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Small bowel adenocarcinoma

Tumor Board
Englewood Hospital and Medical Center

Donald Baril
Department of Surgery
Mount Sinai School of Medicine
December 10, 2004

Case presentation R.H.

79 yo F presented with progressive fatigue and


shortness of breath

PMHx: Esophageal cancer, papillary bladder cancer,


endocarditis, hypertension, atrial fibrillation, CAD,
hypothyroidism, CVA

PSurgHx: Esophagogastrectomy/Splenectomy (6/03),


CABG/MVR (5/03)

Case presentation R.H.

Found to be markedly anemic with a hematocrit of 18

October 2004 negative endoscopy and colonoscopy;


capsule endoscopy showed two small bowel ulcers

CT scan lumen constricting lesion of mid-small


bowel

Planned exploratory laparoscopy in mid-November

November 2004 right hemispheric stroke

Case presentation R.H.

November 23 Exploratory laparoscopy converted to


open lysis of adhesions, small bowel resection

Returned emergently to the OR immediately postoperatively for intraabdominal bleeding

Case presentation R.H.: Pathology

Moderately differentiated invasive adenocarcinoma


with focal adenosquamous features and minor
mucinous component

Transmural invasion

Lymphovascular invasion

Lymph node metastasis (1/7 lymph nodes)

Epidemiology of small bowel adenocarcinoma

Small intestine accounts for approximately 75% of the


length of the GI tract and more than 90% of the mucosal
surface

Fewer than 2% of GI malignancies arise in the small


intestine

Incidence of small bowel malignancies is 1 per 100,000

Estimated to be less than 5000 cases per year diagnosed


in the U.S.

Small bowel tumors

Small bowel malignancies

30-50% are adenocarcinomas

25-30% are carcinoids

15-20% are lymphomas

10-20% are gastrointestinal stromal tumors

Anti-neoplastic environment of the small


intestine
1.

2.

3.

4.

5.

Liquid contents cause less irritation than more solid


contents of large bowel
Rapid transit of intestinal contents provides shorter
exposure of mucosa to carcinogens
Lower bacterial load may result in decreased
conversion of bile acids into potential carcinogens
Benzopyrene hydroxylase, enzyme responsible for the
conversion of the known carcinogen benzopyrene, is
present in higher concentrations in the small bowel
Increased lymphoid tissue and higher levels of IgA

Clinical presentation

Abdominal pain
Nausea and vomiting
Bleeding/Anemia
Weight loss
Gastric outlet obstruction
Diarrhea
Mean time to diagnosis from the onset of the initial
complaint is 7 months
50% of patients present emergently with
obstruction or bleeding

Diagnosis of small bowel malignancies

Plain abdominal radiographs


Obstruction
Calcified mass

UGI/SBFT
Mass
Mucosal defect
Intussusception

Diagnosis of small bowel malignancies

Enteroclysis

NGT directed to the jejunum and a combination of


barium and methylcellulose is instilled

Reported sensitivity of 90%


for detecting small bowel
tumors vs. 50% for SBFT

Diagnosis of small bowel malignancies

CT

Study of choice for preoperative staging and evaluation of


metastases

CT enteroclysis

MRI

Ultrasound

Diagnosis of small bowel malignancies

Endoscopy/Enteroscopy
Push enteroscopy allows for visualization of 40-60
cm of small bowel beyond the ligament of Treitz
Intraoperative endoscopy

EUS

Useful in the evaluation of ampullary tumors

Diagnosis of small bowel malignancies

Capsule endosocopy

Diagnosis of small bowel malignancies

Exploratory laparotomy/laparoscopy

Most sensitive diagnostic modality

Preoperative diagnosis of small bowel malignancy


is made in only 50% of cases

Should be considered for all cases in patients with


occult GI bleeding, weight loss, unexplained
abdominal pain

Clinical features of small bowel adenocarcinoma

Majority arise in the duodenum and jejunum


Increased exposure to pancreatic and biliary
secretions
Exception is in patients with Crohns, in whom the
most common site is the terminal ileum

Peak incidence is in the 7th decade

Male: Female ratio of 2.4:1

Risk factors for small bowel adenocarcinoma

Pre-existing adenoma, either single or multiple

300-fold increased risk in patients with FAP

Crohns
Celiac disease
IgA deficiency
Alcohol abuse
Neurofibromatosis
Urinary diversion procedures
? Red meat

Crohns disease and adenocarcinoma

12-fold increased risk of small bowel cancer


Symptoms often mimic symptoms of Crohns
Risk factors

Long duration of disease


Male gender
Fistulas
Surgically excluded loops of small bowel
Strictures
Immunosuppressive drugs

Staging of adenocarcinoma of the small intestine

Stage I tumor confined to the lamina propria, submucosa, or


muscularis propria

Stage II tumor extending beyond the muscularis propria or


invading adjacent structures

Stage III tumors with any bowel wall extension and positive
lymph nodes

Stage IV tumor with any degree of bowel wall invasion, with


or without lymph node metastases, and with distant disease

Adenocarcinoma of the small intestine


Study

Cunningham et
al.
Annals of Surgery
1997

Talamonti et
al.
Archives of Surgery
2002

Location

Stage at presentation

Duodenum
and jejunum

Ileum

II

III

IV

79%

21%

6.9%

24%

24%

45%

76%

24%

4.8%

19%

38%

38%

Adenocarcinoma and therapy

Surgery is the treatment of choice


Procedure of choice is determined by location of tumor:
1st and 2nd portion of the duodenum
pancreaticoduodenectomy

Distal duodenum resection and duodenojejunostomy

Jejunum and ileum segmental resection including


wide mesentery resection (6 inches)

Terminal ileum right hemicolectomy

Surgical pearls

Resection of adequate mesentery is often limited by


proximity of nodes or tumor to the SMA

Margin-status must be confirmed by frozen-section if


in question

Patients with metastatic disease should undergo


resection in most cases to prevent later complications

Adjuvant therapy

Patients who undergo radical surgery often later die


from distant disease recurrence

No proven survival benefit

No prospective studies

5-fluorouracil has shown the most promise

Adenocarcinoma of the small bowel


Dabaja SD et al. Cancer June 2004

Survival

Overall 5-year survival of 26%

Median survival time of 20 months

Aggressive treatment and increased survival

Prognosis

Overall 5-year survival of 30%


40-60% for resected tumors
15-30% for non-resected tumors

Stage I 100%
Stage II 52%
Stage III 45%
Stage IV 0%

Prognosis
Study

Cunningham et
al.
Annals of Surgery
1997

Curative
resection
rate

Overall 5
year
survival

66%

62%

Median survival time


(months)
Noncurativ
e resection

Curative
resection

30%

23

37%

40

Talamonti et al.
Archives of Surgery
2002

Prognosis

Poor prognosis correlated with:


Mural penetration
Nodal involvement
Distant metastasis
Perineural involvement
Large tumor size
Poor histologic grade

Metastatic disease involving small bowel

Secondary neoplastic involvement of small intestine


is more frequent than primary small bowel neoplasia

Primary tumors of the colon, ovary, uterus, and


stomach typically involve the colon by direct
invasion or intraperitoneal spread

Primary tumors from breast, lung, and melanoma


metastasize to small bowel hematogenously

Metastatic disease involving small bowel

Treatment is palliative

Limited resection
Intestinal bypass

Melanoma

Metastatic focus may further disseminate to small


bowel mesentery and draining lymph nodes
Aggressive resection may improve disease-free
survival

Esophageal cancer and metastases

Patients with esophageal cancer usually present with


recurrence within 2 years

Treatment of solitary metastasis appropriate when:

Contained with a single organ that can be easily resected


Good overall patient function
No local recurrence of primary tumor
> 1 year after the initial treatment

Gastrointestinal stromal tumors

Visceral sarcomas, previously classified as leiyomyomas


and leiyomyosarcomas

Now classified as GISTs with a range of biological


behaviors from low grade to high grade malignancies

Traditionally, microscopic findings were used to define


malignancy including:

Increased cell size


Increased cell irregularity
Lack of cell differentiation
Presence of cells with hyperchromic and multiple nuclei

GISTs Tumor biology

Proposed to arise from the interstitial cell of Cajal, an


intestinal pacemaker cell of mesodermal origin

Similar cell markers to those of normal Cajal cells


1) myeloid stem cell antigen CD34
2) KIT receptor tyrosine kinase
3) variably positive for smooth-muscle actin
4) usually negative for desmin

Previously thought to be smooth muscle neoplasms but now


accepted to have:
1) myogenic features (smooth muscle GIST)
2) neural features (GI autonomic nerve tumor)
3) myogenic and neural features (mixed GIST)

Clinical features of GISTs

Most commonly present with pain and weight loss

Most commonly present in the 6th and 7th decades but


may occur at any age

Distribution of occurrence is proportional to the length


of the segments of the small bowel

Lesions occur in extraluminal, subserosal locations

Often develop central ischemia and necrosis that leads


to bleeding

GISTs of the small intestine


Study

Cunningham et
al.
Annals of Surgery
1997

Location

Stage at presentation

Duodenum
and jejunum

Ileum

II

III

IV

75%

25%

25%

12.5%

0%

63.5%

80%

20%

12%

20%

48%

20%

Talamonti et al.
Archives of Surgery
2002

GISTs of the small intestine


Study

Cunningham et
al.
Annals of Surgery
1997

Curative
resection
rate

Overall 5
year
survival

50%

84%

Median survival time


(months)
Noncurative
resection

Curative
resection

25%

66

22%

22

66

Talamonti et al.
Archives of Surgery
2002

Prognostic factors and therapy of GISTs

Only complete resection has been found to be a


significant favorable prognostic factor

Surgical resection is therefore the mainstay of therapy


and should include any involved adjacent organs

Complete resection results in 3 and 5-year survival rates of 54% and


42% compared to 13% and 9% after incomplete resection

No added benefit to wide resections or extensive


lymphadenectomies

Prognostic factors and therapy of GISTs

Poor prognostic factors include tumors greater than 5


cm, non-smooth muscle cell differentiation, and those
classified as high grade

Metastases present in 30%; most commonly hepatic

Recurrence rates of 25-50% reported

No demonstrable benefit of adjuvant therapy

GISTs and STI-571 Molecular therapeutic options

Most GISTs (52-85%) have a gain-of-function


mutation in the c-kit proto-oncogene

Results in ligand-independent activation of the KIT


receptor tyrosine kinase

Unopposed stimulus for cell growth

STI-571

molecule which inhibits:


Enzymatic activity of the KIT tyrosine kinases,
Platelet-derived growth factor receptor
BCR-ABL fusion protein

GISTs and STI-571 Molecular therapeutic options

Initial phase II trial of STI-571 in patients with metastatic


GISTs (follow-up of three months)

Partial response rate in 59%


Stable disease in 27%
Progression of disease in 13%
86% had a mutation in c-kit and were more likely to respond

EORTC study showed similar results

Partial response rate in 69%


Stable disease in 19%
Progression of disease in 11%
Dematteo et al. Human Pathology.
Pathology. May 2002

Carcinoid Tumors of the Small Intestine

Originally described by Oberndorfer in 1907

Arise from Kulchitsky cells

Type of enterochromaffin cell

Cells of the amine precursor uptake decarboxylase


(APUD) system which have the ability to synthesize
biologically active substances

Clinical features of carcinoid tumors

Most commonly present in the 7th decade

Often present with nonspecific complaints

Up to 50% of patients present with obstruction

Carcinoid syndrome, marked by flushing and diarrhea, is rare


and occurs in only 5-7% of patients

Right sided valvular fibrosis occurs late in the disease

Increasing frequency from the duodenum to the ileum

Pathological features of carcinoid tumors

Carcinoid invasion into the mesentery leads to


fibrosis and often kinking of the small intestine

Thickening of the vessel wall is also present and may


lead to ischemic changes in the gut

Serotonin is postulated to be responsible for these


features

Diagnosis of Carcinoid Tumors

Traditional studies may fail to demonstrate the primary


tumor

Indium-labeled octreotide scan is the most accurate


(sensitivity of 90%) means of localizing a carcinoid
tumor

Tumor cells express somatostatin receptors which take up


octreotide

24-hour urine levels of 5-hydroxyindoleacetic acid (5HIAA) may alone be diagnostic

Serotonin is metabolized in the liver to 5-HIAA and


excreted in the urine

Carcinoid tumors of the small intestine


Study

Cunningham et
al.
Annals of Surgery
1997

Location

Stage at presentation

Duodenum
and jejunum

Ileum

II

III

IV

28%

72%

11%

0%

22%

66%

22%

78%

8%

24%

38%

30%

Talamonti et al.
Archives of Surgery
2002

Carcinoid tumors of the small intestine


Study

Cunningham et
al.
Annals of Surgery
1997

Curative
resection
rate

Overall 5
year
survival

67%

65%

Median survival time


(months)
Noncurative
resection

Curative
resection

Not
reported

18

81

64%

32

Not
reached

Talamonti et al.
Archives of Surgery
2002

Surgical therapy of carcinoid tumors

Surgical excision is the mainstay of therapy

Isolated disease is widely resected

Synchronous tumors are found in 33-40% of patients


and should all be excised if feasible

Noncarcinoid synchronous tumors are found in up to


25% of patients

Typically tumors of the breast, lung, stomach, or colon

Surgical therapy of carcinoid tumors

Tumor size is an unreliable predictor of metastatic


disease

Aggressive attempts should be made to resect


metastatic disease

Decreases the need for medical therapy


Prolongs survival

Hepatic metastases

Surgical resection
Hepatic artery embolization
Cryosugery
Radiofrequency ablation
Transplantation

Medical therapy of small bowel carcinoid tumors

Octreotide inhibits tumor secretion of hormones

May have a direct tumor control effect on carcinoid tumors

Relieves flushing in 76% of patients

Improves diarrhea in 83%

Decreases the urinary 5-HIAA levels in 80%

Interferes with endo-and exocrine pancreas function

Medical therapy of small bowel carcinoid tumors

Interferon-alpha has shown improvement in


symptoms in 68% and a biochemical response in 42%

Response to chemotherapy has been variable and


short lived

Use limited by high incidence of side effects

Combination of streptozocin and 5-fluorouracil has shown a


20-30% response rate

No proven benefit of radiotherapy

Conclusions

Small bowel malignancies although rare are associated with


relatively poor 5-year survival rates

Abdominal pain of unknown origin should prompt a limited


investigation for these tumors

Surgical therapy remains the mainstay of therapy

Future directions in the therapy of these tumors include the use


of direct molecular modification and immunotherapy