Gastrointestinal stromal tumors (GISTs) have been reported to occasionally occur in patients with
neurofi bromatosis type 1 (NF-1), and many cases have had multiple lesions predominantly involving
the small intestine. We report herein a case of multiple GISTs associated with NF-1 from whom laparoscopic
surgery was benefi cial. In a 79-year-old female admitted with anemia and melena, the
abdominal computed tomography revealed a tumor arising from the small intestine. Laparoscopic
surgery was performed, and another small tumor was revealed during laparoscopic observation.
Extracorporeal partial and wedge resection of the small intestine were undertaken. Both lesions
were diagnosed as typical GISTs of low risk. Laparoscopic surgery would be useful for examination
and a minimally invasive approach to tumors of the small intestine, especially on cases with the possibility
of multiple tumors.</p

Hirai, Ryuji

Ikeda, Eiji

Kunitomo, Tadayoshi

Miyake, Takayoshi

Moriyama, Shigeharu

Muraoka, Takayuki

Nawa, Sugato

Takagi, Shoji

Tsuji, Hisashi

Tsukuda, Kazunori

Watanabe, Keitaro

Okayama University Scientific Achievement Repository

Acta Medica OkayamaVolume 61, Issue 1 2007 Article 7FEBRUARY 2007Multiple gastrointestinal stromal tumors inneurofi bromatosis type 1 treated withlaparoscopic surgeryKazunori Tsukuda, Okayama Red Cross General HospitalEiji Ikeda, Okayama Red Cross General HospitalShoji Takagi, Okayama Red Cross General HospitalTakayoshi Miyake, Okayama Red Cross General HospitalTakayuki Muraoka, Okayama Red Cross General HospitalKeitaro Watanabe, Okayama Red Cross General HospitalRyuji Hirai, Okayama Red Cross General HospitalShigeharu Moriyama, Okayama Red Cross General HospitalSugato Nawa, Okayama Red Cross General HospitalTadayoshi Kunitomo, Okayama Red Cross General HospitalHisashi Tsuji, Okayama Red Cross General HospitalCopyright c©1999 OKAYAMA UNIVERSITY MEDICAL SCHOOL. All rights reserved.Multiple gastrointestinal stromal tumors inneurofi bromatosis type 1 treated withlaparoscopic surgery∗Kazunori Tsukuda, Eiji Ikeda, Shoji Takagi, Takayoshi Miyake, TakayukiMuraoka, Keitaro Watanabe, Ryuji Hirai, Shigeharu Moriyama, Sugato Nawa,Tadayoshi Kunitomo, and Hisashi TsujiAbstractGastrointestinal stromal tumors (GISTs) have been reported to occasionally occur in patientswith neurofi bromatosis type 1 (NF-1), and many cases have had multiple lesions predominantlyinvolving the small intestine. We report herein a case of multiple GISTs associated with NF-1 fromwhom laparoscopic surgery was benefi cial. In a 79-year-old female admitted with anemia andmelena, the abdominal computed tomography revealed a tumor arising from the small intestine.Laparoscopic surgery was performed, and another small tumor was revealed during laparoscopicobservation. Extracorporeal partial and wedge resection of the small intestine were undertaken.Both lesions were diagnosed as typical GISTs of low risk. Laparoscopic surgery would be usefulfor examination and a minimally invasive approach to tumors of the small intestine, especially oncases with the possibility of multiple tumors.KEYWORDS: gastrointestinal stromal tumor, neurofi bromatosis type 1, laparoscopic surgery∗PMID: 17332842 [PubMed - in process]Copyright (C) OKAYAMA UNIVERSITY MEDICAL SCHOOLMultiple Gastrointestinal Stromal Tumors in Neuroﬁ bromatosis Type 1 Treated with Laparoscopic SurgeryKazunori Tsukudaa＊,  Eiji Ikedaa,  Shoji Takagia,  Takayoshi Miyakeb,  Takayuki Muraokaa,  Keitaro Watanabea,  Ryuji Hiraia,  Shigeharu Moriyamaa,  Sugato Nawaa,  Tadayoshi Kunitomob, and Hisashi TsujiaDepartments of aSurgery and bPathology,  Okayama Red Cross General Hospital,  Okayama 700ﾝ8607,  Japanastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract arising from the Cajal’s cells expressing c-kit [1]. GISTs commonly occur sporadically but have been reported to occur with increased tendency in patients with neuroﬁ bromatosis type 1 (NF-1).  NF-1,  also known as von Recklinghausen disease,  is one of the most common human single gene disorders,  aﬀ ecting at least 1 million persons throughout the world.  It encompasses a spectrum of multifacted disorders and may present with a wide range of clinical manifesta-tions,  including abnormalities of the skin,  nervous tissue,  bones,  and soft tissues.  The clinicopathologi-cal characteristics of GISTs in NF-1 are diﬀ erent from those of sporadic cases ; most cases show multi-ple GISTs predominantly involving the small intes-tine,  and mutations of c-kit or platelet-derived growth factor receptor A (PDGFRA) are rare [2ﾝ7].  Those multiple tumors are sometimes problematic for surgi-cal treatments.　　Laparoscopic surgery is a minimally invasive approach to common surgical problems in the abdo-men that results in much less surgical trauma and postoperative pain.  Another advantage of laparo-scopic surgery is providing a magniﬁ ed view of the patient’s internal organs on a television monitor, which helps with precise observation of the whole abdominal cavity.  We present herein a case of multi-ple GISTs of the small intestine in which laparo-scopic surgery was useful for examination and treat-GGastrointestinal stromal tumors (GISTs) have been reported to occasionally occur in patients with neuroﬁ bromatosis type 1 (NF-1),  and many cases have had multiple lesions predominantly involving the small intestine.  We report herein a case of multiple GISTs associated with NF-1 from whom lapa-roscopic surgery was beneﬁ cial.  In a 79-year-old female admitted with anemia and melena,  the abdominal computed tomography revealed a tumor arising from the small intestine.  Laparoscopic surgery was performed,  and another small tumor was revealed during laparoscopic observation. Extracorporeal partial and wedge resection of the small intestine were undertaken.  Both lesions were diagnosed as typical GISTs of low risk.  Laparoscopic surgery would be useful for examination and a minimally invasive approach to tumors of the small intestine,  especially on cases with the pos-sibility of multiple tumors.Key words : gastrointestinal stromal tumor,  neuroﬁ bromatosis type 1,  laparoscopic surgeryActa Med.  Okayama,  2007Vol.  61,  No.  1,  pp.  47ﾝ50http ://www.lib.okayama-u.ac.jp/www/acta/CopyrightⒸ 2007 by Okayama University Medical School.Case ReportReceived August 21, 2006 ; accepted October 24, 2006. ＊Corresponding author. Phone : ＋81ﾝ86ﾝ222ﾝ8811 ; Fax : ＋81ﾝ86ﾝ222ﾝ8841E-mail : kazu.tsukuda@nifty.com (K. Tsukuda)1Tsukuda et al.: Multiple gastrointestinal stromal tumors in neurofi bromatosisProduced by The Berkeley Electronic Press, 2007ment.Case Report　　A 79-year-old female patient,  with known NF-1, felt general fatigue and consulted a physician. Severe anemia and melena were found and the patient was referred to our institution for the exploration of gastrointestinal bleeding.  The patient presented café-au-lait spots over her whole body,  but no abdominal mass or tenderness was noted.  Laboratory analysis showed severe anemia with a hemoglobin count of 4.8 g/dl (Table 1).  Upper gastroendoscopic and colo-noscopic examinations were negative.  Computed tomography revealed a round,  approximately 3.0 cm × 2.5 cm,  lower abdominal mass that seemed to arise from the small intestine (Fig.  1).  The tumor was suspected to be a GIST and the cause of gastro-intestinal bleeding.  After blood transfusion,  laparo-scopic surgery was undertaken.　　A laparoscope was inserted through a 10-mm can-ula on the left side of the navel.  Two additional 5-mm side ports were inserted to manipulate the intestine.  Laparoscopy clearly located the main tumor protruding from the ileum and showed another 5 mm × 4 mm tumor of the terminal ileum (Fig.  2). There was no sign of peritoneal dissemination.  By lengthening the canula incision,  extracorporeal par-tial and wedge resection of small intestine were undertaken.  The main tumor had ulcer formation on the mucosa (Fig.  3).  Upon histological examination, both lesions were diagnosed as typical GISTs,  with 48 Acta Med.  Okayama　Vol.  61,  No.  1Tsukuda et al.Table 1　　Preoperative data of blood testWBC 6900 /mm3 LDH 194 IU/lRBC 216×104 /mm3 γ-GTP 9 U/lHb 4.8 g/dl T.Bil 0.2 mg/dlHt 16.4 % BUN 20.9 mg/dlPlt 33.0×104 /mm3 Cr 0.58 mg/dlT.P 5.8 g/dl Na 137 mEq/lAlb 3.6 g/dl K 4.4 mEq/lAST 18 IU/l Cl 105 mEq/lALT 9 IU/l CEA 0.9 ng/mlCRP 0.3 mg/dl CA19ﾝ9 3 U/dlALP 240 IU/lABFig. 2　　A,  Laparoscopic view of the main tumor,  which protrudes from the ileum ; B,  Laparoscopic view of a smaller tumor of the terminal ileum.Fig. 1　　The contrast-enhanced computed tomography revealed a lower abdominal tumor arising from the small intestine (arrow).2Acta Medica Okayama, Vol. 61 [2007], Iss. 1, Art. 7http://escholarship.lib.okayama-u.ac.jp/amo/vol61/iss1/7a low risk of malignancy and CD117 (c-kit)-and CD34-positive.  The patient had an uneventful post-operative course and was discharged on the 12 th day following the surgery.  No adjuvant treatment was performed,  and there had been no evidence of recur-rence at 1 year.Discussion　　Laparoscopic surgery is a minimally invasive approach to abdominal problems,  including cancers, obesity,  functional diseases of the gut,  and parietal defects,  carried out through small openings while watching the internal organs on a television monitor. Less surgical trauma results in less postoperative pain,  a shorter hospital stay,  a faster return to a solid food diet,  and a quicker return of bowel func-tion.  Another advantage of laparoscopic surgery is providing a magniﬁ ed view of the patient’s internal organs,  which allows better visualization of the oper-ative site for more precise work [8].  Nguyen et al. have attempted laparoscopic surgery for GISTs,  and most tumors were successfully removed laparoscopi-cally with intracorporeal or extracorporeal anasto-moses [9].  In their study,  the conversion to open surgery was associated with coincidental pathology in addition to the GIST.  Recent consensus reports have stated that GISTs are of uncertain malignant poten-tial,  and that all tumors should be resected despite an uncertain diagnosis.  Therefore,  laparoscopic sur-gery is advantageous for observation and treatment for tumors in the small intestine.  However,  laparo-scopic procedures also have several limitations.  The surgeon should be careful not to destroy the capsule of the GIST because destruction of GIST may cause peritoneal dissemination.  It is important to hold the adjacent normal intestine but to avoid directly hold-ing the tumor with laparoscopic devices.  The limited observation of stomach and colon,  especially their posterior walls,  may explain why multiple lesions are sometimes overlooked.  We chose laparoscopic sur-gery in the present case because the patient had undergone upper gastroendoscopic and colonoscopic examinations,  and the issue of limited observation also exists in open surgery.　　18F-Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is a useful technique for assessing GIST,  and the FDG uptake is considered to predict the malignant potential of GIST because of the cor-relation between FDG uptake and both the Ki67 index and the mitotic index [10].  In addition,  com-bined PET and CT oﬀ ers several advantages over PET alone,  and the use of this technique has spread widely over the past few years [11].  Some studies have described PET/CT imaging of GISTs [12]. The sensitivity has been found to be 93ｵ for CT and 86ｵ for PET for the diagnosis of GIST,  and a false negative on PET scan appears to be related to small lesions.  The minimum lesion detected has been reported to be 0.4 cm,  which is almost the same size as our smaller tumor.  PET/CT is often used to monitor the response to imatinib with malignant GIST,  but our case also appeared to be a good can-didate for follow-up with PET/CT scan,  because the patients with NF-1 tend to have multiple GISTs.　　The phenotypic and genotypic characteristics of GIST in NF-1 patients have been described recently. A great majority of tumors occur in the jejunum or ileum,  and most cases are multi-focus.  Though most tumors are stained for CD117 and CD34 and are morphologically indistinguishable from sporadic GISTs,  few GISTs with NF-1 have a c-kit mutation or PDGFRA mutation,  which is typically seen in spo-radic GISTs [2ﾝ6,  13,  14].  These characteristics indicate that GISTs in NF-1 patients have a diﬀ erent pathogenesis than sporadic GISTs.  The genetic dis-order of NF-1 is a germline mutations of NF1 which encodes neuroﬁ bromin and functions as a negative 49Multiple GISTs in NF-1February 2007Fig. 3　　Macroscopically appearances of large intestinal GIST involving the intestinal wall and small GIST protruding to the serosa.3Tsukuda et al.: Multiple gastrointestinal stromal tumors in neurofi bromatosisProduced by The Berkeley Electronic Press, 2007regulator of Ras activity.  Additional somatic inacti-vation of the wild-type NF1 allele has recently been shown in GISTs ; the homozygous inactivation of NF1 may therefore favor GIST formation [15].  Because of these genetic disorders,  patients with NF-1 are estimated to develop GISTs at a rate at least 45 times greater than sporadic cases,  but most GIST patients with NF-1 have revealed a good prognosis with long-term follow up [2].　　In conclusion,  we have described a NF-1 patient with multiple GISTs for whom laparoscopic surgery was useful for ﬁ nding another small lesion. Laparoscopic surgery appears to be useful for exami-nation and a minimally invasive approach to tumors of the small intestine,  especially in cases with the possibility of multiple tumors.References 1. Fletcher CD,  Berman JJ,  Corless C,  Gorstein F,  Lasota J, Longley BJ,  Miettinen M,  O’Leary TJ,  Remotti H,  Rubin BP, Shmookler B,  Sobin LH and Weiss SW : Diagnosis of gastrointes-tinal stromal tumors : a consensus approach.  Hum Pathol (2002) 33 : 459ﾝ465. 2. Miettinen M,  Fetsch JF,  Sobin LH and Lasota J : Gastrointestinal stromal tumors in patients with neuroﬁ bromatosis 1.  Am J Surg Pathol (2006) 30 : 90ﾝ96. 3. Takazawa Y,  Sakurai S,  Sakuma Y,  Ikeda T,  Yamaguchi J, Hashizume Y,  Yokoyama S,  Motegi A and Fukayama M : Gastrointestinal stromal tumors of neuroﬁ bromatosis type I (von Recklinghausen’s disease).  Am J Surg Pathol (2005) 29 : 755ﾝ763. 4. Kinoshita K,  Hirota S,  Isozaki K,  Ohashi A,  Nishida T,  Kitamura Y, Shinomura Y and Matsuzawa Y : Absence of c-kit gene mutations in gastrointestinal stromal tumours from neuroﬁ bromatosis type 1 patients.  J Pathol (2004) 202 : 80ﾝ85. 5. Yantiss RK,  Rosenberg AE,  Sarran L,  Besmer P and Antonescu CR : Mulitple gastrointestinal stromal tumors in type I neuroﬁ bro-matosis : a pathologic and molecular study.  Mod Pathol (2005)18 : 475ﾝ484. 6. Andersson J,  Sihto H,  Meis-Kindblom JM,  Joensuu H,  Nupponen N and Kindblom G : NF1-associated gastrointestinal stromal tumors have unique clinical,  phenotypic,  and genotypic character-istics.  Am J Surg Pathol (2005) 29 : 1170ﾝ1176. 7. Maertens O,  Prenen H,  Debiec-Rychter M,  Wozniak A,  Sciot R, Pauwels P,  De Wever I,  Vermeesch JR,  de Raedt T,  De Paepe A, Speleman F,  van Oosterom A,  Messiaen L and Legius E : Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients.  Hum Mol Genet (2006) 15 : 1015ﾝ1023. 8. Cueto J,  Vazquez-Frias JA,  Castaneda-Leeder P,  Baquera-Heredia J and Weber-Sanchez A : Laparoscopic-assisted resection of a bleeding gastrointestinal stromal tumor.  JSLS (1999) 3 : 225ﾝ228. 9. Nguyen SQ,  Divino CM,  Wang JL and Dikman SH : Laparoscopic management of gastrointestinal stromal tumors.  Surg Endosc (2006) 20 : 713ﾝ716.10. Kamiyama Y,  Aihara R,  Nakayayashi T,  Mochiki E,  Asao T, Kuwano H,  Oriuchi N and Endo K : 18F-ﬂ uorodeoxyglucose posi-tron emission tomography : useful technique for predicting malig-nant potential of gastrointestinal stromal tumors.  World J Surg (2005) 29 : 1429ﾝ1435.11. Rosenbaum SJ,  Stergar H,  Antoch G,  Veit P,  Bockisch A and Kuhl H : Staging and follow-up of gastrointestinal tumors with PET/CT.  Abdom Imaging (2006) 31 : 25ﾝ35.12. Gayed I,  Vu T,  Iyer R,  Johnson M,  Macapinlac H,  Swanston N and Podoloﬀ  D : The role of 18F-FDG PET in staging and early prediction of response to therapy of recurrent gastrointestinal stro-mal tumors.  J Nucl Med (2004) 45 : 17ﾝ21.13. Corless CL,  Fletcher JA and Heinrich MC : Biology of gastrointes-tinal stromal tumors.  J Clin Oncol (2004) 22 : 3813ﾝ3825.14. Shinomura Y,  Kinoshita K,  Tsutsui S and Hirota S : Pathophysiology,  diagnosis,  and treatment of gastrointestinal stromal tumors.  J Gastroenterol (2005) 40 : 775ﾝ780.15. Maertens O,  Prenen H,  Debiec-Rychter M,  Wozniak A,  Sciot R, Pauwels P,  De Weber I,  Vermeesch JR,  de Raedt T,  DePaepe A, Speleman F,  van Oosterom A,  Messiaen L and Legius E : Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients.  Hum Mol Genet (2006) 15 : 1015ﾝ1023.50 Acta Med.  Okayama　Vol.  61,  No.  1Tsukuda et al.4Acta Medica Okayama, Vol. 61 [2007], Iss. 1, Art. 7http://escholarship.lib.okayama-u.ac.jp/amo/vol61/iss1/7

Multiple gastrointestinal stromal tumors in neurofi bromatosis type 1 treated with laparoscopic surgery

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Multiple gastrointestinal stromal tumors in neurofi bromatosis type 1 treated with laparoscopic surgery

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