Introduction
Colorectal cancer (CRC) is the third most common cancer in the world and the second
leading cause of cancer-related deaths [1]. Most CRCs develop over a long period via a multistep process through the adenoma-carcinoma
sequence [2]. About two-thirds of sporadic CRCs arise from conventional adenomas [3]
[4]. The process of colorectal carcinogenesis often begins with inactivation of the
APC/β-catenin signaling pathway, followed by KRAS and TP53 mutations. However, serrated adenomas (SAs), especially sessile serrated adenoma/polyps
(SSA/Ps), have recently been described as immediate precursors for CRCs that develop
via an alternative pathway with CpG island methylator phenotype (CIMP) and BRAF mutation [5]. In addition, CIMP cancer may develop via either a mutator (microsatellite instability)
pathway or a pathway that leads to microsatellite stability [5]. This alternative pathway is called the serrated pathway.
Hyperplastic polyps (HPs) are often detected in the colorectum, especially in the
sigmoid colon and rectum, of elderly patients [6]
[7]. For many years, HPs have been considered to be non-neoplastic lesions without malignant
potential. Thus, they have been dismissed as innocuous. However, some HPs show molecular
features similar to those of CRCs [8]
[9]. Recently, the serrated pathway has been proposed to begin with HPs, and then progress
through SSA/Ps (with or without cytological dysplasia) to CRCs [5]. The serrated pathway appears to be involved in the formation of approximately 10 %
of CRCs [10].
Because of improvements in endoscopic imaging, details of the colorectal mucosa surface
can be observed with colonoscopies. However, several studies [11]
[12] have reported a low diagnostic accuracy of any of the novel endoscopic imaging techniques
for differentiating SSAs from HPs. However, Kimura et al. [13] have proposed a type II open-shape pit pattern (Type II-O) which was specific to
SSA/Ps. This crypt pattern was similar to the hyperplastic crypt pattern (stellar
or papillary pits) but the pits were wider and more rounded in shape, reflecting dilatation
of the crypts. However, their sensitivity and negative predictive value for the diagnosis
of SSA/P were still insufficient. Our previous study [14] indicated that SAs occasionally showed a hyperplastic crypt pattern and that they
presented distinct molecular features compared to SAs with a non-hyperplastic pit
pattern. These are implicated in the therapeutic management of serrated polyps (SPs).
We hypothesized that biological or molecular differences exist among SPs with a hyperplastic
crypt pattern, and that these features are associated with their different pathways
of progression to CRCs. To test this hypothesis, the molecular features of SPs with
a hyperplastic crypt pattern were investigated.
Methods
Patients and samples
In total, 4149 colorectal polyps were evaluated for their mucosal crypt patterns and
then endoscopically resected at the Showa University Hospital between February 2009
and August 2012. Of these polyps, 318 revealed a hyperplastic pit pattern (Kudo’s
type II) under chromoendoscopy. These 318 polyps were examined and included 33 dysplastic
SPs (10.4 %), 136 SSA/Ps (42.8 %), 102 HPs (32.1 %), 43 conventional adenomas (13.5 %),
one inflammatory polyp (0.3 %), and three polyps without histological evaluation (0.9 %).
Overall, 271 lesions were SPs (85 %, 271/318). Among the 271 SPs, we examined 114
SPs with a hyperplastic pit pattern (Kudo’s type II) from 85 patients. The tissue
samples were selected solely based on tissue availability. However, there were no
significant differences in the clinicopathological features between overall and studied
SP groups ([Table S1]).
TableS1
Comparison of clinicopathological features between overall and studied serrated polyps.
|
|
Overall SP samples
(n = 271)
|
Studied SP samples
(n = 114)
|
|
|
Dysplastic SP
(n = 33)
|
SSA/P
(n = 136)
|
HP
(n = 102)
|
Dysplastic SP
(n = 5)
|
SSA/P
(n = 63)
|
HP
(n = 46)
|
|
Gender
|
Male
|
18 (55 %)
|
79 (58 %)
|
71 (70 %)
|
3 (60 %)
|
38 (60 %)
|
33 (72 %)
|
|
Female
|
15 (45 %)
|
57 (42 %)
|
31 (30 %)
|
2 (40 %)
|
25 (40 %)
|
13 (28 %)
|
|
Age
|
(Median, years)
|
62
|
60
|
59
|
54
|
61
|
63
|
|
(Range, years)
|
23 – 82
|
32 – 84
|
35 – 82
|
23 – 69
|
33 – 79
|
35 – 80
|
|
Tumor location
|
Proximal
|
19 (58 %)
|
108 (79 %)
|
52 (51 %)
|
4 (80 %)
|
55 (87 %)
|
17 (37 %)
|
|
Distal
|
14 (42 %)
|
28 (21 %)
|
50 (49 %)
|
1 (20 %)
|
8 (13 %)
|
29 (63 %)
|
|
Size
|
(Median, mm)
|
8
|
10
|
7
|
8
|
10
|
7
|
|
(Range, mm)
|
5 – 45
|
4 – 25
|
3 – 20
|
7 – 12
|
5 – 23
|
4 – 11
|
|
Macroscopic type
|
Protruded
|
7 (21 %)
|
0
|
13 (13 %)
|
0
|
1 (2 %)
|
7 (15 %)
|
|
Superficial
|
26 (79 %)
|
135 (99 %)
|
88 (86 %)
|
5 (100 %)
|
61 (96 %)
|
37 (81 %)
|
|
Combined
|
0
|
1 (1 %)
|
1 (1 %)
|
0
|
1 (2 %)
|
2 (4 %)
|
Dysplastic SPs include traditional serrated adenoma and SSA/P with cytological dysplasia.
SP, serrated polyp; SSA/P, sessile serrated adenoma/polyp; HP, hyperplastic polyp.
Before SP samples were selected, patients with a) a familial predisposition to cancers
such as familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer
or hyperplastic polyposis, or b) inflammatory bowel disease such as ulcerative colitis
were excluded. The procedures for tissue collection and analysis were approved by
the ethics committee of the Showa University School of Medicine. Written informed
consent was obtained from each patient.
Endoscopic evaluation
All patients were prepared for the procedure with administration of 1.8 L of an oral
electrolyte lavage solution. Colonoscopists with extensive experience performed all
examinations using high definition colonoscopes (CF260AI; Olympus Optical Co., Tokyo,
Japan) or high definition magnifying colonoscopes (PCF240Z or CF260HZI; Olympus Optical
Co., Tokyo, Japan). The lesions found during colonoscopy were classified as polypoid
or nonpolypoid on the basis of the Paris endoscopic classification [15]. We followed a procedure previously reported for the observation of mucosal crypt
patterns on the surface of the lesion [16]. The mucosal crypt pattern of each lesion was determined according to the modified
classification of Kudo et al. [17]. Briefly, Kudo’s type II (stellar or papillary pits) mucosal crypt patterns were
defined as a hyperplastic pattern ([Fig. 1 b]). If the lesion revealed this pit pattern, we considered whether it should be included
in this study. However, the lesion was excluded from this study when it presented
a mixed pattern comprised of a combination of a hyperplastic pattern and other patterns.
Fig. 1 Endoscopic appearance of serrated polyps (all lesions were observed after spraying
with indigo carmine dye): a Ordinary view of sessile serrated adenoma/polyp; b Magnifying view of hyperplastic pit pattern (Kudo’s type II) on the surface of the
polyp by magnifying chromoendoscopy.
SSA/Ps are typically 10 mm or greater in size, located in the proximal colon and covered
with a mucus cap ([Fig. 1 a]). Their mucosal crypt pattern is usually the Kudo’s type II pit pattern, which is
similar to the hyperplastic polyp. Thus, the following criteria were used to decide
whether lesions that exhibited a hyperplastic pattern on their surface should be removed
endoscopically: (i) typical location of HPs in the rectosigmoid area, and (ii) small
size (usually ≤ 5 mm in diameter) and a symmetrical and uniform shape. If a colonoscopist
established a diagnosis of typical HP, no further endoscopic treatment was performed.
Otherwise, lesions were removed using coagulation-biopsy (“hot biopsy”) or endoscopic
resection (i. e., endoscopic mucosal resection or polypectomy).
Tissue samples and histological evaluation
Serial sections (3 μm) were obtained from paraffin blocks and prepared for hematoxylin
and eosin (H&E) staining. All H&E-stained slides were reviewed by a senior pathologist
(TY) who was blinded to the endoscopic findings. SPs were classified into HP, SSA/P,
or traditional serrated adenoma (TSA) on the basis of the WHO classification [18] ([Fig. 2]). A SSA/P accompanied by a cytologically dysplastic area was defined as a SSA/P
with cytological dysplasia (SSA/P-cd) ([Fig. 2 b]). In the present study, dysplastic SPs and SSA/Ps were defined as serrated neoplasias
(SNs). Moreover, HPs were divided into three subtypes, namely, the microvesicular
hyperplastic polyp (MVHP) ([Fig. 2 c]), the goblet cell-rich hyperplastic polyp (GCHP) ([Fig. 2 d]), and the mucin-poor hyperplastic polyp on the basis of the WHO classification [18].
Fig. 2 Histopathology of serrated polyps: a Sessile serrated adenoma/polyp (SSA/P). The crypts with serration are distorted and
dilated, L-shaped, inverted T-shaped or anchor-shaped; b SSA/P with cytological dysplasia. The cytological dysplasia in SSA/P is histologically
different from conventional adenoma. The nuclei have more open chromatin and prominent
nucleoli. The cytoplasm is more eosinophilic than that observed in conventional adenoma;
c Microvesicular hyperplastic polyps; d Goblet cell-rich hyperplastic polyps.
Genomic DNA was extracted from 45 formalin-fixed, paraffin-embedded samples and 69
frozen tissue samples. The frozen tissue samples were obtained from the lesions using
colonoscopic biopsy before endoscopic resection and were stored at – 80 °C. We distinguished
between tumor and adjacent colonic mucosa based on pit patterns observed by chromoendoscopy.
DNA was extracted from the frozen tissue samples using the standard proteinase K/phenol/chloroform
method. As for formalin-fixed, paraffin-embedded samples, serial slides were obtained
from the archival blocks of formalin-fixed, paraffin-embedded tumor tissues, which
were resected endoscopically. One slide was stained with H&E for microdissection.
After microdissection, DNA was extracted using the QIAamp DNA mini kit (QIAGEN Inc.,
Valencia, CA).
Bisulfite polymerase chain reaction (PCR) and pyrosequencing analysis of DNA methylation
Bisulfite treatment was performed as previously described [19]. Bisulfite-treated DNA (2 or 3 μL) was used as the template for PCR. The primers
and PCR conditions used for the amplification of specific DNA fragments of various
target genes were set according to those described in our previous report [20]. The protocol for pyrosequencing, a quantitative tool for methylation density, was
previously described in detail [20].
Methylation-related genes and definition of the CpG island methylator phenotype (CIMP)
It has been reported that sporadic CRCs can be classified into two groups: CIMP-positive
and CIMP-negative according to the frequency of methylation of the CpG islands in
the promoter of five genes (MINT1, MINT2, MINT31, CDKN2A (p16), and MLH1) [21]. The determination of CIMP status required a quantitative tool, and methylation
positivity was defined as a methylation density greater than 15 %. A tumor was considered
to be CIMP-positive if two or more of the CIMP markers were methylated as previously
described [20]. All others were defined as CIMP-negative.
KRAS and BRAF mutations
PCR-based pyrosequencing assays were used to analyze samples for the presence of activating
mutations in codons 12 and 13 of KRAS and in codon 600 of BRAF, as previously described [22].
Data analysis and statistics
We analyzed 114 SPs as follows: 1) clinicopathological and molecular features were
investigated by histological findings or by tumor location, and 2) the relationship
between CIMP and clinicopathological/molecular features was evaluated. As for the
latter analysis, we first examined the relationship between CIMP-positive SPs and
gender, age, tumor location (proximal vs. distal), tumor size, macroscopic type (protruded
vs. superficial, elevated), histology (SN vs. HP), or genetic alterations (BRAF and KRAS mutations) by univariate analysis. In this analysis, gender, tumor location, macroscopic
type, histology, and genetic alterations were considered to be categorical variables,
whereas age and tumor size were continuous variables. Next, logistic regression analysis
was used to calculate the relationship between CIMP-positive SPs and significant factors
that were selected by univariate analysis.
Continuous variables (i. e., age and tumor size) were analyzed using the Wilcoxon
test. Categorical variables were compared between tumor groups using the χ2 test or Fisher’s exact test when testing small samples. The odds ratio (OR) and 95 %
confidence interval (CI) were determined for a variety of factors. All tests were
two-sided, and P < 0.05 was considered statistically significant. However, when multiple comparisons
were performed, P values were considered to be significant at a Bonferroni-corrected alpha of 0.05 /6
for four groups. All statistical analyses were performed with SAS version 9.2 and
JMP version 10 (SAS Institute, Inc., Cary, NC).
Results
Comparison of clinicopathological and molecular features among SPs with type II pit
pattern
The 114 SPs were histologically classified into five dysplastic SPs (four SSA/P-cd
and one TSA), 63 SSA/Ps, 36 MVHPs and 10 GCHPs. [Table 1] shows the clinicopathological and molecular features of these lesions. Compared
to MVHPs and GCHPs, dysplastic SPs and SSA/Ps were found more frequently in the proximal
colon. The differences between SSA/Ps and MVHPs or GCHPs were statistically significant
(P < 0.0001). Regarding lesion size, dysplastic SPs and SSA/Ps were larger than MVHPs
or GCHPs (SSA/Ps vs. MVHPs, P < 0.0001; SSA/Ps vs. GCHPs, P = 0.0005). Macroscopically, nonpolypoid configuration (superficial, elevated type)
was more frequently found in dysplastic SPs and SSA/Ps than in MVHPs or GCHPs. There
were significant differences between SSA/Ps and GCHPs (P = 0.0068). The frequency of the BRAF mutation was significantly higher in dysplastic SPs, SSA/Ps or MVHPs than in GCHPs
(P < 0.008). A higher frequency of CIMP was observed in dysplastic SPs and SSA/Ps than
in MVHPs or GCHPs. The difference between SSA/Ps and GCHPs was statistically significant
(P = 0.0068).
Table 1
Clinicopathological characteristics of serrated polyps with type II pit pattern.
|
|
Dysplastic SP[1]
(n = 5)
|
SSA/P[2]
(n = 63)
|
MVHP
(n = 36)
|
GCHP
(n = 10)
|
|
Gender
|
Male
|
3 (60 %)
|
38 (60 %)
|
28 (78 %)
|
5 (50 %)
|
|
Female
|
2 (40 %)
|
25 (40 %)
|
8 (22 %)
|
5 (50 %)
|
|
Age
|
(Median, years)
|
54
|
61
|
63
|
64
|
|
(Range, years)
|
23 – 69
|
33 – 79
|
35 – 80
|
49 – 77
|
|
Tumor location[3]
|
Proximal
|
4 (80 %)
|
55 (87 %)
|
14 (39 %)
|
3 (30 %)
|
|
Distal
|
1 (20 %)
|
8 (13 %)
|
22 (61 %)
|
7 (70 %)
|
|
Size[4]
|
(Median, mm)
|
8
|
10
|
6.5
|
6.5
|
|
(Range, mm)
|
7 – 12
|
5 – 23
|
4 – 11
|
5 – 10
|
|
Macroscopic type[5]
|
Protruded
|
0
|
1 (2 %)
|
5 (14 %)
|
2 (20 %)
|
|
Superficial
|
5 (100 %)
|
61 (96 %)
|
29 (81 %)
|
8 (80 %)
|
|
Combined
|
0
|
1 (2 %)
|
2 (5 %)
|
0
|
|
BRAF
[6]
|
Mut +
|
3 (60 %)
|
28 (44 %)
|
17 (47 %)
|
0
|
|
Mut –
|
2 (40 %)
|
35 (56 %)
|
19 (53 %)
|
10 (100 %)
|
|
KRAS
|
Mut +
|
0
|
6 (10 %)
|
3 (8 %)
|
3 (30 %)
|
|
Mut –
|
5 (100 %)
|
57 (90 %)
|
33(92 %)
|
7 (70 %)
|
|
CIMP[7]
|
Presence
|
3 (60 %)
|
35 (56 %)
|
12 (33 %)
|
1 (10 %)
|
|
Absence
|
2 (40 %)
|
27 (44 %)
|
24 (67 %)
|
9 (90 %)
|
SP, serrated polyp; SSA/P, sessile serrated adenoma/polyp; HP, hyperplastic polyp;
MVHP, microvesicular HP; GCHP, goblet-cell rich HP; Mut + , presence of mutation;
Mut – , absence of mutation.
1 Dysplastic SPs include traditional serrated adenoma and SSA/P with cytological dysplasia.
2 One SSA/P could not be determined CIMP status.
3 SSA/P vs. MVHP or GCHP, P < 0.0001.
4 SSA/P vs. MVHP or GCHP, P < 0.0001 or P = 0.0005.
5 SSA/P vs. GCHP, P = 0.0068.
6 GCHP vs. TSA, SSA/P or MVHP, P = 0.0082, P = 0.0077 or P = 0.0068.
7 GCHP vs. SSA/P, P = 0.0068.
Comparison of clinicopathological and molecular features between proximal and distal
SPs with type II pit pattern
GCHPs were excluded from this analysis since significant differences were observed
in the molecular features between GCHPs and others. As shown in [Table 2], proximal SNs were significantly larger than proximal MVHPs (P < 0.0001). Moreover, a significant difference in the frequency of CIMP was observed
between proximal and distal SNs (64 % vs. 11 %, P = 0.0032). Although the frequency of CIMP was higher in the proximal than in the
distal MVHPs, this difference was not statistically significant (50 % vs. 23 %, P = 0.0952).
Table 2
Clinicopathological findings of serrated polyps by tumor location.
|
|
Proximal
|
Distal
|
|
|
SN[1]
(n = 59)
|
MVHP
(n = 14)
|
SN
(n = 9)
|
MVHP
(n = 22)
|
|
Gender
|
Male
|
37 (63 %)
|
9 (64 %)
|
4 (44 %)
|
19 (86 %)
|
|
Female
|
22 (37 %)
|
5 (36 %)
|
5 (56 %)
|
3 (14 %)
|
|
Age
|
(Median, years)
|
61
|
71.5
|
51
|
60
|
|
(Range, years)
|
23 – 79
|
50 – 80
|
33 – 76
|
35 – 78
|
|
Size[2]
|
(Median, mm)
|
10
|
5.5
|
9.5
|
7
|
|
(Range, mm)
|
5 – 23
|
4 – 10
|
5 – 12
|
4 – 11
|
|
Macroscopic type
|
Protruded
|
1 (2 %)
|
0
|
0
|
5 (23 %)
|
|
Superficial
|
57 (96 %)
|
13 (93 %)
|
9 (100 %)
|
16 (73 %)
|
|
Combined
|
1 (2 %)
|
1 (7 %)
|
0
|
1 (4 %)
|
|
BRAF
|
Mut +
|
27 (46 %)
|
4 (29 %)
|
4 (44 %)
|
13 (59 %)
|
|
Mut –
|
32 (54 %)
|
10 (71 %)
|
5 (56 %)
|
9 (41 %)
|
|
KRAS
|
Mut +
|
5 (8 %)
|
1 (7 %)
|
1 (11 %)
|
2 (9 %)
|
|
Mut –
|
54 (92 %)
|
13 (93 %)
|
8 (89 %)
|
20 (91 %)
|
|
CIMP[3]
|
Presence
|
37 (64 %)
|
7 (50 %)
|
1 (11 %)
|
5 (23 %)
|
|
Absence
|
21 (36 %)
|
7 (50 %)
|
8 (89 %)
|
17 (77 %)
|
SN, serrated neoplasia; MVHP, microvesicular hyperplastic polyp; Mut + , presence
of mutation; Mut – , absence of mutation.
1 One SSA/P where CIMP status could not be determined.
2 Proximal SN vs. proximal MVHP, P < 0.0001.
3 Proximal SN vs. distal SN, P = 0.0032.
Factors related to CIMP in SPs with type II pit pattern
In the univariate analysis, five significant factors related to CIMP (tumor location,
tumor size, macroscopic type, histology, and BRAF mutation) were selected. Finally, logistic regression analysis revealed that proximal
location as well as BRAF mutation was significantly associated with an increased risk of CIMP ([Table 3]).
Table 3
Clinicopathological and molecular factors associated with CIMP-positive serrated polyps
|
|
CIMP
|
Univariate
|
Multivariate
|
|
|
|
Presence
(n = 51)
|
Absence
(n = 62)
|
P value
|
Odds ratio (95 %CI)
|
P value
|
|
Gender
|
Male
|
34 (67 %)
|
39 (63 %)
|
0.698
|
|
|
|
Female
|
17 (33 %)
|
23 (37 %)
|
|
|
|
|
Age
|
(years)
|
62.2
|
59.6
|
0.242
|
|
|
|
Tumor location
|
Proximal
|
45 (88 %)
|
30 (48 %)
|
< 0.001
|
18.6 (5.1 – 68.3)
|
< 0.001
|
|
Distal
|
6 (12 %)
|
32 (52 %)
|
|
|
|
|
Size
|
(mm)
|
10.6
|
8.4
|
0.006
|
|
|
|
Macroscopic type
|
Protruded[1]
|
11 (22 %)
|
25 (40 %)
|
0.043
|
|
|
|
Superficial
|
40 (78 %)
|
37 (60 %)
|
|
|
|
|
Histology
|
SN[2]
|
38 (75 %)
|
29 (47 %)
|
0.004
|
|
|
|
HP
|
13 (25 %)
|
33 (53 %)
|
|
|
|
|
BRAF
|
Mut +
|
33 (65 %)
|
15 (24 %)
|
< 0.001
|
13.0 (4.1 – 41.3)
|
< 0.001
|
|
Mut –
|
18 (35 %)
|
47 (76 %)
|
|
|
|
|
KRAS
|
Mut +
|
5 (10 %)
|
7 (11 %)
|
> 0.999
|
|
|
|
Mut –
|
46 (90 %)
|
55 (89 %)
|
|
|
|
CIMP, CpG island methylator phenotype; SN, serrated neoplasia; HP, hyperplastic polyp;
Mut + , presence of mutation; Mut – , absence of mutation.
1 Protruded type lesions include three combined type lesions.
2 One SSA/P, where CIMP status could not be determined, was excluded from this analysis.
Discussion
SAs, especially SSA/Ps, are thought to be precursor lesions of CIMP-positive CRCs
[5]. The association of molecular alterations with the histologic subtypes of SPs and
CIMP CRCs has led to the description of the sequential pathway from HP through SSA/P
with or without cytological dysplasia to CIMP CRC [5]. This sequence occurs more often in the proximal than in the distal colon. However,
it remains uncertain whether SSA/Ps could develop directly from HPs or normal colon
mucosa. Our data are in agreement with Buda et al. [23] who reported no significant differences in the frequency of BRAF mutations between proximal and distal SNs or MVHPs. Moreover, our data indicated
that proximal MVHPs and SSA/Ps presented higher frequencies of CIMP than distal lesions.
These observations suggest that proximal MVHPs could progress through SSA/Ps along
with CIMP.
TSAs are more likely to be more molecularly diverse than SSA/Ps in that they might
show either KRAS or BRAF mutations, or either low or high levels of CIMP [5]
[24]. In our study, only one TSA with a type II pit pattern had BRAF mutations and CIMP (data not shown). We previously reported a higher frequency of
BRAF mutations and CIMP in TSAs with a hyperplastic pit pattern, compared to those with
other pit patterns [14]. Molecular diversity might be associated with mucosal crypt pattern on the surface
of TSAs.
The current issue is considering the types of SP that should be removed endoscopically
in clinical practice. However, several endoscopic features have recently been identified.
SSA/Ps, especially in the proximal colon, are often covered with a tenacious mucus
cap [25]. A recent prospective study reported that 64 % of SSA/Ps presented a mucus cap [26]. Furthermore, a rim of debris and bubbles, alteration of the contour of a fold and
interruption of the underlying vascular pattern were identified as endoscopic features
of SSA/Ps but not frequently found [26]. A dye-spraying or image-enhancing technique may allow for a reliable differentiation
of SSA/Ps from HPs during colonoscopy. A type II-O pit pattern observed on the surface
of the lesion is specific to SSA/P [13]. However, this is not sensitive for SSA/P (lower sensitivity and negative predictive
value) [13]. Moreover, magnifying colonoscopy, which is rarely available in western countries,
is necessary to recognize the type II-O pit pattern [25]. We previously reported that Kudo’s type II pit pattern can be observed on the surface
of SPs using non-magnifying colonoscopy [14].
Although our study was retrospective, several issues of therapeutic strategy for SPs
have been addressed. Rex et al. [25] recommended the complete endoscopic removal of all SPs, apart from diminutive sigmoid
or rectal lesions. Our criteria used to select the treatment of SPs with hyperplastic
pattern were similar to their recommendations. In our study, 85.3 % of polyps with
a type II pit pattern, which were removed endoscopically in this study, showed serrated
histology (SSA/P, TSA, and HP). However, the precursor polyp of CIMP CRCs needs to
be removed effectively. Our logistic regression analysis indicated that proximal location
as well as BRAF mutation were independent risk factors for SPs with CIMP. Therefore, endoscopists
should aggressively remove proximal SPs when SPs with a type-II pit pattern measuring
6 mm or larger in size are detected by chromoendoscopy or electronic chromoendoscopy
(e. g., narrow-band imaging).
In summary, our results indicate that proximal and distal SPs with a hyperplastic
crypt pattern have distinctive molecular features and that proximal MVHPs may develop
more frequently through SSA/Ps with or without cytological dysplasia to CIMP CRCs,
compared to distal MVHPs. The appropriate screening and therapeutic intervention programs
for CRCs should take these observations into account.
