Small & large gut

SMALL & LARGE
INTESTINE
PATHOLOGY

Important features
► Villous to crypt length ratio is 3:1, 5:1
► One lymphocyte per five enterocytes
► Paneth cells secrete defensins present up to
ascending colon
► Peyer patches , M cells
► Small intestine 6 meters (25cm duodenum)
► Large intestine 1.5 meters (20cm Rectum)
► Anal canal 4cm
► Enteritis(duodenitis, ileitis), Colitis(typhilitis,
proctitis), Cryptitis

Major Causes of Malabsorption
Defective 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 dysfunction
Primary Mucosal Cell Abnormalities
Defective terminal digestion
• Disaccharidase deficiency (lactose intolerance)
• Bacterial overgrowth, with brush border damage
Defective epithelial transport
• Abetalipoproteinemia
• Primary bile acid malabsorption owing to mutations in the ileal bile acid transporter
Reduced Small Intestinal Surface Area
Gluten-sensitive enteropathy (celiac disease)
Crohn disease
Lymphatic Obstruction
Lymphoma,Tuberculosis and tuberculous lymphadenitis
Infection
Acute infectious enteritis or Parasitic infestation
Tropical sprue, Whipple disease (Tropheryma whippelii)
Iatrogenic
Subtotal or total gastrectomy
Short-gut syndrome, following extensive surgical resection or by pass

CELIAC DISEASE
► Celiac disease (celiac sprue, gluten-
sensitive enteropathy) a chronic disease,
characteristic mucosal lesion of small
intestine and impaired nutrient absorption,
which improves on withdrawal of wheat
gliadins and related grain proteins from diet
► Celiac disease occurs largely in Caucasians
and is rare or nonexistent among native
Africans, Japanese, and Chinese
► Infants, yet adults in 5 th decade of life may
seek attention

Pathogenesis
Sensitivity to gluten, alcohol-soluble, water-insoluble protein component
gliadin (protein found in gluten fraction of wheat) and closely related grains
(oat, barley, and rye)
Interplay between genetic predisposing factors, host immune response, and
environmental factors is central to disease pathogenesis

► Exposure to gliadin results in T-cell mediated chronic inflammatory reaction
with accumulation of intraepithelial CD8+ T cells and large numbers of
lamina propria CD4+ T cells, which are sensitized to gliadin results in
circulating antibodies against gliadin
► Epithelial cells secrete large amount of IL5 that activate CD8+ T cells
(increases risk of T cell lymphoma)

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

► Proposed that gliadin is deamidated by enzyme transglutaminase into
peptides which binds to DQ2 and DQ8, recognition of these peptides by
CD4+ T cells leads `to secretion of Gamma interferon which damages
intestinal wall

CELIAC DISEASE
Gross:
Duodenal folds are absent or reduced
Microscopy:
 Atrophic villi (Usually complete)
 Normal thickness of mucosa
 Villous crypt ratio decreased
 Crypt hyperplastic-elongated tortuous
 Increase mitoses
 Increase in no of lymphocytes, plasma cells,
eosinophils, macrophages
 Intraepithelial leucocytes
 Vacuolar degeneration and loss of brush borders
of surface epithelium

Out come of Celiac Disease
► Intestinal Non Hodgkin T-cell lymphoma
► Chronic nonspecific duodenojejunoileitis
► Small intestine adenocarcinoma
► Squamous cell carcinoma of esophagus
► Dermatitis herpitiformis blistering skin lesion

Diagnosis of Celiac Disease
► Clinical malabsorption (Diarrhea ,flatulence,
wt loss, fatigue, failure to thrive in childern
► Small bowel biopsy Villous atrophy
► Responds to gluten with drawl from diet
► Antigliaden or antiendomysial antibodies
► Antitransglutiminase IgA, IgG
► Antireticulin antibodies

TROPICAL SPRUE
► Definite geographic distribution
► Bacterial etiology with or with out additive effects
of fat.
► Unaffected by gluten ingestion, responds to folic
acid, vit B12, tetracycline.
► There is partial villous atrophy

WHIPPLE’S DISEASE
► Male to female ratio 10:1
► Large macrophages in lamina propria, distorting
the villi, alternating with empty spaces.
► Histiocytes cytoplasm contains diastase-resistant
PAS positive & gram positive abundant bacilli
Tropheryma whippelii
► Diagnosis by PCR, immuno, electron microscopy.
► Biopsy of peripheral lymph nodes – presence of
typical macrophages.

AMEBIC COLITIS
► Simulate ulcerative colitis or Crohn’s disease
► Gross: ulceration covered by exudate, with normal
intervening mucosa
► Site: cecum and ascending colon
► L/M: nonspecific
► Flask shaped ulcer, relative paucity of inflammatory
cells beneath ulcer
► Trophozoites of E. histolytica
► Erythrocytosis by trophozoites usually present
► Can be detected by PAS stain
► Stool R/E

Major Causes of Bacterial Enterocolitis

Escherichia coli
• ETEC EHEC EPEC EIEC
Salmonella
Shigella
Campylobacter
Yersinia enterocolitica
Vibrio cholerae,
Clostridium difficile
Clostridium perfringens
Mycobacterium tuberculosis

Protozoa
Amebic colitis

Ulcers of Intestine
► Oval- Salmonella typhi long axes along axes of ileum
► Linear-Salmonella paratyphi
► Flask shaped –amebic
► Irregular –Shigella
► Multiple superficial ulcers-Campylobacter jejuni
► Ulcer along transverse axes- Tuberculosis
► Early Aphthous & late long linear serpintine-Crohn
► Extensive broad base – Ulcerative colitis
► Solitary Rectal Ulcer
► Malignant ulcers

Granulomatous lesions of Intestine
► Tuberculosis caseating granulomas
► Crohn disease non-caseating granulomas
► Foreigen body granulomas
► Necrotizing granulomas-Yersinia
enterocolitica, Y. pseudetuberculosis
► Oliogranuloma-against fat

SOLITARY RECTAL ULCER
► Solitary ulcerated or polypoid lesion 4-18cm from anal
margin
► Associated with rectal prolapse
► S/S: passage of blood and mucus , altered bowel habits
and pain
L/M: superficial and irregular mucosal ulceration
► Hyperplasia of crypts, villous configuration
► Obliteration of lamina propria by fibroblasts, elastin and
smooth muscles
► Thickened muscularis mucosae
► ↓ lymphocytes and plasma cells
► Chronic form– similar to colitis cystica profunda

HIRSCHSPRUNG’S DISEASE
Cause: lack of coordinated Sex: 80% ♂
movements of distal large
► Association with
bowel due to loss of
intrinsic inhibitory intestinal atresia and
innervations anorectal malformation
► Absent parasympathetic S/S: abdominal distention,
ganglion cells in delayed meconium
intramural and passage, tight anus
submucosal plexus due to ► Proximal bowel dilatation
failure of migration of & hypertrophy of muscle
neural crest cells or ► Complications: acute
immune mediated intestinal obstruction,
neuronal necrosis enterocolitis, megacolon,
► Age: 1st yr life perforation, sepsis

L/M:
► Aganglionosis in both plexus of segment of bowel
► Hypertrophied nerves, altered distribution of
interstitial cells of Cajal, fibromuscular dysplasia
of arteries, hyperplasia of lymphoglandular
complex
Biopsy types:
► Full thickness biopsy of rectum
► Biopsy should be 2cm above anal valve in infant
and 3cm in older children
► Suction or mucosal rectal biopsy

TYPES
1. Classic: aganglionic segment begins in distal
colorectum and extend in adjacent proximal
dilated bowel
2. Short segment: involvement of rectum and
rectosigmoid for few cm
3. Ultra-short: involved segment very narrow,
easily missed
4. Long-segment: involves most or all of large
bowel, may extend into small bowel
5. Zonal colonic aganglionosis: only short segment
involved, ganglion cells present below and
above aganglionic segment

► ↑Acetylcholinesterase activity in lamina
propria and muscularis mucosae
► NSE, neurofilaments, highlight hypertrophied
nerves and absent ganglion cells
► S-100—absent normal periganglionic satellite
cells
Acquired Megacolon
► IBD, Chagas disease, intestinal obstruction,
psychosomatic disorders

Acquired Megacolon
IBD
Chagas disease
Intestinal obstruction,
Psychosomatic disorders

Pathogenesis Acute Appendicitis
Appendiceal inflammation is associated with obstruction
in 50% to 80% of cases, usually in the form of a fecalith
and, less commonly, a gallstone, tumor, or ball of worms
(oxyuriasis
vermicularis). Continued secretion of mucinous fluid in
the obstructed viscus presumably leads to a progressive
increase in intraluminal pressure sufficient to cause
eventual collapse of the
draining veins. Ischemic injury then favors bacterial
proliferation with additional inflammatory edema and
exudation, further embarrassing the blood supply.
Nevertheless, a significant minority of inflamed
appendices have no demonstrable luminal obstruction,
and the pathogenesis of the inflammation remains
unknown.

Acute Appendicitis
Morphology:
► Earliest stages, scant neutrophilic exudate in mucosa, submucosa,
and muscularis propria. Subserosal vessels congested, and often
perivascular neutrophilic infiltrate. Normal glistening serosa changes
into dull, granular, red membrane
► Later stage, a prominent neutrophilic exudate generates a
fibrinopurulent reaction over the serosa , abscess formation within
wall, along with ulcerations and foci of suppurative necrosis in mucosa
acute suppurative appendicitis .
► Large areas of hemorrhagic ulceration of mucosa and green-black
gangrenous necrosis of wall, extending to serosa, creating acute
gangrenous appendicitis , followed by rupture and suppurative
peritonitis

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

Acute Appendicitis
ACUTE APPENDICITIS
OBSTRUCTIVE
► fecolith
► foreign body
► calculus-gall stone
► Mucocoele
► Tumor: primary secondary--- cecum
► Diffuse lymphoid hyperplasia (10 to 19 yrs)
► Oxyuris vermicularis
NON OBSTRUCTIVE
► Secondary to generalized infection (viral-Measles)

Fungal
 candidiasis,
 cryptosporidiosis
Others
 crohn disease
 ulcerative colitis
 sarcoidosis
 yersiniosis

ACUTE APPENDICITIS

D/D
 Mesenteric lymphadenitis
 Gynecologic lesions
 Acute diverticulitis
 Meckel’s diverticulitis
 Infarction of greater omentum
 Ureteric colic
 Chemotherapy induced typhilitis

Tumors of Appendix
Non-neoplastic:
MUCOSAL HYPERPLASIA
Neoplastic:
MUCINOUS TUMORS
Mucinous cystadenomas
Mucinous cystadenocarcinoma
ADENOCARCINOMA
Primary
secondary
CARCINOID

CARCINOID
► Most common tumor of appendix
► One in 300 appendicectomies
► Peak incidence in 3rd and 4th decades of life
► Mostly incidental
► Mostly occur at the tip
► Mostly less than 1cm in diameter
► GROSS
► Firm, grayish white
► Fairly well circumscribed
► Not encapsulated
► Characteristic yellow coloration after
formalin fixation.

Histologic Pattern of Carcinoid

► Classic insular type
► Carcinoids with glandular differentiation
► Tubular type
► Goblet cell carcinoid

CLASSIC TYPE

► Solid nests of small monotonous cells with
occasional acinar or rosette formation.
► Mitoses rare
► Peculiar retraction of tumor periphery from the
stroma
► Invasion of muscle and lymph vessels is the rule
► Spread to the peritoneal surface not rare

IMMUNOHISTOCHEMISTRY
Tumor cells are positive for:
► argentaffin
► argyrophil

Ultrastructurally: filled with pleomorphic dense core
secretory granules
Immunohistochemically reactive for:
► neuron-specific enolase,
► chromogranin
► 5-HT

Major Causes of Intestinal Obstruction
Mechanical Obstruction
► Adhesions
► Hernias, internal or external
► Volvulus
► Intussusception
► Tumors
► Inflammatory strictures
► Obstructive gallstones, fecaliths, foreign bodies
► Congenital strictures; atresias
► Congenital bands
► Meconium in mucoviscoidosis
► Parasites
► Imperforate anus
Pseudo-obstruction
► Paralytic ileus (e.g., postoperative)
► Vascular—bowel infarction
► Myopathies and neuropathies (e.g., Hirschsprung)

Ischemic Bowel Disease
Acute occlusion of Celiac, superior and
inferior mesenteric arteries
Types
► Mucosal-hypoperfusion acute or chronic
► Mural- “ “ “ “
► Transmural- occlusion of major mesenteric
blood vessels

Predisposing conditions for ischemia
► Arterial Thrombosis- atherosclerosis,
vasculitis
► Arterial Embolism-cardiac vegetations
► Venous Thrombosis-Oral contraceptives,
postoperative state
► Non occlusive ischemia- cardiac failure,
shock, dehydration
► Miscellaneous-radiation injury, volvulus,
stricture, amyloidosis, Diabetes mellitus

Ischemic injury two phases
► Initial hypoxic injury
► Secondary reperfusion injury-generation of
oxygen free radicals, neutrophils infiltration,
production of inflammatory mediators

ISCHEMIC COLITIS
Age: >50yrs—arteriosclerosis, diabetes, vascular surgery
► Younger pts—collagen-vascular diseases, Wegener’s
granulomatosis, amyloidosis, oral contraceptives
► S/S: sudden onset of bleeding, abdominal pain, bloody
diarrhea, vomiting
► Site: segmental disease, splenic flexure commonly
involved
► D/D: IBD

ISCHEMIC COLITIS
X-ray: gas within bowel wall, thumb printing
Gross: pseudopolyps, ulceration and fibrosis
L/M: in chronic ischemia ulcer covered by
granulation tissue extending into submucosa
► Hemosiderin abundant, hyaline thrombi
► Ischemic necrosis—full thickness mucosal
necrosis, hyalinized lamina propria,
hemorrhage and atrophic crypts in healed stage

Inflammatory Bowel Disease
Chronic relapsing inflammatory disorder-obscure origin
► Crohn disease
Autoimmune, affect any part of GIT
► Ulcerative colitis
Chronic inflammatory disease limited to colon &
rectum

Both exhibit extra-intestinal inflammatory
manifestations

Etiology-Pathogenesis
Idiopathic-cause unknown
Two key pathogenic abnormalities
► Strong immune response against normal
microbial flora in genetic susceptible
individuals
► Defects in epithelial barrier function

Pathogenesis of IBD
A-Genetic Susceptibility
1. Associated genes with CD are HLA-
DR1/DQw5, NOD2
2. HLA-DR 2 increase in U. Colitis
B-Intestinal Flora increase immune reaction by providing antigens
and inducing co-stimulators and cytokines contribute to T-cell
activation, defects in epithelial barrier allow luminal flora to gain
access to mucosal lymphoid tissue –trigger immune response
C-Abnormal T-Cell response to much T-cell activation and/or too
little control by regulatory T- lymphocytes results in damaging
the mucosa

Diagnosis of IBD
 Clinical history
 Radiographic- string sign in CD, Lead pipe in
UC
 Lab Findings (serum antibodies):
 pANCA positive in75%of UC & 11%in CD
 ASCA Elevated in CD
 Tissue Diagnosis

CROHN DISEASE

EPIDEMIOLOGY
► Both sexes female more than males
► All ages peak age 2nd &3rd decade
► Primarily disease of Western developed populations
► Annual incidence in USA 3per 100,000
Fully developed CD is pathologically characterized
by;
1. Sharply delimited, transmural inflammatory process with
mucosal damage
2. Non-caseating granulomas
3. Fissures and fistulae

GROSS
► Skip lesions
► Cobblestone appearance
► Transmural involvement, Creeping fat
► Early- aphthous ulcers
► Late-Ulcer linear, serpentine and discontinuous
with intervening normal or edematous mucosa
► Healing→ long rail-track scars
► Pseudopolyps or mural bridging lesions may
develop
► Stricture, fissure, fistulas
► Mesenteric lymphadenopathy

Crohn Disease
MICROSCOPY
► Tranmural inflammation
► Fissures
► Non caseating granulomas
► Mucosa relatively normal, normal content of mucin
► Glandular architecture maintained
► submucosal lymph edema, lymphoid hyperplasia, patchy
necrosis, atrophy or regenerative hyperplasia.
COMPLICATIONS
► Intramural abscess
► Fistulas, perforation
► Occasionally carcinoma.

CROHN DISEASE of COLON
(GRANULOMATOUS COLITIS)
►Involve large bowel in 40% cases, with or
without ileal component
►Ileum involved-50%
►Anal lesions-75%

Complications:
Fistula, skin ulceration, toxic megacolon,
colonic Ca (risk < UC)

Crohn- Cobble Stone &
Sharp Demarcation

C/F of CD
► Intermittent attacks of mild diarrhea, fever, and abdominal
pain spaced by asymptomatic periods lasting for weeks to
many months
► Attacks precipitated by emotional stress
► Colonic involvement can result in fecal blood loss
► Sometime present as a case of acute appendicitis or acute
bowel perforation
► Extensive involvement of ileum result in marked loss of
albumin- protein losing enteropathy
► Malabsorption of vit B12 P.anemia
► Malabsorption of bile salts –steatorrhea
► Fistulae and Fissures with urinarry bladder, vagina,
perianal skin
► Extraintestinal manifesintations migratory polyarthritis,
sacroilitis, ankylosing spondylitis, erythema nodusum
clubbing of fingers, hepatic primary sclerosing cholangitis

ULCERATIVE COLITIS
► Age: 20-30yrs
► Sex: ♂=♀
► Etiology: unknown
► S/S: prolonged duration, many remissions and
exacerbations
► Site: left sided colon, begins in rectosigmoid
► Ulcerative proctitis—disease localized to rectum
► Pancolitis—involve entire colon

ULCERATIVE COLITIS
Gross: varies with stage
► Acute: mucosal surface wet and glare
 Petechial hemorrhages
 Ulcers undermining mucosa, mucosal bridges
 Pseudopolyps
► Advanced: bowel—fibrotic, narrowed and shortened
 Atrophy of all components of wall
 Increased pericolic fat
► Quiescent: no ulceration, mucosa atrophic
► Back wash ileitis

ULCERATIVE COLITIS
L/M: mucosal and submucosal disease
► Acute: ↑ inflammatory cells in lamina propria
► Inflammation remain above muscularis mucosae
► Crypt abscess, cyrptitis
► Marked ↓ cytoplasmic mucus, irregularly shaped glands,
paneth cell metaplasia
► Atrophic and regenerative changes in glands
► Nuclear enlargement, ↑ mitosis
► Dilated blood vessels, mucosal capillary thrombi
► Ulcers covered by granulation tissue
► Pseudopolyps= granulation tissue + inflammed mucosa

ULCERATIVE COLITIS
► Submucosa—normal, inflammed, hyperemic,
infiltrated by fat or fibrosed (depending on stage)
► Submucosal endarteritis obliterans (10%)
► Muscularis externa—hypertrophic/normal
► Subserosal fibrosis
Quiescent stage:
Mucosa grossly normal
Mucin content restored, irregularly branched glands,
paneth cells, neutrophils in lamina propria

ULCERATIVE COLITIS
Extraintestinal manifestations:
liver disease, Arthritis, Uvietis
Pyoderma gangreonosum
Complications:
perforation, peritonitis, abscess, toxic megacolon,
venous thrombosis
Increase risk of dysplasia/carcinoma

Clinical Manifestation Of UC

► Relapsing disorder, asymptomatic interval of
months to years
► Attacks of bloody mucoid diarrhea persist
for days, weeks to months
► Initial attack may lead to serious bleeding
with fluid and electrolyte imbalance
► Toxic megacolon may lead to perforation

Dysplasia 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
Ulcerative Colitis

Macroscopic
► Bowel region Ileum ± colon Colon ± ileum Colon only
► Distribution Skip lesions Skip lesions Diffuse
► Stricture Early Variable Late/rare
► Wall appearance Thickened Thin Thin
► Dilation No Yes Yes

Microscopic
► Inflammation Transmural Transmural Limited in mucosa
► Pseudopolyps No to slight Marked Marked
► Crypt Abscess Not seen Common
► Ulcers Deep, linear Deep, linear Superficial
► Lymphoid reaction Marked Marked Mild
► Fibrosis Marked Moderate Mild
► Serositis Marked Variable Mild to none
► Granulomas Yes (50%) Yes (50%) No
► Fistulae/sinuses Yes Yes No
► Lymph node Granulomas Do Reactive

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

Tumors Small & Large Intestine
Non-neoplastic (Benign) Polyps
► Hyperplastic polyps
► Hamartomatous polyps
• Juvenile polyps
• Peutz-Jeghers polyps
► Inflammatory polyps
► Lymphoid polyps

Neoplastic Epithelial Lesions
Benign
• Adenoma *
Malignant
• Adenocarcinoma *
• Carcinoid tumor
• Anal zone carcinoma
Mesenchymal Lesions
► Gastrointestinal stromal tumor (GIST)
► Other benign lesions • Lipoma • Neuroma • Angioma
► Kaposi sarcoma
Lymphoma
Metastatic

BENIGN EPITHELIAL TUMORS
BRUNNER’S GLAND ADENOMA
► Nodular proliferation of histologically normal
Brunner’s glands, accompanied by ducts
and scattered stromal elements, cilliated
cysts and adipose tissue.
► Focal multifocal or diffuse
► Located commonly at posterior wall of
duodenum at junction of first and second
parts.

BENIGN EPITHELIAL TUMORS
ADENOMAS
► More often In duodenum and jejunum’ single or multiple, sessile or
pedunculated
► Microscopically can be villoglandular polyp, adenomatous polyp or
villous adenoma.
► Malignant transformation can occur mostly when lesion is large
villous or multiple.
HAMARTOMATOUS POLYP
Benign juvenile Rectal polyp
► Jejunoileum– (in Peutz Jeghers syndrome)
► Glands supported by broad bands of smooth muscle fibers
► Several types of epithelial cells are present.
► Associated with adenocarcinima and adenoma malignum of uterine
cervix, ovarian mucinous tumors, breast carcinoma.

ADENOCARCINOMA
► Both sexes elderly population less common than counterpart
in colon.
► More common in upper portion of small bowel
► Associated with hereditary nonpolyposis colorectal
carcinoma syndrome, Peutz-Jeghers syndrome, Reckling-
huasen’s disease, bowel duplication, Crohn’s disease, at
ileostomy sites, jejunal limb of Roux-en-Y
esophagojejunostomy.
► GROSS- duodenal carcinoma; papillary configuration,
distal lesions; napkin-ring, polypoid or fungating appearance
► MICROSCOPY- moderately well differentiated
adenocarcinoma. Mucin production, CEA reactivity is the
rule
► Commonly positive for chromogranin 5-HT
► IMMUNO- COX-2, sPLA2 cPLA2.peptide hormones
► ULTRASTRUCTURE- prominent development of
microvilli.

SMALL CELL NEUROENDOCRINE
CARCINOMA
► Rare,
► MICROSCOPY- Small round oval cells, scanty
cytoplasm, hyperchromatic nucleus.
► ULTRASTRUCTURE- dense-core granules of
neurosecretory type
► IMMUNORECTIVE for neuroendocrine markers
► Deeply invasive, prone to metastasis, very poor
prognosis.
ANAPLASTIC CARCINOMA
► Highly bizarre tumor cells, multinucleated with abundant
cytoplasm, no glandular differentiation.
► Aggressive

CARCINOID TUMORS
► Low grade neoplasm originating from the diffuse
neuroendocrine system outside of pancreas and thyroid
C cells.
► Adults,
► Located in ileum mostly
► GROSS- intact mucosa , tumor infiltrating the
submucosa and extending to muscularis externa.
► Buckling of bowel wall due to fibrosis
► Brightly yellow color
► MICROSCOPY- solid nests of monotonous population
of cells having small round nuclei scant to moderate
granular cytoplasm fine nucleoli.
► Peripheral palisading common , scanty mitotic figures,
lymphatic and neural invasion common.
► Microscopic types from A to E : insular,
trabecular, glandular, undifferentiated, mixed.

CARCINOID TUMORS
► HISTOCHEMISTRY- argentafin argyrophilic positive,
negative for mucin
► ULTRASTRUCTURE- dense core pleomorphic
secretory granules
► IMMUNO- keratin CK7, CK 20 +ve, pan-endocrine
markers +ve, 5-HT, substance P gastrin, somatostatin,
glucagon , PP, bombesin, GRP +ve
► MOLECULAR AND GENETIC FEATURES-
aneuploidy common, MEN-1 Negative, p53 rare
► SPREAD AND METASTASIS- low grade , slow
growth rate, highly invasive, metastasis to regional lymph
nodes and liver.
► CARCINOID SYNDROME- cyanosis of face, chest,
intermittent hypertension, palpitations, watery stools.

MALIGNANT LYMPHOMA AND RELATED
DISORDERS
► Most common site for extra nodal lymphoma
T-CELL LYMPHOMA
► Mostly a complication of celiac sprue and other
malabsorption syndromes.
► CD56 +ve, associated with EBV.
► Intense eosinophilic infiltrate may obscure the diagnosis
B-CELL LYMPHOMA
► Arise from mucosa associated lymphoid tissue
► Mostly solitary , common in ileum
► Diffusely infiltrating bulky mass with garden hose
appearance, extensive ulcerations.
► Regional lymph nodes usually also involved.

DISORDERS
IMMUNOPROLIFERATIVE SMALL INTESTINAL
DISEASE IPSID
► Common among Arabs, Jews, blacks of South Africa.
► Associated with diarrhea and malabsorption
► Low grade form- heavy lymphoplasmacytic infiltration of
cells of slightly immature appearance, monoclonal alpha
heavy chains.
► High grade form- highly pleomorphic large cell
lymphoma with immunoblastic and plasmacellular features.
Immunocytochemical positivety for alpha chains
► Prominent starry sky appearance or follicular lymphoid
hyperplasia my be present

DISORDERS
LOW GRADE B-CELL LYMPHOMA (MALT TYPE)
► Predominance of small lymphoid cells, formation of
lymphoepithelial lesions, reactive follicles.
► Large cell lymphoma high grade form may be associated
with low grade or present in absence of low grade
component. Mostly plasmacytoid cells
FOLLICULAR LYMPHOMA
► Predilection for terminal ileum, innumerable small
polypoidal masses,
► Translocation 14:18 typical
► Arises from local antigen responsive B cells

► TABLE 17-13 -- Hereditary Syndromes Involving the Gastrointestinal Tract
► Syndromes Altered Gene Pathology in GI Tract
► Familial adenomatous polyposis (FAP) APC Multiple adenomatous polyps
► • Classic FAP
► • Attenuated FAP
► • Gardner syndrome
► • Turcot syndrome
► Peutz-Jeghers syndrome STK11 Hamartomatous polyps
► Juvenile polyposis syndrome SMAD4 Juvenile polyps
► BMPRIA
► Hereditary nonpolyposis colorectal carcinoma Defects in mismatch DNA repair
genes Colon cancer
► Tuberous sclerosis TSC1 Inflammatory polyps
► TSC2
► Cowden disease PTEN Hamartomatous polyps

► Non-Neoplastic Polyps
► The overwhelming majority of intestinal polyps occur on a sporadic basis, particularly in the colon,
and increase in frequency with age. Non-neoplastic polyps include the hyperplastic
► polyp, the hamartomatous polyp, the inflammatory polyp, and the lymphoid polyp. Hyperplastic
polyps represent about 90% of all epithelial polyps in the large intestine. They may arise at
► any age but usually are discovered incidentally in the sixth and seventh decades. They are found in
more than half of all persons age 60 and older. It is believed that the hyperplastic polyp
► results from decreased epithelial cell turnover and accumulation of mature cells on the surface.
Harmatomatous polyps are malformations of the glands and the stroma. They can occur
► sporadically or occur in the setting of genetic syndromes ( Table 17-13 ). Inflammatory polyps, also
known as pseudopolyps, represent islands of inflamed regenerating mucosa surrounded
► by ulceration. These are seen primarily in patients with severe, active IBD. Lymphoid polyps are an
essentially normal variant of the mucosal bumps containing intramucosal lymphoid
► tissue.
► .hyperplastic polyp

► Hamartomatous Polyps.
► Juvenile polyps represent focal hamartomatous malformations of the mucosal epithelium and
lamina propria. For the most part they are sporadic lesions, with the vast majority occurring
► in children younger than age 5. Isolated hamartomatous polyps may be identified in the colon of
adults; these incidental lesions are referred to as retention polyps . In both age groups,
► nearly 80% of the polyps occur in the rectum, but they may be scattered throughout the colon.
Juvenile polyps tend to be large (1 to 3 cm in diameter), rounded, smooth or slightly
► lobulated lesions with stalks up to 2 cm in length; retention polyps tend to be smaller (<1 cm
diameter). Histologically, lamina propria comprises the bulk of the polyp, enclosing abundant
► cystically dilated glands. Inflammation is common, and the surface may be congested or ulcerated. In
general they occur singly and being hamartomatous lesions have no malignant
► potential. However, the rare autosomal dominant juvenile polyposis syndrome, in which there
are multiple (50 to 100) juvenile polyps in the gastrointestinal tract, does carry a risk of
► adenomas and hence adenocarcinoma. Mutations in the SMAD4/DPC4 gene (which encodes a TGF-
b signaling intermediate) account for some cases of juvenile polyposis syndrome.[79]

► Peutz-Jeghers polyps are hamartomatous polyps that involve the
mucosal epithelium, lamina propria, and muscularis mucosa. These
hamartomatous lesions may also occur singly or
► multiply in the Peutz-Jeghers syndrome . This rare autosomal
dominant syndrome is characterized by multiple hamartomatous
polyps scattered throughout the entire gastrointestinal tract
► and melanotic mucosal and cutaneous pigmentation around the lips,
oral mucosa, face, genitalia, and palmar surfaces of the hands.
Patients with this syndrome are at risk for
► intussusception, which is a common cause of mortality. Peutz-Jeghers
polyps tend to be large and pedunculated with a firm lobulated contour.
Histologically, an arborizing network of
► connective tissue and well-developed smooth muscle extends into the
polyp and surrounds normal abundant

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 which
additional mutations occur. .

► TABLE 17-14 -- TNM Classification of Carcinoma of the Colon and Rectum
► Tumor Stage Histologic Features of the Neoplasm
► Tis Carcinoma in situ (high-grade dysplasia) or intramucosal carcinoma (lamina propria
invasion)
► T1 Tumor invades submucosa
► T2 Extending into the muscularis propria but not penetrating through it
► T3 Penetrating through the muscularis propria into subserosa
► T4 Tumor directly invades other organs or structures
► Nx Regional lymph nodes cannot be assessed
► N0 No regional lymph node metastasis
► N1 Metastasis in 1 to 3 lymph nodes
► N2 Metastasis in 4 or more lymph nodes
► Mx Distant metastasis cannot be assessed
► M0 No distant metastasis
► M1 Distant metastasis
► 867
► Figure 17-

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

► GASTROINTESTINAL LYMPHOMA
► Any segment of the gastrointestinal tract may be secondarily involved by systemic dissemination of
non-Hodgkin lymphomas. However, up to 40% of lymphomas arise in sites other than
► lymph nodes, and the gut is the most common location. Conversely, about 1% to 4% of all
gastrointestinal malignancies are lymphomas. By definition, primary gastrointestinal lymphomas
► exhibit no evidence of liver, spleen, mediastinal lymph node, or bone marrow involvement at the time
of diagnosis—regional lymph node involvement may be present. Primary
► gastrointestinal lymphomas usually arise as sporadic neoplasms but also occur more frequently in
certain patient populations: (1) Chronic gastritis caused by H. pylori, (2) chronic
► spruelike syndromes, (3) natives of the Mediterranean region, (4) congenital immunodeficiency
states, (5) infection with human immunodeficiency virus, and (6) following organ
► transplantation with immunosuppression.
► Intestinal tract lymphomas can be classified into B-cell and T-cell lymphomas. The B-cell lymphoma
can be subdivided into MALT lymphoma, immunoproliferative small-intestinal
► disease (IPSID), and Burkitt lymphoma.
► 1. MALT lymphoma is a sporadic lymphoma, which arises from the B cells of MALT (mucosa-
associated lymphoid tissue, described under gastric lymphoma). This type of lymphoma

► 1. MALT lymphoma is a sporadic lymphoma, which arises from the B cells of MALT (mucosa-
associated lymphoid tissue, described under gastric lymphoma). This type of lymphoma
► is the most common form in the Western hemisphere. The biologic features of these lymphomas are
different from node-based lymphomas in that (1) many behave as focal tumors
► in their early stages and are amenable to surgical resection; (2) relapse may occur exclusively in the
gastrointestinal tract; (3) genotypic changes are different than those observed in
► nodal lymphomas: the t(11;18) translocation is relatively common in MALT lymphoma; and (4) the
cells are usually CD5- and CD10-negative. This type of gastrointestinal
► lymphoma usually affects adults, has no gender predilection, and may arise anywhere in the gut:
stomach (55% to 60% of cases); small intestine (25% to 30%), proximal colon
► (10% to 15%), and distal colon (up to 10%). The appendix and esophagus are only rarely involved.
► The pathogenesis of these lymphomas is under intense scrutiny. The concept has been advanced
that lymphomas of MALT origin arise in the setting of mucosal lymphoid
► activation and that these lymphomas are the malignant counterparts of hypermutated, postgerminal-
center memory B cells. As discussed earlier, Helicobacter-associated chronic
► gastritis, in particular, has been proposed as a driving force for the development of gastric MALT
lymphoma, the result of antigen-driven somatic mutation of
► 869
► gastric lymphoid tissue. However, the etiologic factors for intestinal lymphoma are still unknown,
although history of IBD appears to increase the risk.
► 2. IPSID is also referred to as Mediterranean lymphoma. It is an unusual intestinal B-cell lymphoma
arising in patients with Mediterranean ancestry, having a background of chronic

► 2. IPSID is also referred to as Mediterranean lymphoma. It is an unusual intestinal B-cell
lymphoma arising in patients with Mediterranean ancestry, having a background of chronic
► diffuse mucosal plasmacytosis. The plasma cells synthesize an abnormal Iga heavy chain, in
which the variable portion has been deleted. A high proportion of patients have
► malabsorption and weight loss preceding the development of the lymphoma. The diagnosis is
made most commonly in children and young adults, and both sexes appear to be
► affected equally. The exact etiology of this type of lymphoma is not known, although infection
appears to play a role.[95]
► 3. The intestinal T-cell lymphoma is usually associated with a long-standing malabsorption
syndrome (such as celiac disease) that may not constitute a true gluten-sensitive
► enteropathy. This lymphoma occurs in relatively young individuals (age 30 to 40), often following
a 10- to 20-year history of symptomatic malabsorption. Alternatively, a diffuse
► enteropathy with malabsorption may accompany the development of a lymphoma. Intestinal T-
cell lymphoma arises most often in the proximal small bowel, and its overall
► prognosis is poor (reported 11% five-year survival rate).
► Morphology.
► Gastrointestinal lymphomas can assume a variety of gross appearances. Since all the gut
lymphoid tissue is mucosal and submucosal

► Morphology.
► Gastrointestinal lymphomas can assume a variety of gross appearances. Since all the gut lymphoid tissue is mucosal
and submucosal, early lesions appear as plaque-like expansions of the
► mucosa and submucosa. Diffusely infiltrating lesions may produce full-thickness mural thickening, with effacement of
the overlying mucosal folds and focal ulceration. Others may be
► polypoid, protruding into the lumen, or form large, fungating, ulcerated masses. Tumor infiltration into the muscularis
propria splays the muscle fibers, gradually destroying them. Because
► of this feature, advanced lesions frequently cause motility problems with secondary obstruction. Large tumors
sometimes perforate because of lack of stromal support; reduction in tumor
► bulk during chemotherapy also may lead to perforation.
► In the earliest histologic lesions, atypical lymphoid cells may be seen infiltrating the mucosa, with effacement and loss
of glands and massive expansion of lymphoid tissue. Extreme
► numbers of atypical lymphoid cells may populate the superficial or glandular epithelium (lymphoepithelial lesion). With
established lymphomas, the mucosa, submucosa, and even muscle
► wall are replaced by a monotonous infiltrate of malignant cells, consisting of a mixture of small lymphocytes and
immunoblasts in varying proportions. Lymphoid follicles are occasionally
► formed. Most gut lymphomas are of B-cell type (over 95%) and are evenly split between low- and high-grade tumors.
The small fraction of T-cell lymphomas occurring in the intestine are
► commonly high-grade lesions.
► Clinical Features.
► With the exception of T-cell lymphomas, primary gastrointestinal lymphomas generally have a better prognosis than do
those arising in other sites. Ten-year survival for patients with
► localized mucosal or submucosal disease approaches 85%. Early discovery is key to survival; thus, gastric
lymphomas generally have a better outcome than those of the small or large
► bowel. In general, the depth of local invasion, size of the tumor, the histologic grade of the tumor, and extension into
adjacent viscera are important determinants of prognosis

CA & DYSPLASIA IN UC
► Incidence of colorectal Ca-- ↑ in pt with UC
► 5-10% in older series, current rate—2%
► Risk is ↑ when:
► Entire colon involved, disease is continuous,
unremitting, long standing and when disease
begins in childhood
► Gross: thick mucosa with nodular or velvety
surface

CA & DYSPLASIA IN UC
L/M: adenocarcinoma with varying degrees of
differentiation
► Mucinous and poorly differentiated Ca proportion
relatively ↑
► Frank Ca always preceded by dysplasia in flat
atrophic mucosa
► Multiple rectal biopsies recommended for detection
of dysplasia
► IHC: ↑ CEA, sialomucin ,↓ Ig, strong p53 & MIB-1
staining

CLASSIFICATION OF DYSPLASIA

1. Negative for dysplasia
2. Indefinite for dysplasia, probably negative
3. Indefinite for dysplasia, unknown
4. Indefinite for dysplasia, probably positive
5. Positive for dysplasia, low grade
6. Positive for dysplasia, high grade

FOLLOW UP
► Category 1+2→ regular follow up
► Category 3+4 → short-term follow up
► Category 6 → colectomy
► Category 5 → short term follow up or
consider colectomy
► Surveillance for pt with UC: started after 8-
10yrs of extensive colitis and 15 yrs of left sided
colitis

► COMPLICATIONS

►perforation leading to
 diffuse peritonitis
 peri appendiceal abscess
 fibrous induration
► venous spread to liver---pylephlebitic abscess
► peri appendicitis
 primary from appendix
 secondary inflammation in surrounding struct25

► Morphology.
► Hyperplastic Polyps.
► These are small (usually <5 mm in diameter) epithelial polyps that appear as nipple-like, hemispheric,
smooth, moist protrusions of the mucosa, usually positioned on the tops of mucosal
► folds. They may occur singly but more often are multiple, and over half are found in the rectosigmoid
colon. Histologically, they are composed of well-formed glands and crypts lined by
► non-neoplastic epithelial cells, most of which show differentiation into mature goblet or absorptive
cells. The delayed shedding of surface epithelial cells leads to infoldings of the crowded
► epithelial cells and fission of the crypts, creating a serrated epithelial profile and an irregular crypt
architecture ( Fig. 17-56A ). Although large hyperplastic polyps may rarely coexist with
► foci of adenomatous change, the usual small, hyperplastic polyp is considered to have
virtually no malignant potential . However, the hyperplastic polyps occurring in the setting of
► the rare hyperplastic polyposis syndrome can harbor epithelial cell dysplasia (adenoma), and hence
are considered at risk for carcinoma. The
► 859
► underlying genetic basis for this syndrome is not known.
► Hamartomatous Polyps.

DISORDERS
MANTEL CELL LYMPHOMA
► Rare.
► Multiple lymphoid polyps
TRUE HISTIOCYTIC LYMPHOMAS
► Cells positive for morphologic and histochemical markers
of histiocytes and lacking reactivity for lymphoid markers
Other lymphomas include
► BURKITT’S LYMPHOMA
► HODGKIN’S LYMPHOMA
► ANAPLASTIC LARGE CELL LYMPHOMA
► MULTIPLE MYELOMA
► FOLLICULAR DENDRITIC CELL TUMOR

EPITHELIAL POLYPS
1. Adenomatous polyps
2. Familial polyposis
3. Gardner’s syndrome
4. Turcot’s syndrome
5. Villous adenoma
6. Hyperplastic polyps
7. Juvenile (retention) polyp
8. Peutz-Jeghers polyp
9. Transitional polyp

ADENOMATOUS POLYP
► Site: 40% rt colon, 40% left colon, 20% rectum
► Familial, autosomal dominant
► S/S: asymptomatic or bleeding, change in bowel
habits or intussusception
► Gross: mostly <1cm, sessile or pedunculated.
Single or multiple
L/M: ↑ in no. of glands and cells/unit area
► Cells crowding, hyperchromatic nuclei, ↑mitosis
► Mucin usually ↓

ADENOMATOUS POLYP
► IHC: CEA, CK+
► Genetics: aneuploidy, p53+, bcl-2+
► E/M: nuclear and cytoplasmic alterations, abnormal
secretory dropletss
► Focal areas of villous type can be seen
► Villous=glandular→ villoglandular polyps
Atypia in polyp related to:
► ↑ age, no. of polyps/pt, size of polyp, villous change
► Atypia grading: mild, moderate, severe

ADENOMATOUS POLYP
► Atypical glands maybe seen in polyp beneath
muscularis mucosae. D/D: malignant transformation in
polyp
► Helpful differential features:
1. Cytological features of glands same as surface
2. Glands surrounded by loose inflammed stroma and
scattered muscle bundles
3. Hemosiderin granules around glands
► Glands may become cystic and rupture→ mucin lakes
► Squamous metaplasia, morula formation, clear cell
change, endocrine cells—maybe seen in polyp

FAMILIAL POLYPOSIS
► Autosomal dominant
► Gene: APC localized to 5q21, k-ras mutation
► Mechanism: persistence of DNA synthesis in epithelial cells
► Age: 2nd decade of life
► Gross: bowel studded with polyp ranging from slightly
elevated to large masses, maybe flat or depressed
► 100 polyps—familial polyposis
► May involve other parts of GIT: stomach and small bowel
► Untreated cases may develop Ca (20 yrs earlier than ordinary
colorectal Ca)
► Early colectomy recommended

GARDNER’S SYNDROME
► Familial condition
► S/S: Adenomatous polyp of large bowel and sometimes
small bowel and stomach, osteoma of skull, mandible,
multiple keratinous cysts of skin and soft tissue tumors
especially intraabdominal fibromatosis
► Gene: mutation of APC
► Tendency for large bowel Ca is high
► May also develop Ca of small bowel (periampullary)

TURCOT’S SYNDROME
► S/S: colorectal adenomatous polyps and
glioblastoma multiforme
► Genetics: Autosomal recessive
► Mutation of APC or mismatch-repair gene

VILLOUS ADENOMA
► Age: older patients
► Site: rectum or rectosigmoid
► S/S: fluid and electrolyte depletion
► Gross: single mass that may grow to encircle bowel
completely
► Papillary villous projection and attached by wide base,
10%--pedunculated
► L/M: villous projections ramify through long, paillary
growth
► IHC: CEA+, mucin-ve
► Complications: Ca -29-70%
► Treatment: local excision or APR depending on size of
tumor

HYPERPLASTIC (METAPLASTIC)
POLYP
► Sessile, small sized(5mm), rarely pedunculated and
large sized
L/M: elongated glands with intraluminal foldings—saw
toothed appearance
► Mitotis ↑ at base
► Abundant cytoplasm, inconspicuous basal nucleus
► Thickened basement membrane
► Surface epithelium has micropapillary appearance
► IHC: CEA+, sialomucin↓

MIXED HYPERPLASTIC—
ADENOMATOUS POLYP
► Prominent sawtoothed appearance—serrated adenoma
► Some malignant potential
INVERTED HYPERPLASTIC POLYP:
► Site: right colon
► L/M: endophytic growth, penetration of muscularis
mucosae
MULTIPLE HYPERPLASTIC POLYPOSIS
SYNDROME:
► Large polyps, maybe associated with adenocarcinoma

JUVENILE POLYP
► Age: common in children, 1/3rd –adults
► Site: rectosigmoid
► S/S: rectal bleeding, autoamputation common
► Gross: granular, red surface and cystic, lattice like
appearance on cut section
L/M: ulceration covered by granulation tissue
► Cystically dilated glands with mucus, no atypia
► Stroma—inflammation and edema
► MULTIPLE JUVENILE POLYPOSIS— multiple polyps
of juvenile type
► Ass with adenomatous polyp and adenoca of large bowel,
duodenum, stomach or pancreas

PEUTZ-JEGHERS POLYPS

► Similar to small bowel counterpart
► Disorganized glands, several types of cells, no
atypia, smooth muscle fibers from muscularis
mucosae
► Genetics: mutation of LKB1 gene

RELATIONSHIP WITH CA
1. Malignant transformation of solitary hyperplastic polyps,
retention polyps and polyps of Peutz-Jeghers in negligible
2. Polyposis syndrome— risk ↑
 Familial polyposis & Gardner’s syndrome—100% risk
 Juvenile polyposis, hyperplastic polyposis and Peutz-
Jegher syndrome—risk ↓ but definitely ↑ed
 ↑ risk of duodenal and amupullary adenocarcinoma
3. Villous adenoma→ malignant—29-70% cases
4. Adenomatous polyp (flat, villoglandular)→ malignant
5. Not all adenomas→ malignant
– Larger and villous the polyp →↑ chance of focal
Carcinoma
6. Parallelism between adenomatous polyp and adenocarcinoma

ADENOMA-CARCINOMA
Chromosome SEQUENCE
alteration 18q 17p
12p
gene 5q DNA Loss loss
Mutation
mutation or hypomethylation DCC p53
K ras
loss AFP

Normal Hyper Early Intermedia Late
epithelium proliferativ adenoma te adenoma
epithelium adenoma
Other alterations

Carcinoma Metastasis

TREATMENT OF POLYPS
► Solitary juvenile polyps—simple removal
► Familial polyposis—colectomy even in young pts
► Villous adenoma—removal in toto, determination of Ca in
specimen—effect further surgery
► Solitary adenomatous polyp:
 under reach of rectosigmoidoscope removed
endoscopically
 High up polyp—fiberoptic scope removal
► Proximally located polyp large—anterior resection of segment
of bowel

PRESENCE OF CA IN POLYP
► Carcinomatous glands may be present only in mucosa and
lamina propria above muscularis mucosae— ca in situ
 No lymph node mets
 Require simply polypectomy
► May extend beyond muscularis mucosae but not invading stalk
—
 Lymph node mets—1%
 Simple polypectomy
► May extend to base of stalk or beyond— focal Ca with stalk
invasion
 Lymph node mets— ↑
 colectomy

CARCINOMA
► Age: 62yrs—mean age
► Sex: ♂=♀
► Etiology: dietary fats and animal protein
► Genetics—familial polyposis, hereditary
nonpolyposis colorectal cancer sydrome (Lynch
syndrome)
► Torre-muir syndrome
► Patients with IBD have↑ predisposition for Ca
► Complication of irradiation for Ca Cx

CARCINOMA
► S/S: change in bowel habit, rectal bleeding, anemia,
vague abdominal pain
► Intestinal obstruction—left sided tumor
► Perforation
► Serum CEA —detected in 72-97% cases of
colorectal Ca, disappears after tumor resection,
reappears after recurrence or mets
► CEA used for monitoring therapy
► Can be detected in tissues as well
► Detection of mutations of ras and APC genes in stool

RAISED SERUM CEA
► SEEN IN:
► Colorectal Ca
► Ca stomach
► Ca pancreas
► Ca breast
► Ca prostate
► CLD
► Chronic renal disease
► ↑ CEA never detected in normal individuals

CARCINOMA
Site: rectosigmoid—50%
► Rt sided tumor—↑ common in elderly, blacks and with
diverticular disease
► Multicentric Ca—3-6% cases
Gross:
► Polypoid—bulky mass with well defined rolled magins
► Ulcerative/infiltrating—less elevated surface with central
ulceration
► Flat or depressed Ca—deep stromal and lymphovascular
invasion
► Wall invasion can be seen grossly
► Mucinous Ca—gelatinous or glaring
► Determine pericolic extension and vein invasion on gross
► Determine appearance of rest of colon—polyp or Ca
elsewhere

HISTOPATHOLOGY
► Well to modeately differentiated adenocarcinoma
with variable mucin
► Cells—columnar, goblet and few endocrine
► Inflammatory and desmoplastic reaction
► Invasion of all layers of bowel
► Pericolic extension, perineural and veinous
invasion
► Metaplastic bone formation—very rare
► Residual polyp or hyperplastic glands seen at
tumor edge

MICROSCOPIC TYPES
1. Mucinous Ca
2. Signet ring Ca
3. Basaloid (cloacogenic Ca)
4. Clear cell Ca
5. Hepatoid adenoca
6. Medullary (solid, poorly differentiated) adenocarcinoma
7. Anaplastic (solid, giant cell, sarcomatoid) ca
8. Squamous differentiation
9. Trophoblastic differentiation
10. Endocrine differentiation
11. Rhabdoid differentiation

SIGNET RING CARCINOMA
► Rare form
► Age: young
► Gross: diffuse infiltration of bowel wall, maybe seen in
adenomatous polyp as well
L/M: diffuse growth, with few gland formation
► Signet ring cells
► Mets: lymph nodes, peritoneal surface and ovary rather
than liver
► Prognosis: very poor
D/D: gastric signet ring ca or breast ca
► Benign signet ring change seen in pseudomembranous
colitis and inflammatory conditions
► IHC: CK7-/CK20+

BASALOID CA: MEDULLARY CA:
► Same as anal couterpart ► Site: cecum, rt colon

CLEAR CELL CA: ► Sex: ♀
► Not specific entity ► Genetics: microsatellite
► Morphological variant of instability
adenocarcinoma with ANAPLASTIC CA:
glycogen accumulation in ► Aggressive behavior
cells SQUAMOUS
HEPATOIDADENOCA: DIFFERENTIATION:
► Similar to gastric counterpart ► Site: cecum
► RHABDOID FEATURES: ► Adenosquamous Ca
► Site: cecum ► Squamous cell Ca
► Aggressive behavior

TROPHOBLASTIC 2. In tumors with mixed
DIFFRENTIATION: composition
► Focal change in adenoca ► Typcial adenoca+clear cut
► hCG+ enodcrine differentitation
► Rarely—choriocarcinoma or 3. Neuroendocrine Ca
glassy cell Ca form ► Organoid appearance
ENDOCRINE ► Large cells
DIFFERENTIATION: 4) Small cell
1. As scttered endocrine cells (neuroendocrine) Ca
in typical adenoca ► Similar to pulmonary
► Seen in mucinous ca counterpart
► ↑ seen after chemo or ► E/M: few dense core
radiotherapy secretory granules
► IHC: NSE+
5. Carcinoid tumor

HISTOCHEMISTRY:
► Mucin+ (PAS)
IHC:
► MUC1 and MUC3+, MUC2-ve, MUC5AC-ve
► CK20+/CK7- : helps to differentiate from Ca ovary and lung
► CEA+: seen as a rule, -ivity means that tumor is not colorectal
in origin
► CDX2+
► TAG-72+, LEA+
► Loss of blood gp Ag, HLA A,B,C expression—poorly
differentiated Ca
► Abnormalities of lectin binding
► Villin+, cathepsinB+
► Calretenin+--undifferentiated
► hCG—mucinous and poorly differentiated tumors
► PLAP+ 10%
► ER/PR -ve

MOLECULAR GENTICS
► Somatic mutations of genes:
► APC, mismatch repair genes, p53, k-ras and DCC
► Microsatellite instability associated tumors—mucinous or poorly
differentiated, right sided, prominent host response and with
circumferential growth
► Β catenin is associated with APC gene
► E-cadherin and α-catenin correlates with local invasion and mets
► p53 mutation
► Mutation of ras oncogene
► Deletion of von Hippel-Lindau gene
► Enhanced expression of c-myc oncogene
► Ki-67--↑ proliferative activity

COLORECTAL CARCINOMA
BIOPSY:
► +ve biopsy should be obtained before definitive treatment
► Larger lesion—multiple biopsies
► Better differentiated tumors and signet ring Ca—difficult to
identify
► Rectal tumors—biopsy the submucosal invasive tumor front
CYTOLOGY:
► Accurate via of diagnosing colorectal Ca
► Brush cytology via fiberoptic scope
► Rectal lesion can be sampled through cytology

GRADING & STAGING
► Dukes staging system—1973 :
 A: tumor involve wall of bowel only
 B: tumor extend through the wall
 C1: tumors with regional lypmh node mets
 C2: tumors with +ve lymph nodes at point of mesenteric
blood vessel ligature
 D: distant mets
► Astler and Coller—1954:
 A: limited to mucosa
 B1: involving muscularis externa but not penetrating it
 B2: penetrating through muscularis externa
 C1: confined to bowel wall but with nodal mets
 C2: penetrating through wall and with nodal mets

GRADING & STAGING
► TNM:

► GRADING:
 I Well differentiated
 II Moderately differentiated
 III Poorly differentiated
 Grading should be determined by worst pattern
rahter than the predominant one

SPREAD AND METASTASIS
► Most common sites of colonic mets:
► Regional lymph nodes and liver
► Lymph nodes ↑ common—poorly differentiated areas and
highly infiltrative pattern
► Minimum number of nodes recovered from surgical
specimen of colorectal Ca should be 14-15
► Lymph nodes micromets req—serial H&E section, IHC for
CK, PCR for CK19/20 or mutant k-ras
► Pericolonic tumor deposits—tumor nodules in perineural,
perivascular or intravascular location beyond muscularis
propria
► Other metastatic site: preitoneum, lung, ovaries
► Rare– CNS, bone, testis, uterus and oral cavity

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

PROGNOSIS
► 5 yr survival rate after curative resection—40-60%
► Local recurrence and regional lymph node mets90% of failure
cases
► AJCC divided prognostic factors into certain categories:
► Category I: well supported by literature, generally used in pt
management and of sufficient importance to modify TNM system
► Category IIA: extensively studied biologically &/or clinically.
Prognostic value for therapy, sufficient to be noted in pathology
report
► Category IIB: well studied but not sufficiently established for
Category I or IIA
► Category III: not yet established to meet criteria for Category I
or II
► Category IV: studied and shows no consistent prognostic
significance

PROGNOSTIC FACTORS
1. Age: very young and very old—poor prognosis
– Young—advanced stage, UC, signet ring and mucinous tumors—
bad prognosis
 More important in rectal than colonic tumors
2. Sex: ♀ better than ♂
3. CEA serum levels: >5 ng/ml—adverse prognosis
4. Tumor location: controversial, however left sided lesion better
5. Tumor multiplicity: no difference
6. Local extent: better for focal microscopic tumor and tumor
restricted to mucosa or submucosa
– Worse for tumors extending beyond wall
7. Tumor size: not a reliable factor (category III)
8. Tumor edge: non polypoid edge worse than polypoid
(category III)

PROGNOSTIC FACTORS
9. Obstruction: worse prognosis in some series
10. Perforation: poor prognosis
11. Tumor margins and inflammatory reaction:
– Pushing margins and inflammatory infiltrate—better
prognosis (IIA)
– Tumor infiltration by eosinophils and S-100+ dendritic
cells—better prognosis
– ≥ 4 mast cells x 30 oil immersion fields—poor prognosis
9. Vascular invasion: ↓ survival rate
– Lymph vessel invasion less importance than venous
invasion (IIA)
9. Perineural invasion: sign of advanced disease (IIA)

PROGNOSTIC FACTORS
14. Surgical margins:
– involvement of radial margin—single most ciritical
factor in determining recurrence (IIA)
– Recurrence chance ↑--tumor <2m away from
circumferential margin
15. Tumor thickness: correlates with node and liver mets
16. Microscopic type:
– Mucinous, signet ring and anaplastic—worse prognosis
– Medullary Ca—imporved outcome (IIB)
15. Acinar morphology: microacinar growth—poor prognosis
16. Neuroendocrine cells: controversial (III)
17. Tumor angiogenesis: recurrence and ↓ survival (III)
18. Mucin related Ag: MUC1 and sialyl-Lewis(x)—tumor
progression (III)

PROGNOSTIC FACTORS
21. HLA-DR: better prognosis
22. hCG: not an adverse prognostic factor
23. bcl-2: improved prognosis (IIB)
24. DNA ploidy: prognostic value doubtful
25. Cell proliferation: controversial
26. Allelic loss of chromosome 18q: negative prognosis (IIB)
27. TGF-β mutation: favorable prognosis
28. Oncogene expression:
– K-ras mutation—recurrent disease (IIB)
– ras p21—recurrent disease
– P53—independent prognostic factor (IIB)
– c-myc—correlated with degree of differentiation
– Microsatellite instability—improved survival
– Thymidylate synthatase mRNA—poor prognosis
– Lack of p27—poor prognosis (IIB)

PROGNOSTIC FACTORS
29. Lymph node involement: poor prognosis (I)
– Location and extent of node important
– ↑ nodes involved→↑ worse the prognosis
– Micromets in nodes—poor survival (III)
29. Pattern of lymph node reaction: regional nodes showing
cell mediated immune response—better survival
30. Staging: correlates with prognosis (I)
31. Microscopic grade: correlates with prognosis (IIA)

TNM CLASSIFICATION
► PRIMARY TUMOR (t)
► TX Primary tumor can’t be assessed
► T0 No evidence of primary tumor
► Tis Ca in situ: intraepithelial or invasion of lamina
propria
► T1 Tumor invades submucosa
► T2 Tumor invades muscularis propria
► T3 Tumor invades through muscularis propria into
subsersosa or into nonperitonealized pericolic or
perirectal tissue
► T4 Tumor directly invades other organs or
structures and / or perforates visceral
peritoneum

TNM CLASSIFICATION
► REGIONAL LYMPH NODES (N)
► NX Regional lymph nodes can’t be assessed
► N0 No regional lymph node metastasis
► N1 Metastasis in 1 to 3 regional lymph nodes
► N2 Metastasis in ≥ 4 regional lymph nodes

► DISTANT METASTASIS (M)
► MX Distant metastasis can’t be assessed
► M0 No distant metastasis
► M1 Distant metastasis

STAGE GROUPING
STAGE 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 TUMOR
Site:
► Rectum—more common, anterior or lateral wall, round shape,
usually <0.5cm, nodal mets rare, maybe seen in ass with UC or
CD, ovarian carcinoid and as collision tumor with
adenomatous component
► May occur in any part of large bowel
► Colonic carcinoid— large, penetrate wall deeply with regional
nodal mets
► S/S: never ass with carcinoid syndrome
Gross:
► flat or slightly depressed plaque or polypoid lesion
► Yellow color after formalin fixation

CARCINOID TUMOR
L/M:
► Ribbon and festoons, minor tubular and acinar component with
mucin
► Crypt cell proliferative micronests
► Argyrophil+, argentaffin-ve
IHC:
► Panendocrine markers+ (NSE, synaptophysin, crhromogranin)
► Somatostatin, glucagon, substance P, peptide YY+
► Gastrin/cholecystokinin, calcitonin, pancreatic polypeptide and
motilin +
► Rectal—CEA+, hCG+, prostatic acid phosphatase+
Treatment: rectal carcinoid <2cm, limited to mucosa or submucosa
by local excision
► Large tumors/ invasion of muscularis propria—radical surgery

LYMPHOMA
► Less frequently seen in large bowel compared to stomach and
small bowel
► Seen in HIV infected or transplant recipients or in pts with UC
Gross: prominent mucosal folds, ulceration, large mass or
solitary/multiple polyps
► Regional nodes involved—50% cases
L/M: non hodgkin lymphoma
► Low grade—MALToma—plasmacytoid differentiation
► Mantle cell lymphoma
► Anaplastic large cell lymphoma
► AILD like lymphoma
► Hodgkin’s lymphoma

METASTATIC TUMORS

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

Small & large gut

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