Introduction

Colorectal cancer (CRC) remains a significant global health concern and is one of the leading causes of cancer-related deaths worldwide. With advancements in science, the understanding of its development, particularly from sessile serrated lesions (SSLs) with dysplasia, is becoming increasingly crucial for prevention, early detection, and treatment. A pioneering study recently published in ‘Human Pathology’ has broken new ground in characterizing sessile serrated adenomas with dysplasia, providing valuable insights into the mechanisms through which these lesions can progress to colorectal carcinoma with the menacing microsatellite instability (MSI) phenotype.

Main Article

Researchers from Japan, led by Dr. Tamotsu Sugai of the Iwate Medical University, have recently completed an extensive study that elucidates the clinicopathological and molecular characteristics of sessile serrated lesions with dysplasia (SSLD) that may lead to the development of CRC with an MSI phenotype.

Study Design

In this groundbreaking work, the expert team evaluated 54 SSLDs, which included 20 serrated dysplasia cases and 17 intestinal dysplasia cases comprising 30 instances of low-grade dysplasia (LGD), 7 of high-grade dysplasia (HGD), and 17 of intramucosal adenocarcinomas (IMAs). An additional comparison group of 41 CRC cases with an MSI phenotype (where the cancer invasion was beyond the submucosa) was also investigated. The researchers employed a battery of molecular diagnostic tools, including immunohistochemical analysis, DNA methylation status checks, and multiple genetic mutation assessments using next-generation sequencing.

Key Findings

The study uncovered that mismatch repair (MMR) deficiency existed in 32.4% of the SSLD cases examined. Interestingly, SSLDs with serrated dysplasia showed a much higher frequency of loss of MMR protein expression and notable changes in methylation status when compared to other types. The loss of MMR protein expression was also significantly different between the stages of LGD and IMA, signifying a potential biomarker for malignancy risk.

In addition to these discoveries, the frequency of mutations in the TP53 gene, often associated with various cancers, was significantly higher in IMAs than in LGD cases. This finding provides crucial evidence supporting that mutations in the TP53 gene are likely to play a significant role in the progression of dysplastic lesions to cancerous states.

Implications and Future Directions

This study’s findings are pivotal because they highlight specific molecular and pathological markers that could aid in the early identification of lesions with a higher risk of progressing to CRC. As SSLDs can be challenging to detect and diagnose due to their flat morphology, this research offers an opportunity to develop more effective surveillance strategies for those at risk of developing MSI-related CRC.

DOI

The study, “Characterization of sessile serrated adenomas with dysplasia including intramucosal adenocarcinoma and colorectal carcinoma with a microsatellite instability phenotype,” can be accessed at https://doi.org/10.1016/j.humpath.2023.12.007, providing the complete in-depth analysis of the study’s results.

References

1. Sugai, T., Uesugi, N., Osakabe, M., Yao, T., Yanagawa, N., & Ajioka, Y. (2024). Characterization of sessile serrated adenomas with dysplasia including intramucosal adenocarcinoma and colorectal carcinoma with a microsatellite instability phenotype. Human Pathology, [S0046-8177(23)00254-X]. https://doi.org/10.1016/j.humpath.2023.12.007

2. Kim, M. J., Lee, E. J., Suh, J. P., & Han, H. S. (2019). Clinicopathologic characteristics and malignant potential of colorectal sessile serrated adenomas/lesions. Annals of Coloproctology, 35(2), 59–66. https://doi.org/10.3393/ac.2018.12.15

3. Paydary, K., Seraj, S. M., Zadeh, M. Z., Emamzadehfard, S., Shamchi, S. P., Gholami, S., & Werner, T. J. (2021). The evolving role of FDG-PET/CT in the diagnosis, staging, and treatment of colorectal cancer. Molecular Imaging and Biology, 23(1), 1-11. https://doi.org/10.1007/s11307-020-01531-3

4. Crockett, S. D., & Nagtegaal, I. D. (2019). Terminology, molecular features, epidemiology, and management of serrated colorectal neoplasia. Gastroenterology, 157(4), 949–966.e4. https://doi.org/10.1053/j.gastro.2019.04.042

5. Guinney, J., Dienstmann, R., Wang, X., de Reynies, A., Schlicker, A., Soneson, C., … & Sadanandam, A. (2015). The consensus molecular subtypes of colorectal cancer. Nature Medicine, 21(11), 1350–1356. https://doi.org/10.1038/nm.3967

Keywords

1. Sessile Serrated Lesions
2. Colorectal Cancer Progression
3. Microsatellite Instability Phenotype
4. Mismatch Repair Deficiency
5. Next-Generation Sequencing in CRC

Conclusion

The study by Dr. Sugai and his team represents a notable advancement in the field of colorectal pathology and cancer research. By dissecting the morphological and genetic variances in SSLDs, the team has laid a robust foundation for future studies and potential interventions. Their findings are vital for clinicians and pathologists in formulating better diagnostic and therapeutic approaches to combat the ominous trajectory from SSLDs to CRC with MSI, ultimately paving the way for improved patient outcomes in the fight against this formidable disease.