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Gastrointestinal stromal tumors associated with neurofibromatosis 1: a single centre experience and systematic review of the literature including 252 cases.

1. Introduction

Neurofibromatosis type 1 (NF1, von Recklinghausen's disease) is an autosomal-dominant disorder occurring in 1 out of 3,000 births that is caused by the inactivation of the NF1 gene. NF1 is a tumor suppressor that encodes for the neurofibromin protein, a member of the Ras family. The inactivation might be a familial condition with an autosomal-dominant inheritance pattern; otherwise it might be sporadic [1, 2].

The disease is characterized by cutaneous neurofibromas, cafe au lait macules, axillary and inguinal freckling, and Lisch nodules.

NF1 is also associated with several tumors, including tumors of the nervous system (central and peripheral) and of the gastrointestinal (GI) tract, with the gastrointestinal stromal tumors (GISTs) indicated as the most common GI NF1-associated tumors [3].

GISTs are mesenchymal and usually kit positive tumors, originating from the interstitial cell of Cajal or their related stem cells [4,5]. The incidence of the GISTs has been reported in 10-20 new cases per million/year [6]. GISTs represent 80% of mesenchymal GI tumors and 0.1-3% of all GI malignancies [7-10]. GIST's pathogenesis is related to kit and platelet-derived growth factor receptor alpha (PDGFRa) mutation. Kit and PDGFRa encode for similar type III receptor tyrosine kinase proteins: these mutations are somatic and occur only in the neoplastic tissue of sporadic GISTs, whereas constitutional mutations in familial GISTs occur in every cell ofthe bodyand are inheritable [11-14].

Over the last few years several case reports documented the association between GISTs and NF1 syndrome; however to date there is a lack of reviews in this field with the objective of describing the clinical and pathological features of GISTs presenting in NF1 patients.

Aims of this study were (a) to report our experience regarding this association; (b) to provide a systematic review of the literature in this field including 252 GISTs described in 126 NF1 patients with the objective of analyzing the clinical, pathological, and molecular features of these tumors in patients affected by this condition; and (c) to compare the clinical/pathological features of GISTs presenting associated with NF1 with those reported in sporadic GISTs.

2. Materials and Methods

2.1. Systematic Review: Data Source and Search Strategies. This investigation has been conducted adhering at the PRISMA statements for review and meta-analysis (Figure 1). We conducted a systematic review of the literature by searching PubMed database for all published series and case reports investigating the association of NF1 and GIST (Keywords: "GIST and NF1", language: English; filter "human" studies); the Medline search was conducted at the beginning of September 2013 and retrieved 24 papers. We also included references from the retrieved publications (n 3 manuscripts).

Published series with the aim to investigate exclusively the molecular profile (n 1 study), the NF1 radiological features (n 1 study), or its association with other gastrointestinal tumors, for example, gastrointestinal schwannomas (n 1 article), were excluded.

Moreover we also excluded those reviews in this field that did not include patients' presentation (n 2 studies), one paper that reported GISTs without signs of NF1 syndrome and another study investigating the intestinal neurofibromatosis.

The same search strategies have been applied to the Ovid database and provided the addition of 3 more papers (after the manual removal of duplicate references).

Overall the systematic review has been conducted on 23 articles published from 2004 to date [15-37], plus the two patients we herein presented.

Authors conducting this review of the literature were blinded to authors' and journals' names and did not consider any journal's score (e.g., journal's Impact Factors) of the published case/series as an exclusion criteria for this study.

We collected data regarding study populations, number of investigated patients and GISTs, familiar or sporadic history of NF1, age at presentation of the GISTs, symptoms, sex of the patients, tumors' location, tumors' diameter, and number of mitoses. The morphologic appearance and cellular descriptions (generally referred to as epithelioid, spindle, and mixed cells) were also recorded along with the immunohistochemistry for CD117 (c-kit), S-100 protein, CD-34, and SMA-alpha. Whenever available, we included data regarding GIST risk classification and the studies investigating c-kit and PDGFRa mutations.

2.2. Statistical Analysis. With respect to the systematic review, we pooled together the data obtained from different studies in order to analyze a large series of patients and of clinical and pathological variables. Patients' clinical features and tumors' pathological records were thus analysed using means and standard deviations for quantitative variables and using frequencies and percents for categorical variables.

Moreover, the clinical and pathological features of the GISTs presenting associated with the NF1 syndrome (including age at presentation, M/F ratio, symptoms, tumors' diameter and localization, and risk criteria) retrieved from the international literature have been compared for statistical purpose to those obtained in a personal case series of sporadic GISTs undergone surgical resection at our department. Variables were compared using the t-test for continuous variable and the Chi-square test for categorical variables; all test were two-tailed and a P < 0.05 was considered of statistical significance value. All statistical evaluations were conducted with the statistical software MedCalc version

3. Results

3.1. Personal Cases Series Presentation

Case 1. A 71-year-old male patient with a history of NF1 presented with an abdominal mass incidentally detected in the work-up of an abdominal aortic aneurism.

The patient's past medical history was consistent with hypertension and cholecystectomy for lithiasis. The abdominal CT scan documented a gastric mass of 3.6 cm (Figure 2); the patient underwent a gastroscopy that documented an atrophic gastritis. The patient was scheduled for a surgical procedure and a laparoscopic wedge resection of the posterior gastric wall was performed. The postoperative course was uneventful and the patient was discharged on 6th postoperative day.

The pathological examination documented agastric GIST (c-KIT+, DOG1+) with spindle cell morphology, with a mitotic count of 2/50 HPF thus classified as a "low grade risk," according to Miettinen's classification. The patient is currently disease-free, 8 months after the surgical resection.

Case 2. A 56-year-old man was admitted to our department with a familial history of NF1 (Figure 3) and a past medical history consistent with a pheochromocytoma in 1994. The patient underwent a surgical resection elsewhere for a duodenal GIST (third portion) and presented to our attention with a relapse of the disease 7 months after the primary surgical resection. The patient was scheduled for a surgical procedure of duodenotomy and excision of the recurrence. The pathological description was consistent with a 4 cm c-KIT and CD34 positive GIST with 9 mitosis/50 HPF thus classified as at "intermediate risk" according to Miettinen's classification. The postoperative course was uneventful and the patient was discharged in 9th postoperative day. The patient is disease-free, 8 years after the surgical treatment.

3.2. Systematic Review. Table 1 summarizes the studies included in the present review of the literature. For the purpose of this investigation we pooled patients from different studies (23 articles, plus the present single centre experience), obtaining the clinical and pathological records of 252 GISTs detected in 126 NF1 patients [15-37].

As documented in Table 1, the vast majority of the studies reported single cases or small case series, excluding the article by Miettinen reporting 45 patients followed by the experience of Liegl and Andersson (resp., 16 and 15 NF1 patients) [18,19,27].

Table 2 shows the results of the data analysis. Patients were documented homogeneous regarding the M/F ratio (M/F 1), with a mean age at presentation of 52.8 years. Data regarding the NF1 syndrome (as a sporadic or familial disorder) has been detected exclusively in 17 out of the 126 NF1 included patients (13.5% of the series) and notably it has been documented as familial syndrome in the vast majority 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 ileus in 30.6% of the cases. GISTs appeared to be incidental in the majority of the cases (52.5%) and were reported with a mean diameter of 3.8 cm. The mean mitotic count was documented to be 3.0/50 HPF and the pathological morphology was consistent with spindle-shaped cell tumors in almost the totality of the GISTs (93.0%). Indeed 97.4% were c-kit positive and 81.6% CD34 positive; moreover, even though data regarding the DOG-1 expression were available exclusively in 17 patients, 88.2% were reported as DOG-1 positive. Opposite anti-SMA antibodies were positive in 24.1% of the cases and S-100 protein was expressed in 30.3% of the tumors. Notably desmin expression has been documented negative in all the 109 tumors analyzed. Wild-type c-kit and PDGRF alpha genes were reported in 95.2% of the tumors analyzed for any mutations.

Of note, the 64.9% of the GISTs were reported as low risk tumors, otherwise the 17.5% were considered at intermediate risk and the 17.5% as high risk GISTs.

3.3. Comparison with Sporadic GISTs. Clinical and pathological features of GISTs associated with NF1 syndrome (including mean age at presentation, M/F ratio, tumors' localizations, symptoms at presentation, mean diameters, and risk classification) were compared for statistical purpose with those documented in sporadic GISTs in a subset of patients undergone surgical resection at our centre from 1999 to 2009 (n 47 patients) [38]. Table 3 summarizes results of the statistical analysis. We documented a difference of statistical value analyzing the mean age at presentation: indeed according to our results patients affected by NF1 were younger compared to sporadic GISTs patients (t-test P 0.0001). Moreover, in this subset of patients, tumors were significantly smaller (t-test P 0.0003). Tumors were located mainly in the jejunum/ileus in the NF1 subgroup whereas the main localization in the sporadic group was the stomach (Chi-square test P < 0.0001); moreover in the former group the vast majority of the GISTs were incidentally detected (Chi-square test P 0.002). Moreover, even though we did not document a significant difference analyzing the M/F ratios (Chi-square test P ns), we reported a prevalence of low-risk criteria in the NF1 subgroup compared with the sporadic GISTs (Chi-square test P 0.03).

4. Discussion

In this review we highlighted the clinical, pathological, and molecular features of GISTs detected in NF1 patients and, to the best of our knowledge, this is the first and most numerically relevant

systematic analysis of the literature in this field. Moreover we reported our single centre experience regarding 2 GISTs detected in NF1 patients. Of note, from 1999 to date we treated 91 GISTs; thus the cases herein reported represent 2.2% of our series.

GISTs are commonly associated with NF1 syndrome, since a past study conducted on an autopsy series documented a GIST in one third of the NF1 patients [39].

GISTs associated with NF1 syndrome seem to have however a distinct phenotype: Miettinen reported that they occur in younger patients compared with sporadic GISTs that are often multiple and occur in the duodenum or small intestine [40].

Consistently with these findings, in our systematic review we highlighted that the mean age at presentation was 52.8 years and they are detected as multiple lesions in 35.3% of the cases, occurring in distal sites as the jejunum and small intestine.

Indeed in our previous research conducted on 47 primary GISTs patients, we reported a mean age at presentation of 61.4 years (median 62 years), none of the patients presented multiple lesions, and the most reported localization was the stomach, representing 59.6% of the tumors' sites [38].

Moreover, GISTs associated with NF1 patients have been described as clinically indolent and often asymptomatic, with low mitotic rates [40]. Indeed, we reported that 52.5% of the cases were described as incidental findings, whereas in our previous case series on GISTs, the patients were reported asymptomatic in 19.2% of the cases. Mean mitotic rate has been herein documented as 3/50 HPF; however also in our previous research 74.5% of the tumors had a mitotic count <5/50 HPF [38].

Notably a mutation in kit or PDGFR alpha genes has been reported exclusively in 4.8% of the cases.

Recently those GISTs associated with Carney Triad, Carney-Stratakis syndrome, along with young and pediatric GISTs have been documented to have a loss of succinate dehydrogenase subunit B (SDHB) expression, a mitochondrial protein [41-43]. On the basis of the SDHB expression, it has been recently proposed that GISTs could be differentiated into 2 characteristic subgroups: type 1 SDHB-positive and type 2 SDHB-negative [41]. Type 1 GISTs usually occur in adults with no predilection of tumor's locations, show homogeneous M/F, present KIT or PDGFRA mutations, and, generally, may benefit from the imatinib treatment. Type 2 GISTs occur usually in paediatric/young female patients almost exclusively in the stomach and present an epithelioid morphology. These tumors are usually c-kit and PDGFRa wildtype and do not respond to the molecular treatment with imatinib [44].

Even though NF1 associated GISTs have been documented to be type 1 SDHB-positive tumors [43], they could be differentiated by several features including the predilection of localization to jejunum/small intestines, common tumor multiplicity, and the lack of GIST-specific mutations (kit and PDGFRa); moreover and alike the SDHB type 2 tumors, they do not respond well to imatinib treatment [43, 45, 46].

In conclusion, a wide review of the literature in this field documented that GISTs detected in NF1 patients seem to have a peculiar and distinct phenotype, different than the one commonly reported GISTs including younger age at presentation, distal localization, small diameter, low mitotic rate, and absence of kit and/or PDGRFa mutations. Moreover the vast majority of these tumors were documented to be kit positive consistent with spindle-shaped cells and were considered as low-risk neoplasms.

Authors' Contribution

Pier Federico Salvi and Laura Lorenzon contributed equally to the study.


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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 Grottarossa 1035-39, 00189 Rome, Italy

Correspondence should be addressed to Laura Lorenzon;

Received 29 July 2013; Revised 6 October 2013; Accepted 20 October 2013

Academic Editor: Steven N. Hochwald

TABLE 1: Systematic review of the literature from 2004 to date.

Reference          Author                    Journal             Year

[15]            Cheng et al.           Digestive Diseases        2004
                                          and Sciences
[16]          Kinoshita et al.             The Journal           2004
                                          of pathology
[17]          Takazawa et al.         The American Journal       2005
                                      of Surgical pathology
[18]          Andersson et al.        The American Journal       2005
                                      of Surgical pathology
[19]          Miettinen et al.        The American Journal       2006
                                      of Surgical pathology
[20]          Maertens et al.       Human Molecular Genetics     2006
[21]           Nemoto et al.       Journal of Gastroenterology   2006
[22]           Bumming et al.         Scandinavian Journal       2006
                                       of Gastroenterology
[23]          Teramoto et al.         International Journal      2007
                                           of Urology
[24]           Stewart et al.          Journal of Medical        2007
[25]           Kramer et al.            World Journal of         2007
[26]         Invernizzi et al.               Tumori              2008
[27]            Liegl et al.         The American Journal of     2009
                                       Surgical pathology
[28]          Yamamoto et al.       Journal ofCancer Research    2009
                                      and Clinical Oncology
[29]        Dell'Avanzato et al.          Surgery Today          2009
[30]          Hirashima et al.            Surgery Today          2009
[31]          Cavallaro et al.        The American Journal       2010
                                           of Surgery
[32]           Relles et al.       Journal of Gastrointestinal   2010
[33]           Izquierdo and            Anticancer Drugs         2012
[34]           Agaimy et al.          International Journal      2012
                                         of Clinical and
                                     Experimental pathology
[35]           Ozcinar et al.       International Journal of     2013
                                      Surgery Case Reports
[36]          Vlenterie et al.          American Journal         2013
                                           of medicine
[37]           Sawalhi et al.           World Journal of         2013
                                        Clinical Oncology
                                       Present experience        2013

Reference    No. of    No. of
            patients   GISTs

[15]           3         5
[16]           7         29
[17]           9         36
[18]           15        27
[19]           45        45
[20]           3         7
[21]           1         1
[22]           1         4
[23]           2         2
[24]           2         3
[25]           1         1
[26]           1         1
[27]           16        16
[28]           5         31
[29]           1         2
[30]           1         17
[31]           2         2
[32]           2         5
[33]           1         4
[34]           2         3
[35]           1         4
[36]           2         4
[37]           1         1
               2         2
Total         126       252

TABLE 2: Clinical and pathological features from 252
GISTs in 126 NF1 patients.

Sex                          n         %

  M                        59.0      50.0
  F                        59.0      50.0
  Total available          118.0     100.0
Age (years)
  Mean; SD                         52.8; 13
  Range                            19.0-82.0
Familial history             n         %
  Sporadic                  5.0      29.4
  Familial                 12.0      70.6
  Total available          17.0      100.0
Number of GISTs              n         %
  1                        77.0      64.7
  >1                       42.0      35.3
  Total available          119.0     100.0
Localization                 n         %
  Stomach                  12.0       5.4
  Duodenum                 44.0      19.8
  Jejunum                  87.0      39.2
  Ileus                    68.0      30.6
  Colon                     4.0       1.8
  Other                     6.0       2.7
  Not specified             1.0       0.5
  Total available          222.0     100.0
Symptoms                     n         %
  Incidental               21.0      52.5
  Bleeding                 11.1      27.5
  Pain                      4.0      10.0
  Palpable mass             4.0      10.0
  Total available          40.0      100.0
GIST's diameter (cm)
  Mean                             3.8; 4.3
  Range                            0.1-29.0
Mitotic index (n/50 HPF)
  Mean                             3.0; 8.2
  Range                            0.0-57.0
Morphology                   n         %
  Spindle-shaped           159.0     93.0
  Epithelioid               9.0       5.3
  Mix                       3.0       1.7
  Total available          171.0     100.0
c-kit                        n         %
  Positive                 151.0     97.4
  Negative                  4.0       2.6
  Total available          155.0     100.0
CD34                         n         %
  Positive                 84.0      81.6
  Negative                 19.0      18.4
  Total available          103.0     100.0
Anti-SMA                     n         %
  Positive                 19.0      24.1
  Negative                 60.0      75.9
  Total available          79.0      100.0
S-100                        n         %
  Positive                 33.0      30.3
  Negative                 76.0      69.7
  Total available          109.0     100.0
Desmin                       n         %
  Positive                  0.0       0,0
  Negative                 109.0     100.0
  Total available          109.0     100.0
DOG-1                        n         %
  Positive                 15.0      88.2
  Negative                  2.0      11.8
  Total available          17.0      100.0
c-kit/PDGRFa Mutations       n         %
  Presence                  8.0       4.8
  Absence-wild type        157.0     95.2
  Total available          165.0     100.0
Risk classification          n         %
  Low risk                 37.0      64.9
  Intermediate risk        10.0      17.5
  High risk                10.0      17.5
  Total available          57.0      100.0

TABLE 3: Comparison between GISTs presenting in NF1 patients
and sporadic GISTs.

                       GISTs       GIST       P value
                       in NF1    personal
                      patients     case

  Mean (years)          52.8       61.4      0.0001 *
  M/F ratio              1         1.61         0.2
Localization (%)                            ([section])
  Stomach               5.4        56.9
  Jejunum/ileus         69.8       23.4       <0.0001
  Other                 24.8       19.7     ([section])
Symptoms (%)
  Incidental            52.5       19.1        0.002
  Other                 47.5       80.9     ([section])
  Mean (cm)             3.8        7.4       0.0003 *
  Low risk              64.9       41.3
  Intermediate risk     17.5       21.7        0.03
  High risk             17.5       37.0     ([section])

* f-test; ([section]) Chi-square test.
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Author:Salvi, Pier Federico; Lorenzon, Laura; Caterino, Salvatore; Antolino, Laura; Antonelli, Maria Serena
Publication:International Journal of Surgical Oncology
Article Type:Report
Date:Jan 1, 2013
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