Dramatic regression and bleeding of a duodenal GIST during preoperative imatinib therapy: case report and review
- Andreas Hecker†1,
- Birgit Hecker†2,
- Birgit Bassaly3,
- Markus Hirschburger1,
- Thilo Schwandner1Email author,
- Hermann Janßen4 and
- Winfried Padberg1
© Hecker et al; licensee BioMed Central Ltd. 2010
Received: 27 February 2010
Accepted: 2 June 2010
Published: 2 June 2010
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. The majority of GISTs is located in the stomach. Only 3-5% of GISTs are located in the duodenum associated with an increased risk of gastrointestinal bleeding as primary manifestation. With response rates of up to 90%, but complications like bleeding due to tumor necrosis in 3%, imatinib mesylate dramatically altered the pre- and postoperative therapy for GIST patients.
A 58-year-old female patient presented with acute upper gastrointestinal bleeding 2 weeks after a giant GIST of the duodenum had been diagnosed. Neoadjuvant imatinib therapy had been initiated to achieve a tumor downsizing prior to surgery. During emergency laparotomy a partial duodenopancreatectomy was performed to achieve a complete resection of the mass. Histology revealed a high-malignancy GIST infiltrating the duodenal wall. Adjuvant imatinib therapy was initiated. At follow-up (19 months) the patient is still alive and healthy.
Giant GISTs of the duodenum are rare and - in contrast to other localizations - harbour a higher risk of serious bleeding as primary manifestation. Tumor necrosis and tumor bleeding are rare but typical adverse effects of imatinib therapy especially during treatment of high-malignancy GIST. In GIST patients with increased risk of tumor bleeding neoadjuvant imatinib therapy should thoroughly be performed during hospitalization. In cases of duodenal GIST primary surgery should be considered as treatment alternative.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal wall. Originating in the muscular wall of the viscera proliferating cells of a GIST show phenotypic similarities to the interstitial cells of Cajal, which coordinate the peristaltic movements of the gastrointestinal tract [1, 2]. GISTs are defined as mesenchymal, spindle-shaped tumors, which can be distinguished from other soft tissue tumors like leiomyomas, myoblastomas etc. by c-kit protooncogen (CD117) expression . With 33-63% the stomach is the most common site for a GIST, followed by the small intestine (23-38%) and the colorectal localization (5-32%). In contrast GISTs of the duodenum, as presented in this case report, are very rare.
Clinical studies demonstrated that with imatinib (STI 571, Gleevec, Novartis Pharma) objective responses can be reached in more then 50% of patients with an advanced GIST. Unresectable locally advanced tumors, recurrent or metastatic GISTs showed longer progression-free survival under imatinib therapy [4–6]. All in all 80-90% of the patients with GISTs showed at least a partial tumor response . After retrospective small-institutional reports and case series the neoadjuvant use of imatinib in GIST was first evaluated in the RTOG 0132/ACRIN 6665 study. Eisenberg recently published first results underlining the safety of imatinibmesylate in treatment of GISTs . In another study 3% of the probands treated with imatinib developed complications caused by rupture of large tumor masses which became necrotic unter pharmacotherapy . These data correspond to complication rates described in the STI 571 study [9, 10]. To the best of our knowledge these complication rates only referred to common tumor localizations, but not to uncommon GIST sites as duodenum, rectum or others .
We herein report a case of a patients with a giant GIST of the duodenum. After neoadjuvant imatinib therapy was initiated, a dramatic tumor regression led to an upper gastrointestinal bleeding and an emergency laparotomy.
The 58-year-old female patient was hospitalized due to recurrent episodes of upper abdominal pain, anemia, weight loss, fatigue and fever attacks. Under suspicion of a duodenal perforation by a lymphoma or GIST, seen in an ultrasound examination, the patient was transferred to our clinic.
Physical examination of the patient with no history of preexisting diseases revealed a palpable mass in the right upper abdominal quadrant. Hemoglobin was 90 g/l.
Two days after surgery the patient was weaned and successfully extubated. After an uneventfull recovery the patient is alive and without any signs of tumor recurrence. Up to the follow-up of 19 months the patient permanently received an adjuvant imtinib therapy (400 mg per day).
GISTs are defined as mesenchymal tumors arising from the gastrointestinal wall, mesentery, omentum or retroperitoneum. In contrast to leiomyo(sarko)mas GIST cells express the c-kit proto-oncogene (CD117). Distribution of GIST in the gastrointestinal tract was analyzed in several studies. Tumors are mostly localized in the stomach (33-63%), small bowel (23-38%), whereas colon, rectum and esophagus are rare localizations. The female patient of this case report presented with a duodenal GIST as another rare GIST manifestation. Except for one large study on the histopathological pattern of duodenal GIST  only two studies with 8 and 15 patients respectively are published so far [12, 13] analyzing the clinic and the outcome of duodenal GIST patients. Compared to other tumor localizations duodenal GISTs manifestate with tumor-associated bleeding in 90 resp. 75% compared to 54% (stomach)  and 28% (ileo-jejunal) . In contrast to other localizations duodenal GISTs are thus associated with a dramatically increased risk of an upper intestinal bleeding .
Nowadays the dignity of resected tumors is classified in risk categories that are based on size and mitotic rate mainly: In a consensus approach Fletcher et al. came to the result that tumor size (>5 cm) and mitotic activity (>5/50 high-power field) of the mesenchymal cells are the most important independent prognostic factors for tumor progression . In our case postoperative examination of the specimen revealed a tumor mass of 9 × 15 cm in diameter. Ki67 was used as an immunhistochemical marker for cell proliferation. 5-10% of the tumor cells were Ki67+. Histopathological examination revealed a rate of 12 mitoses per 50 high power fields. Following the above-mentioned classification our patient fulfilled all criteria of a malignant tumor progress.
Surgical therapy of duodenal GIST depends on tumor localization and is either partial duodenectomy, or partial pancreaticoduodenectomy. Interestingly, a recent study revealed that duodenal GIST cells express a different pattern of immunhistochemical markers . Additionally authors showed that duodenal GIST are associated with a more favorable prognosis compared to other tumor localizations. . After review of recent literature the duodenal tumor localization in our case is thus associated with a better prognosis, but with an increased bleeding probability. These results are in line with the authors' opinion that primary surgery could be the safest therapeutic option for a GIST of this localization. Beside the increased risk of tumor bleeding, caused by the localization, neoadjuvant imatinib therapy would additionally lead to a higher percentage of patients with a tumor bleeding.
Without any pre- or postoperative pharmacotherapy complete surgical resection can lead to a 5 year survival of up to 45% . The introduction of imatinib mesylate, a tyrosine kinase inhibitor targeting KIT has provided a much needed chemotherapeutical option for patients with both resectable and irresectable GISTs. Despite the noted success of imatinib surgical resection is the main treatment modality for primary GIST of any localization. Imatinib treatment of GISTs is a dynamic process with the permanent risk of pharmacoresistance [4, 18] and a maximal respondance within the first 6 months of therapy . Nevertheless the benefit of adjuvant imatinib for primary GIST has been underlined by several trials completed recently. As a consequence surgeons started to use imatinib in a neoadjuvant therapy to reach tumor-downsizing and thus increased rates of complete tumor resection.
As mentioned above complications like tumor necrosis and tumor bleeding occurr in 3% of patients under imatinib therapy. These data are in line with results of the STI 571 study. In the prospective RTOG study Eisenberg reports on a minimal rate of toxicity or of intraooperative complications under neoadjuvant imatinib therapy in 30 cases . Nevertheless only 1 of 30 patients with imatinib therapy prior to surgery had a duodenal GIST . It thus remains unclear, if the high safety of imatinib can be transferred to patients with GISTs at rare tumor localizations. Alternatively primary surgery should be seen as an alternative therapeutic approach. In cases of duodenal GIST primary surgery could be supported by a preoperative transarterial embolization as published previously .
(1) The review of literature reveals a higher rate of tumor bleeding as primary tumor manifestation in cases of duodenal GIST. (2) Beside the rare and uncommon localization we describe the case of a giant GIST of highest malignancy according to the classification of Fletcher et al.(3). Imatinib led to revolutionary changes in therapy of primary and metastatic GIST, but is associated with rapid tumor regression, necrosis and tumor bleeding in 3%. For the case presented a higher complication rate is to be exspected.
In GIST patients with these localizations and thus an increased risk of tumor bleeding neoadjuvant imatinib therapy should thoroughly be performed during hospitalization. In cases of duodenal GIST primary surgery should be considered as treatment alternative.
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
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