Sessile serrated lesions (SSLs) are a class of colon polyps challenging to detect through current screening methods but highly associated with colon cancer. To improve detection, we sought a biomarker sensitive for SSLs. Recent endoscopic and histopathologic studies suggest that SSLs are associated with alterations in intestinal mucin expression, but the frequency with which this occurs is not known.

We performed a meta-analysis of available pathologic studies comparing mucin expression on SSLs to normal colonic mucosa, tubular adenomas, villous adenomas, traditional serrated adenomas (TSAs), and hyperplastic polyps (HPs). We searched Medline, Pubmed, and Embase and found 440 publications in this topic, and 18 total studies met inclusion.

We found that MUC5AC expression was more common in SSLs compared to normal colonic mucosa (OR = 82.9, P < 0.01), tubular adenoma (OR = 11, P < 0.01), and TSAs (OR = 3.6, P = 0.04). We found no difference in MUC5AC expression between SSLs versus HPs (OR = 2.1, P = 0.09) and no difference in MUC5AC expression between left colon and right colon HPs, with an OR = 1.8, P = 0.23.

We found that MUC5AC expression was found commonly on villous adenoma, SSLs, and TSAs while the frequency on colon cancers declined. MUC5AC is also upregulated in inflammatory bowel disease and in response to intestinal infections. MUC5AC expression highlights the potential of mucins as useful biomarkers, though not specific to SSLs. Further research into the clinical utility of MUC5AC as a pathologic or fecal biomarker could enhance SSL detection.

Traditional serrated adenoma (TSA) is a rare and precancerous lesion of colorectal cancer. The clinical and endoscopic differentiations between TSAs without dysplasia or adenocarcinoma (TSAOs) and TSAs with dysplasia or adenocarcinoma (TSADs) remain unclear.

To evaluate the characteristics of colorectal TSAs and compare the characteristics of TSAOs with those of TSADs.

This retrospective study included 193 patients who underwent endoscopic resection and received a pathologic diagnosis of TSA. We reviewed the medical, endoscopic, and histopathologic records of patients who underwent endoscopic resection of TSAs between January 2010 and December 2023.

TSAs were more frequently located in the rectosigmoid colon. Most TSAs had 0-Ip, 0-Isp, or 0-Is morphologies. The TSAD lesions were larger than TSAO lesions. TSAD lesions more commonly had a red color and an irregular border than TSAO lesions. TSAOs were usually treated using conventional endoscopic mucosal resection, whereas TSADs were treated using conventional endoscopic mucosal resection, endoscopic submucosal dissection, and surgery. Post-polypectomy bleeding was more common with TSADs than with TSAOs. Univariate analysis showed that gastrointestinal bleeding, red color, 0-IIa, irregular border, and lobular mucosal surface were significantly associated with TSADs. Multivariate analysis showed that gastrointestinal bleeding, an irregular border, and a lobular mucosal surface were significantly associated with TSADs.

TSAs with gastrointestinal bleeding, an irregular border, and a lobular mucosal surface are associated with an increased risk of dysplasia or adenocarcinoma.

We present the case of a 68-year-old woman who underwent complete endoscopic resection of a superficial serrated adenoma (SuSA). Due to its rarity and limited case reports, SuSA is often misdiagnosed as a hyperplastic lesion without malignant potential, leading to missed diagnoses. A polypoid lesion was identified in the sigmoid colon during the initial endoscopic evaluation, where it was initially classified as a sessile serrated lesion (SSL). The subsequent endoscopic evaluation, using crystal violet staining, revealed a type IIIL pit pattern. Endoscopic mucosal resection (EMR) was performed, and histopathological analysis confirmed serrated glandular hyperplasia with mild atypia. Immunohistochemical staining showed cytokeratin 20 (CK20) expression predominantly in the upper layer, while Ki-67 and cellular myelocytomatosis oncogene (c-MYC) were distributed in the basal and intermediate layers. Beta-catenin positivity was observed in the cytoplasm of some nuclei, confirming the diagnosis of SuSA. This case underscores the importance of timely recognition and management of SuSA to prevent progression to more severe conditions.

The detection rate of dysplastic colorectal polyps has significantly increased with improved screening programs. Treatment of dysplastic polyps attempt to limit morbidity of a procedure while also considering the risk of occult lymph node metastasis. Therefore, a variety of methods have been developed to predict the rate of lymph node metastasis to help identify the optimal treatment of patients. These include both the endoscopic and pathologic assessment of the lesion. In order to reduce the morbidity of surgery for patients with low-risk lesions, multiple endoscopic therapies have been developed, including endoscopic mucosal resection, endoscopic submucosal dissection, endoscopic intermuscular dissection, and transanal endoscopic surgery.

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 IV_H pit pattern and the flattened area had a stellate to slightly elongated type III_H 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.

Mucin 6 (MUC6) is a secreted gel-forming mucin covering the surfaces of gastrointestinal and other tissues. Published work demonstrates that MUC6 can also be expressed in several cancer types and can aid in the distinction of different tumor entities. To systematically analyze MUC6 expression in normal and cancerous tissues, a tissue microarray containing 15 412 samples from 119 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. At least a weak MUC6 positivity was seen in 50 of 119 (42%) tumor entities. Thirty-three tumor entities included tumors with strong positivity. MUC6 immunostaining was most frequent in mucinous carcinomas of the breast (44%), adenocarcinomas of the stomach (30%-40%) and esophagus (35%), and neuroendocrine carcinomas of the colon. Strong MUC6 staining was linked to advanced pT stage (p = 0.0464), defective mismatch repair status and right-sided tumor location (p < 0.0001 each) in colorectal cancer, as well as to high tumor grade (p = 0.0291), nodal metastasis (p = 0.0485), erb-b2 receptor tyrosine kinase 2 positivity (p < 0.0001) and negative estrogen receptor (p = 0.0332)/progesterone receptor (p = 0.0257) status in breast carcinomas of no special type. The broad range of tumor types with MUC6 expression limits the utility of MUC6 immunohistochemistry for the distinction of different tumor types.

The serrated pathway is a distinct genetic/epigenetic mechanism of the adenoma-carcinoma sequence in colorectal carcinogenesis. Although many groups have reported the genetic-phenotypic correlation of serrated lesions (SLs), previous studies regarding the serrated pathway were conducted on patients with SLs that have different germline and environmental genetic backgrounds. We aimed to compare pure somatic genetic profiles among SLs within identical patient with SPS.

We analyzed SLs from one patient with SPS (Case #1) and compared DNA variant profiles using targeted DNA multigene panels via NGS among the patient's hyperplastic polyp (HP), three sessile serrated lesions (SSLs), and one traditional serrated adenoma (TSA), and separately analyzed three SSLs and one tubular adenoma (TA) within another patient with SPS (Case #2). In two patients, known pathogenic variant of BRAF (c.1799 T > A, p.Val600Glu) was observed in one TSA and one SSL in Case #1, and in three SSLs within Case #2. The pure somatic pathogenic variant BRAF (c.1799 T > A, p.Val600Glu) among SLs with identical germline genetic background supports its importance as a strong contributor for SLs.

Precursor lesions that progress into colorectal cancer (CRC) could be largely classified into sessile serrated lesions (SSLs), traditional serrated adenoma (TSA), and tubular adenoma (TA). We aimed to determine whether high expression of trefoil factor 1 (TFF1) is closely associated with serrated lesions, particularly SSLs. The samples were divided into the first (12 SSLs, 5 TSAs, and 15 TAs) and second cohorts (15 SSLs, 9 TSAs, and 15 TAs). First, we investigated TFF1 expression in isolated gland samples using array-based and reverse-transcription PCR. Second, we performed immunohistochemical analysis of TFF1 expression in paraffin-embedded tissues obtained from SSL, TSA, TA, and hyperplastic polyp (HP) samples. In addition, we compared TFF1 mRNA levels between SSLs and HPs. TFF1 expression was significantly higher in SSLs than in TSA and TA in both cohorts. Additionally, immunohistochemical staining of TFF1 in the HP, SSL, TSA, and TA samples revealed significant differences in the immunohistochemical scores of TFF1 among the four types of lesions (higher expression in SSLs than in the other three lesions). Finally, there were significant differences in TFF1 mRNA expression levels between SSLs and HPs in paraffin-embedded tissues. However, there was considerable overlap in the immunohistochemical scores and expression levels of TFF1 transcripts between SSLs and HPs. The current findings may help elucidate the molecular mechanisms involved in serrated lesion development. In addition, we suggest that despite the limited practical application, upregulation of TFF1 transcripts may help differentiate SSLs from other lesions.

Although serrated polyposis syndrome (SPS) is associated with an increased colorectal cancer (CRC) risk, the carcinogenic mechanisms remain unknown. We investigated clinicopathological characteristics and genetic abnormalities in colorectal polyps and CRC to elucidate carcinogenic mechanisms in SPS.

We retrospectively analyzed clinicopathological features of colorectal polyps in 44 SPS patients, and examined mutations of genes including APC, RAS, BRAF, and TP53, and microsatellite instability (MSI) in CRC tissues.

Of the 44 patients, 25 (56%) fulfilled WHO criterion 1, 11 (25%) fulfilled criterion 2, and 8 (18%) fulfilled both. A total of 956 polyps were observed; 642 (67%) hyperplastic polyps (HP), 204 (21%) sessile serrated lesions (SSL), 10 (1%) traditional serrated adenoma (TSA), and 100 (11%) adenomas. The median numbers of polyps (/patient) were 10.5 (IQR 2.75-23) HPs, 4.0 (2.0-6.0) SSLs, 0 (0-0) TSA, and 1 (0-3.3) adenoma. SSL and HP located preferentially in the proximal and distal colon, respectively. Twenty-two CRCs were found in 18 patients. Based on the histological coexistence of SSL/TSA, BRAF mutation and MSI, 5 CRCs (26%) were classified as serrated-neoplasia pathway. Conversely, based on the coexistence of adenoma, APC/RAS and TP53 mutations, 11 CRCs (58%) were classified as adenoma-carcinoma pathway. The remaining three were unclassifiable. Most CRCs through adenoma-carcinoma pathway were located in the left-side colorectum and patients bearing those met criterion 2, characterized by many HP and advanced adenomas. Adenoma was a significant risk factor for CRC.

Our results suggest that more than half of the CRCs, particularly those in the left-side colorectum, developed through the adenoma-carcinoma pathway in SPS patients. Adenoma was a risk factor for CRCs, suggesting its importance in colorectal carcinogenesis.

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.

We retrospectively evaluated the endoscopic findings of 25 isolated SuSAs and 21 TSA-associated SuSAs that were histologically and molecularly characterized.

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.

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.

Hyperplastic nodules (HNs) have been considered to be hyperplastic lesions among Japanese pathologists, although they have not been recognized worldwide. Here, we examined clinicopathological and molecular differences between goblet cell-rich variant hyperplastic polyp (GCHPs), microvesicular variant HPs (MVHPs), and HNs. Patients with hyperplastic lesions including 61 GCHPs, 62 MVHPs, and 19 HNs were enrolled in the present study. The clinicopathological and molecular features examined included the mucin phenotype expression, p53 overexpression, annexin A10, genetic mutations (BRAF and KRAS), and DNA methylation status (low, intermediate, and high methylation epigenotype). In addition, hierarchical cluster analysis was also performed to identify patterns among the histological features. The lesions were stratified into three subgroups and each lesion was assigned into a subgroup. While GCHP was associated with KRAS mutation, MVHP was closely associated with BRAF mutation; no mutation was found in HN. We list specific histological findings that corresponded to each lesion. Finally, there were no significant differences in the methylation status among lesions. The current result shows that both MVHPs and GCHPs have a neoplastic nature whereas HN is non-neoplastic. We suggest that HNs should be distinguished from HPs, in particular GCHPs, in terms of pathological and genetic features.

DNA mismatch repair (MMR) deficiency leads to changes in the length of nucleotide repeat sequences of tumor DNA. In that situation, DNA replicational errors occur and accumulate during DNA replication. As a result, this mechanism frequently affects the coding regions of oncogenes and tumor suppressor genes and causes carcinogenesis. Recently, DNA MMR deficiency has been recognized as a predictive biomarker for immunotherapy. The aim of this study is to examine the frequency of DNA MMR deficiency and clinicopathological characteristics in surgically resected lung carcinoma (LC) and their correlation.

A total of 1153 LCs were examined. Tissue microarrays were constructed. The status of MMR deficiency was evaluated by immunohistochemical analysis of MMR protein expression (hMLH1, hMSH2, hMSH6, and hPMS2). Microsatellite instability analysis, BRAF mutation, and MLH1 methylation analysis were performed for cases that showed MMR deficiency.

Only 2 of the 1153 cases (0.17%) showed a loss of hMLH1/hPMS2 protein expression. They also had high levels of microsatellite instability (MSI-H), had neither MLH1 promoter methylation nor BRAF mutation, and were male smokers. Histopathologically, one was a squamous cell carcinoma, and the other was combined small cell carcinoma with squamous cell carcinoma. Regarding PD-L1 protein expression, one had high expression, and the other had none.

The frequency of MMR deficiency was very low in LC. However, our two cases were non-adenocarcinoma and differed from previous studies. Because of its very low frequency, MMR deficiency is not a practical biomarker to predict the effect of immune checkpoint inhibitors in LC.