外科的に切除された膵癌におけるST2発現の臨床病理学的及び予後との関連性の検討

概要

CANCER DIAGNOSIS & PROGNOSIS
3: 311-319 (2023)

doi: 10.21873/cdp.10217

Clinicopathological and Prognostic Relevance of Tumoral
Suppression of Tumorigenicity 2 Expression in Patients
With Surgically Resected Pancreatic Carcinoma

MAMIKO NAGASE1, EMI IBUKI2, REIJI HABA2, KEIICHI OKANO3 and KYUICHI KADOTA1
1Department

of Pathology, Faculty of Medicine, Shimane University, Izumo, Japan;
of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Miki-cho, Japan;
3Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki-cho, Japan
2Department

Abstract. Background/Aim: The interleukin (IL)-33/suppression

months; p=0.046). Conclusion: High tumoral ST2 expression is
associated with high T status, lymphatic invasion, and lower
histopathological response grade in patients with pancreatic
carcinoma after neoadjuvant chemoradiotherapy.

of tumorigenicity 2 (ST2) pathway promotes cancer development
and remodels the tumor microenvironment. However, the role of
tumoral ST2 expression remains controversial in some solid
malignancies. In this study, we have investigated the
clinicopathological and prognostic relevance of tumoral ST2
expression in patients with resected pancreatic carcinoma after
neoadjuvant chemoradiotherapy. Patients and Methods: We
analyzed data from 76 patients with surgically resected
pancreatic ductal adenocarcinoma after neoadjuvant
chemoradiotherapy, between 2009 and 2018. Tissue microarrays
were constructed and immunohistochemical analysis was
performed for ST2. Associations between variables were
analyzed using chi-square tests. Disease-specific survival (DSS)
and disease-free survival (DFS) were analyzed using log-rank
tests. Results: High expression of ST2, which was observed in
43 patients (57%), was more frequent in patients with high T
status (p=0.002), lymphatic invasion (p=0.049), and ≤50% of
tumor cells destroyed by chemoradiotherapy (p=0.043; Evans
grade I-IIA vs. IIB). In stage I patients, DFS was significantly
lower in patients with high ST2 expression (median, 10.6
months) than in those with low ST2 expression (median, 43.4

Interleukin-33 (IL-33), a member of the IL-1 cytokine family,
is expressed in endothelial cells, fibroblasts, and epithelial cells
both during homeostasis and inflammation (1, 2). The human
suppression of tumorigenicity 2 (ST2) gene encodes for three
splice variants; soluble ST2 (sST2), transmembrane ST2
(ST2L), and variant ST2 (ST2V) (1). The IL-33 receptor is a
heterodimeric complex consisting of ST2L and IL-1 receptor
accessory protein (2). ST2 is expressed on the membrane of a
variety of immune cell types, such as T helper (Th)2
lymphocytes, group 2 innate lymphoid cells, macrophages,
mast cells, basophils, eosinophils, dendritic cells, and natural
killer (NK) cells (3). IL-33/ST2 signaling is crucial for tissue
repair, type 2 immunity, allergic and non-allergic inflammation,
and viral infection (3).
Recent studies have shown associations between the
biological role of the IL-33/ST2 axis and progression of
malignant tumors. However, the significance of tumoral ST2
expression remains controversial in some malignancies (4).
In this study, we investigated the clinicopathological and
prognostic relevance of tumoral ST2 expression in patients
with resected pancreatic carcinoma after neoadjuvant
chemoradiotherapy.

Correspondence to: Dr. Kyuichi Kadota, MD, Department of
Pathology, Faculty of Medicine, Shimane University, 89-1, Enya,
Izumo, Shimane 693-8501, Japan. Tel: +81 853202143, Fax: +81
853202144, e-mail: kadotak@med.shimane-u.ac.jp

Patients and Methods

Key Words: Suppression of tumorigenicity 2, pancreatic carcinoma,
prognosis.

Patients. This retrospective study was approved by the Institutional
Review Board of Kagawa University (approval number: 2020-090)
and Shimane University (approval number: 20221012-1). All
experiments were performed in accordance with relevant guidelines
and regulations.
We reviewed records from patients with invasive pancreatic
ductal adenocarcinoma who had undergone pancreatic resection
after chemoradiotherapy at Kagawa University between 2009 and

©2023 International Institute of Anticancer Research
www.iiar-anticancer.org

This article is an open access article distributed under the terms and

conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0

international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

311

CANCER DIAGNOSIS & PROGNOSIS 3: 311-319 (2023)

Figure 1. Evaluation of suppression of tumorigenicity 2 (ST2) expression in pancreatic carcinomas with immunohistochemistry using tissue
microarrays. Examples of (A) total score 0, (B) total score 2 (distribution score 1, intensity score 1), (C) total score 4 (distribution score 2, intensity
score 2), and (D) total score 6 (distribution score 3, intensity score 3).

2018 (n=81). After excluding patients with positive surgical margin
(n=3) or ≤10% residual tumor after chemoradiotherapy (n=2), 76
patients were eventually included in our analysis. Clinical data were
collected from a prospectively maintained pancreatic carcinoma
database. Tumor, node, metastasis (TNM) stages were assigned
based on the eighth edition of the American Joint Committee on
Cancer TNM Staging Manual (5).

Using an Olympus BX53 upright microscope (Olympus
Corporation, Tokyo, Japan) with a standard 22-mm-diameter
eyepiece, anti-ST2 stained tumor slides were reviewed by a
pathologist (M.N.), who was blinded to patient outcomes.
Immunohistochemistry scoring was based on the distribution and
intensity of the staining in the main tumor. Distribution was scored
based on a scale of 0 (0-25%), 1 (26-50%), 2 (51-75%), or 3 (76100%) according to the percentage of positive cells in each core.
Staining intensity was scored as 0 (no expression), 1 (mild
expression), 2 (intermediate expression), or 3 (strong expression).
Distribution and intensity scores were summed in a total score (06) for each patient (Figure 1). The score of ST-2 expression was
dichotomized as low or high according to the median value
(median: 2, range=0-6). When the score was equal or greater than
the median, expression was classified as high.

Immunohistochemistry using tissue microarrays and scoring. Formalinfixed, paraffin-embedded tumor specimens from patients who met the
inclusion criteria were used for tissue microarray construction. One
representative main tumor site was marked on Hematoxylin & Eosinstained slides. Using a tissue array (Tissue Microprocessor KIN-2,
Azumaya, Japan), cylindrical 3-mm tissue cores from the corresponding
paraffin block were arrayed on the recipient block.
Four-μm sections from stored formalin-fixed, paraffin-embedded
tumor blocks were stained with an anti-ST2 rabbit polyclonal
antibody (Proteintech, Rosemont, IL, USA; diluted at 1:100) using
a BOND-III automated immunohistochemical slide staining system
(Leica Biosystems). We used diaminobenzidine as chromogen and
hematoxylin as nuclear counterstain.

Statistical analysis. Associations between variables were analyzed
using chi-square tests for categorical variables. Disease-specific
survival (DSS) was defined as the time from resection to the date
of death related to pancreatic carcinoma or last follow-up.
Disease-free survival (DFS) was defined as the time from

312

Nagase et al: ST2 Expression in Pancreatic Carcinoma
Table I. Clinicopathologic characteristics and their associations with ST2 expression.
Variables

Age, years
>70
≥70
Sex
Female
Male
Tumor location
Head/neck
Body/tail
Pathological T category
T1
T2
T3
Pathological N category
N0
N1
N2
Pathological stage
Stage I
Stage II
Stage III
Histologic grade
G1
G2
G3
Lymphatic invasion
Negative
Positive
Vascular invasion
Negative
Positive
Perineural invasion
Negative
Positive
Evans’ classification
Grade I
Grade IIA
Grade IIB

All patients

Significant p-values are shown in bold.

N

N

35
41

50
26

39
37

25
41
10

43
28
5

42
29
5

35
29
12

N

15
18

43
44

20
23

57
56

20
13

40
50

30
13

60
50

16
17

17
12
4

17
14
2

17
14
2

41
46

68
29
40

40
50
40

40
48
40

23
20

8
29
6

26
14
3

25
15
3

%

59
54

32
71
60

60
50
60

60
52
60

18
11
4

51
38
33

17
18
8

49
62
67

7
26

64
40

4
39

36
60

19
14

11
65

6
27

4
49
23

High

p-Value

%

34
42

11
65

Low

ST2 expression

2
17
14

56
33

55
42

50
35
61

15
28

5
38

2
32
9

44
67

45
58

50
65
39

0.93
0.67
0.40
0.002

(T1 vs. T2-3)

0.44

(N0 vs. N1-2)

0.57

(I vs. II-III）

0.19

(G1 vs. G2-3)

0.049
0.14
0.42
0.043

(I-IIA vs. IIB)

resection after chemoradiotherapy (n=76) are summarized
in Table I. During the study period, 52 patients recurred and
33 died from pancreatic carcinoma-related causes. The
median duration of follow-up for patients who were alive at
the time of the last follow-up was 27 months (range=5-113
months).
Univariate analyses of all patient outcomes (DSS and
DFS) with clinicopathological factors are shown in Table II.
None of the clinicopathological factors were associated with
DSS. High T status (p=0.041), lymph node metastasis
(p=0.008), pathological stage (p=0.030), and perineural

resection to disease recurrence. DSS and DFS were estimated
using the Kaplan–Meier method, and non-parametric group
comparisons were performed using the log-rank test. All statistical
tests were two-sided, with the significance level set at 5%.
Statistical analyses were conducted using IBM SPSS Statistics for
Windows (version 23.0; IBM, Armonk, NY, USA).

Results

Patient characteristics and association of clinicopathological
factors with patient outcomes. The clinicopathological
characteristics of all patients who had undergone pancreatic
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CANCER DIAGNOSIS & PROGNOSIS 3: 311-319 (2023)
Table II. Association between clinicopathologic characteristics and clinical outcomes in all patients. ...

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