BACKGROUND: 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.
CONCLUSIONS: 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.

The serrated pathway to colorectal cancers (CRCs) is a significant pathway encompassing five distinct types of lesions, namely hyperplastic polyps (HPs), sessile serrated lesions (SSLs), sessile serrated lesions with dysplasia (SSL-Ds), traditional serrated adenomas (TSAs), and serrated adenoma unclassified. In contrast to the conventional adenoma-carcinoma pathway, the serrated pathway primarily involves two mechanisms: BRAF/KRAS mutations and CpG island methylator phenotype (CIMP). HPs are the most prevalent non-malignant lesions, while SSLs play a crucial role as precursors to CRCs, On the other hand, traditional serrated adenomas (TSAs) are the least frequently encountered subtype, also serving as precursors to CRCs. It is crucial to differentiate these lesions based on their unique morphological characteristics observed in histology and colonoscopy, as the identification and management of these serrated lesions significantly impact colorectal cancer screening programs. The management of these lesions necessitates the crucial steps of removing premalignant lesions and implementing regular surveillance. This article provides a comprehensive summary of the epidemiology, histologic features, molecular features, and detection methods for various serrated polyps, along with recommendations for their management and surveillance.

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.
CONCLUSIONS: 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.

Serrated lesions outside the low digestive tract are scarce, with only two traditional serrated adenomas (TSA) reported in the gallbladder, with limited information about the serrated pathway outside the colon. Our case was an incidental finding in a patient undergoing surgery to treat a cholecystitis, when a polypoid lesion was observed. The epithelium formed gland structures with ectopic crypts, serrated slits and eosinophilic cytoplasm. MUC4 and MUC5A were positive, but mismatch repair proteins (MSI) retained nuclear staining. BRAF showed a not mutated profile and NRAS/KRAS was inconclusive due to the absence of remaining tissue. MSI and CpG island (CIMP), the most common genetic hallmarks of the serrated pathway, have been proven in gallbladder carcinomas, although serrated polyps are not recognized as premalignant precursors. Hereby we report one TSA of the gallbladder without the usual genetic drivers. A larger evidence is needed to improve the diagnosis and management.

BACKGROUND: Serrated polyps are incompletely understood lesions and include serrated sessile lesion (SSL) without or with dysplasia and traditional serrated adenoma (TSA).
OBJECTIVE: We investigated prevalence and characteristics of serrated lesions, especially SSL with dysplasia (mixed polyps).
METHODS: This retrospective study analyzed data from consecutive patients referred for colonoscopy at a tertiary care center. Endoscopic and histopathological characteristics of identified lesions were studied. SSLs with dysplasia were molecularly analyzed for mutations and microsatellite instability.
RESULTS: Among 1147 patients, a total of 436 polyps were found, including 288 adenomas (66.1 %) and 114 serrated lesions (SLDR 26.2 %). PDR was 34.5 % and ADR was of 30.2 %. Serrated lesions included 75 hyperplastic polyps (17.2 %), 24 SSLs without dysplasia (5.5 %), 6 SSLs with dysplasia (mixed polyps) (1.4 %) and 9 TSA (2.1 %). The mixed polyps were evaluated molecularly: these analyses found no KRAS mutation, a single NRAS mutation in one lesion, the Val600Glu BRAF mutation in four lesions in both their serrated non-dysplastic and dysplastic areas, and microsatellite instability in four lesions, limited to the dysplastic areas.
CONCLUSIONS: Our single-center experience confirms the high prevalence of serrated lesions, a part of which are SSL with dysplasia. These lesions seem to carry specific molecular alterations.

Osseous metaplasia is an extremely rare occurrence in traditional serrated adenoma (TSA). We report a case of a 50-year-old female with a TSA with osseous metaplasia (OM). The adenoma was identified during a colonoscopy for endoscopic mucosal resection of a previously identified polyp. The polyp location was the rectum. The colonoscopy was negative for any signs of concurrent malignancy. This case report is the fifth case of OM in a TSA reported in English. The clinical significance of OM is uncertain, and there is limited literature describing these lesions.

A new subtype of serrated lesions, superficially serrated adenoma (SuSA), has been proposed as a lesion that histopathologically exhibits the morphological features of both conventional adenomas and serrated lesions and is difficult to classify as either one. SuSA has been elucidated to be a precursor lesion of KRAS-type traditional serrated adenoma. It has also been reported that SuSA may have malignant potential. We report a case treated with endoscopic submucosal dissection and detailed observation. Endoscopy revealed a raised lesion with a two-tier raised appearance in the sigmoid colon: a tall pinecone-like reddish structure and flattened whitish elevation on white light imaging. Magnifying narrow-band imaging revealed conspicuous blood vessels in the pinecone-like structure and slightly dilated reticular vessels in the flattened area. Crystal violet staining showed that the pinecone-like structure had a type IVH pit pattern and the flattened area had a stellate to slightly elongated type IIIH pit pattern diagnosed based on Kudo\'s classification and other pit pattern classification systems. Ki67-positive cells were distributed in the basal and middle layers of the gland in the flattened elevated area. Genetic analysis results were positive for KRAS mutation and negative for BRAF mutation. Histopathological examination revealed a traditional serrated adenoma in the pinecone-like structure and SuSA in the adjacent flattened elevated area.

The most common site of traditional serrated adenomas (TSA) is the area from the left colon to the rectum; however, there are few reports on TSA in the small intestine. Herein, we report a case of TSA of the ileum with intussusception that was diagnosed and successfully treated with laparoscopic bowel resection. The patient was a 29-year-old female with the chief complaint of recurrent abdominal pain and vomiting. Contrast-enhanced computed tomography showed a mass in the ileum and intussusception with the mass as the lead point. The patient was diagnosed with intussusception secondary to a small intestinal tumor. Due to the difficulty in endoscopic treatment resulting from the localization of the lesion, elective laparoscopic surgery was planned. Intra-abdominal examination revealed intussusception of the small intestine in the pelvic ileum, and an elastic soft mass 400 cm from the ligament of Treitz was identified at the lead point of intussusception. Partial laparoscopic resection of the small intestine was performed, with an operation time of 81 min, and a small amount of bleeding. The pathological diagnosis was TSA of the ileum, and the patient\'s postoperative course was good, with no complications. Seven months after the surgery, no recurrence of symptoms was observed. Therefore, from our case of TSA of the ileum with intussusception that was successfully treated with laparoscopic bowel resection, we conclude that when intussusception of the small intestine occurs, TSA of the ileum with malignant potential is possible, and early diagnosis by resection should be considered.

The case was a 17-year-old young woman with a one-year history of recurrent abdominal pain and discomfort. B-scan ultrasonography identified intussusception and contrast-enhanced computed tomography of the pelvis revealed volvulus. A laparoscopic procedure was planned to identify the reason for the intussusception and obstruction. Intraoperatively, the intussusception was found to be caused by a cauliflower-shaped polypoid tumor measuring approximately 4 × 3 cm. Postoperative pathological examination identified the tumor to be a traditional serrated adenoma of the small intestine, which is rare and has atypical clinical manifestations. If unexplained abdominal pain or gastrointestinal bleeding occurs and an abdominal mass cannot be accurately located, laparoscopic or open surgery should be performed immediately. Early surgery is the most effective and reliable way of securing a prompt diagnosis and a favorable prognosis.

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.
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).
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).
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.