Background: Inflammatory fibroid polyps (IFPs) are rare mesenchymal lesions that affect the gastrointestinal tract. IFPs are generally considered benign, noninvasive lesions; however, we report a case of an invasive gastric IFP. To the best of our knowledge, this is only the second case report of an invasive gastric IFP. Case presentation: A 62-year-old woman presented with complaints of epigastric pain and vomiting. Computed tomography showed a 27-mm, hyper-enhancing tumor in the prepyloric antrum. Upper endoscopy also showed a submucosal tumor causing subtotal obstruction of the gastric outlet. Because a gastrointestinal stromal tumor was suspected, distal gastrectomy was performed. Histopathological examination revealed spindle cell proliferation in the submucosal layer. The spindle cells had invaded the muscularis propria layer and extended to the subserosal layer. The tumor was finally diagnosed as an IFP based on immunohistochemical findings. No mutations were identified in the platelet-derived growth factor receptor alpha (PDGFRA) gene via molecular genetic analysis. Discussion and conclusions: After the discovery that IFPs often harbor PDGFRA mutations, these growths have been considered neoplastic lesions rather than reactive lesions. Based on the present case, IFPs might be considered not only neoplastic but also potentially invasive lesions. Keywords: Inflammatory fibroid polyp, Stomach, Invasion, Platelet-derived growth factor receptor alpha mutation Background gastric IFP, and based on this case, we suggest that the be- Inflammatory fibroid polyps (IFPs) are rare mesenchy- havior of IFPs be reconsidered. mal lesions that affect the gastrointestinal tract. Histo- logically, spindle cells proliferate in the submucosal Case presentation layer, and they rarely invade the muscularis propria [1, 2]. A 62-year-old woman presented with complaints of For a long time, IFPs were considered reactive lesions ; epigastric pain and vomiting for a few weeks. She had a however, recent reports revealed that these growths often history of traffic trauma followed by a brain abscess and contain mutations in the platelet-derived growth factor had also undergone a total hysterectomy for a uterine receptor alpha (PDGFRA) gene [4, 5]. PDGFRA mutations myoma. She was given an antiepileptic agent, a are oncogenic mutations that are often found in gastro- non-steroidal anti-inflammatory drug and a proton intestinal stromal tumors (GISTs) . Recently, IFPs have pump inhibitor at a local hospital. She had no history of been considered neoplastic lesions that are not invasive smoking or alcohol consumption. On physical examin- . In the current report, we describe a case of an invasive ation, her blood pressure was 123/65 mmHg, her temperature 36.8 °C, her respiratory rate 18/min, and her heart rate 56 beats per minute. There was epigastric * Correspondence: firstname.lastname@example.org tenderness on palpation. Laboratory results indicated a Department of Gastroenterology, Ube Industries Central Hospital, 750 white blood cell count of 7090/mm (67.5% neutrophils Nishikiwa, Ube, Yamaguchi 755-0042, Japan Full list of author information is available at the end of the article and 0.8% eosinophils), a hemoglobin level of 12.6 mg/dl, © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Harima et al. BMC Gastroenterology (2018) 18:74 Page 2 of 5 and a platelet count of 275,000/mm . Other blood for beta-catenin was not observed. IgG4-positive plasma biochemistry data were normal. Serum anti-Helicobacter cells were rare in the lesion. For mutational analysis, the pylori (H. pylori) immunoglobulin G antibody was nega- tumor tissue was scraped from unstained slides, and DNA tive (4 IU/ml, < 10 cut-off). Computed tomography (CT) was extracted using a QIAamp DNA FFPE Tissue Kit showed a 27-mm, hyper-enhancing tumor in the sub- (Qiagen, Hilden, Germany). The PDGFRA gene (exons mucosa of the prepyloric antrum as well as thickening of 12, 14 and 18) was amplified by PCR using KOD FX Neo the muscularis propria layer and a hyper-enhancing (Toyobo, Osaka, Japan). The PCR products were sepa- lesion in the subserosa (Fig. 1). Upper endoscopy also rated by electrophoresis and purified with a QIAquick Gel showed a submucosal tumor originating from the pos- Extraction Kit (Qiagen). The purified PCR products were terior wall of the prepyloric antrum (Fig. 2a). The tumor sequenced using an ABI 3130xl Genetic Analyzer (Applied caused subtotal obstruction of the gastric outlet. Mul- Biosystems, Foster City, CA, USA). The results indicated tiple biopsy specimens obtained from the surface of the the lack of mutations in the PDGFRA gene. While the in- submucosal tumor revealed infiltration of inflammatory vasive characteristics were atypical, the histopathological cells. To obtain further histopathological information, and immunohistochemical findings were consistent with endoscopic ultrasound-guided fine-needle aspiration was an IFP. Thus, we finally diagnosed the tumor as an IFP. conducted. The endoscopic ultrasound showed a hypoe- After resection, the patient’s clinical course was good: she choic tumor with slightly heterogeneous internal echoes has been closely followed up and has shown no recurrence. originating from the submucosal area (Fig. 2b). The tumor was punctured using a 22 G needle. The results Discussion indicated a small number of spindle cells, but a defini- IFPs were first described as eosinophilic submucosal tive diagnosis was not made. Considering her clinical granulomas by Vanek in 1949 , and after various findings, a diagnosis of GIST was suspected. Thus, distal names were suggested, Helwig and Ranier established gastrectomy was performed. The resected specimen the term IFP in 1953 . IFPs can occur throughout the revealed thickening of the submucosal layer and the gastrointestinal tract, but they are most commonly muscularis propria layer at the antrum (Fig. 3). Histo- found in the gastric antrum (66–75%) . The growths pathological examination revealed a submucosal tumor are usually asymptomatic and incidentally found during containing proliferating bland fibroblast-like spindle cells endoscopic examinations performed for unrelated with inflammatory infiltrates (Fig. 4a and b). There was reasons. However, depending on the location and size of also a proliferation of small blood vessels. The inflamma- a lesion, various clinical presentations can occur. Similar tory infiltrate contained lymphocytes and plasma cells. to the present case, large gastric IFPs in the gastric The spindle cells invaded the muscularis propria layer and antrum have been shown to cause subtotal obstruction extended to the subserosal layer (Fig. 4c, d and e). Re- of the gastric outlet . Histologically, IFPs are gional lymph node metastasis was not detected. Immuno- submucosa-based lesions containing bland spindle cells histochemical examination revealed that the spindle cells with prominent vasculature. Their morphologic features were diffusely positive for CD34, focally positive for often vary, and although IFPs are characterized by a alpha-smooth muscle actin and CD68, and negative for perivascular “onion skin” appearance, approximately half CD117, discovered on GIST-1 (DOG-1), S100 protein, of the lesions do not have this appearance . Indeed, desmin, cytokeratin AE1/AE3 and anaplastic lymphoma the present case did not have an “onion skin” appearance. kinase (ALK). The Ki-67 (MIB-1) labeling index in the In such cases, immunohistochemical examination is useful spindle cells was less than 1% (Fig. 5). Nuclear positivity for diagnosing an IFP . Immunohistochemically, IFPs Fig. 1 Computed tomography (CT) findings. a Axial view. b Coronal view. c Sagittal view. CT image showing a hyper-enhancing tumor in the submucosa of the prepyloric antrum (arrows). CT showing a thickening of the muscularis propria layer and a hyper-enhancing lesion in the subserosa of the gastric antrum (arrow heads) Harima et al. BMC Gastroenterology (2018) 18:74 Page 3 of 5 Fig. 2 Endoscopic findings. a Upper endoscopy showing a submucosal tumor at the prepyloric antrum causing obstruction of the gastric outlet. b Endoscopic ultrasound showing a hypoechoic tumor located in the submucosal layer are positive for CD34, smooth muscle actin and CD68 At least 1000 IFPs have been described thus far in the and negative for CD117, S100 protein and cytokeratin literature, and their etiology has been widely discussed AE1/AE3 . When histopathologically diagnosing IFPs, . Originally IFPs were hypothesized to result from other spindle cell lesions, such as GISTs, schwannomas, robust host responses to an unknown local injury, infec- and inflammatory myofibroblastic tumors (IMTs), must tion, or allergic reaction . Case reports describing be ruled out, but they can be usually distinguished using morphological changes in IFPs after the eradication of immunohistochemical examination. For example, GISTs H. pylori support this hypothesis . However, because are positive for CD117, schwannomas are positive for IFPs can also occur outside of the stomach, a causative S100 protein, and IMTs are positive for ALK and negative role for H. pylori is difficult to ascertain. In 2008, Schild- for CD34, whereas IFPs are not [2, 11–14]. In the present haus et al. identified PDGFRA mutations in IFPs; these case, the most important differential diagnosis was that of mutations had previously been detected only in GISTs an atypical GIST, because of CD117-negativity. However, . The presence of PDGFRA mutations provides strong because the present case was negative not only for CD117 evidence of clonal proliferation and suggests that IFPs but also for DOG-1, the possibility of the lesion being a have a neoplastic nature. To date, IFPs are considered GIST was less than 5% . true neoplastic lesions rather than reactive lesions . In 2012, Huss S et al. revealed that approximately 55% of IFPs have PDGFRA mutations and that most non-mutated IFPs are small lesions. To explain the existence of non-mutated IFPs exist, they proposed two hypotheses: (i) the low ratio of tumor cells in small lesions leads to false-negative results in mutational analysis; and (ii) mutational analysis can be negative because small lesions do not have oncogenic mutations and remain ‘pre-IFP,’ but once the PDGFRA mutation occurs, the lesions start growing and evolving to- wardsIFPs. In the present case, despite the large size of the lesion, PDGFRA mutations were not detected. Thus, the mechanism by which some IFPs occur and grow in the absence of PDGFRA mutations remains unclear. Although IFPs are generally considered benign, nonin- vasive lesions [1, 2], few cases have been observed to invade the muscularis propria layer . With regard to gastric IFPs, only one invasive case was described in 2015 . Here, we described a second case of an inva- Fig. 3 Macroscopic findings. The resected specimen revealed circumferential wall thickening of the prepyloric antrum (red line: cut sive gastric IFP. In the present case, spindle tumor cells line). Cut-section reveals thickening of the submucosal layer and the invaded the muscularis propria layer and also prolifer- muscularis propria layer (red square: A cut surface of the resected ated in the subserosal layer. These findings imply that specimen shown in Fig. 4a) IFPs might occasionally behave as locally aggressive Harima et al. BMC Gastroenterology (2018) 18:74 Page 4 of 5 Fig. 4 Microscopic findings. a Histopathological view through a low-power microscope. b-e Histopathological view through a medium-power microscope. Microscopic findings reveal spindle cell proliferation and infiltration of lymphocytes and plasma cells in the submucosal layer. Cells invading the muscularis propria layer (arrows) and extending to the subserosal layer (arrowheads) neoplasms with infiltrative growth patterns and may lesion shown on CT corresponded to the tumor invasion exhibit local recurrence after inadequate resection. Al- observed in the subserosal layer. For such cases, surgical though endoscopic treatment is typically indicated for treatment is recommended even with a preoperative diag- IFPs , when a lesion invades the muscularis propria nosis of IFP. layer, this treatment strategy can be inadequate. Indeed, a case of local recurrence after endoscopic removal has Conclusion been reported . In the present case, a hyper-enhancing In conclusion, we present a second case report of an lesion in the subserosa of the gastric antrum was detected invasive gastric IFP. Based on the present case, IFPs on preoperative CT. Comparing CT findings with histo- might be considered not only neoplastic but also poten- pathological findings, the subserosal hyper-enhancing tially invasive lesions. If the invasive characteristics of Fig. 5 Immunohistochemical findings. Immunohistochemical findings revealing spindle cells stained positive for CD34 and smooth muscle actin but negative for CD117, DOG-1 and S100 protein. The Ki-67 labeling index was less than 1%. Scattered mast cells stained positive for CD117, but the spindle cells stained negative. Adipose tissue engulfed by the lesion stained positive for S100 protein, but the spindle cells stained negative Harima et al. BMC Gastroenterology (2018) 18:74 Page 5 of 5 IFPs are observed in further larger studies, the treatment 8. Helwig EB, Ranier A. Inflammatory fibroid polyps of the stomach. Surg Gynecol Obstet. 1953;96:335–67. strategy should be carefully considered to avoid inad- 9. Akbulut S. Intussusception due to inflammatory fibroid polyp: a case report equate treatment. and comprehensive literature review. World J Gastroenterol. 2012;18:5745–52. 10. Saritaş Ü, Üstündağ Y, Gedıkoğlu G. Successful endoscopic treatment of huge Abbreviations gastric inflammatory fibroid polyp. Turk J Gastroenterol. 2011;22:224–6. CT: Computed tomography; DOG-1: Discovered on gastrointestinal stromal 11. Miettinen M, Sobin LH, Sarlomo-Rikala M. Immunohistochemical spectrum tumor-1; GIST: Gastrointestinal stromal tumor; IFP: Inflammatory fibroid polyp; of GISTs at different sites and their differential diagnosis with a reference to IMT: Inflammatory myofibroblastic tumor; PDGFRA: Platelet-derived growth CD117 (KIT). Mod Pathol. 2000;13:1134–42. factor receptor alpha 12. Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, Muhammad Tunio G, Matsuzawa Y, Availability of data and materials Kanakura Y, Shinomura Y, Kitamura Y. Gain-of-function mutations of c-kit in All data are contained within the manuscript. human gastrointestinal stromal tumors. Science. 1998;279:577–80. 13. Sreevathsa MR, Pipara G. Gastric schwannoma: a case report and review of Authors’ contributions literature. Indian J Surg Oncol. 2015;6:123–6. HH drafted the manuscript. TK diagnosed the present case as an 14. Makhlouf HR, Sobin LH. Inflammatory myofibroblastic tumors (inflammatory inflammatory fibroid polyp upon histopathological examination and pseudotumors) of the gastrointestinal tract: how closely are they related to performed molecular genetic analysis. FH, YM, KS, TI, KT and IS critically inflammatory fibroid polyps? Hum Pathol. 2002;33:307–15. revised the manuscript for important intellectual content. All authors read 15. Nishida T, Blay JY, Hirota S, Kitagawa Y, Kang YK. The standard diagnosis, and approved the final manuscript. treatment, and follow-up of gastrointestinal stromal tumors based on guidelines. Gastric Cancer. 2016;9:3–14. Ethics approval and consent to participate 16. Wysocki AP, Taylor G, Windsor JA. Inflammatory fibroid polyps of the Not applicable. duodenum: a review of the literature. Dig Surg. 2007;24:162–8. 17. Shimer GR, Helwig EB. Inflammatory fibroid polyps of the intestine. Am J Consent for publication Clin Pathol. 1984;81:708–14. Written informed consent was obtained from the patient before publication 18. Hirasaki S, Matsubara M, Ikeda F, Taniguchi H, Suzuki S. Gastric inflammatory of this case report. fibroid polyp treated with helicobacter pylori eradication therapy. Intern Med. 2007;46:855–8. Competing interests 19. Huss S, Wardelmann E, Goltz D, Binot E, Hartmann W, Merkelbach-Bruse S, The authors declare that they have no competing interests. Büttner R, Schildhaus HU. Activating PDGFRA mutations in inflammatory fibroid polyps occur in exons 12, 14 and 18 and are associated with tumour localization. Histopathology. 2012;61:59–68. Publisher’sNote 20. Tajima S, Koda K. Locally infiltrative inflammatory fibroid polyp of the ileum: Springer Nature remains neutral with regard to jurisdictional claims in report of a case showing transmural proliferation. Gastroenterol Rep (Oxf). published maps and institutional affiliations. 2016; https://doi.org/10.1093/gastro/gow019. 21. Lee JH, Yoo JS, Jung HY, Kim HM, Ryu H, Cho MY, Kim HS. A case of Author details invasion of Muscularis Propria of gastric inflammatory fibroid polyp. Korean Department of Gastroenterology, Ube Industries Central Hospital, 750 J Helicobacter Up Gastrointest Res. 2015;15:254–7. Nishikiwa, Ube, Yamaguchi 755-0042, Japan. Department of Pathology, 22. Mavrogenis G, Herin M, Natale MD, Hassaini H. Resection of a gastric fibroid Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, inflammatory polyp by means of endoscopic submucosal dissection: how Ube, Yamaguchi 755-8505, Japan. Department of Cancer Screening Center, deep is deep enough? Ann Gastroenterol. 2016;29:380. Ube Industries Central Hospital, 750 Nishikiwa, Ube, Yamaguchi 755-0042, 23. Zinkiewicz K, Zgodzinski W, Dabrowski A, Szumilo J, Cwik G, Wallner G. Japan. Department of Surgery, Ube Industries Central Hospital, 750 Recurrent inflammatory fibroid polyp of cardia: a case report. World J Nishikiwa, Ube, Yamaguchi 755-0042, Japan. Department of Gastroenterol. 2004;10:767–8. Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan. Received: 17 June 2017 Accepted: 24 May 2018 References 1. Stolte M, Finkenzeller G. Inflammatory fibroid polyp of the stomach. Endoscopy. 1990;22:203–7. 2. 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Published: May 31, 2018