Malignant Small Bowel Tumors by rt3463df

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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

   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 post-
    operatively 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

   Fewer than 2% of GI malignancies arise in the small

   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.   Liquid contents cause less irritation than more solid
      contents of large bowel
 2.   Rapid transit of intestinal contents provides shorter
      exposure of mucosa to carcinogens
 3.   Lower bacterial load may result in decreased
      conversion of bile acids into potential carcinogens
 4.   Benzopyrene hydroxylase, enzyme responsible for the
      conversion of the known carcinogen benzopyrene, is
      present in higher concentrations in the small bowel
 5.   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

     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

   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
     Exception is in patients with Crohn’s, 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
   Crohn’s
   Celiac disease
   IgA deficiency
   Alcohol abuse
   Neurofibromatosis
   Urinary diversion procedures
   ? Red meat
        Crohn’s disease and adenocarcinoma

   12-fold increased risk of small bowel cancer
   Symptoms often mimic symptoms of Crohn’s
   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                        Location                  Stage at presentation
                       Duodenum         Ileum    I          II      III        IV
                      and jejunum

Cunningham et
                         79%            21%     6.9%      24%      24%         45%
Annals of Surgery

Talamonti et
                         76%            24%     4.8%      19%      38%         38%
Archives of Surgery
                Adenocarcinoma and therapy

   Surgery is the treatment of choice
   Procedure of choice is determined by location of tumor:
      1 and 2
                nd portion of the duodenum –


       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
   Overall 5-year survival of 26%
   Median survival time of 20 months
Aggressive treatment and increased survival

   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%

Study                 Curative     Overall 5      Median survival time
                      resection      year              (months)
                        rate       survival    Noncurative    Curative
                                                resection     resection
Cunningham et
                        66%          30%           7             23
Annals of Surgery

Talamonti et al.
Archives of Surgery
                        62%          37%           9             40

   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
          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                        Location                 Stage at presentation
                       Duodenum         Ileum    I         II       III        IV
                      and jejunum

Cunningham et
                         75%            25%     25%     12.5%      0%         63.5%
Annals of Surgery

Talamonti et al.
Archives of Surgery
                         80%            20%     12%      20%      48%         20%
                      GISTs of the small intestine

Study                 Curative    Overall 5      Median survival time
                      resection     year              (months)
                        rate      survival    Noncurative    Curative
                                               resection     resection
Cunningham et
                        50%         25%           9             66
Annals of Surgery

Talamonti et al.
Archives of Surgery
                        84%         22%           22            66
         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
        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. 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
               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 cells express somatostatin receptors which take up

   24-hour urine levels of 5-hydroxyindoleacetic acid
    (5-HIAA) 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                        Location                 Stage at presentation
                       Duodenum         Ileum    I         II      III        IV
                      and jejunum

Cunningham et
                         28%            72%     11%       0%      22%         66%
Annals of Surgery

Talamonti et al.
Archives of Surgery
                         22%            78%     8%       24%      38%         30%
              Carcinoid tumors of the small intestine

Study                 Curative    Overall 5      Median survival time
                      resection     year              (months)
                        rate      survival    Noncurative    Curative
                                               resection     resection
Cunningham et
                        67%         Not           18            81
Annals of Surgery

Talamonti et al.
Archives of Surgery
                        65%         64%           32            Not
            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

   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%
       Use limited by high incidence of side effects

   Response to chemotherapy has been variable and
    short lived
       Combination of streptozocin and 5-fluorouracil has shown
        a 20-30% response rate

   No proven benefit of radiotherapy

   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

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