A presentation for general surgery residents for University examinations

1. Neoplasia of small bowel
Nabin Paudyal

2. General considerations
• Small intestine has less than 2% of total GI malignant neoplasms
• Mean age at presentation is 62 for benign neoplasms and 57 for
malignant neoplasms
• Malignant neoplasms account for 75% of small bowel symptoms that lead
to surgery
• Stromal tumors and adenomas are the most frequent diagnosed benign
tumors
• Adenocarcinoma represents the most prevalent malignant neoplasm
followed by NETs

3. Risk factors for Small Bowel Neoplasia
• FAP
• HNPCC
• PJS
• CD
• Gluten sensitive enteropathy
• PUD
• CF
• Biliary diversion
• Smoking
• Heavy alcohol
• Consumption of red meat
• Salty food

4. Genetics for causing small bowel neoplasia
• KRAS gene
• Allelic losses at chromosomes 5q (APC), 17q (p53 gene) and 18q (DCC) and DPC 4
• Inactivated DNA mismatch gene repair and Microsatellite instability are
seen in 15% of population
• MSI-H is typical of small bowel carcinomas associated with celiac disease
linked by CpG island methylation.
• Microarray analysis shows small bowel tumors expressing EGFR and VEGF
which may contribute to carcinogenesis

5. Clinical features
• Vague and nonspecific
• Include dyspepsia, anorexia, malaise and dull abdominal pain
(intermittent and colicky)
• May be present for months or years before diagnosis.
• Most patients with benign neoplasms remain asymptomatic
• Sometimes the symptoms may be in the form of obstruction,
intussusception and hemorrhage.
• Hemorrhage may be Hematochezia, Hematemesis or Occult GI bleeding

6. Diagnosis
• Mostly diagnosed due to suspicion.
• Pre-operative diagnosis is made only in 50% of symptomatic patients
1. Plain films Obstruction features may be present
2. UGI series with small bowel follow through Accurate diagnosis in 53-
83% of patients
3. CT abdomen Extraluminal tumors (GIST)
4. CT and MRI enteroclysis sensitivity and specificity reaching up to 97-
98%
5. Flexible Endoscopy visualization and biopsy of ileal neoplasms
6. Capsule endoscopy variable sensitivity and specificity

7. Benign neoplasms of small
intestine

8. Benign neoplasms
• MC benign neoplasm of small intestine include
• stromal tumors (mc tumors producing symptoms)
• Adenomas (mc tumors in autopsy)
• Lipomas
• When benign tumor is identified at operation, resection MUST be
done
• Once the tumor is identified, thorough search of the bowel must be
done because other tumors may also be present

9. Adenomas
• Account for almost 15% of all benign tumors of the small bowel
• Types
• Brunner gland adenoma
• Villous adenoma
• True adenoma
• Location wise
• Duodenal adenoma (20%)
• Jejunal adenoma (30%)
• Ileal adenoma (50%)
• Most are found singly and incidentally and are asymptomatic
• MC presentation BLEEDING and OBSTRUCTION
• True and villous adenomas proceed through the same Adenoma-Carcinoma
sequence as CRC and should be considered pre-malignant

10. • Malignant potential of villous adenoma is from 35-55%.
• Treatment is both endoscopic and surgical
• Jejunal and ileal tumors Surgical resection is treatment of choice
• In duodenum Decisions about surgical management must be carefully
planned because of potential morbidity associated with duodenal resection by
pancreaticoduodenectomy OR pancreas-preserving duodenectomy
• Before surgery pre-operative EUS has recently emerged as a useful modality
• Helps guide management
• Endoscopic submucosal resection is a safe alternative ( yet risk for recurrence is 50%).
Especially duodenal adenomas and Brunner gland tumors are managed using ESmR.
• If the tumor is invasive OR evidence of recurrence is seen, definitive approach
(Pancreaticoduodenectomy) is done.

11. FAP in small intestine
• Familial adenomas are present in patients with FAP syndrome. Most FAP
neoplasms occur in duodenum.
• Extracolonic manifestations are usually present and also have different
algorithm in management.
• Adenomas in duodenum can be found in 50-90% of cases.
• FAP Neoplasms grow very slowly, there is 5% risk of duodenal adenocarcinoma
• Life long surveillance is a priority in patients with duodenal FAP
• Any adenoma > 3 cm should be biopsied
• Additional duodenal biopsy must also be done
• Spigelman classification is used to guide the surveillance for patients with
FAP adenoma

13. FAP in small intestine (duodenum)-Management
• Spigelman Stage I-III
• Large adenomas EMR, surgical polypectomy
• Ablative therapy Argon beam coagulation, Photodynamic therapy
• Spigelman Stage IV
• Carcinoma in-situ OR High grade dysplasia Pancreaticoduodenectomy Or
pancreas-preserving duodenectomy

14. Lipomas
• Most common in the ileum and manifested as single intramural lesion
in submucosa
• Occur in 6-7th decade
• Men>> Women
• Features may be obstruction and bleeding from superficial ulceration
• Symptomatic lesions Excision

15. Hemangiomas
• Developmental malformations consisting of submucosal proliferation
of blood vessels
• Jejunum mostly affected
• Hemangiomas account for 3-4 % of all benign tumors of small bowel
and is multifocal
• May occur as a part of inherited disorder known as Osler-Weber-
Rendu disease, Turner syndrome

16. Malignant neoplasms of small
intestine

17. Introduction
• Incidence of malignant neoplasms have increased during past three decades
• Increased up to as much as four fold.
• SEER database 5 year survival rate of 34.9 %
• Chemotherapy for small bowel adenocarcinomas has not improved overall survival
• Malignant neoplasms almost always produce symptoms, most of which includes
pain and weight loss. Intussusception in malignancy suggests tumor infiltration
and adhesion.
• Other symptoms may be  Diarrhoea, Tenesmus, GI bleeding, palpable mass,
perforation ( sarcomas, lymphomas)

18. Neuroendocrine Neoplasms (NENs)
• Arise from Kulchitsky cells
(enterochromaffin cells) situated
at the base of the crypts of
Lieberkühn
• Also called argentaffin cell tumors
(affinity to silver stains)
• Lubarsch (1888) identified the
tumor for the first time
• Oberndorfer coined the term
Karzinoide to indicate carcinoma
like appearance and the lack of
malignant potential
• Term “Carcinoid” is misnomer now
and is not used as all NENs have
some intrinsic malignant potential.
• NENs may occur in
• Lungs
• Bronchi
• GI tract
• Age at diagnosis 7th decade of
life, median age of 63 years
• Classification of NENs based on
tumor grade and differentiation.

19. Classification of NENs
• May be benign or well
differentiated malignant type
• Malignant type may be
• Low grade
• Intermediate grade
• High grade
• Classification based on appearance,
mitotic rates, behavior and Ki-67
proliferation index.
• All neuroendocrine carcinomas are
G3, poorly differentiated
malignant neoplasms.
• Based on embryologic site of
origin and secretory product
Origin Secreted product
Foregut Low serotonin
High ACTH
High 5 Hydroxytryptophan
Midgut High serotonin
Hindgut Somatostatin
Neuropeptide YY

20. • NENs are usually located in appendix.
• Small intestine is the second most common site.
• In small intestine, NETs is almost always located within last 2 feet of the
ileum.
• Why are we worried about NENs?
• Inherent malignant potential
• Carcinoid syndrome (cutaneous flushing, bronchospasm, diarrhoea, vasomotor
collapse)
• Primary tumors that secrete directly into the venous system, bypassing portal
system give rise to carcinoid syndrome without metastasis.

21. Pathology
• 80% of NETs are asymptomatic and found incidentally at the time of
surgery
• 90% of NETs are found in 5 typical sites
• Small intestine
• Rectum
• Colon
• Stomach
• Unknown sites
• Malignant potential of the tumor is related to
• LOCATION (ileal )
• DEPTH OF INVASION
• SIZE (> 2cm)
• GROWTH PATTERN OF TUMOR

22. • 3% appendiceal NET metastasize, 35% ileal NETs are associated with
metastasis
• Approximately 75% GIT NET are < 1cm in size
• NETs of size > 2cm are metastatic in 80-90% of cases.
• Gross appearance
• Small, firm, submucosal, yellowish, usually along the antimesenteric border of small
intestine
• Histological appearance
• Slow growing tumors
• However after invasion into the serosa, tumors have intense desmoplastic reaction
• Mesenteric fibrosis, intestinal kinking, intermittent obstruction are seen
• Multicentric tumors
• Frequent co-existence of the tumor with second primary tumor of different histologic
subtype (synchronous adenocarcinoma). MC seen in large intestine
• May be associated with MEN 1

24. Clinical features
• MC symptom Abdominal pain
• a/w partial or complete small bowel
obstruction
• Intussusception  Note this a/w
• Diarrhoea (due to obstruction)
• Weight loss
• As mesenteric and nodal extension
progresses Local venous
engorgement, ischemia of affected
segment may occur
• Malignant carcinoid syndrome
• Rare (<10% of patients with NET)
• Usually seen in gastrointestinal NET
(small bowel)
• Features include
• Vasomotor, cardiac and GIT manifestations
• Hormones responsible: Serotonin, 5HT,
histamine, dopamine, tachykinin, kallikrein,
substance P, prostaglandin, neuropeptide K
• Most patients who have symptoms
have massive hepatic metastasis
• Ovarian and retroperitoneal NETs may
bypass liver and produce symptoms.
• Symptoms See next slide

25. • Symptoms include:
• Cutaneous flushing
• Diarrhoea
• Hepatomegaly
• Cardiac lesions (Right sided valvular heart disease)
• Asthma

26. Diarrhoea
• Episodic
• Usually occurring after meal
• Watery
• Explosive
Cardiac lesion
• Right heart involved
• Can lead to congestive heart failure
• Pulmonary stenosis
• Tricuspid insufficiency
• Tricuspid stenosis

27. Asthma
• Observed during flushing
• Due to serotonin and bradykinin
Malnutrition
• Pellagra due to tryptophan use for
making serotonin

28. Diagnosis
• Elevated levels of 5-HIAA in urine
during 24 hours with high
performance liquid chromatography
• Chromogranin A (CgA) (in more than
80% cases)
• A combination of serum CgA and 24-
hour urinary 5-HIAA is more
diagnostic
• Serum CgA and N-terminal pro-brain
natriuretic peptide may also be used
• For surveillance, CgA levels have
proven efficacy over urinary 5-HIAA
• Plasma serotonin, substance P,
neurotensin, neurokinin Am
neuropeptide K levels can be
measured
• Provocative tests  Penta gastrin,
calcium, epinephrine may be used to
reproduce symptoms of NETs. (but
rarely used at present)

29. 5-HIAA, CgA and N-terminal pro
BNP together increase overall
diagnostic reliability of the
condition.

30. • NETs of small intestine are rarely diagnosed preoperatively
• Barium radiographic studies of small may exhibit multiple filling defects as a
result of kinking and fibrosis of the bowel.
• A combination of anatomic and functional imaging techniques is routinely
performed to optimize sensitivity and specificity.

31. Radiological investigation
• CT scan
• Depends upon size, degree of mesenteric invasion, desmoplastic reaction and
regional LN invasion
• If these are not well defined, CT scan may not fully diagnose the condition
• CT thus has limited diagnostic capability
• CT scan reveals solid mass with spiculated borders and radiating surrounding
strands that is associated with linear strands within mesenteric fat and kinking
of the bowel

33. Other diagnostic tools
• CT angiography
• MRI T1-weighted (low signal intensity) and T2-weighted (high signal
intensity) help in identifying liver metastasis
• Peripheral enhancement in hepatic arterial phase
• Hypointense defects in portal venous phase.
• Functional nuclear imaging studies Indium labeled pentetriotide which binds
to somatostatin receptors Helps in diagnosing extra abdominal metastatic
disease
• 18FDG-PET scan, 18F-DOPA scan, Somatostatin receptor imaging with
Gadolinium 68 (68 Ga-DOTATATE PET-CT)

34. Somatostatin receptor imaging with
Gadolinium 68 (68 Ga-DOTATATE PET-CT)
• Helps localize primary tumor in patients
with NETs of unknown origin
• Define the existence of disease and extent
of metastasis
• 64 Cu-DOTATATE has also been recently
FDA approved

35. Management of NETs
•Surgical therapy
• Based upon the tumor size, location, and presence of metastatic disease
• For lesions < 1 cm in diameter
• Segmental resection of intestine is enough
• There should be no evidence of regional LN metastasis
• For lesions > 1cm in diameter or multiple tumors or with regional LN
metastasis
• Wide excision of bowel and mesentery

37. Precautions for surgery
• Carcinoid crisis
• Featured by
• Hypotension
• Bronchospasm
• Flushing
• Tachyarrhythmia
• Often caused prior OT secondary to anesthetic agents
• Managed using IV Octreotide 50-100 mcg bolus followed by infusion at 50
mcg/hr.

38. • Examination of abdomen to look for multicentric lesions
• In cases where mesentery is involved, dissection of the tumor off the
mesenteric vessels with preservation of blood supply to unaffected bowel is
appropriate.
• Patients with NETs and widespread metastatic disease:
• Role of surgical debulking is definite
• Limited hepatic metastasis Metastasectomy
• Extensive hepatic metastasis Surgical resection if there is no extrahepatic
metastases, LFT not compromised, no diffuse bilobar hepatic involvement
• Recurrence is >75%
• In recurrent cases Trans arterial chemoembolization OR radioembolization can be an
option

39. Medical management of NETs
• Basis: Relief of symptoms produced by increased production of humoral
factors
• Drug classes:
a. Somatostatin analogs (SSAs ): Octreotide/ Lanreotide
1. Helps to delay cancer progression as well
2. PROMID trial Octreotide utility
3. CLARINET trial  Lanreotide utility for management of non functioning
pancreatic NETs
• Follow up diagnostic imaging is required after 3-6 months.
• Second generation SSAs (Pasireotide) as well as chimeric dimers are
currently being developed for current use

40. b. mTOR inhibitor Everolimus
• Non-functional gastrointestinal NET
• RADIANT-4 trial Tumor PFS for 4-11 months
c. Peptide receptor radionuclides
• NETTER 1 trial 177-Lu-DOTATATE (Lu-DOTA) was shown to increase tumor PFS by 79%
compared to high-dose Octreotide.
d. Interferon-α (no longer recommended due to adverse effects)
e. For somatostatin refractory diarrhoea TELESTAR trial telotristat
f. For metastatic NETs combination cytotoxic therapy Streptozocin, 5-FU,
Cyclophosphamide
• Used for patients with G2 metastatic disease. Duration of response is however short
lived.
• Other investigational therapy Temozolomide (monotherapy), Temozolomide +
Capecitabine (combination) therapy, etoposide+cisplatin (combination therapy for
poorly differentiated NETs)

41. Management of metastatic NETs
• Multidisciplinary approach
• Combined modalities using
• Surgical debulking
• Hepatic artery embolization
• Chemoembolization or radioembolization
• Medical therapy
• Targeted therapy (Sunitinib PDGFR and VEGF receptor inhibitor)

43. Prognosis
• Best prognosis of all small bowel tumors
• Resection of localized primary almost 100% survival rate
• 5-year survival rate
• Regional  65%
• Distant 25-35%
• Tumor metastasis 20-50%
• Tumor recurrence 40-60%
• An elevated level of CgA is an independent predictor of an adverse
prognosis