Canadian Journal of Gastroenterology and Hepatology
Volume 2019 (2019), Article ID 3960920, 26 pages
https://doi.org/10.1155/2019/3960920

Review Article

An Update on Clinicopathological and Molecular Features of Plexiform Fibromyxoma

Hsuan-An Su,¹ Hsu-Heng Yen,2,3 and Chih-Jung Chen3,4,5

¹Department of Medical Education, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
²Endoscopy Center, Changhua Christian Hospital, Changhua, Taiwan
³School of Medicine, Chung Shan Medical University, Taichung, Taiwan
⁴Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan
⁵Department of Pathology and Laboratory Medicine, Taichung Veterans General Hospital, Taiwan

Correspondence should be addressed to Hsu-Heng Yen; blaneyen@gmail.com and Chih-Jung Chen; cjchen1016@gmail.com

Received 29 April 2019; Accepted 16 June 2019; Published 7 July 2019

Academic Editor: Maikel P. Peppelenbosch

Copyright © 2019 Hsuan-An Su et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.

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 Table 1. 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 (Table 3). 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. The C-KIT and PDGFRA 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 involving glioma-associated oncogene homologue 1 (GLI1) and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) have been identified in a subset of PF cases [54, 59], with GLI1 gene translocation reported in 6 cases (24%) and GLI1 polysomy reported in 2 cases (8%), out of overall 25 cases with GLI1 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 with GLI1 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 the GLI1 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 and C-KIT or PDGFRA 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.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this article.

Authors’ Contributions

Research idea and study design were accomplished by Chih-Jung Chen; acquisition of data was the responsibility of Hsuan-An Su; data analysis and/or interpretation were done by Hsuan-An Su, Hsu-Heng Yen, and Chih-Jung Chen; drafting of manuscript was performed by Hsuan-An Su; critical revision was carried out by Hsu-Heng Yen and Chih-Jung Chen; supervision or mentorship was conducted by Hsu-Heng Yen and Chih-Jung Chen. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

Acknowledgments

This work was supported by the research grants from Changhua Christian Hospital (grant numbers: 108-CCH-IRP-018 and 106-CCH-IRP-030). The financial support is gratefully acknowledged.

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