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Correspondence to: Yoshihiko Kitajima, MD, PhD, Department of Surgery, Saga University Faculty of Medicine, 5-1-1 Nabeshima, Saga 849-8501, Japan. pj.ca.u-agas.cc@yijatik
Telephone: +81-952-342349 Fax: +81-952-342019
A 77-year-old Japanese male patient was admitted to our hospital complaining of general fatigue and melena. A gastroduodenal endoscopic examination revealed no definitive localized lesions. However, both a large amount of cruor and blood flow from the small intestine into the ascending colon was observed during the colonoscopic examination. At least three tumors, believed to originate from the small intestine, were detected by abdominal computed tomography. Based on these findings, multiple and hemorrhagic small intestinal tumors were diagnosed and surgical treatment of the tumors planned. During the celiotomy, twelve tumors were found in the small intestine. Intestinal wedge or partial resection was applied. All excised specimens demonstrated morphology of a submucosal tumor and the largest tumor had a delle with coagulation on the mucosal face. In the histological findings, hematoxylin and eosin staining showed spindle cell morphology. The immunohistochemical examination revealed that the tumor cells were diffusely positive for KIT and CD34. The myenteric plexus layer of the small intestine was focal-positive for KIT and showed no intestinal cells of Cajal hyperplasia. The tumor sequencing results revealed an identical missense mutation in codon 642 of c-kit exon 13 leading to the replacement of lysine by glutamic acid and a silent germ-line mutation in exon 12 of the PDGFRA gene concerning whole blood, normal mucosa and tumors. We concluded that the current subject was categorized as having multiple sporadic-type gastrointestinal stromal tumor with identical mutational types. Although the patient did not receive any adjuvant chemotherapy, there has been no sign of recurrence over the 3 years since the surgery.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, and are derived from the interstinal cells of Cajal (ICCs). Somatic mutations in the c-kit or platelet derived growth factor receptor A (PDGFRA) genes are frequently found in most GISTs, and are recognized as gatekeeper molecular events[1-3]. GIST generally occurs as a sporadic solitary neoplasm whereas the occurrence of multiple primary neoplasms is considered to be an exceptional event, restricted to Carney’s syndrome, pediatric GISTs, type 1 neurofibromatosis (NF1)-associated GISTs[6-8], familial GISTs[9,10] and multiple sporadic GISTs[10-12]. We herein report a case of twelve simultaneous sporadic GISTs in the small intestine that were successfully treated with surgical resection and were immunohistochemically examined and genetically analyzed the c-kit and PDGFRA mutations.
A 77-year-old Japanese male patient was admitted to our hospital complaining of general fatigue and melena. The physical examination revealed no remarkable abnormalities except for anemia in the conjunctiva. There was no notable family history. Diabetes mellitus and benign prostatic hyperplasia were concomitant illnesses in the patient. Laboratory studies performed at the time of patient admission showed anemia (hemoglobin, 6.8 g/dL, hematocrit, 19.7%), elevation of the blood urea nitrogen (38.3 mg/dL) and a decrease in the total protein and albumin (5.0 g/dL, 3.5 g/dL respectively). Because hemorrhage from an alimentary tract was strongly suspected, an upper gastrointestinal endoscopy and colonoscopy were performed. A gastroduodenal endoscopic examination revealed no definitive localized lesions. However, both a large amount of cruor and blood flow from the small intestine into the ascending colon was observed during the colonoscopic examination. At least three tumors, believed to originate from the small intestine, were detected by abdominal computed tomography (CT) (Figure (Figure1).1). Based on these findings, multiple and hemorrhagic small intestinal tumors were preoperatively diagnosed and surgical treatment of the tumors planned. During the celiotomy, twelve tumors were found in the small intestine (Figure (Figure2A);2A); the distances from the Treitz’ ligament were 20, 50, 100, 150, 170, 180, 200, 220, 240, 290, 295 and 300 cm respectively (Table (Table1).1). The sizes of the tumors ranged from 2 to 70 mm in diameter (Table (Table1).1). No other lesions were found in other organs. Intestinal wedge or partial resection was applied (Table (Table1)1) and the remnant small intestine was 170 cm in length. All excised specimens demonstrated morphology of a submucosal tumor and the largest tumor had a delle with coagulation on the mucosal face (Figure (Figure2B).2B). In the histological findings, hematoxylin and eosin staining showed spindle cell morphology (Figure (Figure3A).3A). The mitotic count in all the tumors was less than 3 per 50 high-power fields. The MIB-1 index was less than 2%. The immunohistochemical examination revealed that the tumor cells were diffusely positive for KIT (Figure (Figure3B)3B) and CD34, focal-positive for SMA and S-100 and negative for desmin. The myenteric plexus layer of the small intestine was focal-positive for KIT and showed no ICCs hyperplasia. According to the mitotic count and tumor size, the present patient was finally diagnosed as having multiple GISTs with an intermediate risk for aggressive behavior (Table (Table11). The mutation analysis was performed in relation with exons 9, 11, 13 and 17 of the c-kit gene and exons 12, 14 and 18 of the PDGFRA gene in the whole blood, normal intestinal mucosa, the largest (tumor #10) and the second largest tumor (tumor #5) using polymerase chain reaction (PCR) and direct sequencing of the PCR products as previously described[10,11]. The tumor sequencing results revealed an identical missense mutation in exon 13 of the c-kit gene and a silent germ-line mutation in exon 12 of the PDGFRA gene concerning whole blood, normal mucosa and tumors (Figure (Figure4,4, Table Table2).2). The patient’s course was uneventful after surgery and he was discharged from the hospital on the 8th postoperative day. Although the patient did not receive any adjuvant chemotherapy, there has been no sign of recurrence over the 3 years since the surgery. The family including sibling and children and relatives did not exhibit GIST.
Most sporadic GISTs occur as solitary lesions and multiple tumors are extremely rare. Multifocal GISTs in adults are classified as sporadic with distinct or identical mutations, familial GISTs, NF1-associated GISTs and metastatic disease, according to the clinical features, family history, histology, immunohistochemical studies and mutation patterns (Table (Table33)[10,12]. In the present case, the discrimination of the multiple GISTs was considered as follows.
Concerning clinical features, patients with NF-1 are generally characterized as having systemic pigmented skin spots, skin and subcutaneous multiple neurofibromas and Lisch nodules[6-8]. Familial GIST is also characterized by hyperpigmentation, urticaria pigmentosa and dysphagia even though a small number of cases did not demonstrate any symptoms. The present case did not show any symptoms as mentioned above. In addition, the family and relatives did not exhibit corresponding symptoms. Thus, we concluded that the present case was not categorized as familial GIST.
In the case of multiple tumors in the abdomen, peritoneal disseminated metastasis is a very common differential diagnosis. The present case showed multiple tumors and all twelve tumors were located in the small intestine. The preoperative examinations, celiotomy and postoperative follow-up confirmed that there were no neoplasms in the other abdominal organs. Furthermore, the histological and immunohistochemical studies showed an overlying serosal membrane on the tumors, thus suggesting that all twelve tumors were of small intestinal origin. Based on these findings, we considered that the tumors were multiple GISTs rather than disseminated GISTs.
The immunohistochemical study of the normal tissues in the present small intestine demonstrated no ICC hyperplasia. Because multiple sporadic GISTs show no ICC hyperplasia, NF1-associated GISTs demonstrate focal or mild hyperplasia and familial GISTs reveal diffuse hyperplasia, the current subject was classified as having multiple sporadic GISTs.
GISTs have activating mutations of c-kit in exons 9, 11, 13 and 17 and exons 12, 14 and 18 of PDGFRA[14,15]. The most frequent mutation is identified in exon 11 of the c-kit gene, resulting in activation of the KIT receptor. Several studies in the analysis of DNA sequence of multiple GISTs reported that sporadic GISTs showed somatic mutations[10,12] and NF1-associated GISTs had no mutations or few mutations[6-8] and familial GISTs revealed germline mutations. In the present case, we identified conserved tumor missense mutations at exon 13 of c-kit and a silent germline mutation in exon 12 of the PDGFRA gene in patient whole blood, normal mucosa and tumors. The silent mutation in exon 12 of PDGFRA did not correspond to the known mutation site in the hot spots of this gene. In addition, this silent mutation did not result in a change to the amino acid sequence of protein. However, the missense mutation in codon 642 of c-kit exon 13 led to the replacement of lysine by glutamic acid (K642E). Furthermore, this mutation corresponded to the previous report by Isozaki in 2000. Isozaki et al reported two patients with familial multiple GISTs: a female patient and her son presented with 20 and 13 multiple GISTs respectively. In the sequencing analysis, the authors identified this point mutation in both tumors and normal pancreatic tissues. These results suggest that a point mutation in codon 642 of exon 13 of the c-kit gene may play an important role in the development of multiple GISTs. Taken together, we concluded that the current subject was categorized as having multiple sporadic-type GISTs with identical mutational types based on the physical examination, family history and the appearance of ICCs.
A surgical resection is still considered to be the standard treatment for GIST and a sufficient margin should be removed to complete the resection, even if the tumor is small. Dissection of regional lymph nodes is unnecessary because GISTs rarely involve lymph node metastasis. Although twelve tumors were scattered throughout the small intestine in the current case, our treatment strategy was to perform complete resection and to preserve the small intestine to prevent short-bowel syndrome. At least 30% of the normal intestinal length must be preserved for proper nutrient absorption[19,20] and we were able to preserve approximately 41.5% (170 cm) of small intestine by wedge resections and partial resection. The present patient is doing well without any loss of his body weight. In a treatment of multiple tumors of the small intestine, the length of the remnant small intestine and the preserved function must be taken into consideration. As a surgical treatment, the efficacy of the laparoscopic resection for multiple GISTs is reported[21,22]. Although we considered performing laparoscopic surgery, laparoscopic surgery is recommended when the tumor measures less than 5 cm in diameter. In addition, a subject with multiple GISTs should be evaluated and the precise number and sites of all the tumors to be resected. These careful intra-operative evaluations are sometimes difficult because a tactile sensation is lacking during laparoscopic surgery.
There is growing evidence that the adjuvant therapy of imatinib mesylate has been shown to improve the outcomes of surgical resection[23,24]. Recently, adjuvant therapy for the GIST is recommended for intermediated and especially high-risk GIST. In addition, GIST with KIT exon 11 mutation appear to be sensitive to imatinib and sunitinib has shown clinical benefit in all major GIST mutational subtypes, particularly in patients with wild-type or KIT exon 9 genotype and against GIST with secondary KIT exon 13 or 14 mutations. We should have performed the adjuvant therapy in this case due to the intermediated risk. However, the adjuvant therapy for complete resection with tumor-free margin was controversial when we experienced this case in 2007. In spite of the fact that the patient did not receive adjuvant therapy, he has been well without any recurrence. Thus, further investigation or analysis of the multiple GIST, focusing not only on risk stratification but also on total number of tumor in other cases with multiple GIST, is needed.
In conclusion, we experienced a rare case with multiple sporadic GISTs in the small intestine which was successfully treated by surgical resection. The tumor characterization using the DNA sequence analysis is thus considered to be useful for categorizing multiple GISTs and careful intra-operative evaluation is important to perform the complete resection of tumors. As biological behaviors of multiple GISTs are still unknown, further investigation will be necessary.
Peer reviewers: Yukinori Kurokawa, MD, PhD, Department of Surgery, Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka 540-0006, Japan; Seong Woo Jeon, MD, PhD, Assistant Professor, Department of Internal Medicine, Kyungpook National University Hospital, 50, Samduk-2Ga, Chung-gu, Daegu 700-721, South Korea
S- Editor Wang JL L- Editor Roemmele A E- Editor Yang C