Objectives: Laterally spreading tumours (LSTs) are a heterogeneous group of adenomas that are emerging as important precursors of colorectal cancer and in which the risk for cancer is related to their endoscopically definable morphology. It is currently unclear whether different molecular alterations determine their morphologies. We aimed to assess this relationship in LSTs using strict morphological classifications.
Methods: We characterized 135 sessile adenomatous lesions (≥ 20 mm) according to histopathology and the Paris classification. We investigated key molecular changes commonly found in colorectal neoplasms, namely mutation of KRAS, BRAF, APC and CTNNB1 and microsatellite instability, and determined their relationship with morphology.
Results: The Paris classification revealed a heterogeneous cohort comprising Is/IIa+Is (41.5%), IIa/IIb (53.3%) and IIc/IIa+IIc (5.2%) lesions. Histopathological analysis showed that 19 (14.1%) of these were sessile serrated adenomas. Here, we defined a group of 58 lesions that showed either Paris IIa or IIb morphology with no serrated histopathology. These 'classical LSTs' showed the following molecular characteristics: microsatellite instability 0/56 (0%), APC mutation 29/30 (96.7%), CTNNB1 mutation 2/55 (3.6%), KRAS mutation 24/55 (43.6%) and BRAF mutation 2/55 (3.6%). Separation of lesions according to surface morphology showed that KRAS mutations occurred much more frequently in granular (56.4%, 22/39) than in nongranular LSTs (12.5%, 1/16, P=0.004).
Conclusion: The microsatellite instable pathway is not important in the development of LSTs, which are instead likely to develop along a divergent chromosomal instability pathway. We demonstrate the biological significance of endoscopic findings by showing that the morphological characteristics of LSTs are underpinned by distinctive molecular profiles.