What about Gastric Schwannoma? A systematic review REVIEW

Background Gastric schwannomas (Gs) are rare mesenchymal neoplasms of the gastrointestinal tract. Diagnosis is commonly achieved by pathological examination of resected specimen. In most cases surgical resection of submucosal gastric lesions is performed with wide margins. New minimally invasive techniques are described in an increasing number of cases. Methods A Pubmed, Cochrane and Embase systematic review of the literature has been performed. Original papers, review articles, case reports published between 1988 and 2019 were considered eligible. Only papers written in English with full text available have been included. Articles reporting a follow up period, the type of treatment of the primary tumor and the appearance of local or distant recurrence were compared and analysed. Statistical analysis of data has been performed using GraphPad Prism 7 software. Results 328 articles were found and a total of 102 were included in the analysis. Fifty-three papers reported the follow-up information, ranging from 1-417 months across different studies. Among them, 31 patients underwent endoscopic removal of the gastric lesions, 140 patients local surgery, including wedge resection or partial gastrectomy and 148 patients underwent subtotal or total gastrectomy. The median follow-up was of 27-38-33 months respectively. No recurrence or distant metastasis were detected in endoscopic group. Among local surgery group, liver metastasis was reported in one case; in extended surgery group one patient died for multiple liver metastases. Conclusions In comparison with endoscopic group, local or more extended surgery involved a larger cohort of patients and reported satisfactory long-term results. Surgical approach in absence of a definite pre-operative diagnosis is considered the gold standard treatment for resectable Gs due to the excellent long-term outcome. Further studies are warranted to define the role of endoscopic treatment.


Abstract
Background Gastric schwannomas (Gs) are rare mesenchymal neoplasms of the gastrointestinal tract. Diagnosis is commonly achieved by pathological examination of resected specimen. In most cases surgical resection of submucosal gastric lesions is performed with wide margins. New minimally invasive techniques are described in an increasing number of cases.
Methods A Pubmed, Cochrane and Embase systematic review of the literature has been performed. Original papers, review articles, case reports published between 1988 and 2019 were considered eligible. Only papers written in English with full text available have been included. Articles reporting a follow up period, the type of treatment of the primary tumor and the appearance of local or distant recurrence were compared and analysed.
Statistical analysis of data has been performed using GraphPad Prism 7 software.
Results 328 articles were found and a total of 102 were included in the analysis. Fiftythree papers reported the follow-up information, ranging from 1-417 months across different studies. Among them, 31 patients underwent endoscopic removal of the gastric lesions, 140 patients local surgery, including wedge resection or partial gastrectomy and 148 patients underwent subtotal or total gastrectomy. The median follow-up was of 27-38-33 months respectively. No recurrence or distant metastasis were detected in endoscopic group. Among local surgery group, liver metastasis was reported in one case; in extended surgery group one patient died for multiple liver metastases.
Conclusions In comparison with endoscopic group, local or more extended surgery involved a larger cohort of patients and reported satisfactory long-term results. Surgical approach in absence of a definite pre-operative diagnosis is considered the gold standard treatment for resectable Gs due to the excellent long-term outcome. Further studies are warranted to define the role of endoscopic treatment.
Keywords : Schwannoma, neurinoma, gastric neurinoma, gastric schwannoma. Background Schwannomas, also known as neurilemmomas, are rare tumors arising from Schwann cells in the peripheral aspect of the nerve and are encapsulated by a fibrous band.
Epidemiological data from literature indicate that Gastrointestinal schwannomas (GIs) are uncommon neoplasms representing 2-7% of mesenchymal gastrointestinal tumors and account for 0.2% of all gastric tumors 1 .Usually detected during the fifth decade with a female predominance, Gs are considered benign tumors. In most cases patients show unspecific symptoms such as upper abdominal pain, dyspepsia, bleeding, abdominal mass, these symptoms are mostly related to the tumor size and location. Gs usually appear as submucosal or muscular masses, posing a difficult differential diagnosis with GastroIntestinal Stromal Tumors (GISTs), leiomyomas and leiomyosarcomas. Most cases undergo surgical treatment on the basis of a clinical and radiological diagnosis of gastric stromal mass, and the definitive diagnoses of Gs, based on the pathological examination on the surgical specimen 2 , is made only postoperatively. Malignant transformation is uncommon and surgical resection of the primary tumor is recommended.
A systematic review of the literature regarding the incidence, clinical features and treatment options of Gs has also been performed. The association between treatment options, follow-up period and the appearance of local or distant recurrence has also been investigated.

Methods
In order to assess the long-term oncological outcomes of endoscopic resection in comparison with local or more extended surgery for resectable Gs, a systematic review of the literature using PUBMED, COCHRANE and EMBASE databases has been performed.
Keywords used for the research were: schwannoma, neurinoma, gastric neurinoma, gastric schwannoma. Original papers, case reports and review articles published between 1988 and 2019 were considered eligible for the review. Articles reporting a median follow-up were included and analyzed in our research. Only papers written in English with full text available have been included. Papers with repeated case series and incorrect citations were excluded. Factors including year of publication, number of patients for each suitable papers and tumor sizes were also recorded. The choice of treatment (endoscopic, partial or more extended surgery), the median follow-up and the appearance of local or distance recurrence were compared. Statistical analysis of data has been performed using GraphPad Prism 7 software.

Results
Three hundred twenty-eight (n = 328) original articles were found. Two hundred-twentysix (n = 226) papers were removed because written in other language than English (n = 36), no complete articles or abstract (n = 29), off topic (n = 128) or because no gastric schwannoma (n = 33). Studies selection has been performed using PRISMA flow diagram ( Fig.1). One hundred four (n = 102) original articles including ten (n = 10) systematic review of literature, were considered eligible for our search (Table 1). A large cohort of patients (n = 647 patients) with Gs was examined.
Fifty-three (n = 53) articles reported the follow-up information (Table 2). Only three (n = 3) papers reported disease recurrence in 4 patients: one (n = 1) patient with local recurrence and three (n = 3) with liver metastases. No distant or local recurrence during a mean 28-month follow-up period were observed in our two cases. The median follow-up time was 22,75 months (95% Cl: 12-36), the median tumor size was 2,9 cm (95% Cl: 2,17-4), the median number of cases was 1. Subtotal or total gastrectomy was performed in 46% of the patients, local surgery in 44% and 10% underwent endoscopic surgery. (Fig. 2) Thirty-one (n = 31) patients underwent endoscopic removal of the gastric lesions and the median follow-up among this group was of 27 months; no recurrence or distant metastasis were detected. Local surgery, including wedge resection or partial gastrectomy were performed among one-hundred forty (n = 140) patients and the median follow-up among this group was of 38 months. Liver metastasis diagnosis 1 year after surgery was reported in 1 case. Despite aggressive chemotherapy the patient died few months later. Extended surgical approach, including subtotal or total gastrectomy, was performed among one hundred forty-eight (n = 148) patients. One patient died for multiple liver metastases despite a surgery with curative intent. The median follow-up among this group was of 33 months. One more local and one distant recurrence are reported but the type of treatment is not recorded for these patients (Table 2). Gs are usually observed in the fifth and sixth decade of life with a female predominance 6 , the most common site is the gastric body, followed by gastric antrum and fundus. Clinical detection of these tumors is difficult and patients usually present unspecific symptoms like epigastric discomfort, epigastric pain, gastrointestinal bleeding or palpable mass.

Discussion
Patients may be asymptomatic and the tumor can be discovered incidentally ,4 .
The preoperative differential diagnosis is still challenging, and the main problem is the differentiation of Gs from GIST and smooth muscle tumors. Compared to GIST on CT examination, schwannomas appear as a mass developing inside the gastric lumen with an exophytic or mixed growth pattern, and do not usually show signs of haemorrhage, Endoscopy usually reveals a submucosal elevated lesion with a smooth overlying normal mucosa, a central ulcer can be seen in 25-50% of cases, due to ischemic changes in the covering mucosa 8 . However, it may be difficult to achieve the correct histological diagnosis with only a standard endoscopic biopsy, because the surface of a gastric SMT is covered with normal epithelium and superficial endoscopic biopsy usually shows normal mucosa. EUS features may be helpful for differentiating gastric schwannomas from other mesenchymal tumors, especially GISTs . Although endoscopic ultrasonography (EUS) is a useful tool for diagnosing gastric SMTs, it is not always possible to differentiate a schwannoma from a GIST or a leiomyoma by EUS, as the tumor originates from the muscularis propria layer. Endoscopic ultrasonography scans (EUS) can be used to delineate the full depth of the tumor and to direct needle biopsy. Histological diagnosis by an EUS-fine-needle aspiration biopsy (FNAB) represents a reliable, useful and suitable method for the histological evaluation of gastric submucosal tumors (SMTs) including Gs .
The overall diagnostic rate for SMT by an EUS-FNAB has been reported to be relatively high (83%.9) combining both diagnostic and suspicious results. However, the accuracy diagnostic rate may be influenced by the tumor lesion's size and only a limited number of patients perform this procedure.
Schwannomas grows as a nodular, well-circumscribed, encapsulated mass on the periphery of a nerve. Histologically are spindle cell neoplasms that typically have two components: compact spindle cell Schwann cell components (Antoni A areas),, showing occasional palisading (Verocay Bodies) alternating with and looser hypocellular areas (Antoni B areas). Focal nuclear atypia and mitotic activity may be present. Thick-walled, hyalinized blood vessels are commonly present. By immunohistochemistry, tumor cells are strongly and uniformly positive for S100 protein and usually positive for glial fibrillary acid protein (GFAP); EMA-positivity may be encountered in subcapsular areas. As Schwannomas are negative for CD117, DOG1, CD34, SMA and desmin, they can be easily distinguished from GISTs which are positive for CD117 and DOG-1 or from leiomyoma as they are typically positive for SMA and desmin.
According to literature surgical approach in absence of a definite pre-operative diagnosis is considered the gold standard treatment for respectable Gs due to the excellent longterm outcome 2 .
The disease recurrence was not related to the type of surgery performed. Out of the 4 cases of disease recurrence, one patient underwent to local resection, one patient to more extended surgery and in two cases the type of surgery was not reported. The literature analysis showed that one-hundred forty (n = 140) patients performed a local resection with a median follow-up of thirty-eight (n = 38) months. Extended surgery, including subtotal or total gastrectomy was performed among one hundred forty-eight (n = 148) patients, mean follow up was 33 months. Both groups reported satisfactory long-term results but a significant statistically difference was not observed. Although only few articles regarding the endoscopic resection of Gs reporting a follow-up period have been Thus, preoperative pathological diagnosis seems to be mandatory in order to perform minimally invasive treatment. EUS-FNAB is safe, reliable and recommended when gastric stromal lesions are detected in order to define the risk features of GIST and select cases with indication to neoadjuvant treatment 24 . A further benefit of such approach is to identify the cases of Gs that can be treated with a minimally invasive approach. Nowadays surgical resection is currently considered the gold standard treatment: the groups involving a partial or more extended surgery included a larger cohort of patients and reported satisfactory long-term results. However, a statistically significant difference was not observed comparing the groups.
Mortality and recurrence were not observed in endoscopic group, which includes a smaller number of cases. Further studies encouraging the use of endoscopic resection for Gs and reporting a follow-up period are needed.

Conclusion
Surgical approach in absence of a definite pre-operative diagnosis is considered the gold standard treatment for resectable Gs due to the excellent long-term outcome.
Further studies are warranted in order to define the role of endoscopic treatment.

Supplementary Files
This is a list of supplementary files associated with the primary manuscript. Click to download. PRISMA_update_protocol_20180214.pdf