We present the case of an 80-year-old man, with no relevant medical history, referred to our center for a 45-mm mixed granular Laterally Spreading Tumor (LST) of the transverse colon, identified on a previous colonoscopy. After discussing therapeutic options with the patient, endoscopic submucosal dissection (ESD) was proposed for removal of the lesion.

The procedure was performed under light sedation, confirming at 60 cm from the anal verge the presence of a 45-mm mixed granular LST with a main nodule >1 cm, involving approximately 50% of the luminal circumference. The crypt/microvascular pattern was preserved (JNET type 2B). In this context, an attempt was made to remove the lesion using the ESD technique.

During submucosal dissection, the appearance of apparent “mucus bubbles” was observed, mimicking the fish-mouth sign seen in main-duct IPMNs, initially raising the suspicion of a possible perforation. The procedure was continued and, after careful evaluation with redefinition of the dissection plane, perforation was excluded. It was suspected that these findings represented encapsulated mucinous components in the submucosa underlying the main nodular component. The procedure was completed, achieving complete en-bloc resection. It lasted 150 minutes, with no recorded complications.

The histopathological examination confirmed a low-grade adenocarcinoma, Sm1a, with evidence of acellular mucin extravasation, no lymphovascular invasion, low-grade budding, and complete resection.

To the authors’ knowledge, images of mucin “bubbles” during submucosal dissection have only recently been described in a case report, making this the second reported case documenting this “sign.” This case is presented due to its rarity, the correlation between optical diagnosis and histopathology, and the importance of recognizing this finding during endoscopic resection in order to suspect neoplasms with a mucinous component and avoid misdiagnosis. Illustrative iconography of the procedure is provided.