Introduction

At present, there are three developmental pathways for colorectal cancers, namely, the adenoma-carcinoma sequence, serrated pathway, and de novo pathway. The adenomatous route of colorectal cancer carcinogenesis has been extensively reviewed in the literature. Conversely, the de novo pathway, which leads depressed type polyps to colorectal cancer, lacking an adenomatous phase, recently has garnered increasing attention. Research has indicated that nonpolypoid lesions demonstrate a greater potential for malignancy, underscoring the need for their early detection. This study aims to explore the endoscopic characteristics of depressed type colorectal neoplasms by using magnifying endoscopy (pit pattern classification) and endocytoscopy (EC classification). Both the structural and cellular atypias can be observed in vivo, thus enabling more comprehensive evaluation of the disease.

Aims & Methods

A total of 40719 colorectal neoplasms resected endoscopically or surgically in our institution from April 2001 to June 2022 were subject of this study. Advanced cancers were excluded. Of these, 1463 lesions were submucosally invasive (T1) carcinomas, 6839 lesions were high-grade dysplasia and 32417 lesions were characterized as low-grade dysplasia. Morphologically, they were divided into 3 types: depressed, flat and protruded type comprising 1.2%, 42.9% and 55.9%, respectively. Specifically, the distinctive features of depressed type neoplasms concerning its pit pattern and EC classification were examined.

Results

Most of the flat (93.3%) and protruded type (94.7%) lesions showed type III _L or IV pit pattern, which are common findings in adenomas.On the other hand, most of the depressed type lesions(92.4%) classified by type III s, V _I or V _N pit patterns, are typically seen in carcinomas. As for endocytoscopy, most of the flat and protruded type lesions were identified as EC2 corresponding to adenomas. In contrast, a relatively high rate of depressed type lesions was categorized as EC3a (40.0%) and EC3b (52.0%), consistent with invasive carcinomas. The proportion of T1 carcinomas in depressed type lesions was 61.3%, whereas in the flat and protruded type lesions it was 2.9% and 2.9%, respectively. Also, 10% of lesions less than 5mm in diameter were depressed, 0.01% were flat and 0% were protruded.

Conclusion

This investigation has revealed that depressed lesions can be classified in magnifying endoscopy as type III s, V I or V N pit patterns, and as types EC3a or EC3b in endocytoscopy. Lesions that have these features or these pit patterns also have a propensity to invade the submucosal layer even when they are small in size. Despite their elevated malignant potential, depressed type lesions are frequently disregarded, underscoring the critical importance of recognizing their distinctive features and accurately diagnosing lesions based on their morphology, pit pattern, and EC classification.

Disclosure

None.

Introduction

Non-alcoholic fatty liver disease (NAFLD) often advances to more severe stages, namely steatohepatitis (NASH), and may further progress towards hepatocellular carcinoma (HCC). Still, the cellular and molecular mechanisms governing disease progression - and that may be ammendable to therapeutic intervention - remain elusive.

Aims & Methods

Here, we evaluated the role of hsa-miRNA-21-5p in NASH-related hepatocarcinogenesis.
Hepatic hsa-miR-21-5p expression was evaluated in two cohorts of patients with biopsy-proven NAFLD (n=199) or HCC (n=366 HCC and n=11 NAFLD-HCC). Serum/liver metabolomic profiles were correlated with hsa-miR-21-5p in NAFLD obese patients. Wild-type (WT) and Mir21 KO mice were fed a choline-deficient, amino acid-defined (CDAA) diet for 32 weeks to induce NASH; and for 66 weeks to induce NASH-HCC.

Results

Results showed that hsa-miR-21-5p expression increased with NAFLD severity and associated with a hepatic lipotoxic profile in obese patients. CDAA-fed WT mice displayed increased hepatic mmu-miR-21-5p levels and progressively developed NASH and fibrosis, with livers presenting macroscopically discernible pre-neoplastic nodules, hyperplastic foci and deregulated cancer-related pathways. Mir21 KO mice displayed increased peroxisome-proliferator activated receptor alpha (PPARalpha) protein levels, augmented mitochondrial activity, reduced liver injury and NAS below the threshold for NASH diagnosis. Further, the pro-inflammatory/fibrogenic milieu was reduced. Mir21 KO mice presented with a lower number of pre-neoplastic nodules, impaired hepatocyte proliferation and downgraded oncogenic signaling, thus being protected from NASH-related carcinogenesis. The hsa-miRNA-21-5p/PPARalpha pathway was similarly deregulated in patients with HCC or NASH-related HCC, correlating with HCC markers and worse prognosis.

Conclusion

In conclusion, hsa-miR-21-5p is a key inducer of whole-spectrum NAFLD progression, from simple steatosis to NASH and NASH-associated carcinogenesis. Inhibition of hsa-miR-21-5p, leading to a pro-metabolomic profile, might constitute an appealing therapeutic approach to ameliorate NASH and prevent progression towards HCC (EXPL/MED-OUT/1317/2021, FCT, Portugal).