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Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2013, Article ID 398570, 8 pages http://dx.doi.org/10.1155/2013/398570 Review Article Gastrointestinal Stromal Tumors Associated with Neurofibromatosis 1: A Single Centre Experience and Systematic Review of the Literature Including 252 Cases Pier Federico Salvi, Laura Lorenzon, Salvatore Caterino, Laura Antolino, Maria Serena Antonelli, and Genoveffa Balducci Surgical and Medical Department of Translational Medicine, Sant’Andrea Hospital, Faculty of Medicine and Psychology, University of Rome La Sapienza,St. Andrea Hospital,Via di Grottarossa1035-39,00189 Rome,Italy Correspondence should be addressed to Laura Lorenzon; email@example.com Received 29 July 2013; Revised 6 October 2013; Accepted 20 October 2013 Academic Editor: Steven N. Hochwald Copyright © 2013 Pier Federico Salvi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Aims. eTh objectives of this study were (a) to report our experience regarding the association between neurob fi romatosis type 1 (NF1) and gastrointestinal stromal tumors (GISTs); (b) to provide a systematic review of the literature in this field; and (c) to compare the features of NF1-associated GISTs with those reported in sporadic GISTs. Methods. We reported two cases of NF1-associated GISTs. Moreover we reviewed 23 case reports/series including 252 GISTs detected in 126 NF1 patients; the data obtained from different studies were analyzed and compared to those of the sporadic GISTs undergone surgical treatment at our centre. Results.NF1 patients presenting with GISTs had a homogeneous M/F ratio with a mean age of 52.8 years. NF1-associated GISTs were oeft n reported as multiple tumors, mainly incidental, localized at the jejunum, with a mean diameter of 3.8 cm, a mean mitotic count of 3.0/50 HPF, and KIT/PDGFR𝛼 wild type. We reported a statistical difference comparing the age and the symptoms at presentation, the tumors’ diameters and localizations, and the risk criteria of the NF1-associated GISTs comparing to those documented in sporadic GISTs. Conclusions. NF1-associated GISTs seem to have a distinct phenotype, specifically younger age, distal localization, small diameter, and absence of KIT/PDGRF𝛼 mutations. 1. Introduction GISTs are mesenchymal and usually kit positive tumors, originating from the interstitial cell of Cajal or their related Neurofibromatosis type 1 (NF1, von Recklinghausen’s disease) stem cells [4, 5]. The incidence of the GISTs has been reported is an autosomal-dominant disorder occurring in 1 out of in 10–20 new cases per million/year . GISTs represent 80% 3,000 births that is caused by the inactivation of the NF1 gene. of mesenchymal GI tumors and 0.1–3% of all GI malignancies NF1 is a tumor suppressor that encodes for the neurob fi romin [7–10]. GIST’s pathogenesis is related to kit and platelet- protein, a member of the Ras family. The inactivation might derived growth factor receptor alpha (PDGFRa) mutation. be a familial condition with an autosomal-dominant inheri- Kit and PDGFRa encode for similar type III receptor tyrosine tance pattern; otherwise it might be sporadic [1, 2]. kinase proteins: these mutations are somatic and occur The disease is characterized by cutaneous neurofibromas, only in the neoplastic tissue of sporadic GISTs, whereas cafe´ au lait macules, axillary and inguinal freckling, and Lisch constitutional mutations in familial GISTs occur in every cell nodules. of the body and are inheritable [11–14]. NF1 is also associated with several tumors, including Over the last few years several case reports documented tumors of the nervous system (central and peripheral) and the association between GISTs and NF1 syndrome; however of the gastrointestinal (GI) tract, with the gastrointestinal to date there is a lack of reviews in this el fi d with the objective stromal tumors (GISTs) indicated as the most common GI of describing the clinical and pathological features of GISTs NF1-associated tumors . presenting in NF1 patients. 2 International Journal of Surgical Oncology Aims of this study were (a) to report our experience PubMed search GIST and NF1 regarding this association; (b) to provide a systematic review of the literature in this eld fi including 252 GISTs described Limits: English; humans; in 126 NF1 patients with the objective of analyzing the case reports; case series clinical, pathological, and molecular features of these tumors in patients affected by this condition; and (c) to compare the 24 studies clinical/pathological features of GISTs presenting associated with NF1 with those reported in sporadic GISTs. Exclusion: 7 studies 2. Materials and Methods 17 studies + 3 studies obtained by manual search: (references from the retrieved publications) 2.1. Systematic Review: Data Source and Search Strategies. This investigation has been conducted adhering at the Ovid search (same criteria): PRISMA statements for review and meta-analysis (Figure 1). 3 studies We conducted a systematic review of the literature by search- ingPubMeddatabasefor allpublished series andcasereports 23 studies investigating the association of NF1 and GIST (Keywords: including 252 GISTs from 126 NF1 patients “GIST and NF1”, language: English; filter “human” studies); theMedlinesearchwas conductedatthe beginning of Figure 1: Systematic review: study design according to the PRISMA September 2013 and retrieved 24 papers. We also included statement. references from the retrieved publications (n 3 manuscripts). Published series with the aim to investigate exclusively the means and standard deviations for quantitative variables and molecular profile (n 1 study), the NF1 radiological features (n using frequencies and percents for categorical variables. 1 study), or its association with other gastrointestinal tumors, Moreover, the clinical and pathological features of the for example, gastrointestinal schwannomas (n 1 article), were GISTs presenting associated with the NF1 syndrome (includ- excluded. ing age at presentation, M/F ratio, symptoms, tumors’ diame- Moreover we also excluded those reviews in this field ter and localization, and risk criteria) retrieved from the inter- that did not include patients’ presentation (n 2 studies), one national literature have been compared for statistical purpose paper that reported GISTs without signs of NF1 syndrome and to those obtained in a personal case series of sporadic GISTs another study investigating the intestinal neurob fi romatosis. undergone surgical resection at our department. Variables The same search strategies have been applied to the Ovid were compared using the𝑡 -test for continuous variable and database and provided the addition of 3 more papers (aer ft the Chi-square test for categorical variables; all test were two- the manual removal of duplicate references). tailed and a𝑃<0.05 was considered of statistical significance Overall the systematic review has been conducted on 23 value. All statistical evaluations were conducted with the articles published from 2004 to date [15–37], plus the two statistical software MedCalc version 220.127.116.11. patients we herein presented. Authors conducting this review of the literature were 3. Results blinded to authors’ and journals’ names and did not consider any journal’s score (e.g., journal’s Impact Factors) of the 3.1. Personal Cases Series Presentation published case/series as an exclusion criteria for this study. We collected data regarding study populations, number Case 1. A 71-year-old male patient with a history of NF1 of investigated patients and GISTs, familiar or sporadic presented with an abdominal mass incidentally detected in history of NF1, age at presentation of the GISTs, symptoms, the work-up of an abdominal aortic aneurism. sex of the patients, tumors’ location, tumors’ diameter, and The patient’s past medical history was consistent with number of mitoses. The morphologic appearance and cellular hypertension andcholecystectomy forlithiasis.Theabdomi- descriptions (generally referred to as epithelioid, spindle, and nal CT scan documented a gastric mass of 3.6 cm (Figure 2); mixed cells) were also recorded along with the immuno- the patient underwent a gastroscopy that documented an histochemistry for CD117 (c-kit), S-100 protein, CD-34, and atrophic gastritis. The patient was scheduled for a surgical SMA-alpha. Whenever available, we included data regarding procedure and a laparoscopic wedge resection of the posterior GIST risk classica fi tion and the studies investigating c-kit and gastric wall was performed. eTh postoperative course was PDGFRa mutations. uneventful and the patient was discharged on 6th postopera- tive day. 2.2. Statistical Analysis. With respect to the systematic The pathological examination documented a gastric GIST review, we pooled together the data obtained from different (c-KIT+, DOG1+) with spindle cell morphology, with a studies in order to analyze a large series of patients and of mitotic count of 2/50 HPF thus classified as a “low grade clinical and pathological variables. Patients’ clinical features risk,” according to Miettinen’s classification. The patient is and tumors’ pathological records were thus analysed using currently disease-free, 8 months aeft r the surgical resection. International Journal of Surgical Oncology 3 Figure 2: Abdominal CT scan documenting a 3.6 cm GIST of the stomach. (a) (b) Figure 3: Cutaneous neurofibromas in patient aeff cted by NF1 and duodenal GIST of the hand (a) and back (b). Case 2. A 56-year-old man was admitted to our department obtaining the clinical and pathological records of 252 GISTs with a familial history of NF1 (Figure 3)and apastmedical detected in 126 NF1 patients [15–37]. As documented in Table 1, the vast majority of the studies history consistent with a pheochromocytoma in 1994. eTh reported single cases or small case series, excluding the article patient underwent a surgical resection elsewhere for a duo- by Miettinen reporting 45 patients followed by the experience denal GIST (third portion) and presented to our attention of Liegl and Andersson (resp., 16 and 15 NF1 patients) [18, 19, with a relapse of the disease 7 months aeft r the primary 27]. surgical resection. The patient was scheduled for a surgical Table 2 showsthe resultsofthe data analysis.Patients procedure of duodenotomy and excision of the recurrence. were documented homogeneous regarding the M/F ratio The pathological description was consistent with a 4 cm (M/F 1), with a mean age at presentation of 52.8 years. c-KIT and CD34 positive GIST with 9 mitosis/50 HPF thus Data regarding the NF1 syndrome (as a sporadic or familial classified as at “intermediate risk” according to Miettinen’s disorder) has been detected exclusively in 17 out of the 126 classification. The postoperative course was uneventful and NF1 included patients (13.5% of the series) and notably it has the patient was discharged in 9th postoperative day. eTh been documented as familial syndrome in the vast majority patient is disease-free, 8 years aeft r the surgical treatment. of the cases (70.6%). GISTs were reported as multiple tumors in the 35.3% of the patients and the prevalent localization was documented at the jejunum site 39.2%, followed by 3.2. Systematic Review. Table 1 summarizes the studies included in the present review of the literature. For the pur- ileus in 30.6% of the cases. GISTs appeared to be incidental in the majority of the cases (52.5%) and were reported pose of this investigation we pooled patients from different with ameandiameterof3.8cm.Themeanmitotic count studies (23 articles, plus the present single centre experience), 4 International Journal of Surgical Oncology Table 1: Systematic review of the literature from 2004 to date. Reference Author Journal Year No. of patients No. of GISTs  Cheng et al. Digestive Diseases and Sciences 2004 3 5  Kinoshita et al. eTh Journal of pathology 2004 7 29  Takazawa et al. eTh American Journal of Surgical pathology 2005 9 36  Andersson et al. eTh American Journal of Surgical pathology 2005 15 27  Miettinen et al. eTh American Journal of Surgical pathology 2006 45 45  Maertens et al. Human Molecular Genetics 2006 3 7  Nemoto et al. Journal of Gastroenterology 2006 1 1 Bummin ¨ g et al. Scandinavian Journal of Gastroenterology 2006 1 4  Teramoto et al. lnternational Journal of Urology 2007 2 2  Stewart et al. Journal of Medical Genetics 2007 2 3  Kramer et al. World Journal of Gastroenterology 2007 1 1  Invernizzi et al. Tumori 2008 1 1  Liegl et al. eTh American Journal of Surgical pathology 2009 16 16  Yamamoto et al. Journal of Cancer Research and Clinical Oncology 2009 5 31  Dell’Avanzato et al. Surgery Today 2009 1 2  Hirashima et al. Surgery Today 2009 1 17  Cavallaro et al. eTh American Journal of Surgery 2010 2 2  Relles et al. Journal of Gastrointestinal Surgery 2010 2 5  Izquierdo and Bonastre Anticancer Drugs 2012 1 4  Agaimy et al. lnternational Journal of Clinical and Experimental pathology 2012 2 3  Ozcinar et al. International Journal of Surgery Case Reports 2013 1 4  Vlenterie et al. American Journal of medicine 2013 2 4  Sawalhi et al. World Journal of Clinical Oncology 2013 1 1 Present experience 2013 2 2 Total 126 252 was documented to be 3.0/50 HPF and the pathological statistical value analyzing the mean age at presentation: morphology was consistent with spindle-shaped cell tumors indeed according to our results patients aeff cted by NF1 in almost the totality of the GISTs (93.0%). Indeed 97.4% were younger compared to sporadic GISTs patients (𝑡 -test were c-kit positive and 81.6% CD34 positive; moreover, even 𝑃 0.0001). Moreover, in this subset of patients, tumors were though data regarding the DOG-1 expression were available significantly smaller ( 𝑡 -test𝑃 0.0003). Tumors were located exclusively in 17 patients, 88.2% were reported as DOG-1 mainly in the jejunum/ileus in the NF1 subgroup whereas positive. Opposite anti-SMA antibodies were positive in the main localization in the sporadic group was the stomach 24.1% of the cases and S-100 protein was expressed in 30.3% of (Chi-square test𝑃<0.0001 ); moreover in the former group the tumors. Notably desmin expression has been documented the vast majority of the GISTs were incidentally detected negative in all the 109 tumors analyzed. Wild-type c-kit and (Chi-square test𝑃 0.002). Moreover, even though we did not PDGRF alpha genes were reported in 95.2% of the tumors document a significant difference analyzing the M/F ratios analyzed for any mutations. (Chi-square test𝑃 ns), we reported a prevalence of low-risk Of note, the 64.9% of the GISTs were reported as low risk criteria in the NF1 subgroup compared with the sporadic tumors, otherwise the 17.5% were considered at intermediate GISTs (Chi-square test𝑃 0.03). risk and the 17.5% as high risk GISTs. 4. Discussion 3.3. Comparison with Sporadic GISTs. Clinical and patho- logical features of GISTs associated with NF1 syndrome In this review we highlighted the clinical, pathological, and (including mean age at presentation, M/F ratio, tumors’ molecular features of GISTs detected in NF1 patients and, localizations, symptoms at presentation, mean diameters, to the best of our knowledge, this is the rfi st and most and risk classicfi ation) were compared for statistical purpose numerically relevant systematic analysis of the literature in with those documented in sporadic GISTs in a subset of this field. Moreover we reported our single centre experience patients undergone surgical resection at our centre from regarding 2 GISTs detected in NF1 patients. Of note, from 1999 to 2009 (n 47 patients) . Table 3 summarizes results 1999 to date we treated 91 GISTs; thus the cases herein of the statistical analysis. We documented a dieff rence of reported represent 2.2% of our series. International Journal of Surgical Oncology 5 Table 2: Clinical and pathological features from 252 GISTs in 126 Table 2: Continued. NF1 patients. Anti-SMA 𝑛 % Sex 𝑛 % Positive 19.0 24.1 Negative 60.0 75.9 M 59.0 50.0 Total available 79.0 100.0 F 59.0 50.0 S-100 𝑛 % Total available 118.0 100.0 Positive 33.0 30.3 Age (years) Negative 76.0 69.7 Mean; SD 52.8; 13 Total available 109.0 100.0 Range 19.0–82.0 Desmin 𝑛 % Familial history 𝑛 % Positive 0.0 0,0 Sporadic 5.0 29.4 Negative 109.0 100.0 Familial 12.0 70.6 Total available 109.0 100.0 Total available 17.0 100.0 DOG-1 𝑛 % Number of GISTs 𝑛 % Positive 15.0 88.2 1 77.0 64.7 Negative 2.0 11.8 >1 42.0 35.3 Total available 17.0 100.0 Total available 119.0 100.0 c-kit/PDGRFa Mutations 𝑛 % Localization 𝑛 % Presence 8.0 4.8 Stomach 12.0 5.4 Absence—wild type 157.0 95.2 Duodenum 44.0 19.8 Total available 165.0 100.0 Jejunum 87.0 39.2 Risk classification 𝑛 % Ileus 68.0 30.6 Low risk 37.0 64.9 Colon 4.0 1.8 Intermediate risk 10.0 17.5 Other 6.0 2.7 High risk 10.0 17.5 Not specified 1.0 0.5 Total available 57.0 100.0 Total available 222.0 100.0 Symptoms 𝑛 % Incidental 21.0 52.5 GISTs are commonly associated with NF1 syndrome, Bleeding 11.1 27.5 since a past study conducted on an autopsy series docu- Pain 4.0 10.0 mented a GIST in one third of the NF1 patients . Palpable mass 4.0 10.0 GISTs associated with NF1 syndrome seem to have Total available 40.0 100.0 however a distinct phenotype: Miettinen reported that they GIST’s diameter (cm) occur in younger patients compared with sporadic GISTs Mean 3.8; 4.3 that are oeft n multiple and occur in the duodenum or small Range 0.1–29.0 intestine . Mitotic index (𝑛 /50 HPF) Consistently with these n fi dings, in our systematic review Mean 3.0; 8.2 we highlighted that the mean age at presentation was 52.8 Range 0.0–57.0 years and they are detected as multiple lesions in 35.3% of Morphology 𝑛 % the cases, occurring in distal sites as the jejunum and small intestine. Spindle-shaped 159.0 93.0 Indeed in our previous research conducted on 47 primary Epithelioid 9.0 5.3 GISTs patients, we reported a mean age at presentation of Mix 3.0 1.7 61.4 years (median 62 years), none of the patients presented Total available 171.0 100.0 multiple lesions, and the most reported localization was the stomach, representing 59.6% of the tumors’ sites . c-kit 𝑛 % Moreover, GISTs associated with NF1 patients have been Positive 151.0 97.4 described as clinically indolent and oeft n asymptomatic, with Negative 4.0 2.6 low mitotic rates . Indeed, we reported that 52.5% of the Total available 155.0 100.0 cases were described as incidental ndin fi gs, whereas in our CD34 𝑛 % previous case series on GISTs, the patients were reported asymptomatic in 19.2% of the cases. Mean mitotic rate has Positive 84.0 81.6 been herein documented as 3/50 HPF; however also in our Negative 19.0 18.4 previous research 74.5% of the tumors had a mitotic count Total available 103.0 100.0 <5/50 HPF . 6 International Journal of Surgical Oncology Table 3: Comparison between GISTs presenting in NF1 patients and sporadic GISTs. GISTs in NF1 patients GIST personal case series 𝑃 value Age Mean (years) 52.8 61.4 0.0001 Sex M/F ratio 1 1.61 0.2 Localization (%) Stomach 5.4 56.9 Jejunum/ileus 69.8 23.4 <0.0001 Other 24.8 19.7 Symptoms (%) Incidental 52.5 19.1 0.002 Other 47.5 80.9 Diameter Mean (cm) 3.8 7.4 0.0003 Risk classification (%) Low risk 64.9 41.3 0.03 Intermediate risk 17.5 21.7 High risk 17.5 37.0 ∗ § 𝑡 -test; Chi-square test. Notably a mutation in kit or PDGFR alpha genes has been Authors’ Contribution reported exclusively in 4.8% of the cases. Pier Federico Salvi and Laura Lorenzon contributed equally Recently those GISTs associated with Carney Triad, to the study. 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Published: Dec 9, 2013
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