SLIDE REVIEW HANDOUT: GI 02 – SMALL INTESTINE 04/29/2020

Table 5: Comparison of Selected Inflammatory-Associated Lesions

CELIAC DISEASE (CD) TROPICAL SPRUE (TS) GI ENTEROPATHY ASSOCIATED T-CELL LYMPHOMA
(EATL)
CLINICAL  ~1% of population (US)  AKA: post-infective tropical malabsorption  RARE (<5% of GI lymphomas)
 AKA: celiac sprue, gluten-sensitive enteropathy, gluten-induced  Considered endemic in areas close to equator (Puerto o 10% of LONG-STANDING celiac disease
enteropathy Rico, Venezuela, Columbia, Mexico, India, SE Asia, o RARE reports of no celiac disease
 Bimodal age (children/adults) but M = F Caribbean)  Adults (ave 60 YO); M = F
 Caucasian >>> African/Asian ethnicity o Can manifest in residents and visitors!  Often celiac dx was adult-onset (when present)
 Diarrhea, steatorrhea (malabsorption), abdominal pain, weight o NOT identified in Jamaica, sub-Saharan  Abdominal pain, malabsorption (can be debilitating!),
loss, IDA (iron-deficiency anemia), FTT (failure to thrive); +/- Africa weight loss, obstruction, ulceration/perforation
IBS-like symptoms  No age or gender predilection  2 types of refractory celiac disease (RCD):
 Unknown etiology (see PPT for more info) o Type I: T-cells are polyclonal, normal
 Diarrhea, abdominal pain, myalgia, fever, anemia, immunophenotype
weight loss, glossitis, angular stomatitis, corneal o Type II: T-cells are monoclonal, abnormal
xerosis, nightblindess immunophenotype (downregulated/absent CD8)
GROSS  Endoscopy: scalloping/loss of folds in duodenum (not specific!)  Endoscopy: typically involves jejunum and ileum (can  Endoscopy: multiple masses (often raised/ulcerated), can
 BIOPSIES SHOULD BE TAKEN FROM DUODENAL BULB AND include terminal ileum) be single mass!
DISTAL DUODENUM  Site: proximal jejunum (most common)
MICROSCOPY  ↑ numbers of intraepithelial lymphocytes (IELs) (T cells) and  +/-Blunting of villi (takes ~4 months to develop, tends  +/-Adjacent celiac disease
plasma cells (PCs within lamina propria): to not be completely flat), + ↑ intraepithelial  Neoplastic intraepithelial lymphocytes (IELs)
o Upper limit of normal: 25 IEL/100 epithelial cells lymphocytes (IELs) o +Medium/large cells, vesicular/angulated nuclei,
o CD3 is NOT helpful to diagnose CD  +Eosinophils (lamina propria) – more pronounced than prominent nucleoli; often increased in adjacent
o ↑ IELs present at tips of villi (> 6/20 epithelial cells) CD; may be increased along with increased IELs in mucosa (+/-blunted villi)
 DO NOT count IELs around lymphoid aggregates (↑ colon  +Diffuse lymphocytic infiltrate (+mucosal/mural
IELs in these areas is normal!); if focal ↑ = get levels  +/-Megaloblastic nuclei (enterocytes) if B12 deficient infiltration); +/-deep ulcers/perforation/obstruction
to see if lymphoid aggregate present (similar to changes present in bone marrow)  Anaplastic variant (resembles ALCL)
 Marsh lesions can be useful but are non-specific o Accompanied by chronic inflammatory cell infiltrate
 +Crypt hyperplasia (+/-mitoses (may be numerous); +/- (eosinophils (may be prominent), histiocytes,
neutrophils in lamina propria/epithelium (if peptic duodenitis normal T-cells
also present)
IHC  Tissue transglutaminase (tTG) IgG/IgA titers – 90% specific and  NONE  Positive stains (Flow is the same): CD3, CD7, CD103,
sensitive granzyme B, perforin, TIA1; variable CD30
 Anti-endomysial Ab (EMA) – similar to tTG but labor intensive  Monomorphic Variant (Type II): CD8+, CD56+, TCRβ+
 Titers can be used to follow patient response to treatment  Negative stains: CD4, CD5, CD56
MOLECULAR  Positive for HLA-DQ2 (95%) or HLA-DQ8 (5%)  Possible connection to ↑ HLA-Aw19 and HLA-Aw31  +HLA-DQB1 (DQB1*0201) often seen  also in celiac dx!
 +T-cell receptor (TCR) rearrangements (β and γ)
 +9q, +7q, +1q, +5q, -16q, -8p, -9p, -13q
TREATMENT  Gluten-free diet (lifelong)  Long-term tetracycline/folate (6 months!) +/-B12  Surgical debulking + chemo (CHOP/hyper-CVAD) +/- BMT
PROGNOSIS  Most cases respond to diet change in 48 hours with full  Excellent with proper treatment  Poor prognosis: 2-year survival 15-20%
remission in weeks/months  Often missed/misdiagnosed as CD (DOES NOT  EATL associated with Type-II RCD has worse prognosis
 Complications: RESPOND TO GLUTEN-FREE DIET) than spontaneous EATL
 Refractory CD (when gluten-free diet doesn’t work!)  High relapse rate in endemic areas
o Type 1 (polyclonal T cells) – better prognosis
o Type 2 (monoclonal T cells) – poor prognosis
 Ulcerative jejunoileitis, enteropathy-associated T-cell
lymphoma (EATL), collagenous sprue, adenocarcinoma (small
intestine), squamous cell carcinoma (head/neck)
SLIDE REVIEW HANDOUT: GI 02 – SMALL INTESTINE 04/29/2020
Table 6: Comparison of Selected Infectious Lesions

WHIPPLE DISEASE GIARDIASIS MICROSPORIDOSIS CYCLOSPORA

CLINICAL  AKA: Whipple bacillus  Most common protozoal infection (US)  Infection by Encephalitozoon intestinalis(  Seen worldwide
 Infection by Tropheryma whipplei  Present in water (chlorine-resistant!) (most common) and Enterocytozoon  Ingestion of contaminated food/water
(bacilli)  MANY ASYMPTOMATIC; diarrhea bieneusi  these 2 can infect humans and person-to-person contact
 Adults (40-50 YO); M > F (explosive/watery/foul-smelling)   Originally thought to be a protozoan  Diarrhea (watery/mucoid/non-bloody),
 Caucasian dehydration  FTT (infants/children); (now classified as a fungus!) malabsorption, weight loss, anorexia,
 Diarrhea, malabsorption, weight loss, abdominal pain, malabsorption,  Present in water and animal hosts generalized malaise, abdominal pain,
arthritis, endocarditis, generalized nausea/emesis, fever; RARE peripheral worldwide (human-human AND fecal- nausea/emesis, fever; can cause
lymphadenopathy (LAD), and eosinophilia, urticaria oral spread are common) acalculous cholecystitis if biliary tree
neuropsychiatric symptoms  Risk factors: pediatric,  Diarrhea (chronic, non-bloody, non- infected
immunocompromised, use of untreated mucoid; worsens with food),  Risk factors: immunocompromised,
water, travel to foreign countries dehydration, malabsorption, weight loss travel to foreign countries (can cause
 Risk factors: immunocompromised traveler’s diarrhea – Haiti, Central/South
(HIV+) (RARE in immunocompetent) America)
GROSS  Sites: small bowel (most common); may  Sites: small bowel (most common;  Sites: small bowel (most common);  NONE
affect stomach, colon, appendix, lymph proximal); stomach and colon (RARE) affect any part of biliary tree 
nodes, brain, heart, eyes  Endoscopy: unremarkable sclerosing cholangitis
 Endoscopy: thickened mucosal folds,  ***E. Intestinalis can disseminate***
folds may be covered in white-yellow  Endoscopy: unremarkable
plaques; +/-friable/erythematous
MICROSCOPY  Peripheral smear: may see bacteria  Trophozoites: pear-shaped, 2  Often “normal”, +/-focal/mild villous  +/-Villous blunting (mild when present in
clinging to RBCs round/ovoid nuclei; found at luminal blunting; patchy lymphoplasmacytic small intestine); + increased
 Lamina propria infiltrated by numerous surface infiltrate (lamina propria); +/- increased intraepithelial lymphocytes (IELs) (mild);
foamy macrophages (WILL BE FULL OF o Scattered parasites = “falling IELs +/-lamina propria inflammation (variable
leaves” pattern but NOT prominent in most cases);
BACTERIA); variable neutrophils present;  + Epithelial disarray (superficial) +subtle
-monocytic infiltrate (usually); +/-small  +/-Mild to moderate villous blunting, vacuolization of epithelium (can “cup”
+superficial epithelial disarray
foci of adipose within lamina propria crypt hyperplasia (+apoptosis)
OR flatten nucleus (luminal aspect!)
o RARE granulomas (more common o +/-Increased inflammatory cells in  Organisms: +found within upper 1/3 of
 Organism: epithelial cell (towards surface); +round
in liver and lymph nodes) lamina propria (OFTEN NONE!)
o Spores (2-3 μm), +larger plasmodia forms (2-3 µm)/crescentic merozoites
o ***Macrophages can persist in  Always check to see if plasma o Located towards lumen (above
lamina propria/submucosa for (5-6 µm) (PRESENT IN VACUOLES =
cells are present in lamina nucleus!); +/-present in lamina
months/years AFTER treatment parasitophorous vacuoles)
propria propria macrophages (E. o Similar to Cystoisospora (Isospora)
 Villous blunting intestinalis); +/-polarizable on H&E but smaller!
o ***Rare submucosal variant ***  Electron microscopy (EM) may be
 +/-May see vacuolization of enterocytes required to diagnose!
IHC  Positive stains: PAS (bacillus shows  Multiplex PCR assays may be useful  Positive stains: giemsa, gram stain,  Positive stains: Acid fast (partial)
intense positivity) (organism identification in stool) modified trichrome, Warthin-Starry  Stool Exam: ova/parasites are partially
 PCR of CSF/joint fluid is specific (may be  Multiplex PCR assays have higher acid fast
part of gut flora/commensal organism) specificity and sensitivity than stool  Rt-PCR assays can be used to identify
exams and histology
MOLECULAR  Positive HLA-B27  NONE  NONE  NONE
TREATMENT  Antibiotic (ABX) therapy – long-term  Antibiotic (ABX) therapy – usually  Supportive +/- antimicrobial (variable  Antibiotic (ABX) therapy – usually
metronidazole (Flagyl) success); Fumagillin (both); Albendazole trimethoprim/sulfamethoxazole
(NOT effective for E. bieneusi) (Bactrim) + supportive care
PROGNOSIS  Often responsive to ABX (months to 1  Excellent prognosis with ABX  Difficult to treat in  Self-limited disease
year)  Some cases resolve spontaneously immunocompromised patients (immunocompetent); lasting upwards of
 Chronic giardiasis in 3 weeks to 1 month; severe for
immunocompromised patients immunocompromised (often HIV+)
SLIDE REVIEW HANDOUT: GI 02 – SMALL INTESTINE 04/29/2020

Location and Relative Size of Coccidia within the Small Celiac Disease vs. Peptic Duodenitis (ExpertPath)
Intestine (ExpertPath) These lesions can look identical at low power!

Celiac Disease (intraepithelial lymphocytes)

1. Cyclospora Peptic Duodenitis (neutrophils)

2. Cystoisospora (Isospora)
3. Microsporidia
4. Cryptosporidia
SLIDE REVIEW HANDOUT: GI 02 – SMALL INTESTINE 04/29/2020
Table 7: Comparison of Selected Epithelial Lesions

MECKEL’S DIVERTICULUM ADENOCARCINOMA

CLINICAL  MOST COMMON congenital malformation of GIT  2.4% of all GI tract malignancies
 1-4% of the population  Adults; M > F (2:1)
 ANY AGE; M > F (3:1)  Symptoms: abdominal pain, GI bleed, anemia, weight loss, jaundice (ampullary tumors)
o Most cases are asymptomatic (4.2% lifetime risk of becoming symptomatic)
 Risk Factors:
o Adults: obstruction (40%), diverticulitis (20%)
o Crohn disease; Celiac disease (increased relative risk – 10-80X! most are
o Children: GI bleed <2 YO; most common cause of GI bleed in children!
microsatellite UNSTABLE – methylation of MLH1)
 Complications: perforation, abscess formation, obstructive symptoms
o Polyposis syndromes: Familial adenomatous polyposis (FAP), Lynch syndrome
(intussusception/volvulus), enteroliths, malignancy (RARE; NET and lymphomas) (hereditary nonpolyposis colorectal cancer (HNPCC)), Neurofibromatosis type 1
(NF1), Peutz-Jeghers syndrome
GROSS  Sites: blind pouch/diverticulum present on antimesenteric ileal border  Sites: duodenum (55%), jejunum (18%), ileum (13%), NOS (14%)
 Imaging: Nuclear medicine (Tc-99m pertechnetate scan) is most specific test (will settle as
a “hot spot” in the gastric mucosa within the RLQ (DDX: appendicitis)
o Beware: false negatives in patients without gastric mucosa!
MICROSCOPY  True diverticulum (all layers of GI tract are present!)  Nearly identical to colorectal carcinoma
o +/- Dirty necrosis; +/- mucin production (may be abundant)
 +/- Ectopic gastric or pancreatic mucosa (30-50% of cases)
o Arises from adenomas or dysplasia (Crohn disease)
o If gastric: acid production  +/-ulceration/bleeding o Desmoplasia may be absent in setting of Crohn-associated dysplasia/cancer
 Duodenal tumors may have intestinal, gastric, or pancreaticobiliary phenotype
IHC  NONE  Positive stains: CK7; variable CK20
MOLECULAR  NONE  LACK mutations in APC gene (unless FAP case)
 Tp53 and SMAD4 mutations often present
TREATMENT  Excision (curative)  Segmental resection of small bowel and mesentery; whipple resection
(ampullary/duodenal tumors)
 Chemotherapy (similar to CRC but not enough data)
PROGNOSIS  Excellent (post-surgery)  Prognosis is linked to stage of disease (see below for staging)
o Overall 5-year survival (30.5%)
 Duodenal tumors have worse prognosis

The Marsh-Oberhuber Classification of Celiac Disease (Marsh Lesions)

RULES OF 2: MECKEL’S DIVERTICULUM
Prevalence: 1-4% (ave 2% of the population)

Clinical: present before age 2 with GI bleeds

Location: within 2 feet of the ileocecal valve

Gross: measures 2 inches in length (average)

Micro: contains 2 types of mucosa

(https://ars.els-cdn.com/content/image/3-s2.0-B9780323548434000155-
f15-02-9780323548434.jpg)
 SLIDE REVIEW HANDOUT: GI 02 – SMALL INTESTINE 04/29/2020

Staging Carcinoma of the Small Intestine

Primary tumor (pT): Regional lymph nodes (pN): (non-ampullary duodenal LN =

 TX: primary tumor cannot be assessed retropancreatic, hepatic artery, inferior pancreaticoduodenal, superior
 T0: no evidence of primary tumor mesenteric) (jejunal/ileal LN = mesenteric, superior mesenteric, + ADD FOR
 Tis: high grade dysplasia / carcinoma in situ TERMINAL ILEUM = cecal, ileocolic)
 T1: tumor invades the lamina propria or submucosa  NX: regional lymph nodes cannot be assessed
o T1a: tumor invades the lamina propria  N0: no regional lymph node metastasis
o T1b: tumor invades the submucosa  N1: metastasis in one or two regional lymph nodes
 T2: tumor invades the muscularis propria  N2: metastasis in three or more regional lymph nodes
 T3: tumor invades through the muscularis propria into the subserosa or
extends into non-peritonealized perimuscular tissue (mesentery or Distant metastasis (pM)
retroperitoneum) without serosal penetration
 M0: no distant metastasis
o Non-peritonealized perimuscular tissue in jejunal/ileal lesions is part of the
 M1: distant metastasis
mesentery
o Non-peritonealized perimuscular tissue in duodenal lesions (were serosa is
not present), is part of the interface between the duodenum and pancreas Stage grouping
 T4: tumor perforates the visceral peritoneum or directly invades other
Stage 0: Tis N0 M0
organs or structures (e.g., other loops of small intestine, mesentery of
adjacent loops of bowel and abdominal wall by way of serosa; for duodenum Stage I: T1 N0 M0
only, invasion of pancreas or bile duct) T2 N0 M0
Stage IIA: T3 N0 M0
Stage IIB: T4 N0 M0
Stage IIIA: any T N1 M0
Stage IIIB: any T N2 M0
Stage IV: any T any N M1
SLIDE REVIEW HANDOUT: GI 02 – SMALL INTESTINE 04/29/2020
Table 8: Comparison of Selected Stromal Lesions

GASTROINTESTINAL STROMAL TUMOR SCHWANNOMA LYMPHANGIOMA NEUROENDOCRINE TUMOR

(GIST)
CLINICAL  ~4500 cases/year in US  RARE  MANY associated names!  Incidence but ~2/100,000 (US/EU)
 Any age (ave 60 years); M = F  Adults (ave 60 YO); F > M (4:1 in  Any age but children > adults  Adults (>50 YO; increases with age)
 Middle aged adults  NF1 stomach)  Children (mesenteric; <5 YO); M > F  Small bowel NEC: M > F
 Rare in children  Carney triad  Asymptomatic, abdominal pain, GI  Adults (luminal/mucosal lymphangioma)  African American ~2X Caucasian
 African Americans (most common for bleeding, obstructive  Asymptomatic to acute abdomen  Often asymptomatic; abdominal pain,
malignant GISTs)  EXTREMELY RARE association with (obstruction/perforation/infarct); can obstruction; <10% of patients present
 GI bleeding (most common), abdominal neurofibromatosis (non-GI induce volvulus/intussusception with carcinoid syndrome BUT 2/3 have
pain, obstruction; may be incidental! schwannomas often associated  Familial associations: Turner/Noonan fibrous thickening right endocardium!
 Familial cases (see PPT!) with NF2) syndromes (cystic hygroma), Maffucci  Risk factors: well-diff NEC (1st degree
syndrome, trisomy (13 (Patau), 18 relative); NEC: obesity, male, older,
(Edwards), and 21 (Downs)) menopausal hormone therapy
GROSS  Sites: stomach (60%; SDH-def GIST),  Sites: stomach (most common)  Sites: Intraabdominal: distal terminal  Sites: duodenum (multiple types of NE
jejunum/ileum (30%; NF1-associated);  Well-circumscribed, firm, tan-gray ileum (most common), colorectal, tumors), jejunum/ileum (multifocal in
duodenum (5%), colorectal (<5%); RARE to yellow-white mass esophageal, mesentery, omentum, ~1/3)
esophageal/appendix/primary retroperitoneal
extraintestinal  Sessile/pedunculated (partially!) or
whitish plaque; smooth mucosal surface;
multiple cystic spaces (+serous to white
fluid); +/-serosanguinous “oozing”
MICROSCOPY  Lobular arrangement of monotonous  GI schwannomas differ from ST  +Variable sized anastomosing/dilated  +Nested/trabecular pattern of
spindled/epithelioid; +eosinophilic counterparts! vascular spaces/channels; +thin walls; monotonous cells;+abundant cytoplasm;
+single endothelial layer +/-glandular/ pseudoglandular/duct-
cytoplasm (usually have cytoplasmic  –Fibrous capsule/vascular
(monotonous/bland/ovoid- like/rosette patterns; +vascular pattern
vacuoles); +/-myxoid/myxochondroid hyalinization flattened/hyperchromatic nuclei); +/- (often and prominent)
background; +/-cystic areas; +inconspicuous  +Bland spindle cells; +palisading papillary projection/tufting; large vessels  Well-differentiated: +bland “salt &
vessels; minimal to no inflammation (focal); +nuclear pleomorphism +/- smooth muscle in walls pepper chromatin” nuclei; +scattered
 +/-"Skeinoid" fibers = haphazard (mild); -degenerative changes o +++Eosinophilic proteinaceous mitoses; low Ki-67 (<2%)
debris; +/-RBCs/fluid/lymphocytes
arrangement of coarse/wire-like collagen (RARE when present); -mitoses  Poorly differentiated: +necrosis;
 +/-Fibrotic interstitial stroma (chronic +frequent mitoses; high Ki-67 (>20%);
bundles  SMALL BOWEL FINDING! (RARE)
lesions) often small cell carcinoma
 +/-Pleomorphism (RARE if present);  +Peripheral lymphoid cuffs o +/-myxoid change; +mast  +LVI common (even if low-grade/well-
dedifferentiation = admixed low and high- (“Crohn-like reaction”); cells/hemosiderin deposits differentiated!)
grade areas; +/-multinucleated cells; +/- +prominent lymphoplasmacytic (common)
tumor necrosis (uncommon) infiltrate within lesion  +lymphoid infiltrates/aggregates (often);
 +/-Extension into mucosa +/-scattered reactive germinal centers
IHC  Positive stains: DOG1, cKIT/CD117, SMA,  Positive stains: S100, SOX10, GFAP  Positive stains: CD31, CD34, D2-40  Positive stains: synaptophysin,
CD34,vimentin, CA-II  Negative stains: CD117, DOG1, chromogranin-A, CD56, PD-L1 (G3 only)
 Negative stains: SDHB, desmin, S100 SMA, desmin, calretinin  24-hr Urine: elevated 5-HIAA
 Serum: elevated chromogranin-A
MOLECULAR  Mutations in cKIT or PDGFRA  Lack NF2 gene alteration  Mutations from hereditary disease  LOH chr18 (70%)
 KIT mutations (exon 11/exon 9): duodenum  FLT4 (VEGFR-3), PROX1, SOX18, FOXC2  Mutations mTOR pathway
TREATMENT  Complete excision  Excision  Incision (surgical or endoscopic) versus  Excision +/- debulking + Somatostatin
 TKI (imatinib (Gleevec)) complete excision analogs +/- Chemo/Rad
PROGNOSIS  See below in handout for more information  Benign (no reported  Excellent (most cases are benign)  Well-diff NET +/- 20 years with mets
recurrence/metastases)  NB: internal organs/mediastinum  Small intestine worse prognosis
 40-50% small bowel GISTs = malignant!
 SLIDE REVIEW HANDOUT: GI 02 – SMALL INTESTINE 04/29/2020

Staging Gastrointestinal Stromal Tumor (GIST):

 DO NOT STAGE pediatric GIST, familial GIST (germline mutants: KIT or PDGFRA), and syndromic GIST  these are not part of AJCC staging!

Primary tumor (pT) (record if ruptured into peritoneal cavity, but this does Prognostic Factors:
not currently change staging  may have to estimate size)
 Poor prognosis features (AKA malignant GIST)
 pTX: Primary tumor cannot be assessed
o >5 cm
 pT0: No evidence of primary tumor
 pT1: Tumor ≤ 2 cm in greatest dimension o tumor necrosis
 pT2: Tumor > 2 cm and ≤ 5 cm
 pT3: Tumor > 5 cm and ≤ 10 cm o hemorrhage (unrelated to procedure)
 pT4: Tumor > 10 cm in greatest dimension o Hypercellular

o Marked/bizarre atypia
Regional lymph nodes (pN) (do not use pNX – list nothing for pN if
no LN are present!) o High mitotic index (5+ MIT/HPF)
 pN0: No regional lymph node metastasis
 pN1: Regional lymph node metastasis o smaller cell carcinoma

 High risk: > 1 cm and > 5 MF/50 HPF; also infiltrative border within muscularis
Distant metastasis (pM) propria

 pM1: Distant metastasis  Intermediate risk: 1 - 5 MF/50 HPF and > 1 cm

 Low risk: < 1 cm (often are serosal)

Histologic grade (G)
 Specific to Duodenum:
 Low mitotic rate: ≤ 5 mitoses per 5 mm 2

 Poor prognostic factors:

 High mitotic rate: > 5 mitoses per 5 mm 2

o > 5 cm, > 5 mitoses/50 HPF

o Epithelioid pattern AND mucosal invasion

See AJCC 8th Edition for Prognostic Stage (NB: this is different
between gastric GIST and GIST at other locations!)  Good prognostic factors:

o < 2 cm and < 5 mitoses/50 HPF

o Organoid pattern with low cellularity

 SLIDE REVIEW HANDOUT: GI 02 – SMALL INTESTINE 04/29/2020

Staging Neuroendocrine Tumors of the Small Intestine

Staging for Duodenal/Ampullary Tumors:
NOTE: DOES NOT INCLUDE JEJUNAL/ILEAL NECs (see separate staging); POORLY DIFFERENTIATED NECs USE THE CARCINOMA STAGING

Primary tumor (pT) (NB: pTIS does not exist under AJCC Distant metastasis (pM)
8th Edition staging!)  M0: No distant metastasis
 TX: primary tumor cannot be assessed  M1: Distant metastasis
 T1: tumor invades the mucosa or submucosa only and is ≤ 1 cm (duodenal o M1a: Metastasis confined to liver
tumors); tumor ≤ 1 cm and confined within the sphincter of Oddi (ampullary o M1b: Metastasis in at least one extrahepatic site (e.g., lung, ovary, non-
tumors) regional lymph node, peritoneum, bone)
 T2: tumor invades the muscularis propria or is ≥ 1 cm (duodenal); tumor invades o M1c: Both hepatic and extrahepatic metastases
through sphincter into duodenal submucosa or muscularis propria or is ≥ 1 cm
(ampullary)
Prefixes
 T3: tumor invades the pancreas or peripancreatic adipose tissue
 T4: tumor invades the visceral peritoneum (serosa) or other organ  r: recurrent tumor stage

Stage grouping
Regional lymph nodes (pN) (duodenal, hepatic, pancreatoduodenal,
infrapyloric, gastroduodenal, pyloric, superior mesenteric, pericholedochal)  Stage I:T1N0M0
 Stage II:T2 - T3N0M0
 NX: Regional lymph nodes cannot be assessed
 Stage III:T4N0M0
 N0: No regional lymph node involvement
 any TN1M0
 N1: Regional lymph node involvement
 Stage IV: any T any NM1

Histologic grade
CARCINOID SYNDROME - Symptoms
Common:  Not formally a part of staging but most use ENETS/WHO grading criteria:
Diarrhea o G1: mitotic rate < 2 per 10 high power fields and Ki67 rate < 3%
Flushing o G2: mitotic rate 2 - 20 per 10 high power fields or Ki67 rate 3 - 20%
Variable: o G3: mitotic rate > 20 per 10 high power fields or Ki67 rate > 20%
Bronchospasm
Myopathy
Arthropathy
Scleroderma (skin)
NB: <10% of patients with NET will
present with Carcinoid syndrome
 SLIDE REVIEW HANDOUT: GI 02 – SMALL INTESTINE 04/29/2020

Staging Neuroendocrine Tumors of the Small Intestine

Staging for Jejunum/Ileum:
NOTE: DOES NOT INCLUDE DUODENAL/AMPULLARY NECs (see separate staging); POORLY DIFFERENTIATED NECs USE CARCINOMA STAGING

Primary tumor (pT) o M1b: metastasis in at least one extrahepatic site (e.g., lung, ovary, non-
 TX: primary tumor cannot be assessed regional lymph node, peritoneum, bone)
 T0: no evidence of primary tumor o M1c: both hepatic and extrahepatic metastasis
 T1: invades lamina propria or submucosa and ≤ 1 cm in size
 T2: invades muscularis propria or > 1 cm in size Prefixes
 T3: invades through the muscularis propria into subserosal tissue without
 (m): multiple primary lesions (provide stage for the most advanced lesion)
penetration of overlying serosa
 r: recurrent tumor stage
 T4: invades visceral peritoneum (serosa) or other organs or adjacent structures

Regional lymph nodes (pN) (superior mesenteric, mesenteric; posterior Stage grouping
cecal (terminal ileum lesions!))  Stage I:T1N0M0
 NX: regional lymph nodes cannot be assessed  Stage II:T2 - 3N0M0
 N0: no regional lymph node metastasis  Stage III:T4N0M0
 N1: regional lymph node metastasis in < 12 nodes  any TN1 - 2M0
 N2: large mesenteric masses (> 2 cm) or extensive nodal deposits (≥ 12),  Stage IV: any T any NM1
especially those that encase the superior mesenteric vessels
Histologic grade
Distant metastasis (pM)
 Not formally a part of staging but most use ENETS/WHO grading criteria:
 M0: no distant metastasis o G1: mitotic rate < 2 per 10 high power fields and Ki67 rate < 3%
 M1: distant metastasis o G2: mitotic rate 2 - 20 per 10 high power fields or Ki67 rate 3 - 20%
o M1a: metastasis confined to liver o G3: mitotic rate > 20 per 10 high power fields or Ki67 rate > 20%