# An Update on Clinicopathological and Molecular Features of Plexiform Fibromyxoma

Authors: Hsuan-An Su; Hsu-Heng Yen; Chih-Jung Chen
Journal: Canadian Journal of Gastroenterology and Hepatology
 (2019)

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## Abstract

Plexiform fibromyxoma is a rare and newly described gastric mesenchymal tumor with only 121 reported cases in the literature. Our understanding of plexiform fibromyxoma requires updating since the first case has been reported by Takahashi et al. 12 years ago. The present review summarized reported cases in the literature, and both clinical and pathological aspects of plexiform fibromyxoma were comprehensively discussed. Plexiform fibromyxoma usually causes nonspecific or bleeding signs or symptoms, and therefore clinical recognition of the disease is challenging. Plexiform fibromyxoma is of benign nature without any metastasis or recurrence reported, and more conservative surgical treatment should be considered.


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## Body

## 1. Introduction

Plexiform fibromyxoma (PF), also known as plexiform angiomyxoid myofibroblastic tumor (PAMT), was first described in 2007 by Takahashi et al. This rare tumor of mesenchymal origin is typically seen in the stomach and shows clinically benign behavior. As implied by the name, it features a plexiform cellular architecture of a myofibroblastic nature, encircled by a myxoid intercellular matrix with rich vasculature [1].To date, only 121 cases have been reported in the literature with a designation of PF or PAMT; the clinical features of reported cases are summarized in Table1. Specious case studies were published before the Takahashi’s first report in 2007, terming the condition “gastric fibromyxoma,” “gastric myxoma,” or “fibromyxoangioma” [2–8], but these are not included in the present review because the diagnoses could not be ascertained by immunohistochemical staining despite the similarity of the clinical features. Many cases have been reported since Takahashi first defined the entity 12 years ago; however, as new cases emerge, many facts about PF require updating, including the terminology, epidemiological data, various clinical presentations, diagnosis, diverse strategy on treatment, and prognosis. Correct updated information will help in the clinical recognition of the disease and improve the outcomes of treatments. The aim of this review is to provide a comprehensive updating of PF including the published cases to summarize what we know about PF, to identify what we still need to investigate, and to achieve consensus on all aspects of this disease. Hence, we present a review of the published cases in the literature and discuss clinically significant issues about PF.Table 1
Clinical features of cases reported as PF or PAMT in the literature.
No Year Author Population Age Sex Clinical Presentation Ulcer Location Size (cm) Diagnosis Treatment Prognosis 1[1] 2007 Takahashi Japan 50 M acute abdominal pain (perforation) + pyloric antrum 4 × 4 × 2.5 PAMT distal gastrectomy NA  2[1] 2007 Takahashi Japan 68 M incidental - pyloric antrum 4.5 × 3.5 × 3.0 PAMT partial gastrectomy uneventful for 12 months  3[17] 2008 Galant Belgium 61 M hematemesis erosion antrum 3.7 PAMT partial gastrectomy uneventful for 6 months  4[18] 2008 Rau Germany 50 F morning nausea + antrum 1.9 × 1.8 × 0.8 PAMT Median laparotomy and local excision No recurrence for 3 months  5[9] 2008 Yoshida USA 19 F mass in the stomach - antrum 4.5 × 3.5 × 3.0 PAMT distal gastrectomy uneventful for 9 months  6[9] 2008 Yoshida USA 46 M upper gastrointestinal bleeding + antrum 3.5 PAMT distal gastrectomy uneventful for 4 months  7[11] 2009 Miettinen USA 38 F upper gastrointestinal bleeding, ulcer + antrum, lesser curvature 3 × 2 PF distal gastrectomy lost f/u  8[11] 2009 Miettinen USA 62 M progressive weight loss for months - antrum, pyloric 4 × 4 PF partial gastrectomy, omentectomy lost f/u  9[11] 2009 Miettinen USA 75 F unknown + antrum, serosa 5 PF subtotal gastrectomy died of unknown cause, 2 months  10[11] 2009 Miettinen USA 65 F weight loss, gastric ulcer + antrum, lesser curvature, duodenal bulb 5 × 4.5 × 2.5 PF partial gastrectomy died of unknown cause, 14.5 years  11[11] 2009 Miettinen USA 33 M anemia, weakness + antrum, anterior wall 5.5 × 3.5 × 3.5 PF 50% distal gastrectomy alive without disease for 19.7 years  12[11] 2009 Miettinen USA 43 M gastrointestinal bleeding + antrum, near pylorus 5.5 × 4.5 × 4.5 PF partial gastrectomy alive without disease for 18.4 years  13[11] 2009 Miettinen USA 56 F unknown - pylorus, duodenal bulb 5.5+3 PF partial gastrectomy alive without disease for 19.9 years  14[11] 2009 Miettinen USA 50 M gastric outlet obstruction - antrum, duodenal bulb 7 × 6 × 6 PF distal gastrectomy died of unknown cause, 25.5 years  15[11] 2009 Miettinen USA 21 M syncope, anemia + antrum, prepyloric, duodenal bulb 9 × 6 × 5 PF antrectomy, B1-reconstruction alive with unknown status for 22 years  16[11] 2009 Miettinen USA 16 F hematemesis + antrum, pylorus 10 × 9 × 6 PF distal gastrectomy alive with unknown status for 3 years  17[11] 2009 Miettinen USA 30 F nonhealing gastric ulcer + antrum 10 × 9 × 6 PF distal gastrectomy alive without disease for 9 years, alive with unknown status for 24 years  18[11] 2009 Miettinen USA 7 F emesis, diarrhea, protruding abdominal mass - antrum, pylorus, duodenal bulb 15 × 11 × 8 PF excision of tumor, gastric wall resection at the tumor attachment lost f/u  19[19] 2009 Pailoor Malaysia 23 F melena + antrum 8.0 × 4.0 PAMT partial gastrectomy uneventful for 2 months  20[20] 2010 Sing South Africa (Indian) 35 F cushingoid appearance, amenorrhea - pyloro-antral region, anterior wall of the greater curvature 4 × 3 × 2 PAMT exploratory laparotomy and wide local excision uneventful for 12 months  21[10] 2010 Takahashi Japan 23 M abdominal pain, abdominal discomfort, melena + antrum, duodenal bulb 14 × 14 × 7 PAMT partial gastrectomy uneventful for 12 months  22[21] 2010 Tan Australia (Filipino) 34 M abdominal mass, abdominal discomfort, decreased appetite (perforation) + antrum 3.5 × 3.4 × 2.5 PAMT distal gastrectomy uneventful for 2 months  23[22] 2010 Wang China 54 F abdominal distension, heartburn, hiccup, regurgitation, loss of appetite erosion fundus 1.5 × 1.2 PAMT endoscopic resection uneventful for 6 months  24[23] 2010 Cooper USA 64 M epigastric pain NA antrum 4.0 × 2.0 PAMT laparoscopic excision uneventful for 3 years  25[24] 2010 Cui China 54 F abdominal distension, decreased appetite erosion fundus 0.8 PAMT NA NA  26[14] 2011 Kim Korea 52 M dyspepsia + antrum 3.5 × 2.3 PAMT laparoscopic wedge resection uneventful for 5 months  27[25] 2012 Kang Korea 47 M incidental + mid body, posterior wall and greater curvature 3 × 2 PAMT wedge resection uneventful for 6 years  28[25] 2012 Kang Korea 63 F incidental + lower body, greater curvature 2.2 × 1.6 PAMT endoscopic resection uneventful for 1 month  29[26] 2012 Schulz Germany 59 M heartburn, upper abdominal pain + pylorus 1.5 PAMT combined laparoscopic endoscopic local resection NA  30[27] 2012 Cai China 32 M incidental NA antrum  PF distal gastrectomy NA  31[27] 2012 Cai China 47 F upper abdominal pain NA antrum  PF radical distal gastrectomy NA  32[28] 2012 Wang China 12 M gastrointestinal bleeding NA antrum  PF partial gastrectomy uneventful for 84 months  33[29] 2012 Miettinen USA 49 F NA NA antrum 3.5 × 2.5 × 2.5 PF wedge resection NA  34[30] 2012 Li China 47 F epigastric discomfort, abdominal pain - antrum 5 × 3 × 2 PAMT laparoscopic distal gastrectomy uneventful for 1.5 years  35[31] 2012 Bi China 31 M Abdominal pain - Antrum 8.0 PAMT NA NA  36[31] 2012 Bi China 47 F Abdominal pain + Antrum 4.5 PAMT NA NA  37[31] 2012 Bi China 42 F Abdominal distension - Antrum 4.6 PAMT NA NA  38[32] 2013 Kao China 53 F Abdominal distension, abdominal pain, nausea, acid regurgitation NA NA NA PAMT NA NA  39[33] 2014 Baek Korea 38 F incidental + upper body, posterior wall and greater curvature 3.5 × 2.3 PAMT wedge resection uneventful for 6 months  40[34] 2014 Duckworth USA 16 F chest pain, shortness of breath, finger numbness NA posterior mediastinum near the esophagus at the level of the carina 3.2 PF thoracoscopic resection uneventful for 14 months  41[34] 2014 Duckworth USA 11 F severe iron-deficiency anemia + pylorus 3.5 PF laparoscopic distal gastrectomy uneventful for 15 months  42[35] 2014 Ikemura Japan 27 F epigastric pain, melena, anemia + antrum of the lesser curvature side 4.6 × 3.0 × 2.8 PAMT partial gastrectomy uneventful for 40 months  43[36] 2014 Lee Hong Kong (Filipino) 42 F abdominal pain, fever, anemia (fistulating abscess formation) + antrum 12.9 × 11.9 × 10.6 PF distal gastrectomy uneventful for 3 weeks  44[37] 2014 Li Chinese 32 M incidental - antrum, anterior wall 3.4 × 3.0 PAMT partial gastrectomy uneventful for 3 years  45[38] 2014 Sakamoto Japan 60 M epigastralgia + antrum 2 PF laparoscopic partial gastrectomy uneventful for 12 years  46[39] 2014 Li China 73 F upper abdominal pain NA antrum  PF partial gastrectomy NA  47[40] 2014 Tian China 64 M upper abdominal discomfort - antrum 3.3 × 2.5 PF distal gastrectomy uneventful for 6 months  48[41] 2015 Banerjee India 19 F dull upper abdominal pain, lump in the right hypochondrium + duodenum (D1), posterior 13.8 × 8.6 PAMT distal gastrectomy, proximal duodenectomy, Billroth II gastrojejunostomy uneventful for 6 months  49[42] 2015 Fassan Italy (Caucasian) 55 F cholelithiasis NA gallbladder 1 PF laparoscopic cholecystectomy no postsurgical complication  50[43] 2015 Lu China 26 F progressive abdominal distension, nausea, vomiting, melena NA antrum NA PAMT distal gastrectomy NA  51[44] 2015 Ni China 21 F melena, dizziness, anemia + antrum, greater curvature 4 × 3 × 3 PF distal gastrectomy uneventful for 3 years  52[45] 2015 Wei China 50 F upper abdominal pain NA antrum  PF subtotal gastrectomy uneventful for 3 months  53[46] 2015 Yue China 34 M upper abdominal pain NA antrum  PF distal gastrectomy uneventful for 24 months  54[46] 2015 Yue China 50 F upper abdominal pain NA antrum  PF subtotal gastrectomy uneventful for 3 months  55[47] 2015 Xu China 50 F abdominal pain NA gastric body 3 × 2 PAMT Total gastrectomy uneventful for 6 months  56[15] 2016 Dixit India 51 F abdominal pain, vomiting, weight loss (with synchronous ovarian neoplasms) + pylorus 8.4 × 6.1 × 5 PAMT distal gastrectomy no postsurgical complication  57[48] 2016 Inoue Japan 36 F epigastric pain, anemia + antrum 2.5 × 2.2 × 2.0 PF radical resection with laparoscopic endoscopic cooperative surgery uneventful for unknown period  58[49] 2016 Jonaitis Lithuania (Caucasian) 28 F epigastric pain associated with meals, iron-deficiency anemia, weight loss + antrum, anterior wall 3 PAMT partial gastrectomy of the Billroth I type follow-up not reported; gastroduodenal anastomositis, resolved with conservative treatment  59[50] 2016 Kane USA (Vietnamese) 28 F acute, severe abdominal pain and worsening anemia + antrum 5.5 × 3.5 PF distal gastrectomy with a Roux-en-Y gastrojejunostomy dyspepsia 23 months thereafter, otherwise uneventful for 23 months (only moderate stenosis of anastomosis)  60[51] 2016 Morris USA 9 F intermittent abdominal pain, nausea, vomiting, weight loss + antrum, posterior 5 PF laparotomic anterior gastrotomy with tumor resection uneventful for 6 months  61[52] 2016 Nagahisa Japan 39 M epigastric pain + antrum, anterior wall 3.5 × 3 PAMT partial gastrectomy with laparoscopic endoscopic cooperative surgery uneventful for 9 months  62[53] 2016 Quero Italy 47 M syncope, regurgitation, epigastric discomfort + antrum 6.5 PAMT distal gastrectomy uneventful for 10 months  63[54] 2016 Spans Belgium 19 M NA NA antrum 5.5 PF NA NA  64[54] 2016 Spans Belgium 65 F NA NA antrum 4.3 × 3.0 × 1.7 PF NA NA  65[54] 2016 Spans Belgium 58 F NA NA antrum NA PF NA NA  66[54] 2016 Spans Belgium 51 F NA NA antrum 9.0 × 8.5 × 5.5 PF NA NA  67[54] 2016 Spans Belgium 63 F NA NA jejunum, proximal 3.5 × 3.0 × 2.0 PF NA NA  68[54] 2016 Spans Belgium 76 F NA NA stomach 4 PF NA NA  69[54] 2016 Spans Belgium 62 F NA NA stomach NA PF NA NA  70[54] 2016 Spans Belgium 30 F NA NA stomach 2 PF NA NA  71[54] 2016 Spans Belgium 28 M NA NA gastric body 10 × 6 × 3 PF NA NA  72[54] 2016 Spans Belgium 44 F NA NA stomach NA PF NA NA  73[54] 2016 Spans Belgium 18 F NA NA antrum 4.5 × 3.5 × 2.7 PF NA NA  74[54] 2016 Spans Belgium 19 F NA NA stomach 4.5 PF NA NA  75[54] 2016 Spans Belgium 46 M NA NA antrum 3.5 PF NA NA  76[54] 2016 Spans Belgium 29 M NA NA antrum 6.5 × 4.5 × 4.0 PF NA NA  77[54] 2016 Spans Belgium 36 F NA NA antrum 8 PF NA NA  78[54] 2016 Spans Belgium 47 F NA NA antrum 4.5 × 3.7 PF NA NA  79[55] 2016 Li China 11 M upper abdominal discomfort NA antrum  PF partial gastrectomy uneventful for 12 months  80[56] 2016 Li Chinese 44 F incidental - antrum 0.8 × 0.8 PAMT endoscopic submucosal dissection uneventful for 6 months  81[57] 2016 Zhang China 48 M upper abdominal pain NA antrum  PF partial gastrectomy uneventful for 12 months  82[16] 2017 Akai Japan 55 M incidental NA gastric angle 1.7 PAMT laparoscopic partial gastrectomy NA  83[58] 2017 Gonzalez-Cordero Spain 37 M upper gastrointestinal bleeding with hemodynamic instability NA antrum 5.8 × 5 × 4 PF antrectomy uneventful postoperatively  84[59] 2017 Hu China 26 M abdominal distension + fundus 1.8 PF endoscopic submucosal dissection uneventful for 32 months  85[59] 2017 Hu China 31 F abdominal distension - antrum 2.5 PF endoscopic submucosal dissection NA  86[59] 2017 Hu China 72 F abdominal distension + antrum 7 PF distal subtotal gastrectomy uneventful for 56 months  87[59] 2017 Hu China 59 F abdominal distension + antrum 2.5 PF distal subtotal gastrectomy uneventful for 68 months  88[59] 2017 Hu China 52 M incidental + fundus 1.2 PF endoscopic submucosal dissection uneventful for 24 months  89[59] 2017 Hu China 59 F melena, anemia + antrum 3 PF distal subtotal gastrectomy uneventful for 40 months  90[59] 2017 Hu China 48 M abdominal distension + antrum 3 PF distal subtotal gastrectomy uneventful for 95 months  91[59] 2017 Hu China 58 M abdominal pain + antrum 3.5 PF distal subtotal gastrectomy uneventful for 34 months  92[59] 2017 Hu China 46 M abdominal distension - antrum 4 PF distal subtotal gastrectomy uneventful for 65 months  93[59] 2017 Hu China 40 F melena, anemia + antrum 3.8 PF distal subtotal gastrectomy uneventful for 70 months  94[60] 2017 Kawara Japan 66 M gastric tumor - antrum 4 × 3 PF endoscopic submucosal dissection uneventful for 12 months  95[61] 2017 Kim Korea 51 M incidental - antrum, lesser curvature 2.0 × 1.5 PAMT laparoscopic gastric wedge resection uneventful for 3 years  96[62] 2017 Liang China 11 M right epigastric discomfort with episodic pain - pylorus, anterior 17 × 10.5 × 5 PAMT partial gastrectomy uneventful for 12 months  97[63] 2017 Moris USA 63 M upper gastrointestinal bleeding, anemia, melena NA duodenum 3 × 3 PF pancreas-preserving duodenectomy of the first 2 portions uneventful for 20 months, complicated only by a low output pancreatic skin fistula totally drained after 4 months  98[64] 2017 Qi China 42 M melena + antrum, greater curvature 3 × 2 × 1.8 PF laparoscopic partial gastrectomy uneventful for 12 months  99[64] 2017 Qi China 66 M epigastric pain - antrum, greater curvature 2 × 1 × 0.7 PF endoscopic submucosal dissection uneventful for 12 months  100[65] 2017 Szurian Austria (Caucasian) 16 F anemia, nausea + antrum, anterior wall 6.5 PF distal gastrectomy and retrocolic gastrojejunostomy (Billroth II) pulmonary embolism postoperatively and discharged on day 9, otherwise uneventful for 6 months  101[65] 2017 Szurian Austria 34 M epigastric discomfort, flatulence + pylorus 1.6 PF distal gastrectomy and retrocolic gastrojejunostomy (Billroth II) uneventful for 16 months  102[66] 2017 Wambura Tanzania (Tanzanian) 41 F anemia, epigastric discomfort, melena + antrum 5.5 × 5 PF distal gastrectomy with Roux-en-Y gastrojejunostomy uneventful for 12 months  103[67] 2017 Yang China 50 F abdominal pain - gastric upper body 15 × 10 PF laparoscopic partial gastrectomy uneventful for 2 years  104[68] 2017 Zhou China 51 M epigastric discomfort, heartburn NA antrum, greater curvature 4 × 3 × 1.8 PF total resection uneventful for 15 months  105[69] 2017 Wang China 66 F Abdominal pain, melena, dizziness, abdominal distension erosion Antrum 3 PF NA NA  106[70] 2018 Djurić Serbia 14 M iron-deficiency anemia, fatigue, epigastric pain NA Antrum NA PF partial gastrectomy NA  107[71] 2018 Jang Korea 47 F heartburn - pylorus 2.5 × 2.0 PF antrectomy with Billroth I anastomosis uneventful for 7 months  108[72] 2018 Rohit USA 81 F weight loss of 3.6 kg in 3 months NA gastric body, lesser curvature 2.7 × 2.4 PF non-surgical follow-up symptom resolved 3 months after  109[73] 2018 Wang Chinese 52 F upper abdominal pain + mid gastric body, greater curvature 1.5 × 1.0 × 1.0 PF gastroscope-assisted laparoscopic wedge resection uneventful for 10 months  110[74] 2018 Zhang China 31 F hematochezia, syncope, upper gastrointestinal bleeding, anemia + upper segment of jejunum 1.2 × 1.0 PF exploratory laparotomy and resection of the upper jejunal tumor and local intestine uneventful for 3 years  111 2019 Wu Taiwan (Taiwanese) 59 F acid regurgitation - antrum 2 × 1.2 × 1.2 PF partial gastrectomy uneventful for 20 months  112[75] 2019 Fukazawa Japan 14 F abdominal pain, hematemesis + antrum  PF partial gastrectomy uneventful for 16 months  113[76] 2019 Banerjee USA 65 M anemia, early satiety, dyspepsia, hematemesis + antrum 5 × 2.3 PF wedge resection NA  114[77] 2019 Lai USA 21 F NA NA gastric body  PF partial gastrectomy 4 years  115[77] 2019 Lai USA 42 F NA + antrum  PF partial gastrectomy 4 years  116[77] 2019 Lai USA 79 F NA NA antrum  PF partial gastrectomy 1 year  117[77] 2019 Lai USA 33 M NA NA antrum  PF partial gastrectomy 11 years  118[77] 2019 Lai USA 60 M NA NA antrum  PF partial gastrectomy 1 year  119[77] 2019 Lai USA 77 M NA NA gastric body  PF partial gastrectomy 2 years  120[77] 2019 Lai USA 45 M NA NA antrum  PF only endoscopic biopsy 0.2 years  121[78] 2019 Li China 5 M pale complexion NA antrum 8.2 × 7.5 × 5.5 PF distal gastrectomy 36 months


## 2. History and Nomenclature

Takahashi et al., in 2007, reported 2 cases of gastric plexiform fibromyxoma using the term “plexiform angiomyxoid myofibroblastic tumor (PAMT)” because the condition was morphologically distinct from other gastrointestinal mesenchymal tumors due to its bland spindle cells in a plexiform pattern, myxoid intercellular matrix with hypervascularity, and myofibroblastic nature [1]. In 2008, Yoshida et al. reported 2 additional cases and modified the designation to “plexiform angiomyxoid tumor,” deleting the term “myofibroblastic” due to the evident differentiation into smooth muscle cells that had been absent from the previous report and emphasizing the differentiating potential of myofibroblasts into smooth muscle cells. Yoshida et al. also further characterized the spectrum of fibrous, fibromyxoid, and myxoid stromal patterns of the disease [9]. Takahashi et al. continued to use the designation “myofibroblastic,” because this presentation was seen in the majority of cases [10].In 2009, Miettinen et al. described 12 cases of the disease and designated the tumors as “plexiform fibromyxoma” simply due to their cellular architecture and fibromyxoid nature [11]. They also identified previously reported diseases from 1959 to 1986 that shared similar characteristics with PF by the names “gastric fibromyxoma” or “gastric myxoma” [2, 5, 6, 8, 12]. In 2010, Takahashi et al. argued that the designation “plexiform fibromyxoma” could lead to confusion, since “gastric fibromyxoma” or “gastric myxoma” describes a relatively narrow entity of purely fibroblastic tumors that present a different immunoprofile from that of PAMT; consequently, those cases reported as “gastric fibromyxoma” or “gastric myxoma” might actually differ from PAMT and would require further pathological or immunological evidence [10]. However, the WHO classification of tumors of the digestive system later adopted the term “plexiform fibromyxoma” in 2010 to designate the entity [13]. Since then, both “plexiform fibromyxoma” and “plexiform angiomyxoid myofibroblastic tumor” have both been used as the nomenclature of the disease, with controversy in the literature. Despite the nomenclature set by the WHO classification, many authors still preferred the term PAMT as a better description of both the histogenesis and histology of the tumor [14–16]. In the present review, 85 cases were designated as PF, while 36 were designated as PAMT.Sing et al. proposed that PF and PAMT are two related, but different, entities at two respective fibroblastic and myofibroblastic ends of a spectrum [20]. Yet, due to the generally close similarity of the two, Duckworth et al. considered the two to be a single entity with an acceptable range of histologic, immunohistochemical, and ultrastructural presentations [34]. By contrast, Sing et al. argued that PF occupies the “fibroblastic” end while PAMT occupies the fully differentiated “myofibroblastic” end of the spectrum, and that the size, female exclusiveness of PF, vascular invasion, and extragastric extension are distinguishable between the two, despite the similar location of occurrence and age of onset [20]. Immunohistochemically, Sing et al. suggested that desmin and caldesmon could be used to distinguish PAMT as it shows focally positive results, whereas PF shows negative results. However, on the grounds of the limited case numbers for PF and PAMT and that desmin and caldesmon were not specific for the myofibroblastic form only, we suggest that discrimination of the two designations is unnecessary. In the literature, the cases designated as PF and those as PAMT showed no significant difference in age of onset or mean tumor size and both had female predominance and extragastric involvement. Although vascular invasion had only been reported in PF cases, the number of cases with vascular invasion is very small.Since the WHO classification had designated the nomenclature PF for this entity, to avoid confusion in the literature, we suggest the use of PF in consideration of epidemiological surveillance and scientific communication purposes. The term PAMT literally describes the features of the disease in more detail, but PF could be viewed sensu lato as a broader nomenclature that covers the disease as well as other variants. We consider this to be acceptable, given that the disease is a spectrum with variations. The final designation or subsets under PF could be further categorized in the future after consideration of sufficient case numbers and advanced investigations.


## 3. Epidemiology

According to the 110 cases reported in the literature from 2007 to 2018, the frequency of PF is more than 9.17 cases per year worldwide. However, we feel this is an underestimate, because clinical recognition of the disease has only been increasing since 2007, and some cases are assumed to have been misidentified as gastrointestinal stromal tumors (GISTs) or other entities. Miettinen et al. estimated that the frequency of PF is 150 times lower than gastric GIST [11]; however, about 3,000 cases of gastric GIST are diagnosed yearly in the United States [79]. Therefore, we consider a proportion of 1:150 to be a rather conservative estimation and should be far smaller.The patient ages showed a broad range, from 5 to 81 years (mean age 43.17±18.00 years; median age 46 years). Most patients were middle-aged, with a peak around 30–60 years old. This age distribution of PF was in approximate accordance with previous reviews [10, 51]; however, the adult-to-child ratio was 8:1 by our estimation, unlike the 5:1 ratio stated by Morris’s [51] but more similar to the 7:1 ratio proposed by Fukuzawa’s in a recent systematic review [75]. The previous studies all reported a 1:1 male-female ratio for PF [10, 51, 59], although we found a slight female predominance, with male patients accounting for 43% and female patients for 57%.The races of patients were not provided in most of the studies; consequently, the countries of the studies were substituted for the ethnicity of the patients unless the ethnic information of the patients was given. In terms of regions, most cases were reported from East Asia (N=58; 47.9%), followed by North America (N=29; 24.0%), Europe (N=26; 21.5%), South-East Asia (N=4; 3.3%), South Asia (N=3; 2.5%), and Africa (N=1, 0.8%). In terms of countries, most cases were reported from China (N=41; 33.9%), followed by the United States (N=29; 24.0%), Belgium (N=17; 14.0%), Japan (N=10; 8.3%), and Korea (N=6; 5.0%). This distribution may not reflect the genuine epidemiological status of PF, since a higher frequency may result from a higher quality of healthcare and from a larger population. Nevertheless, it still suggests that PF is a worldwide disease with a predominance in East Asia.


## 4. Clinical Presentation

PF has a benign nature but is associated with hypervascularity; therefore, the clinical presentation can range from incidental findings to nonspecific gastrointestinal (GI) symptoms and further to severe GI hemorrhage. The typical presentation of PF is a nonspecific gastrointestinal complaint, such as abdominal pain, abdominal distension, and abdominal discomfort. Hemorrhagic gastrointestinal presentations are also commonly seen, with consequent GI bleeding-associated presentations like anemia, melena, and hematemesis [10, 36, 68, 74]. The available literature includes 121 cases, with clinical signs and symptoms available for 95 cases. The clinical presentations listed in Table 2 could be sorted into 3 categories, including abdominal signs or symptoms, bleeding signs or symptoms, and others. Most clinical presentations were abdominal signs or symptoms, mostly nonspecific, such as abdominal pain, abdominal distension, abdominal discomfort, abdominal mass, nausea, and heartburn. Many patients also presented with bleeding signs or symptoms, including anemia, melena, GI bleeding, and hematemesis. Severe hemorrhage leading to syncope [11, 53, 74] or hemodynamic instability [58] was also reported. Reflux symptoms might be present, with or without other complaints, and are likely to mask PF if presenting alone or with nonspecific complaints [22, 26, 68, 71, 80]. Among the cases that presented with reflux symptoms, only one tumor was located at the gastric fundus and might have been the cause of the symptoms [22]; other tumors were located at the gastric pylorus or antrum [26, 53, 68, 71, 80]. The likelihood that PF could directly or indirectly provoke reflux symptoms is doubtful, and the reflux symptoms were more likely to be concurrent with PF because of the high GERD prevalence worldwide. Ten cases were diagnosed incidentally, even with ulcerative PF lesions [25, 33, 59]; the size of incidentally diagnosed tumor ranged from 0.8 to 4.5 cm, and 4 tumors were located at gastric body, 1 was located at gastric fundus, and 5 were located at gastric antrum or pylorus [1, 16, 25, 27, 33, 37, 56, 59, 61]. Two cases with hemorrhagic perforation were reported by Takahashi et al. and Tan et al., with maximal tumor diameters of 4 and 3.5 cm, respectively [1, 21]. Other signs or symptoms at presentation included amenorrhea with cushingoid appearance in a 35-year-old female, but her symptoms were actually caused by polycystic ovary syndrome [20]. Chest pain with shortness of breath and finger numbness in a 16-year-old female was probably a result of a mass effect of the 3.2 cm PF in the mediastinum [34], while cholelithiasis was reported in a 55-year-old female with a PF in the gallbladder [42]. Fever was reported in a 42-year-old female with a fistulating abscess formation connecting the tumor and gastric lumen, suggesting possible infection sequelae of PF if left untreated [36]. The pathogenic association between these signs or symptoms and PF could not be proven; however, physicians are reminded of the nonspecific presentation of the disease. If a gastric neoplasm is clinically suspected, further endoscopic diagnostic intervention is indicated.Table 2
Reported clinical presentations of PF in the literature.
Clinical Presentation Count Percentage (%) Abdominal Signs or Symptoms  Abdominal pain 33 20.6 Abdominal distension 13 8.1 Abdominal discomfort 10 6.3 Abdominal mass 5 3.1 Nausea 5 3.1 Heartburning sensation 4 2.5 Acid regurgitation 4 2.5 Vomiting 4 2.5 Decreased appetite 3 1.9 Dyspepsia 2 1.3 Diarrhea 1 0.6 Early satiety 1 0.6 Gastric outlet obstruction 1 0.6 Hiccup 1 0.6  Bleeding Signs or Symptoms  Anemia 18 11.3 Melena 11 6.9 Gastrointestinal bleeding 7 4.4 Hematemesis 4 2.5 Syncope 3 1.9 Dizziness 2 1.3 Gastric ulcer 2 1.3 Fatigue 1 0.6 Hematochezia 1 0.6  Others  Incidental 10 6.3 Weight loss 7 4.4 Amenorrhea 1 0.6 Chest pain 1 0.6 Cholelithiasis 1 0.6 Cushingoid appearance 1 0.6 Fever 1 0.6 Finger numbness 1 0.6 Shortness of breath 1 0.6


## 5. Location

Although initially categorized as a gastrointestinal mesenchymal tumor [1], PF has been reported to occur at locations other than in the gastrointestinal tract. The locations of the tumors were reported in 120 cases. Most of the tumor locations were the gastric antrum (including pylorus and gastric angle, N=95; 79.2%), followed, in decreasing order, by gastric body (N=10; 8.3%), stomach (inside location unspecified, N=5; 4.2%), gastric fundus (N=4; 3.3%), duodenum (N=2; 1.7%), jejunum (N=2; 1.7%), gallbladder (N=1; 0.8%), and mediastinum (N=1; 0.8%). The tumors often involve the pylorus and extended into the duodenal bulbs, probably causing obstruction [10, 11, 71]. Therefore, despite its gastric predominance, PF does not exclusively occur in the stomach and is also not confined to the GI tract, as indicated by 114 gastric tumors and 6 extragastric tumors.


## 6. Endoscopic Findings/Macroscopic Pathological Findings

The size of the tumors, available in 98 cases, ranged from 0.8 to 17 cm in the maximal diameter, with an average size of 4.81±3.30 cm and a median size of 4.0 cm. Endoscopic visualization reveals that PFs are typically pink or reddish and glistening tumors, elastic in texture, and covered with ulcerative, erosive, or smooth mucosa. Endoscopic ultrasonography indicates that PFs are hypoechoic with mild heterogenicity. Macroscopic examination shows a classical PF appearance as a lobulated tan-white or grayish-whitish mass, gelatinous on the cut surface, cystic, with mucinous fluids, a multinodular or polypoidal growth pattern, unencapsulated, and with well-defined (but sometimes ill-defined) margins. Hemorrhage is commonly encountered. PFs mostly originate from the submucosa and muscularis propria, with extension ranging from the mucosa to the serosa, causing ulcer and/or perforation.The condition of the tumor surface was reported in 76 cases: 50 (65.8%) were ulcerated, 22 (28.9%) were nonulcerated, and 4 (5.3%) were covered with eroded mucosa. Ulceration or erosion of the tumor was significantly associated with hemorrhage-related signs or symptoms, as determined by Pearson’s chi-squared test (p<0.0001). The difference in tumor size between ulcerative or erosive lesions and nonulcerative lesions was not statistically significant, as calculated by an independent Student’s t-test (p=0.184).


## 7. Microscopic Findings

The signature of PF, as disclosed in the name PAMT, is the presence of bland ovoid to spindle cells arranged in irregular plexiform or multinodular pattern and separated by abundant myxoid and a variably collagenized extracellular background, interwoven with rich, arborizing, capillary-sized vasculature. The myxoid matrix is consistently Alcian blue positive. The tumor cells demonstrate monomorphous oval nuclei containing indistinct nucleoli and fine chromatin, surrounded by mildly eosinophilic cytoplasm with indistinct borders. Delicate and indistinct nucleoli and fine chromatin may be present. Cellular atypia and mitosis are both rare and are not seen in the majority of the cases. Microscopically, the tumor margin is infiltrative and unencapsulated; in 33 cases reporting the condition tumor margin, 20 were ill-defined and the rest were well-circumscribed. Necrosis was reported in the literature in only 2 cases: a 42-year-old female with fistulating abscess showed central necrosis as well as gas-fluids level [36], and a 31-year-old female with an ulcerative lesion exhibited only surface necrotic tissue coverage without central necrosis [74]. Some lymph nodes display enlargement with reactive changes [19, 67]. Vascular or lymphatic involvement was observed in 5 cases [11, 60].In all, 118 cases reported immunohistochemical profiles of the tumor with various markers (Table3). Immunohistochemical staining in most cases showed positive results for vimentin, smooth muscle actin (SMA), and muscle specific actin (MSA), indicating the fibroblastic, myofibroblastic, and smooth muscle cell natures of PF. Negative results for DOG-1, CD117 (KIT), CD34, S-100 protein, neurofilament, cytokeratin, epithelial membrane antigen (EMA), and ALK suggest that PF is a distinct disease entity from GIST, angiomyxoma, neurogenic tumor, sarcomatoid carcinoma, and inflammatory myofibroblastic tumor. Partial immunoreactive or focally positive results with desmin, caldesmon, and CD10, consistent with a partial or incomplete muscle immunophenotype, suggest possible myofibroblastic differentiation. Ki-67 staining commonly illustrates very low proliferation rates, mostly <2%, indicating a very low grade/indolent mesenchymal tumor; nevertheless, 5% [44, 74], 6% [25], 30% [77], and a vascular endothelial Ki-67 index up to 40% [49] have also been reported.Table 3
Pathological and immunohistochemical profiles of PF cases reported in the literature.
No Year Author Age Sex Ki-67 Vim SMA MSA DOG-1 CD117 CD34 Desmin Cald S-100 protein Calp EMA NF CK ER PR CD10 β-C ALK AE1/AE3 SNP C-KIT PDFGRA 1 2007 Takahashi 50 M <1% + + +  - - - +/- -   - -    -    - -  2 2007 Takahashi 68 M <1% + + +  - - - +/- -   - -    -    - -  3 2008 Galant 61 M  + +   - - -  -  -  4 2008 Rau 50 F 2%  + +  - +/- (focal) +/- (sporadic)  -        - -   - -  5 2008 Yoshida 19 F      - -   -  -   - - -     - -  6 2008 Yoshida 46 M <1%  + +  - - +/- (focal) + (partial) - + (partial)         -  - -  7 2009 Miettinen 38 F   + (8/10)  - - - - - (3/3) -       + (1/3), -(2/3)   - (3/3)  wt (3/3) wt (3/3) 8 2009 Miettinen 62 M    - - - - - 9 2009 Miettinen 75 F    - - - - - 10 2009 Miettinen 65 F    - - - - - 11 2009 Miettinen 33 M    - - - - - 12 2009 Miettinen 43 M    - - - - - 13 2009 Miettinen 56 F    - - - - - 14 2009 Miettinen 50 M    - - - - - 15 2009 Miettinen 21 M    - - - - - 16 2009 Miettinen 16 F    - - - - - 17 2009 Miettinen 30 F    - - - - - 18 2009 Miettinen 7 F    - - - - -  19 2009 Pailoor 23 F  + +   - - +/- (partial)  -  20 2010 Sing 35 F +  + +  - - + + - +    - + - - - -  21 2010 Takahashi 23 M  +  +  - -   -  - - -     -   - -  22 2010 Tan 34 M <2%  +   - - +  -            - -  23 2010 Wang 54 F <1% + +   - -   -  24 2010 Cooper 64 M   + + - - -   -  -      -  25 2011 Kim 52 M   +   -  +/- (partial)  -  26 2012 Kang 47 M 6%  +   - - -  -  - -  27 2012 Kang 63 F   +   - - -  -  -          wt wt  28 2012 Schulz 59 M <2%  +   - - -  -  - -      - -  29 2012 Cai 32 M   + +  - -   -  30 2012 Cai 47 F   + +  - -   -  31 2012 Wang 12 M   + + - - -   -  32 2012 Miettinen 49 F  + +   -           + (variably)  33 2012 Li 47 F <1%  +   - -  - -        - -  34 2012 Bi 31 M   + +        +  35 2012 Bi 47 F   + +  36 2012 Bi 42 F   + +    + +       + +  37 2014 Baek 38 F   +   - -   -  38 2014 Duckworth 16 F 1% (focally 8%)  +  - - - -  -  39 2014 Duckworth 11 F  + +   - - +  - +        - - -  40 2014 Ikemura 27 F Small Percentage  +   - - +/- (partial)       - - +  41 2014 Lee 42 F   + + - - - -  -        -  42 2014 Li 32 M <1% + +/- (partial)  - - - + (partial) + (partial) -        - -  43 2014 Sakamoto 60 M   -  - - -   -       -  44 2014 Li 73 F  + +   - -   -  45 2014 Tian 64 M   +  - - -  46 2015 Banerjee 19 F   - - - - - -  - -      -  47 2015 Fassan 55 F 0% + + +  - + -  -  -     -     - -  48 2015 Lu 26 F  + +  - - -  49 2015 Ni 21 F 5% + +  - - -   -  -  50 2015 Wei 50 F   +  -     -  51 2015 Yue 34 M   + + - - -   -  52 2015 Yue 50 F   + + - - -   -  53 2015 Xu 50 F <1% + +  - - -   -           -  54 2016 Dixit 51 F <1%  +   - -  - -        - -  55 2016 Inoue 36 F  56 2016 Jonaitis 28 F 40% (vascular endothelial Ki-67)  +    - -  -  57 2016 Kane 28 F   +  - - -   -       +/- (focal) -  -  58 2016 Morris 9 F   +  - - - +/- (focal)  - +   -   +/- (focal)  -  59 2016 Nagahisa 39 M   +   - -   -  60 2016 Quero 47 M  + +  - - - +/- (partial) +/- (partial) -  -     +/- (partial)  - +/- (focal) - wt wt  61 2016 Spans 19 M   +   - - -  -         -  62 2016 Spans 65 F   +   - - -  -  -       -  63 2016 Spans 58 F   +   - - -  -  -       -  64 2016 Spans 51 F   +     +/- (focal)  -  65 2016 Spans 63 F   +     +/- (focal)  -  66 2016 Spans 76 F   +/- (focal)     +  67 2016 Spans 62 F        +/- (focal)  -  68 2016 Spans 30 F   +     +  69 2016 Spans 28 M   +    - +/- (focal)  +         -  70 2016 Spans 44 F       +/- (focal) +  -  71 2016 Spans 18 F   +/- (focal)     +/- (focal)  72 2016 Spans 19 F   +   - - -  -  -  73 2016 Spans 46 M   +    - -  -  74 2016 Spans 29 M   +   - - -  -         -  75 2016 Spans 36 F   +   - - -  -  76 2016 Spans 47 F   +   - - -  -  77 2016 Li 11 M   +   - -  +  78 2016 Zhang 48 M  + +  - - -   -  79 2016 Li 44 F  + -   - + -  -  80 2017 Akai 55 M  + -   - + -  -  81 2017 Gonzalez-Cordero 37 M    + - - - +  -       +  -  82 2017 Hu 26 M  + +  - - +/- (negative/focal) +/- (patchy, 5/10) +/- (patchy, 6/10) -     - + (patchy/ diffusely at nucleus, 6/10) + (patchy, 5/10)  -   wt (5/10) wt (5/10) 83 2017 Hu 31 F  + +  - - -     -  - 84 2017 Hu 72 F  + +  - - -     -  - 85 2017 Hu 59 F  + +  - - -     -  - 86 2017 Hu 52 M  + +  - - -     -  - 87 2017 Hu 59 F  + +  - - -     -  - 88 2017 Hu 48 M  + +  - - -     -  - 89 2017 Hu 58 M  + +  - - -     -  - 90 2017 Hu 46 M  + +  - - -     -  - 91 2017 Hu 40 F  + +  - - -     -  -  92 2017 Kawara 66 M 2%  + (focal) + (focal) - - - - - - + (focal)      -  93 2017 Kim 51 M   +   -  94 2017 Liang 11 M   + (focal)  - - - - + (focal) - + (focal)        -  95 2017 Moris 63 M   +  - - - -  -            wt wt  96 2017 Qi 42 M 1% + +  - - - + (partial) + (partial) - + (partial) -     -   -  97 2017 Qi 66 M 1% + +  - - -   -  -     -   -  98 2017 Szurian 16 F   +  - - - + (focal) + (focal) -       +/- (focal) - -   - -  99 2017 Szurian 34 M   +  - - - - - -       +/- (focal) - -  100 2017 Wambura 41 F   +  - -  -  -       -  101 2017 Yang 50 F 3% + +  - - + -  -  -  -   - - -  102 2017 Zhou 51 M 1%  +  - - - -  -          -  - -  103 2018 Djurić 14 M   +  - - - + (focal)  -   -      -  104 2018 Jang 47 F   +  - - - + (focal)  -  -     + (focal)  105 2018 Rohit 81 F   + (patchy)  - - - -  -          -  106 2018 Wang 52 F 1%  +  - - - -  +  -     +  107 2018 Zhang 31 F <5%  +  - - - -  -  -  -   + (partial)  108 2019 Wu 59 F   +  - - - +/- (focal)  -  -      - -  109 2019 Fukazawa 14 F 2% + +  - - - -  -         -  110 2019 Banerjee 65 M   +  - - -   -  111 2019 Lai 21 F   +   - - -  -  112 2019 Lai 42 F     - - - -  -  113 2019 Lai 79 F 30%  +  - - - +/- (focal)  -  114 2019 Lai 33 M   +   - - +/- (focal)  -  115 2019 Lai 60 M   +  - - - + (focal)  -  116 2019 Lai 77 M   +  - - -  117 2019 Lai 45 M   +  - - -  118 2019 Li 5 M  + +  - - - -  -        - †Abbreviations: Dx, diagnosis; Vim, vimentin; Cald, caldesmon; Calp, calponin; NF, neurofilament; CK, cytokeratin; β-C, β-catenin; SNP, synaptophysin; wt, wild type.Significantly or diffusely reactive immunostainings included vimentin (100%), SMA (89.1%), and MSA (90%); however, these are nonspecific markers for mesenchymal and myofibroblastic lineages and were therefore sensitive but specific for diagnosing PF. Equivocal staining results were demonstrated for desmin, caldesmon, calponin, CD10, estrogen receptor (ER), and progesterone receptor (PR). Desmin and caldesmon are more specific markers for muscular lineage toward terminal muscle cell differentiation and exhibited limited and focal reactive results in PF, consistent with the proposed myofibroblastic spectrum of PF cell development.Calponin is a nonspecific muscular marker for differentiated smooth muscle cells, while CD10 indicates cells with fibroblastic traits. The calponin and CD10 results confirmed the variably myofibroblastic nature of PF in the muscular and fibroblastic axes, respectively. The ER showed all negative staining, but the PR were diffusely or focally reactive in 8 of 10 cases [20, 31, 59], one of which revealed a prominent PR positivity in 80% of the tumor cells [20]. The PR positivity implied that PF may be sensitive to hormonal therapy [20, 59], but this might not be clinically practical. PF is reminiscent of extra-uterine or metastatic endometrial stromal sarcoma, which is rare but most commonly occurs in the GI tract [20]. However, it typically presents ER positivity [81], while PF consistently shows negative ER immunostaining result.The rest of the markers mainly had negative results in PF. DOG-1 and CD117 were always negative in the reported cases, which allowed PF to be well-distinguished from GIST [82]. CD34 was mostly negative (95.1%), but focally positive results have been shown in several cases. CD34 could be labeled in cells with fibroblastic nature [83], but CD34 shows strong positive staining in vascular endothelial tissues; therefore, we suggest the possibility that focally positive or equivocal results originate from the rich vascularity of PF or as a result of technical or interpretation errors. The PF cases showed almost entirely negative results according to S-100 protein staining, indicating that PF is not derived from the neural crest; the 2 cases reporting positive results we highly suspect to be biased by technical error. Except for 1 case with a positive EMA staining result and 1 case with focally positive cytokeratin AE1/AE3 staining result, negative outcomes were reported for EMA, neurofilament, cytokeratin, β-catenin, ALK, cytokeratin AE1/AE3, and synaptophysin, thereby excluding epithelial, perineural, neuronal, and neuroendocrine cell lineage and ruling out some of the important differential diagnoses, such as fibromatosis and inflammatory myofibroblastic tumor.Genetic mutation has also been examined in some studies. TheC-KITandPDGFRA gene mutations are important and characteristic in GIST [82], but they were both negative in all PF cases reported, thereby further enhancing the differentiation between PF and GIST. Genetic mutations involvingglioma-associated oncogene homologue 1(GLI1) andmetastasis-associated lung adenocarcinoma transcript 1 (MALAT1) have been identified in a subset of PF cases [54, 59], withGLI1 gene translocation reported in 6 cases (24%) andGLI1 polysomy reported in 2 cases (8%), out of overall 25 cases withGLI1 genetic analysis [54, 59, 78]. The gene translocation t(11;12)(q11;q13) producing functional MALAT1-GLI1 chimeric proteins and the polysomy of GLI1/12q13 both will lead to overexpression of GLI1 protein. The overproduction of GLI1 protein has been recognized in a wide range of neoplasms [84, 85] and occurs via activation of the Hedgehog signaling pathway [54], which plays important roles in gastrointestinal developments, diseases, and neoplasms [86]. Apart from the canonical pathway of Hedgehog signaling, a noncanonical, Patched-dependent, and Smoothened-independent pathway has been recently described, which may be vital for the maintenance of gastrointestinal neoplasms [87]. The molecular pathway of PF development implicates that such neoplasms withGLI1 oncogenesis may be sensitive to Hedgehog pathway inhibitors, targeting either Patched, Smoothened, GLI1, or other Hedgehog pathway components [88]. PF remains an emerging disease entity, and we are far from understanding its genetic profile with such a limited case number. Nevertheless, the present results of genetic analysis that aimed at benefiting differential diagnosis confirm a different genetic profile from GIST, and further research on theGLI1 mutation and Hedgehog signaling may bring about improved understanding of its pathogenesis and even novel therapeutic strategies.


## 8. Diagnosis and Differential Diagnoses

Clinical findings are indecisive for the diagnosis of PF, as a solid, elastic tumor with or without ulceration is most likely to be encountered first during endoscopy, with typically nonspecific or hemorrhagic gastrointestinal signs or symptoms. Diagnosis of PF depends on pathological and immunochemical examinations, which are not achieved by clinical examination alone [73], and a minimum of three microscopic signatures should be observed, including spindle or oval cells in a plexiform growth pattern, rich and small-sized vasculature, and abundant myxoid matrix. The benignity of PF could be speculated by its limited atypia and low mitotic rate [89]. The plexiform pattern is highly characteristic of PF, so the designation of a tumor without plexiform growth pattern as PF is highly unlikely. Immunohistochemically, PF is almost always positive for vimentin and SMA and variably positive for desmin, caldesmon, and CD10. Negativities for DOG-1, CD117, CD34, S-100 protein, EMA, and ALK should be examined to exclude similar mimicking conditions.The most important differential diagnosis of PF is GIST, especially myxoid variants of GIST with spindle-cell histology [77, 89]. Most PF cases were initially treated based on a suspicion of GIST, which is the most common gastrointestinal mesenchymal tumor and potentially fatal [77, 82]. Microscopically, although not totally impossible [89], a plexiform pattern is highly unusual for GIST [9]. In addition, the characteristic immunoprofiles of CD117, CD34, and DOG-1 immunoreactivities andC-KIT orPDGFRA mutations of GIST are adopted widely in routine pathological practice [82].Other pathological differential diagnoses, based on spindle cell morphology and myxoid stromal background, include sarcomatoid carcinoma, peripheral nerve sheath tumor, inflammatory fibroid polyp, and inflammatory myofibroblastic tumor. Primary or secondary sarcomatoid carcinoma with spindle tumor cells and myxoid stroma could be sometimes mistaken as gastrointestinal mesenchymal neoplasm. A clinical cancer history, a more malignant cytological feature, such as brisk mitotic or apoptotic activities, positive epithelial immunoreactivities, and markers for possible metastatic origins, such as TTF-1 for pulmonary origin, are significantly conducive to the correct diagnosis [90].Peripheral nerve sheath tumor includes benign schwannoma, neurofibroma or ganglioneuroma, and malignant peripheral nerve sheath tumor (MPNST); some variants also demonstrate a plexiform growth pattern [89]. Neurogenic markers, such as S-100 protein, SOX10, and neurofilament, highlight nerve sheath differentiation that is absent in PF [91, 92].Inflammatory fibroid polyps consist of bland-looking spindle cells arranged in perivascular whorled pattern in a myxoedematous inflammatory stroma with mostly eosinophils. Positive CD34 immunoreactivity is the key characteristic of this rare tumor, which should be negative in PF except for vascular endothelial cells [93].Inflammatory myofibroblastic tumor is characterized by monotonous spindle cells arranged in fascicles or vague whorls in an inflammatory and edematous stroma full of neutrophils, eosinophils, or lymphoplasma cells. Although the myofibroblastic nature of an inflammatory myofibroblastic tumor is similar to that of PF by morphology and immunohistochemical studies, the lack of a plexiform growth pattern, a predominantly inflammatory cellular microenvironment, and positive ALK immunoreactivity help to distinguish inflammatory myofibroblastic tumor from PF [94].


## 9. Treatment

The mainstream treatment of PF is surgical removal, while medical treatment serves an assistant role for symptomatic management. Among the 121 reported cases, treatments were available in 99 cases and not provided in 22 cases. Partial gastrectomy (N=30) and distal gastrectomy (N=26) are the most frequently performed surgical treatments for PF, followed by local resection (N=12), subtotal gastrectomy (N=10), wedge resection (N=7), submucosal dissection (N=6), antrectomy (N=3), partial duodenectomy (N=2), nonsurgical follow-up with only endoscopic biopsy (N=2), total gastrectomy (N=1), and laparoscopic cholecystectomy (N=1). A laparoscopic operative technique was performed in 10 cases, endoscopic resection in 9 cases (including 1 thoracoscopic resection), and laparoscopic endoscopic cooperative surgery (LECS) in 4 cases. None of the surgically treated cases presented with severe postoperative complications, except for a 63-year-old male patient who had experienced recurrent GI bleeding for 17 years with a duodenal PF and had undergone pancreas-preserving duodenectomy of the first 2 portions, complicated by a low output pancreatic-skin fistula which had totally drained after 4 months. Secondary procedures included Billroth’s operation I (N=3), Billroth’s operation II (N=2), Roux-en-Y anastomosis (N=2), and omentectomy (N=1).Conservative management included endoscopic resection and nonsurgical intervention. Since PF is currently considered a benign disease (though not yet verified by convincing evidence), conservative management may be suitable for PF patients, and particularly for the elderly or selected patients with surgically contraindicated comorbidities [72]; at least, more conservative surgical management than partial gastrectomy could be feasible [23]. However, vascular and lymphatic invasion were reported by Miettinen et al. and Kawara et al. [11, 60], and PF usually develops in a nodular and plexiform pattern with unclear tumor margins [1, 30, 64], suggesting that the possibility of malignancy or local recurrence cannot be fully excluded [9, 73]. Therefore, regardless of the operative technique, we suggest that complete resection still be the first consideration when treating PF rather than consideration of the conservativeness of the operative technique [30, 64, 71]. PF cases with severe clinical presentations, such as perforation [1, 21], infection [36], or considerable hemorrhage [53, 58, 63, 74], and with malignant suspicion, such as significant body weight loss [11, 72] or rapid tumor growth [16], should be addressed with aggressive radical surgical treatment rather than conservative management, despite the benign pathological results.


## 10. Prognosis

PF shows a benign biological behavior [18, 73, 74], with a low proliferation rate and low mitotic rate, and no local recurrence or distant metastasis has been reported so far [74]. However, no consensus has been reached whether PF is actually a benign tumor, and no cases have confirmed that malignant change does not occur, so confirmation of the benign nature of PF still requires longitudinal observational studies with sufficient case numbers. Nevertheless, for the time being, PF should be considered a benign tumor, in response to the strategy of conservative management.Of all the 121 reported cases, follow-up was not reported in 37 cases, and the follow-up period was not reported in 4 cases. No malignant change, local recurrence, or PF-related mortality was reported. Most of the cases were uneventful after treatments, and among the cases that had follow-up periods, the uneventful or alive duration ranged from 0.75 to 396 months, with an average of 44.29±72.5 months and a median of 15 months. An 81-year-old female who underwent nonsurgical management also had her symptoms resolved 3 months after [72], and a 45-year-old male in Lai’s study who underwent only endoscopic biopsy without further resection also led an uneventful life at 0.2-year follow-up [77]. Three cases were reported to have died for unknown causes at 2 months, 14.5 years, and 25.5 years after diagnosis [11]. Vascular or lymphatic invasion was noted in 5 cases, none of which had adverse significance on prognosis [11, 60].


## 11. Conclusion

PF is a rare mesenchymal tumor with increasing clinical attention and occurs mostly but not exclusively in the GI tract. Typical clinical presentations are nonspecific GI signs or symptoms, or upper GI bleeding. Endoscopic biopsy is recommended for visualizing the microscopic features of PF with benign cytological traits, and immunohistochemical staining is required for diagnosis as well as for exclusion of GIST. Surgical local excision is the main treatment; however, more conservative management is suggested within an individually reasonable range because of its very good prognosis.



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*Source: 3960920-2019-07-07.xml*