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Aims: Recently, several morphological variants of traditional serrated adenoma (TSA) of the colorectum have been recognised, and mucin-rich TSA (MR-TSA) and serrated tubulovillous adenoma (S-TVA) were introduced as distinct morphological variants separate from conventional TSA (C-TSA). This aim of this study was to elucidate the immunohistochemical and genetic characteristics of MR-TSAs., Methods and Results: We performed immunostaining for cytokeratins (CKs) (e.g. CK7 and CK20), mucins (e.g. MUC2, MUC5AC, MUC6, and CD10), β-catenin, and MLH1, and direct sequencing of BRAF/KRAS, in 32 MR-TSAs, 35 C-TSAs, and 23 S-TVAs. Immunohistochemically, all studied cases were positive for CK20, whereas few cases were positive for CK7, with no significant differences between the three groups. Regarding mucin-phenotypic expression, all cases were positive for MUC2 but negative for MUC6 and CD10. MUC5AC positivity was found significantly more frequently in MR-TSAs (53%) than in C-TSAs (26%; P = 0.026). Nuclear β-catenin expression in MR-TSAs was significantly less frequent than in S-TVAs (P = 0.002). MLH1 nuclear staining was retained in all cases. Genetically, MR-TSAs (75%) more frequently harboured BRAF mutation than C-TSAs (49%; P = 0.044) or S-TVAs (4%; P < 0.001), whereas only two cases (6%) of MR-TSA harboured a KRAS mutation, a frequency that was significantly lower than that in C-TSAs (26%; P = 0.047) or S-TVAs (57%; P < 0.001)., Conclusions: MR-TSAs more frequently harboured BRAF mutations than C-TSAs, and had distinct immunohistochemical characteristics. Our findings indicated that MR-TSAs could be important precursors of BRAF-mutated, microsatellite-stable subtypes of colorectal carcinoma., (© 2018 John Wiley & Sons Ltd.)

The histopathological characteristics of colorectal submucosal invasive carcinoma arising in sessile serrated adenoma/polyp (SSA/P), a rare malignant tumour, have not yet been fully elucidated. To investigate the features of such, we retrospectively analysed 40 submucosal invasive carcinomas with SSA/P (CA-SSA/P) and compared them to 129 cases of submucosal invasive carcinoma with conventional tubular adenoma (CA-AD). We additionally performed hMLH1 immunostaining. CA-SSA/Ps were significantly smaller than CA-ADs (P < 0.001). Histologically, well to moderately differentiated adenocarcinoma was predominant in both CA-SSA/Ps and CA-ADs. No significant differences in depth of invasion were found between the two groups. However, lymphatic invasion was more often found in CA-SSA/Ps (30%) than in CA-ADs (13%; P = 0.028), as was lymph node metastasis (CA-SSA/Ps, 28%; CA-ADs, 7%; P = 0.011). Furthermore, mucinous component and serrated architecture were significantly more frequent in CA-SSA/Ps (30 and 63%) than in CA-ADs (5 and 18%; P < 0.001, respectively). Tumour-infiltrating lymphocytes and Crohn-like inflammatory reaction were also more frequently found in CA-SSA/Ps (70 and 30%) than in CA-ADs (31 and 9%; P ≤ 0.001, respectively), whereas the opposite was true of desmoplastic reaction (CA-SSA/Ps, 35%; CA-ADs, 67%; P < 0.001). Loss of hMLH1 expression was more frequent in CA-SSA/P cases (93%) than in CA-AD cases (5%; P < 0.001). In conclusion, CA-SSA/P lesions exhibit a higher potential for lymphatic invasion and lymph node metastasis and have distinct histopathological features, including mucinous component, serrated architecture, tumour-infiltrating lymphocytes, Crohn-like inflammatory reaction, and absence of desmoplastic reaction, compared to their conventional counterparts.

Background and Aims: Sessile serrated adenoma/polyp (SSA/P) is a colorectal polyp that has malignant potential. However, the dysplastic components within an SSA/P can be difficult to detect. This study aimed to clarify the endoscopic characteristics of SSA/P with advanced histology., Methods: We examined 462 endoscopically or surgically resected lesions that were pathologically diagnosed as SSA/P, including 414 without and 41 with cytologic dysplasia, and 7 with invasive carcinoma. We retrospectively studied the clinicopathologic and endoscopic characteristics and performed pit pattern analysis., Results: A stepwise increase in the size of the SSA/P series was identified along with their dysplastic progression, although 19 of 48 (39.6%) SSA/Ps with dysplasia/carcinoma were ≤10 mm in size. Most lesions were covered with a mucus cap. Macroscopically, (semi)pedunculated morphology, double elevation, central depression, and reddishness were found more frequently in SSA/P with cytologic dysplasia and invasive carcinoma ([semi]pedunculated morphology, 17.1%/28.6%; double elevation, 63.4%/57.1%; central depression, 9.8%/28.6%; reddishness, 39.0%/85.7%) than in those without dysplasia (4.6%, 4.6%, 3.9%, and 3.4%, respectively). Furthermore, the presence of at least 1 of these 4 markers had high sensitivity (91.7%) for identifying the dysplasia/carcinoma within a SSA/P, with a specificity of 85.3%. In the pit pattern analysis, all SSA/Ps without dysplasia exhibited type II pit pattern only, whereas 94.4% of SSA/Ps with dysplasia/carcinoma showed type II in addition to type III L , IV, V I , or V N pit patterns., Conclusions: In an SSA/P series, endoscopic characteristics, including (semi)pedunculated morphology, double elevation, central depression, and reddishness, in addition to the use of magnifying endoscopy, may be useful to accurately diagnose advanced histology within an SSA/P., (Copyright © 2017 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Sessile serrated adenoma/polyp (SSA/P) is considered as an early precursor in the serrated neoplasia pathway leading to colorectal cancer development. The conventional adenoma-carcinoma sequence is associated with activation of the WNT signaling pathway, although its role in serrated lesions is still controversial. To clarify differences in WNT signaling activation in association with MLH1 methylation or BRAF/KRAS mutations between serrated and conventional routes, we performed β-catenin immunostaining, methylation-specific PCR for MLH1 and WNT signaling associated genes such as AXIN2, APC, and MCC and secreted frizzled-related proteins (SFRPs), and direct sequencing of BRAF/KRAS in 27 SSA/Ps, 14 SSA/Ps with high-grade dysplasia and 9 SSA/Ps with submucosal carcinoma, as well as 19 conventional adenomas, 26 adenomas with high-grade dysplasia and 25 adenomas with submucosal carcinoma. Nuclear β-catenin labelings were significantly lower in the serrated series than in their adenoma counterparts, and a significant increment in those labelings was found from SSA/Ps to those with high-grade dysplasia or submucosal carcinoma. The frequency of MLH1 and SFRP4 methylation was significantly higher in SSA/P series, as compared with corresponding adenoma series. AXIN2 and MCC were more frequently methylated in SSA/Ps with high-grade dysplasia and those with submucosal carcinoma than in adenoma counterparts. Stepwise increment of AXIN2 and MCC methylation was identified from SSA/Ps through those with high-grade dysplasia to those with submucosal carcinoma. A significant correlation was seen between nuclear β-catenin expression and methylation of AXIN2 or MCC in the SSA/P series. BRAF mutation was more frequent, whereas KRAS mutation was less frequent in the SSA/P series as compared with the adenoma series. There was an inverse association of BRAF mutation with AXIN2 methylation in SSA/P series. In conclusion, WNT/β-catenin signal activation mediated by the methylation of SFRP4, MCC, and AXIN2 may make different contributions to colorectal neoplasia between the serrated and conventional routes.

Background and Aims: The serrated colorectal carcinoma (CRC) as proposed to arise from serrated adenoma (SA) is characterized by upregulation of HIF1α, suppression of PTCH or EphB2, loss of DNA repair proteins, and BRAF mutation. The aim of this study was to evaluate alterations of these candidates involved in the serrated pathway in colorectal polyps., Methods: We analyzed immunoreactivity of these proteins, methylation of PTCH and EphB2, and mutation of BRAF and Kras in sessile SAs (SSAs; n = 32), traditional SAs (n = 28), hyperplastic polyps (HPs; n = 24), and conventional adenomas (ADs; n = 21)., Results: Increase of nuclear HIF1α expression was more frequent in SA than HP, but less frequent in SA than AD (P < 0.001). Increase of PTCH expression was not found in SSA or HP, but was evident in about half of traditional SA and all AD (P < 0.001). Decrease of EphB2 expression was more prominent in SA than HP or AD (P ≤ 0.005). Loss of hMLH1 and MGMT expression were most frequent in SSA (P < 0.001). Loss of hMSH2 showed more pronounced in SA and HP than AD (P ≤ 0.004). Methylations of PTCH and EphB2 were rare in all categories. BRAF mutation harbored frequently in SA, but not AD; only AD harbored Kras mutation., Conclusions: This work provides evidence of similarity of HIF1α, EphB2 or DNA repair proteins expression, and BRAF mutation in serrated CRCs and their precursors, especially SSA, compared with AD and HP., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background: Colorectal sessile serrated adenoma/polyps (SSA/Ps) are characterized by asymmetrical distribution of Ki67-positive cells, which varies among crypts and involves the crypt length to a variable extent; the pattern has been designated as aberration of crypt cell compartmentalization. The regenerating gene (REG) Iα is a cell growth and/or anti-apoptotic factor and its overexpression might be associated with aberration of crypt cell compartmentalization in SSA/Ps. We investigated REG Iα expression in SSA/Ps in comparison to hyperplastic polyps (HPs)., Methods: A total of 64 cases of serrated polyps (≥ 10 mm in size), including 53 SSA/Ps and 11 HPs, were included in the present study. Immunostaining was performed using a labeled streptavidin-biotin method. REG Iα expression was classified as follows: (i) expression of endocrine cells: grade 0 (a few positive cells) to 3 (marked increase in positive cells); (ii) expression of goblet cells: grade 0 (negative) to 2 (positive for crypts and surface epithelial cells); (iii) staining intensity of goblet cells: grade 0 (negative) to 2 (strong); (iv) staining intensity of crypt (absorptive) cell membranes: grade 0 (negative) to 2 (strong). The presence of aberration of crypt cell compartmentalization was assessed using Ki67 immunostaining., Results: With regard to the REG Iα expression of endocrine cells, 8 out of 11 HPs (73%) were grade 0, whereas 51 of 53 SSA/Ps (96%) were grade 1 or higher (p < 0.001). With regard to the distribution of REG Iα-immunoreactive goblet cells, 10 of 11 HPs (91%) were grade 1, whereas 50 of 53 SSA/Ps (94%) were grade 2 (p < 0.001). A similar trend was found in the staining intensity of goblet cells or crypt cell membranes (p = 0.011). Aberration of crypt cell compartmentalization was more frequently identified in SSA/Ps (72%) than in HPs (18%; p = 0.002). A significant association was observed between REG Iα overexpression and the aberration of crypt cell compartmentalization in serrated polyps (p = 0.037)., Conclusions: REG Iα overexpression is a characteristic of SSA/Ps, which appears to reflect aberration of crypt cell compartmentalization., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7240956081100040.

Aim: To clarify differences in mucin phenotype, proliferative activity and oncogenetic alteration among subtypes of colorectal laterally spreading tumor (LST)., Methods: LSTs, defined as superficial elevated lesions greater than 10 mm in diameter with a low vertical axis, were macroscopically classified into two subtypes: (1) a granular type (Gr-LST) composed of superficially spreading aggregates of nodules forming a flat-based lesion with a granulonodular and uneven surface; and (2) a non-granular type (NGr-LST) with a flat smooth surface and an absence of granulonodular formation. A total of 69 LSTs, comprising 36 Gr-LSTs and 33 NGr-LSTs, were immunohistochemically stained with MUC2, MUC5AC, MUC6, CD10 (markers of gastrointestinal cell lineage), p53, β-catenin and Ki-67 antibodies, and examined for alteration in exon 1 of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and exon 15 of v-raf murine sarcoma viral oncogene homologue B1 (BRAF) by polymerase chain reaction followed by direct sequencing., Results: Histologically, 15 Gr-LST samples were adenomas with low-grade dysplasia (LGD), 12 were high-grade dysplasia (HGD) and 9 were adenocarcinomas invading the submucosa (INV), while 12 NGr-LSTs demonstrated LGD, 14 HGD and 7 INV. In the proximal colon, MUC5AC expression was significantly higher in the Gr-type than the NGr-type. MUC6 was expressed only in NGr-LST. MUC2 or CD10 did not differ. P53 expression demonstrated a significant stepwise increment in progression through LGD-HGD-INV with both types of LST. Nuclear β-catenin expression was significantly higher in the NGr-type. Ki-67 expression was significantly higher in the Gr-type in the lower one third zone of the tumor. In proximal, but not distal colon tumors, the incidence of KRAS provided mutation was significantly higher in the Gr-type harboring a specific mutational pattern (G12V). BRAF mutations (V600E) were detected only in two Gr-LSTs., Conclusion: The two subtypes of LST, especially in the proximal colon, have differing phenotypes of gastrointestinal cell lineage, proliferation and activation of Wnt/β-catenin or RAS/RAF/extracellular signal-regulated kinase signaling.

Background/aims: Serrated adenomas (SAs) of the colorectum can be broadly divided into two subtypes: type I more closely mimicking hyperplastic polyps, and type II unequivocal traditional adenomas. The aim of this study was to clarify their differential clinicopathologic and colonoscopic features., Methodology: A total of 127 SAs (53 type I, 52 type II and 22 admixed type I+II) were investigated and colonoscopic surface patterns were divided into three categories: speckled, granular and cerebriform., Results: The cerebriform pattern was most frequently observed in all SA types. Types I+II (median size, 7.5 mm) or type II SAs (median size, 10 mm) were generally sessile or pedunculated polyps in the rectosigmoid colon whereas some type I lesions (median size, 5 mm) demonstrated a flat-elevated morphology and were found in the ascending colon and cecum. Co-existing (2/127: 1.6%) invasive carcinomas were only detected with type II SAs. In contrast, synchronous invasive carcinomas distant from SAs were more frequently observed with type I (31%) than types I+II (5%) or II (12%)., Conclusions: Clinicopathologic differences are apparent among the types of SAs. A type II SA-invasive carcinoma sequence might exist. We stress recognition of type I SA as a neoplastic, rather than a hyperplastic lesion, often accompanying invasive carcinomas at a distance from the SA.

Purpose: Serrated adenomas (SAs), which include a wide spectrum of lesions, can be broadly divided into two subtypes: type I, closely mimicking hyperplastic polyps (HPs), and type II, unequivocal adenomatous tumor. Our preliminary findings showed clinicopathologic differences between them. The present study was conducted to investigate apoptotic activity and expression of the cell cycle regulator proteins p21(WAF1/CIP1) and p27(Kip1) in type I and II SAs, as compared with traditional adenomas (TAs) and HPs., Methods: Apoptotic activity was estimated in hematoxylin-eosin stained specimens, and p21(WAF1/CIP1) or p27(Kip1) immunoreactivity was determined in 62 SAs (19 type I and 43 type II), 50 TAs and 19 HPs. The numbers (percentages) of apoptotic or immunoreactive cells were counted per 1,000 epithelial cells in equally separated crypt zones (upper, middle, and lower thirds)., Results: The apoptotic activity in the middle, but not the upper or lower crypt zone was higher in type II SAs (median 0.2%, interquartile range 0.1-0.5%) than in HPs (0.1%, 0.1-0.2%, P<0.01), whereas it was lower in type I SAs (0.2%, 0.1-0.3%) than in TAs (0.5%, 0.2-0.6%, P<0.001). P21(WAF1/CIP1) expression in the lower crypt zone was higher in both type I and type II SAs (19.8%, 7.0-33.2% and 20.4%, 3.9-47.8%, P<0.0001) than in TAs (1.2%, 0.6-5.2%), and a similar tendency was also observed for the middle crypt zone. p27(Kip1) expression did not vary among the groups., Conclusions: The differences in apoptotic activity and p21(WAF1/CIP1) expression between SAs and TAs or HPs indicate that SA should be considered as a distinct subtype of colorectal neoplasm. The two subtypes of SA do not differ in these parameters despite specific clinicopathological features.

Background and Aims The serrated colorectal carcinoma ( CRC) as proposed to arise from serrated adenoma ( SA) is characterized by upregulation of HIF1α, suppression of PTCH or Eph B2, loss of DNA repair proteins, and BRAF mutation. The aim of this study was to evaluate alterations of these candidates involved in the serrated pathway in colorectal polyps. Methods We analyzed immunoreactivity of these proteins, methylation of PTCH and Eph B2, and mutation of BRAF and Kras in sessile SAs ( SSAs; n = 32), traditional SAs ( n = 28), hyperplastic polyps ( HPs; n = 24), and conventional adenomas ( ADs; n = 21). Results Increase of nuclear HIF1α expression was more frequent in SA than HP, but less frequent in SA than AD ( P < 0.001). Increase of PTCH expression was not found in SSA or HP, but was evident in about half of traditional SA and all AD ( P < 0.001). Decrease of EphB2 expression was more prominent in SA than HP or AD ( P ≤ 0.005). Loss of hMLH1 and MGMT expression were most frequent in SSA ( P < 0.001). Loss of hMSH2 showed more pronounced in SA and HP than AD ( P ≤ 0.004). Methylations of PTCH and Eph B2 were rare in all categories. BRAF mutation harbored frequently in SA, but not AD; only AD harbored Kras mutation. Conclusions This work provides evidence of similarity of HIF1α, Eph B2 or DNA repair proteins expression, and BRAF mutation in serrated CRCs and their precursors, especially SSA, compared with AD and HP. [ABSTRACT FROM AUTHOR]

Purpose. Serrated adenomas (SAs), which include a wide spectrum of lesions, can be broadly divided into two subtypes: type I, closely mimicking hyperplastic polyps (HPs), and type II, unequivocal adenomatous tumor. Our preliminary findings showed clinicopathologic differences between them. The present study was conducted to investigate apoptotic activity and expression of the cell cycle regulator proteins p21WAF1/CIP1 and p27Kip1 in type I and II SAs, as compared with traditional adenomas (TAs) and HPs. Methods. Apoptotic activity was estimated in hematoxylin-eosin stained specimens, and p21WAF1/CIP1 or p27Kip1 immunoreactivity was determined in 62 SAs (19 type I and 43 type II), 50 TAs and 19 HPs. The numbers (percentages) of apoptotic or immunoreactive cells were counted per 1,000 epithelial cells in equally separated crypt zones (upper, middle, and lower thirds). Results. The apoptotic activity in the middle, but not the upper or lower crypt zone was higher in type II SAs (median 0.2%, interquartile range 0.1–0.5%) than in HPs (0.1%, 0.1–0.2%, P<0.01), whereas it was lower in type I SAs (0.2%, 0.1–0.3%) than in TAs (0.5%, 0.2–0.6%, P<0.001). P21WAF1/CIP1 expression in the lower crypt zone was higher in both type I and type II SAs (19.8%, 7.0–33.2% and 20.4%, 3.9–47.8%, P<0.0001) than in TAs (1.2%, 0.6–5.2%), and a similar tendency was also observed for the middle crypt zone. p27Kip1 expression did not vary among the groups. Conclusions. The differences in apoptotic activity and p21WAF1/CIP1 expression between SAs and TAs or HPs indicate that SA should be considered as a distinct subtype of colorectal neoplasm. The two subtypes of SA do not differ in these parameters despite specific clinicopathological features. [ABSTRACT FROM AUTHOR]

A case of an aggressive desmoid tumor in a patient with familial adenomatous polyposis is described. The lesion rapidly enlarged with compression of adjacent structures including the ureter and small bowel, and the patient died because of small bowel perforation and hydronephrosis 3 years after detection of small desmoid tumors at the time of a prophylactic coloproctectomy for a colon carcinoma. Immunohistochemically, proliferating cell nuclear antigen (PCNA), p21WAF1/CIP1 cathepsin D indices, but not the bcl-2 index, which were defined as the numbers of immunoreactive tumor cells per 1000 tumor cells, increased in line with tumor progression. The tumor did not show staining for collagen IV, but was characterized by intense staining for basic fibroblast growth factor (bFGF). Accordingly, tumor aggression was related to increases in both cell proliferation and protease activity, as well as an enhanced expression of bFGF. In addition, the desmoid tumor showed deregulation between PCNA and p21WAF1/CIP1 because the normal inverse relation between these two was not apparent. [ABSTRACT FROM AUTHOR]