Multiple gastrointestinal stromal tumors of the ileum and neurofibromatosis type 1

Type 1 neurofibromatosis, also known as von Recklinghausen disease, is one of the most common genetic disorders. Gastrointestinal associations have been well described in these patients, but the true incidence of gastrointestinal tumors and the proportion of these becoming clinically significant are not known. The most common gastrointestinal tumors are stromal tumors, most of which are located in the stomach and jejunum. We discuss the case of a female patient with neurofibromatosis whose initial diagnosis was an ovarian mass. During surgery the diagnosis of an intestinal stromal tumor was made. Operative findings were a multilobulated tumor arising from the ileal wall 50 cm from the ileocecal valve. The tumor did not originate from the nervous myenteric plexus or muscular layer of the small bowel wall; it originated from within the stromal cells of the intestinal wall. Mitotic count showed 3 mitoses per 10 high-power fields. Immunohistochemical stains of the tumor showed positive staining for CD117 and CD34 and negative staining for S100, α-smooth muscle actin, and desmin. The intestinal myenteric plexus showed positive staining for chromegranin A and S100. The histologic characteristics of this patient’s tumor are compatible with an undifferentiated stromal tumor of nonneural or nonmuscular origin.     

1例直肠间质瘤伴发腹腔内神经纤维瘤病1型的诊治过程

正1型神经纤维瘤病(NF1)是一种较常见的遗传性疾病,发病率估计在1/2500～3000,由神经纤维瘤病中的多种突变引起~([1])。NF1患者发生神经、间质性和神经内分泌肿瘤的风险增加并时有报道~([2,3])。胃肠道间质瘤(GIST)为特定的KIT-或PDFGRA-信号传导的间充质肿瘤,NF1伴发GIST患者中,绝大多数肿瘤发生在空肠或回肠,极少发KIT PDGFRA     

Multiple jejunal gastrointestinal stromal tumors and Neurofibromatosis type 1: A rare association

Introduction and importanceThe association between gastrointestinal stromal tumor (GIST), mesenchymal tumor arising from the interstitial cells of cajal and Neurofibromatosis type 1 (NF1), an autosomal dominant disease has been reported in the literature. GIST in NF1 patients are multiple and located in the small intestine. Tumorigenesis in NF1 associated GIST is different to that of sporadic GIST and hence the treatment. Here we report a rare case of an NF1 patient with multiple jejunal GISTs.Case presentationWe here present a rare case of a 57-year-old male diagnosed with NF1 30 years back, presented in our emergency department with complaints of black, tarry stools later diagnosed to have multiple GIST in jejunum. Contrast enhanced computed tomography (CECT) of the abdomen showed a large 10.1 × 7.33 × 6.2 cm heterogeneous, exophytic, solid mass with cystic areas originating from the jejunum. The microscopic examination of the specimen showed spindle shaped tumor cells while immunohistochemistry showed CD117 (c-KIT) and DOG-1 positivity. The primary treatment was complete surgical excision of the tumor.Clinical discussionThe incidence of GISTs in NF1 patient is around 6–7%; however, concomitant presence of multiple GISTs is rare. CECT of abdomen along with histopathological and immunohistochemistry studies are diagnostic. The management of GIST includes surgical and adjuvant therapy methods based on the tumorigenesis and recurrent risk stratification.ConclusionEarly clinical suspicion and imaging aids in early detection of the tumor in patients with NF1 presenting with gastrointestinal symptoms. Postoperatively, screening for recurrence with radiology is of utmost importance.     

Laparoscopic resection of sporadic synchronous gastric and jejunal gastrointestinal stromal tumors: Report of a case

Multicentricity of gastrointestinal stromal tumors (GISTs) has been described only in patients with neurofibromatosis type 1 (NF1) or within the small intestine, and different pathogenetic mechanisms are involved. We report a case of synchronous sporadic gastric and jejunal GISTs, which were resected laparoscopically in a 67-year-old man. Immunohistochemical analysis revealed that both lesions were KIT (CD117)-positive, but that the gastric lesion was CD34-positive, whereas the jejunal one was Vimentin-, S-100-, and SMA-positive. Molecular analysis of mutations in KIT exons 9, 11, 13, and 17, and in PDGFRA exons 12 and 18 revealed the presence of a gastric sporadic GIST with a KIT mutation of the exon 11 and a jejunal sporadic GIST without KIT or PDGFRA mutations. To our knowledge, this is the first report of laparoscopically resected synchronous sporadic gastric and jejunal GISTs.     

Multiple intracranial aneurysms and vascular abnormalities associated with neurofibromatosis type 1: a case report

We present an unusual case of multiple intracranial aneurysms, persistent primitive trigeminal artery (PPTA), and fenestration of the middle cerebral artery (MCA), associated with type 1 neurofibromatosis (NF 1). The patient was a 55-year-old woman in a state of semicoma. We observed widespread neurofibromas and café au lait spots on her trunk and limbs. Computed tomography (CT) scan revealed diffuse subarachnoid hemorrhage and right frontal intracerebral hemorrhage (WFNS grade IV, Fisher's classification group 4). Cerebral angiography showed two intracranial aneurysms at the anterior communicating artery, an aneurysm at the cavernous portion of the right carotid artery, a PPTA, and MCA fenestration. The patient remained in an apallic state, even after successful clipping of the anterior communicating artery aneurysms.     

Multiple gastrointestinal stromal tumors: Clinicopathologic and genetic analysis of 12 patients

Multiple gastrointestinal stromal tumors (GISTs) are extremely rare and usually associated with type 1 neurofibromatosis and familial GIST. The aim of this study was to investigate the clinical, phenotypic, and genetic characteristics of multiple GISTs to gain insights into their underlying pathogenesis and clinical behavior. Forty-seven paraffin blocks of multiple GISTs from 12 patients were analyzed. Genomic DNA was extracted from the tumor and normal mucosa and mutations for 4 exons of KIT gene and 3 exons of PDGFRA gene were determined. Among 12 patients with multiple GISTs, 5 were sporadic, 2 were familial with germline mutations of KIT gene, and 5 were associated with type 1 neurofibromatosis. All but 1 sporadic and familial multiple GISTs showed mutations of KIT gene shared by the same mutation on each GIST mass within a patient. But in 1 sporadic case, different types of KIT mutations were observed. Two familial multiple GIST cases showed diffuse involvement of the gastrointestinal tract with diffuse hyperplasia of interstitial cell of Cajal. Multiple GISTs associated with type 1 neurofibromatosis were located in the jejunum and harbored no mutations of KIT or PDGFRA. Different types of KIT gene mutation found in our case raise a possibility that recurrence of GISTs within a gastrointestinal tract may have a chance to be a rare occurrence of multiple primary GISTs instead of true recurrence. Multiple GISTs show unique clinical, phenotypic, and genotypic characteristics that are dependent on the particular underlying mechanisms, but the overall prognosis is favorable regardless of the numbers or phenotype of GISTs.     

Multiple gastrointestinal stromal tumors and pheochromocytoma in a patient with von Recklinghausen's disease

INTRODUCTIONNeurofibromatosis type 1 is a genetic disease characterized by neoplastic and non neoplastic disorders involving tissues of neuroectodermal and mesenchymal origin. Herein, we present a case with von Recklinghausen's disease, right adrenal heochromocytoma and multiple gastrointestinal stromal tumors.PRESENTATION OF CASEA forty-eight year old male patient was admitted to our Emergency Department with melena. His physical examination revealed multiple neurofibromas all over the skin, kyphosis, multiple cafe au lait spots and Lisch nodules on the eye and, melena on digital rectal examination. Abdominal computerized tomography scan showed a mass on right adrenal gland and multiple soft tissue mass lesions between distal part of pancreas and small bowel. Adrenal mass was determined as a pheochromocytoma and small bowel lesions were verified as stromal tumors.DISCUSSIONIn patients with NF1, pheochromocytomas and GISTs are well known neoplasms seen with increased incidence than the general population.CONCLUSIONIn patients with NF1, any symptoms with other systems should be managed carefully for underlying malignity.     

Neoadjuvant imatinib in a gastrointestinal stromal tumor of the rectum: Report of a case

Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal tract, and of these, GISTs involving the rectum are uncommon. This report describes a case of effective neoadjuvant therapy for a rectal GIST expressing the c-kit gene, where a laparoscopic ultralow anterior resection was successfully performed, thus preserving the anus. A 57-year-old woman visited our hospital due to constipation and was found by a digital examination to have a soft mass on the right wall of the rectum. Computed tomography revealed an 8.0 × 5.0-cm mass with an unclear margin adjacent to the rectum. A biopsy specimen was positive for CD34 and the c-kit gene product, but it was not positive for smooth muscle actin or S-100 protein, and thus the tumor was diagnosed as GIST. An abdominoperineal resection is generally essential for large rectal GISTs; however, she refused this operation. Neoadjuvant treatment with Imatinib decreased the tumor size (4.0 × 3.5 cm) and the anus was preserved by a laparoscopic ultralow anterior resection with direct coloanal anastomosis. She had no evidence of disease for 24 months postoperatively. To preserve the anus, a rectal GIST expressing the c-kit gene is best treated with Imatinib as neoadjuvant therapy.     

Primary large gastrointestinal stromal tumor of the liver: Report of a case

A 30-year-old man was diagnosed to have a large intra-abdominal tumor in 1999. A histological examination of a resected liver specimen from an operation in 2002 revealed a gastrointestinal stromal tumor (GIST), diagnosed based on positive immunostaining for CD34 and c-kit. Two years after the operation, new lesions developed in the residual liver and the lesser curvature of the stomach. An immunohistological examination of both specimens showed the features of a GIST, thus matching those of the first histological examination of the liver GIST. While there were no mutations at exon 11 of c-kit in the liver GISTs resected in 2002 and 2004, the gastric lesion had a mutation at P577L (CCT to CTT) at exon 11. Therefore, the liver GIST and the gastric lesion were diagnosed to be independent. The patient already has survived for more than 9 years after receiving surgery three times and with administration of imatinib.     

Gastrointestinal stromal tumors of neurofibromatosis type I (von Recklinghausen's disease)

Gastrointestinal stromal tumor (GIST), as well as the hyperplastic lesions of intestinal neural tissue and its supporting structures, is a gastrointestinal complication of type 1 neurofibromatosis (NF1) (von Recklinghausen's disease). In the present study, we analyzed the histologic and immunohistochemical features, and the c-kit and PDGFRA gene mutations of 36 GISTs derived from 9 NF1 patients. Distinctively, multiple GISTs arose preferentially in the small intestine. The histologic features of NF1-associated GISTs are almost similar to those of non-NF1 GISTs, but characteristically most of the NF1-associated GISTs contained skeinoid fibers. Thirty-three GISTs (92%) showed immunoreactivity for KIT, and 23 tumors (64%) showed diffuse or mosaic-like immunoreactivity for S-100 protein. Hyperplasic lesions, which may be the hyperplasia of interstitial cells of Cajal, were observed around some GISTs. Exons 9, 11, 13, and 17 of the c-kit gene and exons 12 and 18 of the PDGFRA gene were amplified and directly sequenced. Point mutations of c-kit gene or PDGFRA gene were identified only in three (8%) and two (6%) tumors, respectively. NF1-associated GISTs, showing the dual differentiation of interstitial cells of Cajal and Schwann cells, develop in close association with the myenteric nerve structure of gastrointestinal tract of NF1 patients. The point mutations of c-kit and PDGFRA gene may play a limited role in the tumorigenesis of NF1-associated GISTs.     

DOG1蛋白在胃肠道间质瘤中的表达及其意义

目的 检测胃肠道间质瘤(GIST)组织中DOG1蛋白表达情况,评价DOG1蛋白对GIST诊断的价值.方法 收集北京大学人民医院1987年1月至2008年9月连续且临床病理资料完整的137例GIST肿瘤组织及73例非GIST间叶源性肿瘤组织,采用免疫组织化学染色法检测DOG1蛋白表达情况,并分析其与GIST临床病理指标的关系.结果 (1)本组中80.3%(110/137)的GIST表达DOG1蛋白,27.3%(3/11)的CD117阴性GIST表达DOG1蛋白,1.3%(1/73)的非GIST间叶源性肿痛表达DOG1蛋白;(2)GIST肿瘤组织中DOG1蛋白表达情况与肿瘤发生部位、细胞丰富程度、细胞核异形性及Fletcher危险程度分级有关(P＜0.05).DOG1阴性组和阳性组患者术后1、3、5年总生存率分别为81.3%、74.5%、74.5%和98.5%、85.9%及83.2%,P=0.344.结论 在胃肠道间叶源性肿瘤中,DOG1是GIST敏感且特异性的诊断标志物;DOG1蛋白表达状况与GIST患者的预后无关.     

Malignant stromal tumors of the duodenum. Report of a case

The Authors report a rare case of undifferentiated duodenal malignant stromal tumour in a 69-years-old man radically managed by pancreaticoduodenectomy and resection of a liver metastasis. Several preoperative tests were performed (barium meal, endoscopy, ultrasonography and CT scan) but failed to yield a differential diagnosis between a tumour of the pancreatic head and a retroperitoneal neoplasm. The diagnosis was only histological. The tumour was considered to be high-grade due to its large size, high mitotic index, and the presence of necrosis and liver metastasis. Thorough surveillance revealed several hepatic metastases 29 months after resection, and chemotherapy performed at this stage proved completely ineffective. The patient died 38 months after surgery.     

A malignant peripheral nerve sheath tumor of the mediastinum in a patient with neurofibromatosis type 1: Report of a case

Malignant peripheral nerve sheath tumor (MPNST) is rare, but its association with neurofibromatosis type 1 (NF1) is well known. A 56-year-old man with NF1 was referred to our hospital for investigation of dyspnea. Computed tomography showed a huge mass occupying the right thorax and invading the inferior vena cava. A salvage resection was performed to alleviate the developing hypoxemia. Histological examination confirmed an MPNST. The tumor regrew rapidly and the patient died 6 weeks after the resection. This case report reinforces the importance of monitoring patients with NF1 carefully because of their increased risk of the development of malignant neoplasms.     

Management of gastrointestinal stromal tumors

A gastrointestinal stromal tumor (GIST) is a rare mesenchymal malignancy of the gastrointestinal (GI) tract. Malignant GISTs were first defined as a separate entity from a collection of nonepithelial malignancies of the GI tract in the 1980s and 1990s based on pathologic and clinical behavior. The discovery of activating KIT mutations as a near-uniform occurrence in these tumors greatly influenced the classification [1] and revolutionized therapeutic management of these tumors. To meet the next challenges, newer tyrosine kinase inhibitors and targeted agents are being developed with the goal of providing improved response rates or alternative therapies for patients progressing on established agents. In this article, the authors describe the management of GISTs, concentrating on surgical management and targeted therapies.     

Laparoscopic total gastrectomy for multiple sporadic gastric gastrointestinal stromal tumors: report of a case

A 64-year-old man was admitted to our hospital with hematemesis. Emergency upper gastrointestinal endoscopy revealed bleeding from a submucosal tumor (SMT) in the antrum of the stomach, with two other SMTs at different sites. Based on his family history, we diagnosed familial multiple gastric gastrointestinal stromal tumors (GISTs) and performed laparoscopic total gastrectomy. Three distinct tumors were found: one in the fornix, one in the lesser curvature of the angle, and one in the antrum of the stomach. Microscopic examination of the resected specimens revealed different cytomorphologies, of the spindle and epithelioid type, as well as immunophenotypes in the tumors. Mutation analysis revealed different sites of mutation in c-kit and PDGFRA. No mutation was detected in the normal tissue of the stomach. These findings confirmed a diagnosis of multiple sporadic gastric GISTs. Thus, investigating germline mutation might assist in the preoperative diagnosis of multiple gastric GISTs.     

胃肠道间质瘤的预后

随着对胃肠道间质瘤（gastrointestinal stromal tumor，GIST）分子生物学的认识和激酶抑制剂类靶向治疗药物的诞生，GIST的预后也发生了明显改善，疾病缓解率和手术切除率显著提高，生存期延长。不同的临床病理因素和治疗方法对GIST病人生存期具有根本影响。     

Gastrointestinal stromal tumours in patients with neurofibromatosis type 1: A case report and retrospective review of 72 cases

In the present study, the features of gastrointestinal stromal tumours (GIST) in patients with neurofibromatosis type 1 (NF1) are analysed, and the fundamental differences between NF1‐associated GIST and the common types of GIST are illustrated. We report a case of NF1‐associated GIST, and discuss the clinical and pathological data of 71 reported cases from the PubMed/MEDLINE database over the past two decades. The clinical characteristics, histopathology, biological behaviour, immunohistochemistry, phenotype and gene mutation status of GIST in NF1 are carefully reviewed. A total of 72 cases (35 females and 37 males; median age: 53 years) was included in this study. More than 80 per cent of lesions were located in the small intestine, most of which were multicentric (63.89 per cent), and the median diameter of the tumours was 4 cm (range: 0.3–20 cm). The positive expression rates for transmembrane type III receptor tyrosine kinase (KIT), CD34, S‐100, smooth muscle actin, and desmin were 100 per cent, 94.34 per cent, 37.5 per cent, 35.9 per cent and 7.41 per cent, respectively. There were just six cases found with the KIT gene mutation; no cases were found with mutations in the platelet‐derived growth factor receptor‐α (PDGFRA) gene. Patients with NF1 have a high risk of developing GIST. NF1‐associated GIST are significantly different from common GIST in terms of clinical characteristics, histopathology, biological behaviour, immunohistochemistry and the mutation status of the KIT and PDGFRA genes. In addition, in this research, we indicate that different pathogenetic mechanisms are involved in their evolution, and that imatinib has limited effects on GIST in NF1 patients.     

Neonatal gastrointestinal stromal tumor. Report of a case and review of literature

Gastrointestinal stromal tumor (GIST) is very rare in infancy. Most of the reported cases in the literature are in adults; some are in children but there are a few reported cases in the literature. The present case is a 6-day-old female neonate presenting with lethargy, poor feeding, constipation, abdominal distention, and rectal bleeding. She was operated on with the impression of intestinal obstruction, and right hemicolectomy was performed on her. Surgical specimen showed a well-defined and round 3-cm mass in the cecal area. Diagnosis was made by histologic and immunohistochemical studies which showed a GIST. The tumor showed positive vimentin and c-kit but negative for all other markers (desmin, actin, S100, NSE, and CD-34). So the case was an undifferentiated GIST. After 1 year of follow-up the patient was completely normal.