Identification of Early Events in Serrated Pathway Colorectal Tumorigenesis by Using Digital Spatial Profiling.

INTRODUCTION: The colorectal serrated pathway involves precursor lesions known as sessile serrated lesions (SSL) and traditional serrated adenomas (TSA). Mutations in BRAF or KRAS are crucial early events in this pathway. Additional genetic and epigenetic changes contribute to the progression of these lesions into high-grade lesions and, eventually, invasive carcinoma. METHODS: We employed digital spatial profiling to investigate the transcriptional changes associated with SSL and TSA. The genes identified are confirmed by immunohistochemical (IHC) staining. Colorectal cancer (CRC) cell lines with CEACAM6 overexpression and knockdown were established to study the roles of CEACAM6 on tumorigenesis of CRC. RESULTS: Ten genes were upregulated in SSL and TSA, and seven were upregulated in both types of lesions. IHC staining confirmed overexpression of CEACAM6, LCN2, KRT19, and lysozyme in SSL and TSA. CEACAM6 expression is an early event in the serrated pathway but a late event in the conventional pathway. Using cell line models, we confirmed that CEACAM6 promotes CRC cells' proliferation, migration, and invasion abilities. CONCLUSION: These results highlight that the transcriptional changes in the early stages of tumorigenesis exhibit relative uniformity. Identifying these early events may hold significant promise in elucidating the mechanisms behind tumor initiation.

Downregulation of SMOC1 is associated with progression of colorectal traditional serrated adenomas.

BACKGROUND: Aberrant DNA methylation is prevalent in colorectal serrated lesions. We previously reported that the CpG island of SMOC1 is frequently methylated in traditional serrated adenomas (TSAs) and colorectal cancers (CRCs) but is rarely methylated in sessile serrated lesions (SSLs). In the present study, we aimed to further characterize the expression of SMOC1 in early colorectal lesions. METHODS: SMOC1 expression was analyzed immunohistochemically in a series of colorectal tumors (n = 199) and adjacent normal colonic tissues (n = 112). RESULTS: SMOC1 was abundantly expressed in normal colon and SSLs while it was significantly downregulated in TSAs, advanced adenomas and cancers. Mean immunohistochemistry scores were as follows: normal colon, 24.2; hyperplastic polyp (HP), 18.9; SSL, 23.8; SSL with dysplasia (SSLD)/SSL with early invasive cancer (EIC), 15.8; TSA, 5.4; TSA with high grade dysplasia (HGD)/EIC, 4.7; non-advanced adenoma, 21.4; advanced adenoma, 11.9; EIC, 10.9. Higher levels SMOC1 expression correlated positively with proximal colon locations and flat tumoral morphology, reflecting its abundant expression in SSLs. Among TSAs that contained both flat and protruding components, levels of SMOC1 expression were significantly lower in the protruding components. CONCLUSION: Our results suggest that reduced expression of SMOC1 is associated with progression of TSAs and conventional adenomas and that SMOC1 expression may be a biomarker for diagnosis of serrated lesions and risk prediction in colorectal tumors.

Baseline Characteristics and Longitudinal Outcomes of Traditional Serrated Adenomas: A Cohort Study.

BACKGROUND AND AIMS: Traditional serrated adenomas (TSAs) may confer increased risk for colorectal cancer (CRC). Our objective with this study was to examine clinical characteristics and long-term outcomes associated with TSA diagnosis. METHODS: We conducted a retrospective cohort study of U.S. Veterans ≥18 years of age with ≥1 TSA between 1999 and 2018. Baseline characteristics, colonoscopy findings, and diagnosis of incident and fatal CRC were abstracted. Advanced neoplasia was defined by CRC or adenoma with high-grade dysplasia, villous histology, or size ≥1 cm. Follow-up was through CRC diagnosis, death, or end of study (December 31, 2018). RESULTS: A total of 853 Veterans with a baseline TSA were identified; 74% were ≥60 years of age, 96% were men, 14% were Black, and 73% were non-Hispanic White. About 64% were current or former smokers. Over 2044 total person-years at follow-up, there were 11 incident CRC cases and 1 CRC death. Cumulative CRC incidence was 1.34% (95% confidence interval [CI], 0.67%-2.68%), and cumulative CRC death was 0.12% (95% CI, 0.00%-0.35%). Among the subset of 378 TSA patients with ≥1 surveillance colonoscopy, 65.1% had high-risk neoplasia on follow-up. CRC incidence among TSA patients was significantly higher than in a comparison cohort of patients with normal baseline colonoscopy at baseline (hazard ratio, 3.70; 95% CI, 1.63-8.41) and similar to a comparison cohort with baseline conventional advanced adenoma (hazard ratio, 0.86; 95% CI, 0.45-1.64). CONCLUSION: Individuals with TSA have substantial risk for CRC based on their cumulative CRC incidence, as well as significant risk of developing other high-risk neoplasia at follow-up surveillance colonoscopy. These data underscore importance of current recommendations for close colonoscopy surveillance after TSA diagnosis.

Endoscopic features of isolated and traditional serrated adenoma-associated superficially serrated adenomas of the colorectum.

BACKGROUND AND AIM: Superficially serrated adenoma (SuSA) is a recently proposed subtype of colorectal serrated lesions. It is characterized by distinct clinicopathological and molecular features, including mixed serrated and adenomatous histology and frequent genetic alterations involving KRAS and RSPO. This study aimed to characterize the endoscopic features of isolated and traditional serrated adenoma (TSA)-associated SuSAs. METHODS: We retrospectively evaluated the endoscopic findings of 25 isolated SuSAs and 21 TSA-associated SuSAs that were histologically and molecularly characterized. RESULTS: SuSAs appeared as a sessile polyp or slightly elevated lesion located mostly in the sigmoid colon and rectum (88%). The size was between 3 and 20 mm (median, 6 mm). Most of them exhibited KRAS mutations (96%) and RSPO fusions/overexpression (92%). Endoscopically, many lesions had a whitish color (84%), a distinct border (96%), an irregular border (76%), and a lobulated surface (72%). However, diminutive lesions exhibited overlapping features with hyperplastic polyps. On narrow-band imaging, vessel patterns were invisible or appeared as lacy microvessels in most lesions (80%). Chromoendoscopy invariably showed stellar or elongated/branched stellar pits, indicating a serrated microarchitecture. Most TSA-associated SuSAs typically presented as polyps with a two-tier raised appearance, consisting of whitish lower and reddish higher components corresponding to a SuSA and a TSA, respectively. CONCLUSIONS: SuSAs exhibit several characteristic endoscopic features on white-light and image-enhanced endoscopy. Diminutive lesions exhibit endoscopic features overlapping with hyperplastic polyps. Nonetheless, the endoscopic diagnosis of larger and TSA-associated SuSAs may be feasible.

Linked color imaging improves visibility of colorectal serrated lesion by high color contrast to surrounding mucosa.

OBJECTIVES: This study aimed to objectively evaluate the efficacy of linked color imaging (LCI) in diagnosing colorectal serrated lesions by utilizing visibility scores and color differences. METHODS: We examined 89 serrated lesions, including 36 hyperplastic polyps (HPs), 47 sessile serrated lesions (SSLs), and six traditional serrated adenomas (TSAs). Visibility changes were scored by six endoscopists as follows: 4, excellent; 3, good; 2, fair; and 1, poor. Furthermore, images obtained by white-light imaging (WLI) or LCI were assessed using the CIELAB color space in the lesion and adjacent mucosa. We calculated the mean color values (L*, a*, and b*) measured at five regions of interest of the sample lesion and surrounding mucosa and derived the color difference (ΔE*). RESULTS: The visibility scores of both HPs and SSLs in LCI were significantly higher than that in WLI (HPs, 3.67/2.89, P < 0.001; SSLs, 3.07/2.36, P < 0.001). Furthermore, SSLs showed a significantly higher L* value and significantly lower a* and b* values in LCI than the adjacent mucosae (L*, 61.76/58.23, P = 0.016; a*, 14.91/17.58, P = 0.019; b*, 20.42/24.21, P = 0.007), while WLI produced no significant difference in any color value. A similar trend was apparent in HPs. In all serrated groups, LCI revealed significantly greater ΔE* values between the lesion and adjacent mucosa than WLI (HPs, 11.54/6.12; SSLs, 13.43/7.67; TSAs, 35.00/22.48). CONCLUSION: Linked color imaging showed higher color contrast between serrated lesions and the surrounding mucosae compared with WLI, indicating improved visibility of colorectal serrated lesion using LCI.

Proteome analysis of formalin-fixed paraffin-embedded colorectal adenomas reveals the heterogeneous nature of traditional serrated adenomas compared to other colorectal adenomas.

Traditional serrated adenoma (TSA) remains the least understood of all the colorectal adenomas, although these lesions have been associated with a significant cancer risk, twice that of the conventional adenoma (CAD) and of the sessile serrated adenoma (SSA/P). This study was performed to investigate the proteomic profiles of the different colorectal adenomas to better understand the pathogenesis of TSA. We performed a global quantitative proteome analysis using the label-free quantification (LFQ) method on 44 colorectal adenoma (12 TSAs, 15 CADs, and 17 SSA/Ps) and 17 normal colonic mucosa samples, archived as formalin-fixed paraffin-embedded blocks. Unsupervised consensus hierarchical clustering applied to the whole proteomic profile of the 44 colorectal adenomas identified four subtypes: C1 and C2 were well-individualized clusters composed of all the CADs (15/15) and most of the SSA/Ps (13/17), respectively. This is consistent with the fact that CADs and SSA/Ps are homogeneous and distinct colorectal adenoma entities. In contrast, TSAs were subdivided into C3 and C4 clusters, consistent with the more heterogeneous entity of TSA at the morphologic and molecular levels. Comparison of the proteome expression profile between the adenoma subtypes and normal colonic mucosa further confirmed the heterogeneous nature of TSAs, which overlapped either on CADs or SSA/Ps, whereas CADs and SSAs formed homogeneous and distinct entities. Furthermore, we identified LEFTY1 a new potential marker for TSAs that may be relevant for the pathogenesis of TSA. LEFTY1 is an inhibitor of the Nodal/TGFß pathway, which we found to be one of the most overexpressed proteins specifically in TSAs. This finding was confirmed by immunohistochemistry. Our study confirms that CADs and SSA/Ps form homogeneous and distinct colorectal adenoma entities, whereas TSAs are a heterogeneous entity and may arise from either SSA/Ps or from normal mucosa evolving through a process related to the CAD pathway. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Traditional Serrated Adenomas on CT Colonography: International Multicenter Experience With This Rare Colorectal Neoplasm.

OBJECTIVE. Serrated polyps include hyperplastic polyps, sessile serrated polyps, and traditional serrated adenomas (TSAs). Hyperplastic polyps and sessile serrated polyps account for approximately 99% of all serrated lesions; TSAs are rare. However, both sessile serrated polyps and TSAs are now recognized as precursor lesions to carcinogenesis, representing approximately one-fourth of all sporadic colorectal cancers. We report what is, to our knowledge, the first series describing the characteristics of CTAs on CT colonography (CTC). MATERIALS AND METHODS. An international, multicenter, retrospective review of CT colonography-detected TSAs diagnosed between 2008 and 2018 was conducted. Data collected included patient demographics and data from CTC, optical colonoscopy, and pathologic analysis. RESULTS. A total of 67 proven TSAs in 58 patients (mean age, 67 years) were identified. The majority (66%) were located in the distal colon (descending colon, sigmoid colon, and rectum), and their mean size was 19 mm (range, 3-80 mm). Small (< 10 mm) TSAs typically had a simple sessile or pedunculated morphologic appearance, whereas large (≥ 10 mm) TSAs tended to be more lobulated and irregular, pedunculated, or carpetlike. The majority (88%) showed at least some contrast medium surface coating. CONCLUSION. We report what we believe to be the first multicenter experience describing the characteristics of TSAs on CTC. Unlike sessile serrated lesions, TSAs are more often left-sided and tend to be more lobulated and irregular. However, like sessile serrated polyps, most TSAs show contrast medium surface coating. Detection of these rare lesions on CTC is important, given their malignant potential.

Traditional serrated adenomas (TSA) and the company they keep: TSA presence predicts advanced neoplasm states.

BACKGROUND: The association of TSAs with metachronous neoplasms is well established and suggests that TSAs would also have an association with synchronous neoplasms. METHODS: We compared odds ratios and rates of synchronous neoplasms found in colonoscopies with and without TSAs. RESULTS: There was a mean of 2.44 neoplasms among TSA cases in comparison with 1.72 in non-TSA cases. The odds ratio for advanced neoplasia was highest among cases with one or more TSAs relative to cases with one or more HPs (7.54 [CI, 4.23-13.44]) when compared with adenomas (1.95 [CI, 1.75-2.17]) and SSPs (2.98 [CI, 2.54-3.5]). CONCLUSIONS: In this study population, there is a 7-fold higher risk of synchronous advanced neoplasms among cases with one or more TSAs.

Detection and clinical characteristics of serrated polyps and conventional adenomas between patients in the outpatient and physical checkup unit receiving colonoscopy.

PURPOSE: The sessile serrated adenoma/polyp detection rate (SSA/PDR) among different colonoscopy indications from daily practice has not been fully understood. This study aimed to evaluate the detection and clinical characteristics of serrated polyps and conventional adenomas between outpatient department (OPD) and physical checkup unit (PCU) patients receiving colonoscopy. METHODS: The data for this retrospective study were collected between 2016 and 2017 at Kaohsiung Veterans General Hospital in Taiwan. A total of 7047 individuals were included, and information on polyp and adenoma detection was extracted from the colonoscopy reports. RESULTS: The adenoma detection rate, the SSA/PDR, and the detection rate of traditional serrated adenoma (TSA) were 32.2%, 0.60%, and 0.50%, respectively. Risk analysis revealed no significant difference (p = 0.095) in SSA/PDR between individuals < 50 years and ≥ 50 years, and no trend of increased SSA/PDR as age increased was observed (p = 0.320). SSA/P and TSA had higher risks for synchronous advanced neoplasia than conventional adenoma, but with proximal hyperplastic polyps lower (p < 0.001, respectively). No significant difference of SSA/PDR between OPD and PCU patients was observed (p = 1.000); however, the age of SSA/P was significantly older in OPD than in PCU patients (p = 0.048). CONCLUSION: The detection rates of CA and TSA were associated with age groups; however, SSA/PDR was insignificantly higher among individuals aged < 50 years than those with other age groups. In addition, SSA/PDR between OPD and PCU patients was not significantly found in daily practice of colonoscopies.

Macroscopic and microscopic morphology and molecular profiling to distinguish heterogeneous traditional serrated adenomas of the colorectum.

OBJECTIVES: Serrated lesions of the colorectum often have complex histological morphology, and some groups include subtypes with different molecular biology. This study aimed to characterize serrated lesions with heterogeneous histology that was dominated by a traditional serrated adenoma (TSA) component. METHODS: Representative lesions were selected based on both endoscopic and histological features. If a lesion had more than one component, each of the different structural parts was considered as a separate sample. DNA was extracted from 177 samples of 60 lesions and amplified to screen for BRAF and K/NRAS mutations. RESULTS: Heterogeneous TSA samples were classified into four categories: sessile serrated lesion with TSA (SA-1); TSAs with microvesicular hyperplastic polyp (SA-2); TSAs with unclassified adenoma, characterized by tubulo-serrated histology (SA-3); and TSAs with conventional adenomas (SA-4). On endoscopy, SA-1 lesions had sessile-elevated morphology with the small reddish elevations; SA-2 lesions had a pedunculated appearance with a whitish mucosal component at the stalk; SA-3 lesions had a sessile-elevated component surrounded by flat spreading margins; and SA-4 lesions had mixed adenomatous morphology. Eighteen of the 19 category SA-1 and -2 lesions (95%) had BRAF mutations, and all of the SA-3 and -4 lesions had K/NRAS mutations. CONCLUSIONS: Traditional serrated adenomas were classified into two phenotypes according to their molecular characteristics: microvesicular serrated subtypes with BRAF mutations (SA-1 and -2 lesions) and subtypes containing tubulo-serrated/conventional adenoma with K/NRAS mutations (SA-3 and -4 lesions). Each subtype had characteristic macroscopic and microscopic morphologies and was distinct on endoscopy.

EIF3E-RSPO2 and PIEZO1-RSPO2 fusions in colorectal traditional serrated adenoma.

AIMS: Traditional serrated adenoma (TSA) is an uncommon type of colorectal serrated polyp. RSPO fusions, which potentiate WNT signalling, are common and characteristic genetic alterations in TSA. The aim of this study was to further characterise the prevalence and variation of RSPO fusions in TSA. METHODS AND RESULTS: Quantitative polymerase chain reaction (PCR) analysis of 99 TSAs revealed overexpression of RSPO2 and RSPO3 in six and 29 lesions, respectively. Reverse transcription PCR identified previously reported PTPRK-RSPO3 fusion transcripts in all 29 TSAs with RSPO3 overexpression, confirming that PTPRK-RSPO3 is the predominant RSPO fusion in TSAs. Among the six lesions with RSPO2 overexpression, two overexpressed full-length RSPO2. An EIF3E-RSPO2 fusion, which is a known recurrent RSPO fusion in colorectal cancer, was detected in three lesions. In addition, rapid amplification of cDNA ends identified a novel PIEZO1-RSPO2 fusion in one TSA. All of the four TSAs with RSPO2 fusions concurrently had KRAS mutations and showed the classic histological features. CONCLUSIONS: The present study identified EIF3E-RSPO2 and PIEZO1-RSPO2 in TSAs. Our observations expand the spectrum of RSPO fusions in TSAs, and suggest that TSAs are precursors of colorectal cancers with these RSPO2 fusions.

The inverted appendix - a potentially problematic diagnosis: clinicopathologic analysis of 21 cases.

AIMS: Inverted appendices are rare, but have the potential to cause diagnostic confusion among endoscopists and pathologists. The aim of this study was to describe the clinicopathological features of inverted appendices seen at our institution over the last 30 years. METHODS AND RESULTS: Twenty-one inverted appendices were identified and the clinical and pathological features reviewed. Patients were predominantly middle-aged women. Most cases were detected incidentally on colonoscopy. Endoscopically, inverted appendices appeared polypoid in the proximal caecum. All resections featured associated pathological processes, including endometriosis (n = 3), inflammatory mucocoele (n = 1), low-grade appendiceal mucinous neoplasm (n = 2), traditional serrated adenoma (n = 1) and inflammatory fibroid polyp (n = 1). Five cases were endoscopically mischaracterised as caecal polyps and removed via polypectomy; initial pathological impressions were erroneous in most cases. All polypectomies featured a dome-like configuration covered by mucosa on the convex surface; the majority had aggregates of ganglion cells and neural plexi embedded in muscularis propria. The vast majority of cases, regardless of the procedure, showed lymphoid aggregates. Among post-polypectomy patients with follow-up, none experienced perforation-associated morbidity despite the histological presence of muscularis propria. CONCLUSIONS: The diagnosis of an inverted appendix should be considered in polypectomy specimens from the caecum or appendiceal orifice with (i) dome-like tissue configuration covered by mucosa on the convex surface, (ii) a deep, robust smooth muscle component with ganglion cells (muscularis propria) and (iii) associated lymphoid aggregates. Prompt recognition on H&E will avoid unnecessary time and resource investment.

Validation of serrated polyps (SPs) in Swedish pathology registers.

BACKGROUND: Little is known about the natural history of serrated polyps (SPs), partly due to the lack of large-scale epidemiologic data. In this study, we examined the validity of SP identification according to SNOMED (Systematised Nomenclature of Medicine) codes and free text from colorectal histopathology reports. METHODS: Through the ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) study, we retrieved data on SPs from all pathology departments in Sweden in 2015-2017 by using SNOMED codes and free-text search in colorectal histopathology reports. Randomly selected individuals with a histopathology report of SPs were validated against patient charts using a structured, retrospective review. RESULTS: SPs were confirmed in 101/106 individuals with a histopathology report of SPs, yielding a positive predictive value (PPV) of 95% (95%CI = 89-98%). By year of diagnosis, the PPV was 89% (95%CI = 69-97%), 96% (95%CI = 81-99%) and 97% (95%CI = 89-99%) for individuals diagnosed before 2001 (n = 19), between 2001 and 2010 (n = 26) and after 2010 (n = 61), respectively. According to search method, the PPV for individuals identified by SNOMED codes was 100% (95%CI = 93-100%), and 93% (95%CI = 86-97%) using free-text search. Recorded location (colon vs. rectum) was correct in 94% of all SP histopathology reports (95%CI = 84-98%) identified by SNOMED codes. Individuals with SPs were classified into hyperplastic polyps (n = 34; 32%), traditional serrated adenomas (n = 3; 3%), sessile serrated adenomas/polyps (SSA/Ps) (n = 70; 66%), unspecified SPs (n = 3, 3%), and false positive SPs (n = 5, 5%). For individuals identified by SNOMED codes, SSA/Ps were confirmed in 49/52 individuals, resulting in a PPV of 94% (95%CI: 84-98%). In total, 57% had ≥2 polyps (1: n = 44, 2-3: n = 33 and ≥ 4: n = 27). Some 46% of SPs (n = 71) originated from the proximal colon and 24% were ≥ 10 mm in size (n = 37). Heredity for colorectal cancer, intestinal polyposis syndromes, or both was reported in seven individuals (7%). Common comorbidities included diverticulosis (n = 45, 42%), colorectal cancer (n = 19, 18%), and inflammatory bowel disease (n = 10, 9%). CONCLUSION: Colorectal histopathology reports are a reliable data source to identify individuals with SPs.

Diagnostic and reporting issues of preneoplastic polyps of the large intestine with early carcinoma.

Premalignant polyps of the large intestine are common specimens in surgical pathology. They consist of several different subtypes identifiable by histological criteria that are associated with different molecular characteristics and with the development of different types of colorectal carcinoma. The most common of these is the conventional adenoma, which most commonly leads to carcinomas with a low degree of methylation (CIMP-L) that are microsatellite stable. In Lynch syndrome patients these polyps lead to CIMP-L carcinomas that are microsatellite instable. The second most common is the sessile serrated adenoma, which leads to carcinomas with a high degree of methylation (CIMP-H) that may be either microsatellite stable or instable. The least common premalignant polyp is the traditional serrated adenoma, which can lead to either CIMP-L or CIMP-H carcinomas, most often microsatellite stable. This paper will review the histological features of these lesions, discuss problems in diagnosis and discuss the role of histology in management.

[Comparative assessment of the expression of Muc 2, Muc 5AC, and Muc 6 in serrated neoplasms of the colon]. / Sravnitel'naia otsenka ékspressii Muc 2, Muc 5AC i Muc 6 v zubchatykh novoobrazovaniiakh tolstoi kishki.

In the course of the serrated pathway of carcinogenesis, there are changes in the expression of mucins with a characteristic immunophenotypic sign, such as a late loss of intestinal differentiation and an increase in gastric differentiation. OBJECTIVE: To comparatively assess the expression of Muc 2, Muc 5AC, and Muc 6 in hyperplastic polyps (HPs), sessile serrated adenomas (SSAs) and traditional serrated adenomas (TSAs) of the colon for determination of their role in differential diagnosis. MATERIAL AND METHODS: Sixty-five serrated masses from 52 patients were examined. Among them, there were 26 SSAs, 26 HPs, and 13 TSAs. A histological examination was done using hematoxylin and eosin staining; periodic acid-Schiff reaction in combination with alcian blue, as well as immunohistochemistry with anti-Muc 2, anti-Muc 5AC, and anti-Muc 6 antibodies were used. Genetic testing of the specimens for KRAS and BRAF mutations was also carried out. RESULTS: All the serrated neoplasms of the colon exhibited a pronounced expression of Muc 2. A marked Muc 6 expression in the dilated crypt bases was found in 76.9% of SSAs, while no reaction was seen in 92.3% of HPs and in 100% of TSAs. SSAs were characterized by an intense Muc 5AC expression in the whole length of the crypts and in the surface epithelium in contrast with HPs and TSAs, where the expression of the marker was focal. Comparison of the response of the markers and the presence of gene mutations identified that the SSAs with BRAF mutation intensely expressed along the length of the crypt for Muc 5AC and Muc 6; and the TSAs with KRAS mutation had a moderate focal Muc 5AC expression in the crypt bases in 100% of cases. CONCLUSION: For differential diagnosis of the types of serrated adenomas of the colon, it is useful for a pathologist to apply the immunohistochemical markers Muc 2, Muc 5AC, and Muc 6 in his/her practice.

A morphological and molecular study of proposed early forms of traditional serrated adenoma.

AIMS: Traditional serrated adenoma (TSA) is the least common subtype of serrated colorectal polyp. Large protuberant lesions are easily recognised; however, the origins of TSAs are not known, and early forms have not been described. Some large TSAs present with a flat 'shoulder' component surrounding the central protuberant component. We hypothesised that small polyps with the same histology as these shoulder regions may represent early TSAs. Thus the primary aim of the study is to describe the histology of these presumptive early TSAs. METHODS AND RESULTS: We collected 70 small (<10 mm) polyps that may represent early TSAs on the basis of typical TSA cytology covering the luminal surface. We also identified 12 large TSAs with a shoulder component resembling these small polyps. The study polyp patients had a mean age of 58 years, and 54% were female; the polyps had a mean diameter of 4.1 mm and were predominantly distal (71%). Morphologically, slit-like serrations were present in 81%, ectopic crypt formations were present in 67%, and a villous component was present in 47%. These histological features were similar to those of the 12 shoulder lesions. Immunohistochemical stains showed an absence of ß-catenin nuclear expression in 96% of the small polyps, retained expression of MLH1 in 100%, and Ki67 positivity restricted to the crypt bases and ectopic crypt formations. BRAF and KRAS mutations were identified in 47% and 31% of the polyps, respectively. BRAF-mutated polyps were more likely than KRAS-mutated polyps to arise in a precursor polyp (82% versus 18%, P < 0.001), and were more likely to have slit-like serrations (100% versus 73%, P = 0.003). CONCLUSIONS: These morphological, immunohistochemical and molecular findings are similar to what has been reported in large TSAs, and support the hypothesis that these polyps represent early forms of TSA.

Immunohistochemical and genetic characteristics of a colorectal mucin-rich variant of traditional serrated adenoma.

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), ß-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 ß-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.

Identification of risk factors for sessile and traditional serrated adenomas of the colon by using big data analysis.

BACKGROUND AND AIM: Little is known about the risk factors associated with serrated polyps, because the early studies, which occurred before the new World Health Organization classification was introduced, included mixtures of serrated polyps. This study aimed to evaluate the risk factors associated with the presence of sessile serrated adenomas (SSAs) and traditional serrated adenomas (TSAs) using big data analytics. METHODS: Using a case-control design, we evaluated the risk factors associated with the presence of SSAs and TSAs. Subjects who underwent colonoscopies from 2002 to 2012 as part of the comprehensive health screening programs undertaken at the Samsung Medical Center, Korea, participated in this study. RESULTS: Of the 48 677 individuals who underwent colonoscopies, 183 (0.4%) had SSAs and 212 (0.4%) had TSAs. The multivariate analysis determined that being aged ≥ 50 years (odds ratio [OR] 1.91, 95% confidential interval [CI] 1.27-2.90, P = 0.002) and a history of colorectal cancer among first-degree relatives (OR 3.14, 95% CI 1.57-6.27, P = 0.001) were significant risk factors associated with the presence of SSAs and that being aged ≥ 50 years (OR 2.61, 95% CI 1.79-3.80, P < 0.001), obesity (OR 1.63, 95% CI 1.12-2.36, P = 0.010), and a higher triglyceride level (OR 1.63, 95% CI 1.12-2.36, P = 0.010) were independent risk factors associated with the presence of TSAs. CONCLUSIONS: We used big data analytics to determine the risk factors associated with the presence of specific polyp subgroups, and individuals who have these risk factors should be carefully scrutinized for the presence of SSAs or TSAs during screening colonoscopies.

[Coexpression of CD44 and Ki-67 in colon`s neoplast]. / Koékspressiia CD44 i Ki-67 v novoobrazovaniiakh tolstoi kishki.

AIM: the evaluation of Ki-67 and CD44 expression in the 'serrated' polyps of the colon and comparison them with adenocarcinomas and tubular and tubule-villous adenomas of the colon. MATERIAL AND METHODS: The study is including 49 'serrated' polyps, 34 tubular (AT) and tubulo-villous (ATV) adenomas and 32 adenocarcinomas of the colon. Antibodies CD44 and Ki-67 were used as immunohistochemical markers in this study. RESULTS: A statistically significant difference (p<0.01) was observed between traditional serrated adenomas (TSA) from hyperplastic polyps (HP) and sessile serrated adenomas (SSA) in the Ki-67 level and the localization of the Ki-67 and CD44 reaction: surface areas of the crypts (upper third) in TSA and base of crypts (lower third) in HP and SSA. There was no difference between HP and SSA (p>0.05), neither by marker localization, nor by their level. In all 'serrated' polyps of the colon, the Ki-67 reaction was nuclear; CD44 - membrane (except for 1 TSA). CONCLUSION: we are the first ones who suggested to evaluate not the overall level of reactions of CD44 and Ki-67, but particular level for each third part of crypts. The similarities of TSA, AT and ATV and between HP and SSA are shown as well as the principal statistical difference between these two groups. The cytoplasmic reaction of CD44 in adenocarcinomas and the membrane reaction of CD44 in 98% of the 'serrated' polyps of the colon are described. For the first time coexpression of CD44 and Ki-67 on particulate thirds of crypts in neoplasms of the colon is shown and the potential reasons for this phenomenon are discussed.