathepsinB+Villin+, cathepsinB+► Calretenin+--undifferentiated Calretenin+--undifferentiated ► hCG—mucinous and poorly differentiated tumorshCG—mucinous and poorly differentiated tumors► PLAP+ 10%PLAP+ 10%► ER/PR -veER/PR -ve

MOLECULAR GENTICSMOLECULAR GENTICS

► Somatic mutations of genes:Somatic mutations of genes:► APC, mismatch repair genes, p53, k-ras and DCCAPC, mismatch repair genes, p53, k-ras and DCC► Microsatellite instability associated tumors—mucinous or poorly Microsatellite instability associated tumors—mucinous or poorly

differentiated, right sided, prominent host response and with differentiated, right sided, prominent host response and with circumferential growthcircumferential growth

► ΒΒ catenin is associated with APC gene catenin is associated with APC gene► E-cadherin and E-cadherin and αα-catenin correlates with local invasion and mets-catenin correlates with local invasion and mets► p53 mutation p53 mutation ► Mutation of ras oncogeneMutation of ras oncogene► Deletion of von Hippel-Lindau geneDeletion of von Hippel-Lindau gene► Enhanced expression of c-myc oncogeneEnhanced expression of c-myc oncogene► Ki-67--↑ proliferative activityKi-67--↑ proliferative activity

COLORECTAL CARCINOMACOLORECTAL CARCINOMA

BIOPSY: BIOPSY: ► +ve biopsy should be obtained before definitive treatment+ve biopsy should be obtained before definitive treatment► Larger lesion—multiple biopsiesLarger lesion—multiple biopsies► Better differentiated tumors and signet ring Ca—difficult to Better differentiated tumors and signet ring Ca—difficult to

identifyidentify► Rectal tumors—biopsy the submucosal invasive tumor frontRectal tumors—biopsy the submucosal invasive tumor frontCYTOLOGY:CYTOLOGY:► Accurate via of diagnosing colorectal CaAccurate via of diagnosing colorectal Ca► Brush cytology via fiberoptic scopeBrush cytology via fiberoptic scope► Rectal lesion can be sampled through cytologyRectal lesion can be sampled through cytology

GRADING & STAGINGGRADING & STAGING

► Dukes staging system—1973Dukes staging system—1973 : : A: tumor involve wall of bowel onlyA: tumor involve wall of bowel only B: tumor extend through the wallB: tumor extend through the wall C1: tumors with regional lypmh node metsC1: tumors with regional lypmh node mets C2: tumors with +ve lymph nodes at point of mesenteric C2: tumors with +ve lymph nodes at point of mesenteric

blood vessel ligatureblood vessel ligature D: distant metsD: distant mets

► Astler and Coller—1954:Astler and Coller—1954: A: limited to mucosaA: limited to mucosa B1: involving muscularis externa but not penetrating itB1: involving muscularis externa but not penetrating it B2: penetrating through muscularis externaB2: penetrating through muscularis externa C1: confined to bowel wall but with nodal metsC1: confined to bowel wall but with nodal mets C2: penetrating through wall and with nodal metsC2: penetrating through wall and with nodal mets

GRADING & STAGINGGRADING & STAGING

► TNM:TNM:

► GRADING:GRADING: I I Well differentiatedWell differentiated IIII Moderately differentiatedModerately differentiated IIIIII Poorly differentiatedPoorly differentiated Grading should be determined by worst pattern Grading should be determined by worst pattern

rahter than the predominant onerahter than the predominant one

SPREAD AND METASTASISSPREAD AND METASTASIS

► Most common sites of colonic mets:Most common sites of colonic mets:► Regional lymph nodes and liverRegional lymph nodes and liver► Lymph nodes ↑ common—poorly differentiated areas and Lymph nodes ↑ common—poorly differentiated areas and

highly infiltrative patternhighly infiltrative pattern► Minimum number of nodes recovered from surgical Minimum number of nodes recovered from surgical

specimen of colorectal Ca should be 14-15specimen of colorectal Ca should be 14-15► Lymph nodes micromets req—serial H&E section, IHC for Lymph nodes micromets req—serial H&E section, IHC for

CK, PCR for CK19/20 or mutant k-rasCK, PCR for CK19/20 or mutant k-ras► Pericolonic tumor deposits—tumor nodules in perineural, Pericolonic tumor deposits—tumor nodules in perineural,

perivascular or intravascular location beyond muscularis perivascular or intravascular location beyond muscularis propriapropria

► Other metastatic site:Other metastatic site: preitoneum, lung, ovaries preitoneum, lung, ovaries► RareRare– CNS, bone, testis, uterus and oral cavity– CNS, bone, testis, uterus and oral cavity

TREATMENTTREATMENT

► Surgical resection:Surgical resection:► Ca cecum or ascending colon—ileocolectomyCa cecum or ascending colon—ileocolectomy► Tumors below peritoneal reflection—APRTumors below peritoneal reflection—APR► Ca in other areas of bowel—anterior resectionCa in other areas of bowel—anterior resection► Resectability rate for Ca colorectum—92%Resectability rate for Ca colorectum—92%► Operative mortality—2%Operative mortality—2%► Pre and postoperative radio and chemotherapy—variable Pre and postoperative radio and chemotherapy—variable

results in different centersresults in different centers

PROGNOSISPROGNOSIS

► 5 yr survival rate after curative resection—40-60%5 yr survival rate after curative resection—40-60%► Local recurrence and regional lymph node metsLocal recurrence and regional lymph node mets90% of failure 90% of failure

casescases► AJCC divided prognostic factors into certain categories:AJCC divided prognostic factors into certain categories:► Category I:Category I: well supported by literature, generally used in pt well supported by literature, generally used in pt

management and of sufficient importance to modify TNM systemmanagement and of sufficient importance to modify TNM system► Category IIA:Category IIA: extensively studied biologically &/or clinically. extensively studied biologically &/or clinically.

Prognostic value for therapy, sufficient to be noted in pathology Prognostic value for therapy, sufficient to be noted in pathology reportreport

► Category IIB:Category IIB: well studied but not sufficiently established for well studied but not sufficiently established for Category I or IIACategory I or IIA

► Category III:Category III: not yet established to meet criteria for Category I not yet established to meet criteria for Category I or IIor II

► Category IV:Category IV: studied and shows no consistent prognostic studied and shows no consistent prognostic significancesignificance

PROGNOSTIC FACTORSPROGNOSTIC FACTORS

1.1. Age:Age: very young and very old—poor prognosis very young and very old—poor prognosis– Young—advanced stage, UC, signet ring and mucinous tumors—Young—advanced stage, UC, signet ring and mucinous tumors—

bad prognosisbad prognosis More important in rectal than colonic tumorsMore important in rectal than colonic tumors

2.2. Sex:Sex: ♀ better than ♂♀ better than ♂3.3. CEA serum levels:CEA serum levels: >5 ng/ml—adverse prognosis >5 ng/ml—adverse prognosis4.4. Tumor location:Tumor location: controversial, however left sided lesion better controversial, however left sided lesion better5.5. Tumor multiplicity:Tumor multiplicity: no difference no difference6.6. Local extent:Local extent: better for focal microscopic tumor and tumor better for focal microscopic tumor and tumor

restricted to mucosa or submucosarestricted to mucosa or submucosa– Worse for tumors extending beyond wallWorse for tumors extending beyond wall

7.7. Tumor size:Tumor size: not a reliable factor (category III) not a reliable factor (category III)8.8. Tumor edge:Tumor edge: non polypoid edge worse than polypoid non polypoid edge worse than polypoid

(category III)(category III)

PROGNOSTIC FACTORSPROGNOSTIC FACTORS9.9. Obstruction: Obstruction: worse prognosis in some seriesworse prognosis in some series10.10. Perforation:Perforation: poor prognosis poor prognosis11.11. Tumor margins and inflammatory reaction: Tumor margins and inflammatory reaction:

– Pushing margins and inflammatory infiltrate—better Pushing margins and inflammatory infiltrate—better prognosis (IIA)prognosis (IIA)

– Tumor infiltration by eosinophils and S-100+ dendritic Tumor infiltration by eosinophils and S-100+ dendritic cells—better prognosiscells—better prognosis

– ≥ ≥ 4 mast cells x 30 oil immersion fields—poor 4 mast cells x 30 oil immersion fields—poor prognosisprognosis

12.12. Vascular invasion:Vascular invasion: ↓ survival rate ↓ survival rate– Lymph vessel invasion less importance than venous Lymph vessel invasion less importance than venous

invasion (IIA)invasion (IIA)13.13. Perineural invasion:Perineural invasion: sign of advanced disease (IIA) sign of advanced disease (IIA)

PROGNOSTIC FACTORSPROGNOSTIC FACTORS14.14. Surgical margins:Surgical margins:

– involvement of radial margin—single most ciritical involvement of radial margin—single most ciritical factor in determining recurrence (IIA)factor in determining recurrence (IIA)

– Recurrence chance ↑--tumor <2m away from Recurrence chance ↑--tumor <2m away from circumferential margincircumferential margin

15.15. Tumor thicknessTumor thickness: correlates with node and liver mets: correlates with node and liver mets16.16. Microscopic type: Microscopic type:

– Mucinous, signet ring and anaplastic—worse prognosisMucinous, signet ring and anaplastic—worse prognosis– Medullary Ca—imporved outcome (IIB)Medullary Ca—imporved outcome (IIB)

17.17. Acinar morphology:Acinar morphology: microacinar growth—poor prognosis microacinar growth—poor prognosis18.18. Neuroendocrine cells:Neuroendocrine cells: controversial (III) controversial (III)19.19. Tumor angiogenesis:Tumor angiogenesis: recurrence and ↓ survival (III) recurrence and ↓ survival (III)20.20. Mucin related Ag:Mucin related Ag: MUC1 and sialyl-Lewis(x)—tumor MUC1 and sialyl-Lewis(x)—tumor

progression (III)progression (III)

PROGNOSTIC FACTORSPROGNOSTIC FACTORS21.21. HLA-DR: HLA-DR: better prognosisbetter prognosis22.22. hCG:hCG: not an adverse prognostic factor not an adverse prognostic factor23.23. bcl-2:bcl-2: improved prognosis (IIB) improved prognosis (IIB)24.24. DNA ploidy:DNA ploidy: prognostic value doubtful prognostic value doubtful25.25. Cell proliferation:Cell proliferation: controversial controversial26.26. Allelic loss of chromosome 18q:Allelic loss of chromosome 18q: negative prognosis (IIB) negative prognosis (IIB)27.27. TGF-TGF-ββ mutation: mutation: favorable prognosis favorable prognosis28.28. Oncogene expression: Oncogene expression:

– K-ras mutation—recurrent disease (IIB)K-ras mutation—recurrent disease (IIB)– ras p21—recurrent diseaseras p21—recurrent disease– P53—independent prognostic factor (IIB)P53—independent prognostic factor (IIB)– c-myc—correlated with degree of differentiationc-myc—correlated with degree of differentiation– Microsatellite instability—improved survivalMicrosatellite instability—improved survival– Thymidylate synthatase mRNA—poor prognosisThymidylate synthatase mRNA—poor prognosis– Lack of p27—poor prognosis (IIB)Lack of p27—poor prognosis (IIB)

PROGNOSTIC FACTORSPROGNOSTIC FACTORS

29.29. Lymph node involement: Lymph node involement: poor prognosis (I)poor prognosis (I)– Location and extent of node importantLocation and extent of node important– ↑ ↑ nodes involved→↑ worse the prognosisnodes involved→↑ worse the prognosis– Micromets in nodes—poor survival (III)Micromets in nodes—poor survival (III)

30.30. Pattern of lymph node reaction:Pattern of lymph node reaction: regional nodes showing regional nodes showing cell mediated immune response—better survivalcell mediated immune response—better survival

31.31. Staging:Staging: correlates with prognosis (I) correlates with prognosis (I)32.32. Microscopic grade:Microscopic grade: correlates with prognosis (IIA) correlates with prognosis (IIA)

TNM CLASSIFICATIONTNM CLASSIFICATION

► PRIMARY TUMOR (t)PRIMARY TUMOR (t)► TXTX Primary tumor can’t be assessedPrimary tumor can’t be assessed► T0T0 No evidence of primary tumorNo evidence of primary tumor► TisTis Ca in situ: intraepithelial or invasion of lamina Ca in situ: intraepithelial or invasion of lamina

propriapropria► T1T1 Tumor invades submucosaTumor invades submucosa► T2T2 Tumor invades muscularis propriaTumor invades muscularis propria► T3T3 Tumor invades through muscularis propria into Tumor invades through muscularis propria into

subsersosa or into nonperitonealized pericolic subsersosa or into nonperitonealized pericolic or or perirectal tissueperirectal tissue

► T4T4 Tumor directly invades other organs or Tumor directly invades other organs or structures and / or perforates visceral structures and / or perforates visceral peritoneumperitoneum

TNM CLASSIFICATIONTNM CLASSIFICATION

► REGIONAL LYMPH NODES (N)REGIONAL LYMPH NODES (N)► NXNX Regional lymph nodes can’t be assessedRegional lymph nodes can’t be assessed► N0N0 No regional lymph node metastasisNo regional lymph node metastasis► N1N1 Metastasis in 1 to 3 regional lymph nodesMetastasis in 1 to 3 regional lymph nodes► N2N2 Metastasis in Metastasis in ≥ 4 regional lymph nodes≥ 4 regional lymph nodes

► DISTANT METASTASIS (M)DISTANT METASTASIS (M)► MXMX Distant metastasis can’t be assessedDistant metastasis can’t be assessed► M0M0 No distant metastasisNo distant metastasis► M1M1 Distant metastasisDistant metastasis

STAGE GROUPINGSTAGE 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

CARCINOID TUMORCARCINOID TUMOR

Site:Site:► RectumRectum—more common, anterior or lateral wall, round shape, —more common, anterior or lateral wall, round shape,

usually <0.5cm, nodal mets rare, maybe seen in ass with UC or usually <0.5cm, nodal mets rare, maybe seen in ass with UC or CD, ovarian carcinoid and as collision tumor with CD, ovarian carcinoid and as collision tumor with adenomatous componentadenomatous component

► May occur in any part of large bowelMay occur in any part of large bowel► Colonic carcinoidColonic carcinoid— large, penetrate wall deeply with regional — large, penetrate wall deeply with regional

nodal metsnodal mets► S/S:S/S: never ass with carcinoid syndrome never ass with carcinoid syndromeGross:Gross:► flat or slightly depressed plaque or polypoid lesionflat or slightly depressed plaque or polypoid lesion► Yellow color after formalin fixationYellow color after formalin fixation

CARCINOID TUMORCARCINOID TUMOR

L/M:L/M:► Ribbon and festoons, minor tubular and acinar component with Ribbon and festoons, minor tubular and acinar component with

mucin mucin ► Crypt cell proliferative micronestsCrypt cell proliferative micronests► Argyrophil+, argentaffin-veArgyrophil+, argentaffin-veIHC:IHC:► Panendocrine markers+ (NSE, synaptophysin, crhromogranin)Panendocrine markers+ (NSE, synaptophysin, crhromogranin)► Somatostatin, glucagon, substance P, peptide YY+Somatostatin, glucagon, substance P, peptide YY+► Gastrin/cholecystokinin, calcitonin, pancreatic polypeptide and Gastrin/cholecystokinin, calcitonin, pancreatic polypeptide and

motilin +motilin +► Rectal—CEA+, hCG+, prostatic acid phosphatase+Rectal—CEA+, hCG+, prostatic acid phosphatase+Treatment:Treatment: rectal carcinoid <2cm, limited to mucosa or submucosa rectal carcinoid <2cm, limited to mucosa or submucosa

by local excision by local excision ► Large tumors/ invasion of muscularis propria—radical surgeryLarge tumors/ invasion of muscularis propria—radical surgery

LYMPHOMALYMPHOMA

► Less frequently seen in large bowel compared to stomach and Less frequently seen in large bowel compared to stomach and small bowelsmall bowel

► Seen in HIV infected or transplant recipients or in pts with UCSeen in HIV infected or transplant recipients or in pts with UCGross:Gross: prominent mucosal folds, ulceration, large mass or prominent mucosal folds, ulceration, large mass or

solitary/multiple polypssolitary/multiple polyps► Regional nodes involved—50% casesRegional nodes involved—50% casesL/M:L/M: non hodgkin lymphoma non hodgkin lymphoma► Low grade—MALToma—plasmacytoid differentiationLow grade—MALToma—plasmacytoid differentiation► Mantle cell lymphomaMantle cell lymphoma► Anaplastic large cell lymphoma Anaplastic large cell lymphoma ► AILD like lymphomaAILD like lymphoma► Hodgkin’s lymphomaHodgkin’s lymphoma

METASTATIC TUMORSMETASTATIC TUMORS

► Disk like areas with central ulcerationDisk like areas with central ulceration► Primary: Melanoma, Ca lungPrimary: Melanoma, Ca lung► Prostatic Ca mets may simulate primary rectal CaProstatic Ca mets may simulate primary rectal Ca► Mesothelioma as multiple colonic polypsMesothelioma as multiple colonic polyps

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