Correspondence *Gastrointestinal and Oncologic Surgery, Yale University School of Medicine, 330 Cedar Street, LH 118, New Haven, CT 06520, USA

Email charles.cha@yale.edu

The case

A 74-year-old African-American male with a 3-day history of melena and hematemesis presented to the emergency department of the West Haven Veterans Administration Hospital. The patient was in good health until 3 days prior to presentation, when he experienced one episode of hematemesis, followed by multiple episodes of melena on subsequent days. The patient did not experience abdominal pain, constitutional symptoms, bright red blood per rectum, constipation or diarrhea. His medical history was unremarkable except for benign prostatic hypertrophy, which was diagnosed 10 years earlier. Family and social histories were unremarkable.

The patient's vital signs were stable and physical examination was unremarkable. His abdomen was soft, non-tender and non-distended, with no palpable masses or organomegaly. Esophagogastroduodenoscopy revealed a 3 2 2 cm mass in the cardia, with a central ulceration, about 2 cm distal to the gastroesophageal junction. Biopsy of the mass revealed spindle cells. A CT scan confirmed an endophytic intramural gastric mass with no evidence of metastatic disease (Figure 1). Immunohistochemistry showed positive staining for a number of biochemical protein markers, including KIT, Ki-67 and smooth muscle actin, but was negative for the markers S100 and desmin.

Figure 1 Results from the CT scan.

The CT scan showed an intramural mass with endophytic components.

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A gastric-wedge resection revealed an ulcerated 4.5 cm mass in the lesser curvature of the stomach (Figure 2) and 10 firm white nodules of 1–3 mm throughout the anterior and posterior gastric surface (Figure 3). Exploration of the abdomen during resection revealed two 2 cm carcinoid tumors in the mid-ileum, jejunal diverticula and reactive mesenteric lymphadenopathy.

Figure 2 The ulcerated mass as revealed by gastric-wedge resection.

It was later identified as a gastrointestinal stromal tumor.

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Figure 3 Multiple smaller foci of gastrointestinal stromal tumor on the posterior surface of the stomach (arrows).

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The results from high-throughput cDNA microarray analysis of the ulcerated 4.5 cm mass are shown in Table 1. Quantitative reverse transcriptase-PCR performed on C-KIT and CHROMOGRANIN A confirmed the microarray observations.

Table 1 Results from cDNA microarray gene expression analysis.

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Discussion of diagnosis

Hematemesis requires immediate attention and should be investigated using an upper endoscopy. In the patient, hematemesis was caused by the ulcerated gastric mass, and the endoscopic appearance in the stomach of a smooth rounded mass with a central ulceration gave an important diagnostic clue. The patient's overall lack of symptoms, other than hematemesis in combination with melena, suggested a tumor of mesenchymal origin eroding through the mucosa. Such tumors can also represent extrinsic compression caused by neoplasia arising from nearby organs including the liver, spleen, pancreas, left adrenal gland and retroperitoneum. Diagnosis is made by immunohistochemical staining and standard histologic examination.

Differential diagnosis

Smooth muscle tumor, gastric lymphoma, tumors with a neural/neuroendocrine origin and gastrointestinal stromal tumor (GIST) were considered as potential diagnoses given the patient's presentation.

GIST

GIST is the most common mesenchymal tumor of the gastrointestinal tract and can occur throughout this region. It is diagnosed in 10–20 individuals per million annually in the US, and up to 30% of patients with GIST have metastatic disease at the time of presentation.¹ GISTs usually appear as a smooth or ulcerated mass in the stomach and can cause hematemesis. Histologically, they have a spindle cell, epithelial or mixed appearance and are distinguished from other non-epithelial tumors arising from the muscularis propria by overexpression of CD117, which is not overexpressed in other gastrointestinal tract tumors. The c-Kit expression of GISTs indicates these neoplasms arise from stem cells that differentiate towards the INTERSTITIAL CELLS OF CAJAL.² Gastrointestinal autonomic nerve tumors have been described as a phenotypic variant of GIST that have increased neural differentiation.³ The alterations in the SECRETORY GRANULE NEUROENDOCRINE PROTEIN 1 and chromogranin C may reflect neural differentiation of the tumor.^{4, 5}

GISTs rarely occur concomitantly with other neoplasms. Carney's triad is a rare entity that usually occurs in young women and consists of gastric GIST, paraganglioma and pulmonary chondroma. NEUROFIBROMATOSIS TYPE I (VON RECKLINGHAUSEN DISEASE) can include stromal tumors in association with pancreatic neuroendocrine tumors,⁶ and GISTs have also been reported to occur with Burkitt's lymphoma, osteosarcoma, neuroblastoma and melanoma. There are, however, no reports of gastric GIST occurring with ileal carcinoid tumors. In addition, multiple GIST without evidence of metastatic spread is rare and usually in conjunction with a familial form of GIST.⁷

In the patient, final pathologic examination revealed the main gastric nodule to be a 4.5 cm ulcerated GIST that stained positively for KIT (Figure 4), Ki-67 and smooth muscle actin, but not for desmin. The tumor had 41 mitoses per 50 high-power fields (HPFs). The smaller gastric nodules, on initial examination of a frozen section thought to be multiple leiomyoma, were later, based on positive KIT staining, found to be small GIST tumors with no mitoses per 50 HPFs. The ileal carcinoid tumors showed characteristic morphology and positive staining for chromogranin and synaptophysin. Any relationship between GIST and carcinoid tumors remains unclear, though cDNA microarray data suggest some similarities at the molecular level.

Figure 4 Hematoxylin and eosin staining of the large gastrointestinal stromal tumor.

The inset shows histochemical staining for CD117.

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Treatment and management

The 5-year survival rate for GIST patients is about 35%. This survival rate increases to 54% for patients with tumors that can be completely resected, however, up to 40% of these patients will experience recurrence. The median time to recurrence is 18–24 months. Once recurrence has occurred median survival is 9–16 months. The primary sites of recurrence are the liver and peritoneum, while lymph-node metastases are rare.⁸ Metastases usually occur when tumors are >5 cm and have >10 mitoses per 50 HPFs, however, because up to 20% of patients with GISTs <5 cm develop metastatic disease, it has been proposed that all GISTs have metastatic potential. Tumors arising from the stomach have a better prognosis than those arising elsewhere in the gastrointestinal tract.

Historically, GISTs demonstrated resistance to systemic treatment and were usually treated by surgical resection. Treatment with imatinib mesylate (imatinib), a small-molecule tyrosine kinase inhibitor of KIT, has led to responses in patients with GISTs that cannot be completely resected.⁹ Imatinib can be used as an adjuvant for GIST, however, the ideal dose, timing and duration of treatment is unclear. c-Kit and PDGFRA mutations occur in 80% of GIST patients. In a recent trial, patients with mutations in exon 11 of c-Kit showed a better response to imatinib compared with those who had mutations in exon 9. In the same study, patients with an Asp842Val point mutation in PDGFRA did not respond to imatinib.¹⁰

Several treatment options are available for multiple GISTs occurring synchronously with ileal carcinoid, as found in the patient. Total gastrectomy would eliminate disease and probably provide the best long-term survival, however, the risk of morbidity from the procedure and probable slow progression of the smaller remaining tumors must be considered. Additionally, given the high mitotic index of the primary GIST, the patient could develop widespread metastatic disease, despite total gastrectomy. Adjuvant treatment with imatinib is another option, however, the patient's residual GISTs were of such low volume and low mitotic index that they could remain indolent for some time. Furthermore, they were too small to be seen by standard imaging, making it impossible to determine any response to imatinib therapy. Additional information about c-Kit and PDGFRA mutations in these tumors could be useful in predicting imatinib efficacy.

The size and high mitotic rate of the primary GIST meant it was considered more likely to impact the patient's survival than the relatively indolent ileal carcinoid tumors. The two carcinoid tumors in the mid-ileum were removed by segmental resection. The patient had an uneventful postoperative course and was discharged from hospital 6 days after gastric-wedge resection. The use of adjuvant imatinib was discussed with the patient but, without clear benefit or the ability to follow response to therapy in the multiple residual lesions, the patient elected to defer such treatment pending evidence of disease progression. The patient also refused completion gastrectomy. At 12 months post-surgery, the patient continues to show no evidence of recurrent or progressive disease. The patient will be monitored at 6–12 month intervals with serial CT scans and endoscopic ultrasounds. In the event of progressive GIST, a completion gastrectomy will be performed, assuming patient compliance and localized disease. As there is no effective adjuvant therapy for carcinoid tumors, the patient will be monitored for recurrent carcinoid by 6-month plasma chromogranin measurements and octreoscan.

Conclusion

This case highlights the unusual presentation of multiple gastric GIST in association with ileal carcinoids. Although GISTs can be detected using radiology or histology, immunohistochemical staining for the KIT receptor confirms the diagnosis. The high mitotic index of the patient's main GIST lesion suggests a malignant phenotype, and screening with endoscopy and axial imaging is planned to detect local or distant recurrences. Until recurrence is detected, close observation is warranted for this patient who desires minimal intervention.

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Subject areas under which this article appears: Diagnosis and Imaging