When GIST can cause massive hemorrhage
Departments of Vascular and Endovascular Surgery, Mayo Clinic Foundation, Rochester, MN
Associate Professor of Surgery
Department of SurgeryHarold James
Vice Chair, Educational Programs, Department of Pathology, West Virginia University, Morgantown
How to emergently manage spontaneous rupture of gastrointestinal stromal tumors.
The patient with a gastrointestinal stromal tumor (GIST) may present with non-specific gastrointestinal symptoms such as nausea, abdominal distension, or pain. The clinical presentation of GIST is variable, and only a few cause massive gastrointestinal bleeding and present as surgical emergencies.
We recently treated three patients with GIST—one with a gastric lesion, the others with small-intestine lesions—with segmental gastric (FIGURE 1) and small-bowel resections. Here, we review the work-up, diagnosis, and management options for GIST.
FIGURE 1 Segmental resection
The goal of surgical management for a lesion in the stomach is to excise the affected segment with negative surgical margins because wide margins do not add any oncologic benefit.—Illustration by Molly Borman
Incidence and etiology
Each year, 4000–5000 patients are diagnosed with GIST. Men are affected slightly more than women, and the median age at diagnosis is around 60. Anatomic locations, in decreasing frequency, are:1,2
Small intestine (30%).
Colon and rectum (5%).
Once known as gastrointestinal leiomyomas and leiomyosarcomas, GISTS are the most common mesenchymal tumors of the gastrointestinal tract.316
FIGURE 2 GIST of small bowel
A well-circumscribed spindle cell tumor (arrows) abuts the small-bowel submucosa (4X H&E).
Making the diagnosis
Grossly, a GIST is a well-circumscribed and vascularized tumor with a predominantly extraluminal growth pattern. Endoscopy can reveal the tumor as a submucosal mass. CT would show it as a discrete mass. Like other intra-abdominal neoplasms, GIST exhibits an avid uptake on fused positron emission tomography (PET) scans.
A pathologic study of the resected specimen (FIGURE 2) typically helps make the diagnosis. GISTs may originate from the interstitial cells of Cajal (ICC) of the myenteric plexus, a unique cellular group that regulates gut motility.3 These cells express the KIT proto-oncogene, which codes for a transmembrane glycoprotein called the KIT protein. The natural ligand for KIT is a stem-cell factor (BOX).
Risk of symptoms and rupture
A population-based study showed 70% of GISTs were symptomatic, 20% asymptomatic, and 10% detected at autopsy. The median tumor size for each group was 8.9 cm, 2.7 cm, and 3.4 cm, respectively.1,8
Infrequently, a GIST can rupture freely into the peritoneal cavity, resulting in hemorrhage and shock. It can erode into the lumen of the gastrointestinal tract and present with bleeding.
Localizing the source
Work-up of acute gastrointestinal bleeding after a nondiagnostic esophagogastroduodenoscopy and colonoscopy should prompt a nuclear medicine bleeding scan and arteriography to aid with localization.
GIST growth on the cellular level
Interaction of the KIT ligand receptor results in cell growth and differentiation. The KIT receptor tyrosine kinase (CD117 antigen) is an immunohistochemical marker that pathologists use in diagnosing GIST on a cellular level (FIGURE 3).
Hematopoietic and germ cells also express the KIT. The interaction between the natural ligand and KIT protein initiates intracellular signal cascades essential for cell survival. Gain-of-function KIT mutations result in the ligand-independent activation of the tyrosine kinase function, a mutation pivotal in the transformation of interstitial cells of Cajal to GIST; 80%–90% of GISTs have KIT mutations.
A few GISTs harbor a mutation of a related receptor tyrosine kinase called platelet-derived growth factor receptor alpha (PDGFRA). A high amino acid homology between PDGFRA and KIT has been apparent. Imatinib has an inhibitory effect against the tyrosine kinase activity of KIT and PDGFRA.4-6 Interestingly, the initial therapeutic target of imatinib was abl-bcr tyrosine kinase function seen in Philadelphia (9:22) chromosome-positive chronic myeloid leukemia.7—KMK, SSM, IAR, RSC, DWM, HJW
FIGURE 3 Positive for CD117
The immunoperoxidase method showed the spindle cell tumor (brown) as strongly positive for CD 117 (c-KIT).
Although its length and surface area far exceed that of the rest of the gastrointestinal tract, the small bowel is a least common site of bleeding. In one series based on a 27-year experience, the authors encountered 12 cases of lower-GI hemorrhage attributable to a small-bowel source, 9 of which were due to a neoplastic lesion.9317
A review of 1489 cases of lower-GI hemorrhage found 10 cases in which the small bowel was the source, but only 3 were tumors.10 In another report of 12 cases of small-intestinal hemorrhage, 3 were due to neoplastic pathology.11
GISTs originate in the interstitial cells of Cajal, which regulate intestinal motility.
Diagnostic and therapeutic angioembolization has limited utility for small-bowel bleeding. Sensitivity ranges from 21%–40%.11,12 Bleeding in the small bowel is more likely due to a neoplastic lesion that would require segmental resection and a thorough exploration for any evidence of metastatic tumor deposits.
Risk factors aid in diagnosis
GISTs are mesenchymal spindle cell neoplasms with varying degrees of cytologic atypia and mitotic rate (FIGURE 4). The most important risk factors for determining malignancy are tumor site (intestinal or gastric), size, and mitotic rate (TABLE 1).13
Common causes of GI bleeding
Gastrointestinal hemorrhage accounts for about 2% of acute care-related hospital admissions in the United States. The bleeding can arise in any area of the gastrointestinal tract. More than 80% of major bleeding episodes have been attributed to one of four conditions:14
Less common causes include erosive gastritis, Mallory-Weiss tears, Dieulafoy’s ulcer, aortoenteric fistulas, and inflammatory or infectious colitides.
Need for emergent treatment
About 15% of these affected patients will require emergency diagnosis and intervention. Among factors predictive of an adverse outcome are persistent and recurrent hemorrhage, failed endoscopic and arteriographic interventions, advanced age, and comorbidities.
FIGURE 4 Spindle-cell neoplasm
The tumor consists of interlacing fascicles of spindled cells. The mitosis is the horseshoe-shaped shadow in the center (arrow). Rare mitoses are present in other fields (40X H&E).
Tumor characteristics that predict the malignant potential
Mitotic rate: <5*
|Size: <2 cm
Mitotic rate: <5
||Size: 5–10 cm
Mitotic rate: <5
|Size: 2–5 cm
Mitotic rate: <5
||Size: >10 cm
Mitotic rate: >5
|Size: >5 cm
Mitotic rate: >5
Hemorrhagic shock and an urgent operation place a tremendous physiologic burden on the patient, considerably escalating the risk of a poor outcome. Only 5% to 7% of patients hospitalized with acute hemorrhage require surgery, but this high-risk group can carry a mortality rate of up to 40%.15
GIST and GI hemorrhage
Gastrointestinal stromal tumors are a rare cause of gastrointestinal hemorrhage.16 In one series of 11 cases of acute hemorrhage related to GIST, 5 required urgent surgery.17 At our institution, 3 other cases in the last 2 years outside our series have undergone resection of tumors discovered during the work-up of chronic anemia.
Characteristics of our patients
||Lowest Hb/Hct before surgery
||µ PRBC transfused before surgery
||Size: 4.5x3x2.5 cm
Mitoses: <5/50 HPF
||Size: 3x2.5x3.5 cm
Mitoses: <5/50 HPF
||Size: 4.2x4x4 cm
Mitoses: <5/50 HPF
Surgery and adjuvant therapy
An operation remains the cornerstone of treatment for bleeding GIST. It not only can be lifesaving; it can be an invaluable adjunct to the staging and prognostication in these patients.
The sole aim of an operation should be to achieve negative surgical margins because wide margins do not add any oncologic benefit. Because a GIST rarely metastasizes to the regional lymph nodes, a regional lymphadenectomy is not indicated.2
GISTs rarely metastisize to the regional lymph nodes, so a regional lymphadenectomy is not indicated.
GISTs tend to be fragile. Rupture during resection increases the risk of peritoneal recurrence, so a meticulous operative technique is imperative.
An operation may be indicated in the patient with synchronous, low-volume metastatic disease. In such a case, primary resection and metastatectomy can be a combined.18 The role of imatinib mesylate (STI-571 and Gleevec, Novartis Pharmaceutical Corp, East Hanover, NJ) as an adjuvant and neoadjuvant therapy is currently under trial by the American College of Surgeons Oncology Group.
Determining response to imatinib
First-line treatment for metastatic disease is imatinib, given as a standard 400-mg daily dose. Tumor size alone, as seen on CT scan, is a somewhat unreliable indicator of therapeutic response. However, fused CT-PET scans have proven to be sensitive, rapid, and reliable indicators of response or resistance to imatinib.
In responders, the fluorodeoxyglucose uptake in the tumor declines substantially from baseline as early as 24 hours after a single dose of imatinib. Tumors that respond often change in appearance from a hypervascular lesion to a mass that appears hypoattentuated and homogeneous.
Response to imatinib can render patients, whose lesions were otherwise unresectable with strategically located metastatic deposits, suitable for metastatectomy.19 Liver metastasis can also be approached either operatively or with radiofrequency ablation. The use of imatinib has boosted 48-month survival rates for metastatic disease from 15% to 70%.20
Non-responders to imatinib
Acquired resistance to imatinib is often due to secondary KIT mutations at different exon loci. These tumors can be treated with other newer trial agents such as SU11248 (Sutent, Pfizer, Inc, New York, NY), which is an anti-KIT, anti-platelet-derived growth-factor receptor alpha (PDGFRA), and anti-vascular endothelial cell growth-factor agent.21
Agents under study in imatinib-resistant GIST are RAD001 (Novartis), a mammalian target of rapamycin inhibitor; and AMG 706 (Amgen, Chicago, IL), a multikinase inhibitor.319
Our three cases
From March 2005 to July 2006, we performed 3 urgent abdominal explorations for gastrointestinal hemorrhage secondary to GIST (TABLE 2). Two patients were men
ages 42 and 60. All patients presented with bright red bleeding per rectum and hemodynamic compromise. The 42-year-old man and 84-year-old woman had grade II shock (tachycardia and drop in pulse pressure); the 60-year-old man had grade III shock (hypotension and oliguria).
The tumors can grow quite large before causing any significant symptoms, but rarely present with massive gastrointestinal hemorrhage.
The woman had a known gastric lesion, and was being prepared for elective resection, during which time she presented with massive hemorrhage. In the men, upper and lower endoscopies and arteriography failed to localize the bleeding source. Only a nuclear medicine bleeding scan suggested the source of ongoing hemorrhage. Each patient received an average of 4 µ of preoperative packed red blood cell (PRBC) transfusions.
Operations and postoperative course
The woman had a gastric GIST on the anterior wall of the stomach, for which segmental gastric resection was indicated. The men had lesions in the small intestine that required segmental small-bowel resection. One of the small-bowel lesions was solitary, but the other involved two large and multiple smaller satellite lesions. The intestinal lesions were exophytic and situated on the antimesenteric border of the bowel.
All patients underwent complete resection with clear surgical margins. Postoperative ICU stays averaged 1.3 days (range 1–2) and mean total length of hospital stay was 8 days (range 6–11). All patients recovered without major complications up to 30 days postoperatively.
Our management approach
In our series, the two patients with lesions in the small intestine received a definitive diagnosis only upon study of the pathologic specimen. Irrespective of the tumor site, all three patients presented with hematochezia, testifying to the potential for torrential hemorrhage.
Evidence-based recommendations for treatment of GIST
Work-up of acute gastrointestinal bleeding after a non-diagnostic EGD and colonoscopy should prompt a nuclear medicine bleeding scan and arteriography to aid with localization. Level of evidence: 2b—Based on individual cohort study.
Bleeding in the small bowel is more likely to be due to a neoplastic lesion that would require segmental resection and an exploration for any evidence of metastatic tumor deposits. Level of evidence: 2b.
GISTs rarely metastasize to regional lymph nodes and the aim of the surgery is to obtain negative surgical margins, a regional lymphadenectomy is not needed. Level of evidence: 2a—Systematic review (with homogeneity) of cohort studies.
Use of imatinib mesylate (Gleevec) significantly prolongs survival. Level of evidence: 1b—Individual randomized clinical trial (narrow confidence interval).—KMK
Each patient spent an appropriate amount of time in the initial resuscitation and stabilization. We used less-invasive maneuvers to aid with diagnosis or management, or both, before surgery. Based on tumor site, size, and mitoses, the woman with the gastric lesion fell into the low-risk category for malignant potential. The two men factored as intermediate risks.
One patient had neurofibromatosis type one (NF-1). Authors have suggested the NF-1 patient has a 7% incidence of GIST, with small intestinal tumors more prevalent than gastric types.22 Our patient had multiple contiguous lesions. Although our patient tested positive for CD117, such mutations of KIT and PDGFRA are rare in NF-1 patients, suggesting a different onco-genetic mechanism.
MALPRACTICE MINUTE: GI hemorrhage causes death after esophageal mass is removed. See p 305 or go to contemporarysurgery.com
The authors had no relationships to disclose.
Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era—a population based study in western Sweden.
Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival.
Ann Surg. 2000;231:51–58.
Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal.
Am J Pathol. 1998;152:1259–1269.
Pathophysiology, diagnosis, and treatment of gastrointestinal stromal tumors.
J Gastroenterol. 2005;40:775–780.
A novel gain-of-function mutation of c-kit gene in gastrointestinal stromal tumors.
Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors.
Efficacy and safety of s specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.
N Engl J Med. 2001;344:1031–1037.
, et al.
Malignant gastro-intestinal stromal tumor: distribution, imaging features, and pattern of metastatic spread.
Acute lower gastrointestinal hemorrhage originating in the small intestine.
Rev Esp Enferm Dig. 2006;98:196–203.
Small bowel causes of per rectum hemorrhage.
Ann Acad Med Singapore. 1994;23:866–868. .
Jejunoileal causes of overt gastrointestinal blding: diagnosis, management, and outcome.
Am Surgeon. 2001;67:383–387.
, et al.
Angiography for pre-operative evaluation in patients with lower gastrointestinal bleeding.
Arch Surg. 1998;48:606–616.
Gastrointestinal stromal tumors: definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis.
Virchows Arch. 2001;438:1–12.
Townsend CJ, ed. Sabiston Textbook of Surgery.17th ed. Philadelphia, Pa: Elsevier Saunders; 2004.
Management of the complications of peptic ulcer disease.
Prob Gen Surg. 1997;14:54–68.
Gastrointestinal stromal tumors: A seldom diagnosed cause of severe anemia.
Dig Dis Sci. 2005;50:815–819.
Gut stromal tumors and their clinical behavior.
Am J Surg. 1997;173:390–394.
Gastrointestinal stromal tumors: a spectrum of disease.
Surg Oncol. 2003;12:21–26.
Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.
N Engl J Med. 2002;347:472–480.
Progression-free survival in gastrointestinal stromal tumors with high-dose imatinib: randomized trial.
SU 11248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib resistance caused by diverse genomic mechanisms in patients with metastatic gastrointestinal stromal tumors.
J Clin Oncol. 2004;22:14S.
Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population.