Balan Gabriela Gastrointestinal Stromal Tumor Of The Stomach As A Cause Of Upper Digestive Bleeding A Case Report And Literature R [311247]

CASE PRESENTATION

GASTROINTESTINAL STROMAL TUMOR OF THE STOMACH AS A CAUSE OF UPPER DIGESTIVE BLEEDING – A CASE REPORT AND LITERATURE REVIEW

Gabriela Balan1,2, Dan Botezatu1,2, Gica Rumina Chebac1,2, Carmen Tiutiuca1,2, Doina Carina Voinescu1, Gabriela Gurau1,3, Camelia Busila 1,3, Nicoleta Maftei1

1 Faculty of Medicine and Pharmacy, “Dunarea de Jos” [anonimizat]

2“Sf. Ap. Andrei” [anonimizat], Romania

3“Sf. Ioan” [anonimizat], Romania

[anonimizat]

ABSTRACT

Gastrointestinal stromal tumors (GISTs) [anonimizat], a transmembrane tyrosine kinase receptor for stem cell factor. They are located with higher frequency in the stomach and small bowel. [anonimizat], obstruction and palpable mass. Here, we report the case of a patient with hemorrhagic shock due to hematemesis from a gastrointestinal stromal tumor (GIST) of the stomach. A 57-year-[anonimizat], [anonimizat]. Upper gastrointestinal endoscopy revealed a submucosal tumor located in the posterior wall of the upper area of the stomach and a duodenal ulcer. [anonimizat] a massive hematemesis with hemorrhagic shock and was transferred in the surgical department and then taken to the operation room. Partial gastrectomy under laparotomy was performed. [anonimizat] a GIST, and appeared c-KIT positive by immunostaining. Postoperative course was uneventful. Imatinib mesylate was administered soon after surgery. The 6-[anonimizat]. This case is interesting because the GIST of the stomach was complicated with massive upper gastrointestinal bleeding and severe hemorrhagic shock; also, [anonimizat], which led to difficulties of diagnosis. GIST should be considered in the differential diagnosis of upper gastrointestinal bleeding.

KEYWORDS: gastrointestinal stromal tumors, c-Kit, CD34, [anonimizat] (GISTs) are the most common mesenchymal tumors of the digestive tract usually occurring in the 6th to 7th decade of life. First described by Mazur and Clark in 1983, [anonimizat], because most of them (95%) [anonimizat] (PDGFRA) gain-of-function mutations (1, 2). [anonimizat], [anonimizat], [anonimizat]. [anonimizat], bloating, [anonimizat]. The occurrence of digestive haemorrhage is relatively common. Haemorrhage, [anonimizat] (3). [anonimizat], and anatomic features and helps to confirm the diagnosis of the GIST and assess outcomes. Surgical intervention is the gold standard for treatment of nonmetastatic GISTs (4). Recent advances in molecular-targeted treatment have led to the development of anti-tumor agents for GISTs, including imatinib and sunitinib, selective tyrosine kinase inhibitors that have been used to treat invasive and/or metastatic GISTs.

CASE PRESENTATION

We present the case of a 57-year-old Caucasian male who was admitted in our clinic for hematemesis, melena, occurred after administration of Ibuprofen for flu-like symptoms. He was a regular smoker (37 pack-years). He drank one glass of wine every day and ate a balanced diet. He had no family history of digestive diseases and he has never experienced these episodes before.

Physical examination revealed an overweight patient (28.46kg/m2), skin pallor, mild epigastric pain at deep abdominal palpation. The rectal examination indicated melena. Laboratory tests showed inflammatory syndrome (accelerated ESR 120 mm/1h), severe anemia with a hemoglobin level 6.1g/dl (normal range, 13-17 g/dl); hematocrit, 17.85% (normal range, 39-51%); mean corpuscular volume, 89.10 fl (normal range, 85-95 fl) and mean corpuscular hemoglobin, 29,70 pg (normal range, 27-33 pg) and elevated blood urea nitrogen (120 mg/dl, normal range, 15-44 mg/dl). Ultrasonography of the liver, pancreas, spleen and gallbladder revealed no abnormality. After initial resuscitation, the patient underwent endoscopy of the upper gastrointestinal tract, which revealed a submucosal tumor of 1 cm in size on the lesser curvature of the upper stomach, which was biopsied, and a duodenal ulcer of 5 mm in diameter covered with fibrin on the anterior side of the duodenal bulb, but fistula was not confirmed. Neither of the lesions showed active bleeding at the time of observation.

Figure 1. Gastrointestinal stromal tumor of the stomach (upper digestive endoscopy image)

Figure 2. Duodenal ulcer (upper digestive endoscopy image)

Because the source of the bleeding was not elucidated with an initial upper GI endoscopy, he was treated for a duodenal ulcer induced by nonsteroidal anti-inflammatory drug. One week after admission, he suffered a new episode of massive hematemesis with severe hemorrhagic shock. The patient was transferred in the surgical department and then taken to the operation room. Emergency surgery consisting in partial gastrectomy under laparotomy was performed.

Figure 4. Gastrointestinal stromal tumor of the stomach: A) intraoperatory view; B) Resected GIST of the stomach (3.5/2/6cm); C) Ulcerated GIST (vascular fistula)

Pathological analysis of the resected specimen revealed a 3.5/2/6cm malign gastrointestinal stromal tumor of the stomach consisted of epithelioid and spindle-shaped cells, with vascular fistula, low-grade (G1) with no nodal metastasis and the mitotic index (number of mitosis per high-power fields) was 3/50HPF. The capsule of the tumor did not show any identifiable breaks.

Figure 5. Histological findings of GIST of the stomach (hematoxylin and eosin staining, magnification, 10x (A), 20x (B)).

Immunohistochemical staining was strongly positive for CD117 (c-KIT) (exon 11 mutation), CD34 expression and DOG1 and negative for S100 protein, smooth muscle actin and desmin, features characteristic of GIST. The early postoperative course was uneventful, free from complications. The patient was referred to Oncology Department for further treatment and he was started on Imatinib mesylate 400mg/day soon after surgery. At six months postoperative follow-up, the patient was subjectively well and without clinical and imagistic signs of disease recurrence.

DISCUSSION

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms that originate from the neoplastic transformation of the interstitial cells of Cajal from their precursors. These cells are present inside and around the myenteric plexus and show both myogenic and neural differentiation, a fact that explains the immunohistochemical heterogeneity of the tumors that derive from them (5). GISTs account for 1-2% of all gastrointestinal malignancies and the incidence of GISTs is estimated to be 10 to 20 cases/one million individuals (6). These tumors typically affect people over 50 years of age and there is a slight male predominance but no association with geographic location or ethnicity (7). GISTs can occur anywhere but mainly affects the stomach (60%), jejunum and ileum (30%), duodenum (4-5%), rectum (4%), colon, appendix and esophagus (8). Most cases are sporadic although some families with hereditary GISTs have been described. These tumors are often discovered incidentally during investigative or therapeutic procedures for unrelated diseases (9). Incidental GIST lesions are generally small in size, and the majority shows a low mitotic activity (10). In fact, GISTs that are 2 cm or less in size can be regarded as essentially benign. The majority of GISTs are solitary, well circumscribed tumors with a pseudocapsule and only 10-30% progress to malignancy (1, 11, 12). Dimensions may vary from millimeters to giant tumors. Certain factors create diagnosis challenging. The macroscopic growth of these lesions can be intraluminal, extraluminal, or intramural. Exophytic growth with minimal or no luminal protrusion, which is common, makes endoscopic diagnosis difficult in detecting these tumors as we could see in the presented case. Also, biopsy specimens taken during endoscopy are often negative (13). Recently, fine-needle aspiration (FNA), performed under the guidance of ultrasound or computed tomography, have been developed as reliable methods to obtain tumor cells, and have allowed the preoperative diagnosis of GIST by histological examinations with immunohistochemistry (14).

Immunohistochemical stains like c-Kit/CD117 (a tyrosine kinase inhibitor) – positive in 95% (15), CD34 – positive in 40-50%, SMA (smooth muscle actin) – positive in 20-30% and S100 desmin – in about 10%, Ki67 – marker of cell proliferation (16) are necessary to make a precise diagnosis of GIST and to make the differential diagnosis between GIST and other mesenchymal tumors (17). CD117 (Kit protein) is the product of c-kit proto-oncogene, located on chromosome 4q11-21. This protein is a tyrosine kinase growth factor receptor. Mutation of kit proto-oncogene results in a CD117 receptor that is constitutively stimulated without the presence of the stem-cell growth factor. Mutations in the CD117 gene have been linked to malignant behaviour in GISTs (18). Some GISTs without the Kit mutation have been found to express a mutation in another tyrosine kinase receptor gene – the PDGFRa gene. This gene encodes the platelet-derived growth factor receptor (α receptors) tyrosine kinase protein (19).

The clinical presentation of GIST is erratic. Furthermore, only 70% of the patients are symptomatic, while 20% are asymptomatic and 10% are detected at autopsy. The symptoms and signs are not disease – specific and as a consequence, about 50% of GISTs have already metastases at the time of diagnosis (20). The symptoms of GISTs depend on the site and size of the tumor. The common clinical presentations of GISTs are gastrointestinal bleeding (50%), abdominal pain (20-50%) and obstruction (20%) and approximately one third are detected incidentally (21). They are usually accompanied with gastrointestinal bleeding (22). However, GISTs as a cause of upper GI bleeding is rare.

Abundant bleeding from the tumor is an indication for urgent surgical intervention. Also, surgery resection without rupture of the capsule is the gold standard for treatment of nonmetastatic GIST, while recurrent or advanced disease is best managed with thyrosine kinase inhibitors. In general, complete surgical resection is accomplished in 40-60% of all GIST patients, and in >70% of those with primary non-metastatic GIST (23). In our case we had completely excised the tumor. In general, local recurrence or metastases develop in approximately 50% of patients who had potentially curative operation (24). Lymph-node dissection is generally not indicated because nodal metastases are rare (prevalence is about 1%) (3). The overall 5 year survival rate for resectable GISTs has been shown to range from 46% to 78.5% (25).

Imatinib mesylate is a potent and selective inhibitor of a family of structurally related tyrosine kinases, including KIT, BCR-ABL and PDGFRA. Neo-adjuvant treatment with imatinib may improve resectability by down staging the tumor. Adjuvant therapy is recommended for large tumors, marginally resectable small tumors, and unresectable primary localized GISTs. Imatinib mesylate initially helps control disease in 80% or more of patients (19). Post-treatment, liver lesions become better defined and cyst-like. Drug resistance is not infrequent and serum level surveillance has not been shown to impact management of patients who experience resistance. Five-year survival is about 50% with this figure decreasing to about 35% at 10 years. The median duration of survival is 10-19 months for metastatic or recurrent gastric GISTs. For these patients and those who cannot tolerate imatinib, the newer multikinase inhibitor sunitinib malate may delay median time to tumor progression (26). There are a few patients with GISTs who fail both imatinib and sunitinib treatment. In these cases, research has shown that nilotinib, which specifically inhibits KIT, PDGFRA and BCR-ABL, resolves the problem (27).

The prognostic indicators are represented by tumor size, mitotic index, necrosis, infiltration, mutation in the c-kit gene and metastatic disease – variables that have an independent value for predicting the prognosis of patients with GIST. Large tumor size, tumor site, and tumor rupture, before or during surgery, have also been identified as independent prognostic factors for recurrence (17, 28). Based on the tumor size and mitotic rate, GISTs can have very low risk (tumor <2 cm, <5 mitosis/50HPF), low risk (tumor 2-5 cm, <5 mitosis/50HPF), intermediate risk (tumor 5 cm-10 cm, <5 mitosis/50HPF or tumor <5 cm and 6-10 mitosis/50HPF) and high risk (tumor >5 cm, >5 mitosis/50HPF or tumor >10 cm and any mitotic rate) (29). In the presented case, GIST had a medium size with a low level of mitotic activity which means an intermediate risk.

This case is remarkable for several reasons. First, gastrointestinal stromal tumor of the stomach was complicated with massive upper gastrointestinal bleeding and severe hemorrhagic shock. Secondly, this complication of GIST occurred after nonsteroidal anti-inflammatory drug administration and it was associated with duodenal ulcer which made the diagnosis difficult.

CONCLUSIONS

According to the literature massive upper digestive bleeding is rarely caused by gastrointestinal stromal tumor of the stomach. Although rare, GISTs should be considered in the differential diagnosis of gastrointestinal hemorrhages. Surgical resection is the main form of treatment of gastrointestinal stromal tumors of the digestive system.

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