# Histology of colonic submucosal lesions reveals a high proportion of benign lesions that do not require R0 en bloc endoscopic resection

Pierre Lafeuille, Renato Medas, Benjamin Hamel, Romain Legros, Sarah Leblanc, Maximilien Barret, Vincent Lepilliez, Juliette Leroux, Thimothee Wallenhorst, Dann Joseph Ouizeman, et al.

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## ► To cite this version:

Pierre Lafeuille, Renato Medas, Benjamin Hamel, Romain Legros, Sarah Leblanc, et al.. Histology of colonic submucosal lesions reveals a high proportion of benign lesions that do not require R0 en bloc endoscopic resection. Endoscopy International Open, 2025, 13 (CP), pp.91. 10.1055/a-2641-5256. hal-05248221

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# Histology of colonic submucosal lesions reveals a high proportion of benign lesions that do not require R0 en bloc endoscopic resection

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## Authors

Pierre Lafeuille¹, Renato Medas², Benjamin Hamel³, Romain Legros⁴, Sarah Leblanc⁵, Maximilien Barret⁶, Vincent Lepilliez⁷, Juliette Leroux⁶, Thimothee Wallenhorst⁸, Dann Joseph Ouizeman⁹,¹⁰, Clement Fortier Beaulieu¹¹, Hugo Uchima¹²,¹³, Elena De Cristofaro¹⁴, Yann Le Baleur¹⁵, Antoine Debourdeau¹⁶, Fabien Subtil¹⁷, Tanguy Fenouil¹⁸, Alexandru Lupu¹, Florian Rostain¹, Jérôme Rivory¹, Jeremie Jacques¹⁹, João Santos-Antunes²⁰,²¹, Mathieu Pioche¹

## Institutions

1. Edouard Herriot Hospital, Gastroenterology and Endoscopy Unit, Hospices Civils de Lyon, Lyon, France

2. Gastroenterology, Centro Hospitalar Universitário de São João, Porto, Portugal

3. Department of Gastroenterology, Villefranche-sur-Saône Hospital, Villefranche-sur-Saône, France

4. Gastrenterology, Centre Hospitalier Universitaire Limoges Dupuytren, Limoges, France

5. Gastroenterology, Hopital Prive Jean Mermoz, Lyon, France

6. Hopital Cochin Gastroenterologie et oncologie digestive chirurgie digestive hepatobiliaire et endocrinienne, Paris, France

7. Gastroenterology, Hôpital Privé Jean Mermoz, Lyon, France

8. Department of Endoscopy and Gastroenterology, University Hospital Centre Rennes, Rennes, France

9. Gastroenterology Department, Centre Hospitalier Universitaire de Nice Hôpital L'Archet, Nice, France

10. Gastroenterology Department, Kantys Clinique Saint George, Nice, France

11. Gastroenterology Department, Clinique de la Sauvegarde, Lyon, France

12. Endoscopy Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain

13. Endoscopy Unit, Centro Médico Teknon, Barcelona, Spain

14. Gastroenterology, University of Rome Tor Vergata Faculty of Medicine and Surgery, Rome, Italy

15. Gastroenterology Unit, Fondation Hopital Saint Joseph, Paris, France

16. Gastroenterology Department, CHU de Montpellier, Montpellier, France

17. Biostatistiques, Centre Hospitalier Universitaire de Lyon, Villeurbanne, France

18. Service d'Anatomopathologie, Groupement Hospitalier Edouard Herriot, Lyon, France

19. Service d'Hépato-gastro-entérologie, CHU Dupuytren Limoges, Limoges, France

20. Gastrenterology, Centro Hospitalar S. João, Porto, Portugal

21. Glycobiology and Cancer, IPATIMUP, Porto, Portugal

## Key words

Endoscopy Lower GI Tract, Polyps / adenomas / ..., Tissue diagnosis, Endoscopic resection (polypectomy, ESD, EMRC, ...)

received 12.6.2024

accepted after revision 28.5.2025

accepted manuscript online 23.6.2025

## Bibliography

Endosc Int Open 2025; 13: a26415256

DOI 10.1055/a-2641-5256

ISSN 2364-3722

© 2025. The Author(s).

This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG, Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

## Corresponding author

Dr. Pierre Lafeuille, Hospices Civils de Lyon, Edouard Herriot Hospital, Gastroenterology and Endoscopy Unit, Lyon, France pierre.lafeuille@chu-lyon.fr

## ABSTRACT

**Background and study aims** Submucosal lesions in the colon are much rarer than those in the rectum. Their nature is poorly understood, as is the best technique for their excision. Based on that of rectal lesions, it most often aims for R0 en bloc resection, but without formal proof of efficacy. The aim of this study was to evaluate histology of these lesions and determine whether submucosal lesions of the colon always require R0 en bloc endoscopic resection.
**Patients and methods** We conducted a retrospective international study of all colonic submucosal lesions with confirmed histology by resection or biopsy. We assessed the proportion of lesions correctly managed by endoscopy, so that the proposed resection technique offered a level of tumor resection quality appropriate to the definitive histology of the lesion.

**Results** One hundred patients with 105 colonic submucosal lesions from 13 European centers were included. Histology revealed 91.4% (96/105) non-malignant lesions and 8.6% (9/105) malignant lesions. Endoscopic techniques used were curative in 41.7% (5/12) of cases requiring resection,

non-curative in 58.3% (7/12), and endoscopic resection was not necessary in 88.7% (93/105). There was no delayed surgery for adverse events.

**Conclusions** Most colonic submucosal lesions are non-malignant and do not warrant advanced endoscopic resection. A new therapeutic approach could be first-line use of a low-risk, low-cost histological diagnostic technique followed in a second phase by a more advanced technique in the event of a malignant histological result. Further studies are needed to evaluate this step-up strategy.

## Introduction

Colorectal submucosal lesions are lesions that originate beneath the epithelium, in the submucosa, muscularis mucosa, or muscularis propria. They represent a wide variety of cell types, with malignant potential ranging from totally benign to malignant [1]. Optical diagnosis of colorectal lesions is essential to predict histology and choose the most appropriate type of resection. This optical diagnosis fails for submucosal lesions, as the surface is generally normal [2]. Endoscopically visualized submucosal lesions are mainly located in the rectum [3, 4] and have recently been described in the CONECCT classification, which proposes advanced resection to achieve R0 resection (► Fig. 1). However, submucosal lesions of the colon are much rarer and poorly described, and their common histology is poorly understood. Their resection technique has been little studied, and no clear strategy has been defined. Often, resection techniques for these lesions are similar to those used for rectal submucosal lesions, aiming for R0 en bloc resection, by endoscopic submucosal dissection (ESD) or endoscopic full-thickness resection (EFTR), but without formal proof of efficacy.

Consequently, the question of whether these demanding and not risk-free techniques should be used to treat submucosal lesions of the colon remains uncertain to date and requires further investigation.

Therefore, we conducted a retrospective international multicenter observational study to assess the common histology of colonic submucosal lesions by endoscopic resection or biopsy and determine whether they may always require R0 en bloc endoscopic resection.

## Patients and methods

### Study design

We conducted an international multicenter study based on retrospective data collection of all patients with colonic submucosal lesions with confirmed histology by resection or biopsy between January 2012 and January 2024 in tertiary referral centers in France, Portugal, Italy, and Spain. Selection of the most

appropriate strategy for obtaining lesion histology was left to the discretion of the endoscopist at each center.

The ethics committee of Lyon Edouard Herriot Hospital approved this study, and all patients gave informed consent before their procedures. Inclusion criteria were defined as patients of both genders, older than 18 years old; referred to one of the centers for endoscopic resection of a colonic submucosal lesion; and referred to one of the centers for diagnostic or therapeutic colonoscopy, with incidental discovery of a colonic submucosal lesion during examination. The non-inclusion criteria were patients with no colonic submucosal lesion; with colonic submucosal lesion with a typical aspect of lipoma without histological confirmation needed; with a colonic submucosal lesion with non-contributory histological specimen; with a colonic submucosal lesion with a previous attempt of resection; and with a metastatic lesion diagnosed prior to colonoscopy.

### Procedures

All colonoscopies were performed by highly experienced endoscopists, with the patient under general anesthesia and using CO₂ insufflation. Optical characterization of lesions was performed using high-definition white light endoscopy followed by close-up examination assisted by virtual chromendoscopy, with or without magnification. Histopathological examination was carried out by expert digestive pathologists.

### Study objectives

The primary endpoint was description of the histology of colonic submucosal lesions.

Secondary endpoints were the description of different lesions in terms of endoscopic aspect and assessment of the proportion of lesions correctly managed by endoscopy, so that the proposed resection technique offered a level of quality of tumor resection adapted to the definitive histology of the lesion, defined by: 1) En bloc R0 resection of malignant lesions using advanced techniques: endoscopic mucosal resection (EMR), EFTR, or ESD; 2) En bloc R0 resection of lesions with local invasive potential; and 3) No resection of non-malignant colonic lesions.
<table><thead><tr><th></th><th>OE<br>Neuro-endocrine<br>tumor</th><th>IH<br>Hyperplastic<br>polyp</th><th>IS<br>Sessile serrated<br>lesion (without<br>dysplasia)</th><th>IIA<br>Low-risk<br>adenoma</th><th>IIC<br>High-risk<br>adenoma or<br>superficial ade-<br>nocarcinoma</th><th>IIC+<br>Borderline<br>invasive adeno-<br>carcinoma</th><th>III<br>Deeply invasive<br>adeno-<br>carcinoma</th></tr></thead><tbody><tr><th>Location</th><td>Rectum</td><td>Rectum or<br>sigmoid</td><td>Colorectal</td><td>Colorectal</td><td>Colorectal</td><td>Colorectal</td><td>Colorectal</td></tr><tr><th>Macroscopic<br>aspect</th><td>Subepithelial<br>lesion</td><td>Often &lt;10 mm<br>Paris IIa</td><td>Paris IIa or IIb<br>Cloud aspect<br>Unclear margins</td><td>Paris Ip or Is<br>or IIa<br>or "Valley sign"</td><td>Often IIc<br>or nongranular<br>LST<br>or macronucle<br>(&gt;10 mm) on a<br>granular LST</td><td>Demarcated or<br>depressed area</td><td>Often Illor IIc<br>with a nodule in<br>the depressed<br>area<br>Spontaneous<br>bleeding</td></tr><tr><th>Color<br>(virtual staining)</th><td>Yellowish</td><td>Light Color or<br>equivalent to<br>the background</td><td>Variable yellow<br>mucus (red in<br>VCE)</td><td>Darker than the<br>background</td><td>Often dark</td><td>Dark area</td><td>Heterogeneous<br>lighter and<br>darker in an<br>amorphous area</td></tr><tr><th>Vessels<br>(virtual staining)</th><td>Normal</td><td>None<br>or thin vessels<br>across the lesion,<br>not following<br>the pits</td><td>Round shape<br>Dark spots at<br>the bottom of<br>the pits</td><td>Elongated<br>or branched<br>crypts,<br>cerebriform<br>aspect</td><td>Irregular but<br>persistent<br>No amorphous<br>area</td><td>Absent,<br>amorphous,<br>destroyed area<br>&lt;10 mm (clear<br>demarcation)</td><td>Absent,<br>amorphous,<br>destroyed area<br>&gt;10 mm (clear<br>demarcation)</td></tr><tr><th>Pits<br>(virtual staining)</th><td>Normal<br>(sometimes<br>minimal<br>mucosal lesion)</td><td>Round shape,<br>withish pits</td><td>Round shape<br>Dark spots at<br>the bottom of<br>the pits</td><td>Elongated<br>or branched<br>crypts,<br>cerebriform<br>aspect</td><td>Irregular but<br>persistent<br>No maorphous<br>area</td><td>Absent,<br>amorphous,<br>destroyed area<br>&lt;10 mm (clear<br>demarcation)</td><td>Absent,<br>amorphous,<br>destroyed area<br>&gt;10 mm (clear<br>demarcation)</td></tr><tr><th>Resection<br>method</th><td>R0 (ESD, EID,<br>EFTR)</td><td>No resection if<br>&lt;5 mm</td><td>EN BLOC R0 if possible<br>(Cold snare then discard if &lt;10 mm)<br>PIECE MEAL if not</td><td>En bloc R0 (EMR<br>or ESD)</td><td>En bloc R0 (EMR<br>or ESD)</td><td>Diagnostic<br>resection (ESD,<br>EID, EFTR)</td><td>Staging<br>SURGERY</td></tr></tbody></table>

► **Fig. 1** The CONECC Classification (version 3.1). EID, endoscopic intermuscular dissection; EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection; LST, laterally spreading tumor; VCE, virtual chromoendoscopy. Source: Lafeuille, P, Rivory J, Lupu A, et al. Value of green sign and chicken skin aspects for detecting malignancy of colorectal neoplasia in a prospective characterization study. Endoscopy International Open 2024; 12: E924-931. doi: 10.1055/a-2350-9631

## Data collection

Data collected were patient demographics including sex and age at time of colonoscopy; lesion characteristics: location, size, morphology, and histology; histology confirmation technique (resection or biopsy), residual tumor classification, and adverse events (AEs).

Lesion consistency was defined by resistance when pressed by the endoscope tip or by biopsy forceps. Macroscopic type of lesions was defined as a “hill” aspect when the submucosal curvature showed gentle slopes and as a “sphere” aspect with steep slopes towards the surrounding mucosa.

## Statistical analysis

Continuous variables are presented as mean ± standard deviation. Categorical variables are presented as numbers and percentages.

## Results

### Study population

The study included 100 patients with 105 colonic submucosal lesions from 13 European centers (France: 82 patients, Portugal: 15, Italy: 2, Spain: 1) (► **Fig. 2**). Mean age at diagnosis was 64 years (► **Table 1**). In our tertiary center in Lyon, submucosal lesions accounted for 3.4% of all ESD indications.

### Endoscopic results

Mean lesion size was 13.9 mm. Overall, 58.1% (61/105) of lesions were located beyond the hepatic flexure and 22.9% (24/105) in the sigmoid. Of the lesions, 86.7% (91/105) had the appearance of normal colonic mucosa. Lesion characteristics are detailed in ► **Table 2**.

### Histology of lesions

Histology revealed 91.4% (96/105) of non-malignant lesions with 34.3% (36/105) lipomas, 20.0% (21/105) inflammatory lesions, six benign nervous lesions (ganglioneuromas, perineur-
<figure><img src="image_5.png" /><figcaption>► Fig. 2 Flow chart of the study.</figcaption></figure>

<table><caption>► Table 1 Characteristics of patients.</caption><thead><tr><th>Characteristic</th><th></th></tr></thead><tbody><tr><td>Patients, n</td><td>100</td></tr><tr><td>Gender, n</td><td></td></tr><tr><td>Male</td><td>47</td></tr><tr><td>Female</td><td>53</td></tr><tr><td>Age at diagnosis, y</td><td></td></tr><tr><td>Mean (SD)</td><td>64 (9)</td></tr><tr><td>Center location, n</td><td></td></tr><tr><td>France</td><td>82</td></tr><tr><td>Portugal</td><td>15</td></tr><tr><td>Italy</td><td>2</td></tr><tr><td>Spain</td><td>1</td></tr></tbody></table>

omas), five benign vascular lesions (angiodysplasias, hemangiomas), 11.4% (12/105) leiomyomas, and 15.2% (16/105) other benign lesions, including two hamartomatous lesions and one desmoid tumor, with local invasive potential. There were 8.6% (9/105) malignant lesions: three gastrointestinal

stromal tumors (GISTs), three neuroendocrine neoplasias, one lymphoma, one leiomyosarcoma, and one neuroectodermal tumor.

## Lipomas

Mean size of lipomas was 20.8 mm. Overall, 77.8% (28/36) presented a buff-yellow color. All of the lipomas (18/18) with reported consistency were soft, 47.8% (11/23) of lipomas with reported macroscopic type presented a hilly aspect, and 30.4% (7/23) were pedunculated (► Table 3).

## Inflammatory lesions

Mean size of inflammatory lesions was 9.9 mm. Of inflammatory lesions with reported consistency, 92.9% (13/14) were hard and 70.0% (7/10) of inflammatory lesions with reported macroscopic type presented a sphere aspect. Histology revealed 61.9% (13/21) granulomas (► Fig. 3), 14.3% (3/21) fibronecrotic granular lesions, and 19.0% (4/21) and 4.8% (1/21) inflammatory granulomatous epithelioid and gigantocellular rearrangements with and without caseous necrosis, respectively (► Table 4). Because no patient with caseous necrosis was found to have active tuberculosis, no patient received anti-tuberculosis treatment.
<table><caption>► Table 2 Characteristics of lesions.</caption><thead><tr><th>Characteristic</th><th></th></tr></thead><tbody><tr><td>Lesions, n</td><td>105</td></tr><tr><td>Lesion size: mean (SD), mm</td><td>13.9 (12.3)</td></tr><tr><td>Location, n (%)</td><td></td></tr><tr><td>Appendix</td><td>5 (4.8)</td></tr><tr><td>Cecum</td><td>19 (18.1)</td></tr><tr><td>Right colon</td><td>31 (29.5)</td></tr><tr><td>Hepatic flexure</td><td>6 (5.7)</td></tr><tr><td>Transverse colon</td><td>13 (12.4)</td></tr><tr><td>Splenic flexure</td><td>0</td></tr><tr><td>Left colon</td><td>7 (6.7)</td></tr><tr><td>Sigmoid</td><td>24 (22.9)</td></tr><tr><td>Color, n (%)</td><td></td></tr><tr><td>Buff-yellow</td><td>43 (41.0)</td></tr><tr><td>Same as background</td><td>25 (23.8)</td></tr><tr><td>Lighter than background</td><td>15 (14.3)</td></tr><tr><td>Redish</td><td>6 (5.7)</td></tr><tr><td>NR</td><td>16 (15.2)</td></tr><tr><td>Consistency, n (%)</td><td></td></tr><tr><td>Soft</td><td>26 (24.8)</td></tr><tr><td>Hard</td><td>29 (27.6)</td></tr><tr><td>NR</td><td>50 (47.6)</td></tr><tr><td>Macroscopic type, n (%)</td><td></td></tr><tr><td>Hill</td><td>26 (24.8)</td></tr><tr><td>Sphere</td><td>26 (24.8)</td></tr><tr><td>Pedunculated</td><td>15 (14.3)</td></tr><tr><td>NR</td><td>38 (36.2)</td></tr><tr><td>Mucosal aspect, n (%)</td><td></td></tr><tr><td>Usual colonic</td><td>91 (86.7)</td></tr><tr><td>Adenoma</td><td>1 (1.0)</td></tr><tr><td>Scar</td><td>3 (2.9)</td></tr><tr><td>NR</td><td>10 (9.5)</td></tr><tr><td>Histology, n (%)</td><td></td></tr><tr><td>Benign lesions</td><td>96 (91.4)</td></tr><tr><td>Lipoma</td><td>36 (34.3)</td></tr><tr><td>Inflammatory lesion</td><td>21 (20.0)</td></tr><tr><td>Nervous lesion</td><td>6 (5.7)</td></tr><tr><td>Vascular lesion</td><td>5 (4.8)</td></tr><tr><td>Leiomyoma</td><td>12 (11.4)</td></tr><tr><td>Others</td><td>16 (15.2)</td></tr></tbody></table>

<table><caption>► Table 2 (Continuation)</caption><thead><tr><th>Characteristic</th><th></th></tr></thead><tbody><tr><td>Malignant lesions</td><td>9 (8.6)</td></tr><tr><td>GIST</td><td>3 (2.9)</td></tr><tr><td>Neuroendocrine neoplasia</td><td>3 (2.9)</td></tr><tr><td>Others</td><td>3 (2.9)</td></tr><tr><td>Endoscopy technique, n (%)</td><td></td></tr><tr><td>Forceps</td><td>4 (3.8)</td></tr><tr><td>Cold snare polypectomy</td><td>24 (22.9)</td></tr><tr><td>Hot snare polypectomy</td><td>1 (1.0)</td></tr><tr><td>C-EMR</td><td>29 (27.6)</td></tr><tr><td>U-EMR</td><td>1 (1.0)</td></tr><tr><td>C-ESD</td><td>27 (25.7)</td></tr><tr><td>H-ESD</td><td>2 (1.9)</td></tr><tr><td>EFTR</td><td>17 (16.2)</td></tr><tr><td>Resection, n (%)</td><td></td></tr><tr><td>Biopsy</td><td>4 (3.8)</td></tr><tr><td>R0</td><td>81 (77.1)</td></tr><tr><td>R1</td><td>20 (19.0)</td></tr><tr><td>Quality, n (%)</td><td></td></tr><tr><td>no resection needed</td><td>93 (88.7)</td></tr><tr><td>curative</td><td>7 (6.7)</td></tr><tr><td>not curative</td><td>5 (4.8)</td></tr><tr><td>Perforation, n (%)</td><td></td></tr><tr><td>Intraoperative</td><td>6 (5.7)</td></tr><tr><td>Delayed</td><td>0</td></tr><tr><td>Bleeding, n (%)</td><td></td></tr><tr><td>Intraoperative</td><td>1 (1.0)</td></tr><tr><td>Delayed</td><td>0</td></tr><tr><td>Surgery after complication, n (%)</td><td>0</td></tr></tbody><tfoot><tr><td colspan="2">C-EMR, conventional endoscopic mucosal resection; C-ESD, conventional endoscopic submucosal dissection; GIST, gastrointestinal stromal tumor; H-ESD: hybrid endoscopic submucosal dissection; EFTR: endoscopic full-thickness resection; NR, not reported; U-EMR, underwater endoscopic mucosal resection.</td></tr></tfoot></table>

## Endoscopic resections

Endoscopy techniques used included 3.8% (4/105) biopsy forceps and 96.2% (101/105) resections, with 22.9% (24/105) cold snare polypectomies, 0.9% (1/105) hot snare polypectomy, 27.6% (29/105) conventional EMR, 0.9% (1/105) underwater EMR, 25.7% (27/105) conventional ESD, two hybrid ESD, and 16.2% (17/105) EFTR resections.
<table><caption>► Table 3 Characteristics of lipomas.</caption><thead><tr><th>Characteristic</th><th></th></tr></thead><tbody><tr><td>Lesions, n</td><td>36</td></tr><tr><td>Lesion size: mean (SD), mm</td><td>20.8 (14.7)</td></tr><tr><td>Location, n (%)</td><td></td></tr><tr><td>Appendix</td><td>0</td></tr><tr><td>Cecum</td><td>10 (27.8)</td></tr><tr><td>Right colon</td><td>11 (30.6)</td></tr><tr><td>Hepatic flexure</td><td>2 (5.6)</td></tr><tr><td>Transverse colon</td><td>3 (8.3)</td></tr><tr><td>Splenic flexure</td><td>0</td></tr><tr><td>Left colon</td><td>1 (2.8)</td></tr><tr><td>Sigmoid</td><td>9 (25)</td></tr><tr><td>Color, n (%)</td><td></td></tr><tr><td>Buff-yellow</td><td>28 (77.8)</td></tr><tr><td>Same as background</td><td>3 (8.3)</td></tr><tr><td>Lighter than background</td><td>0</td></tr><tr><td>Redish</td><td>1 (2.8)</td></tr><tr><td>NR</td><td>4 (11.1)</td></tr><tr><td>Consistency, n (%)</td><td></td></tr><tr><td>Soft</td><td>18 (50)</td></tr><tr><td>Hard</td><td>0</td></tr><tr><td>NR</td><td>18 (50)</td></tr><tr><td>Macroscopic type, n (%)</td><td></td></tr><tr><td>Hill</td><td>11 (30.6)</td></tr><tr><td>Sphere</td><td>5 (13.9)</td></tr><tr><td>Pedunculated</td><td>7 (19.4)</td></tr><tr><td>NR</td><td>13 (36.1)</td></tr><tr><td>Endoscopy technique, n (%)</td><td></td></tr><tr><td>Forceps</td><td>4 (11.1)</td></tr><tr><td>Cold snare polypectomy</td><td>14 (38.9)</td></tr><tr><td>Hot snare polypectomy</td><td>1 (2.8)</td></tr><tr><td>C-EMR</td><td>11 (30.6)</td></tr><tr><td>U-EMR</td><td>0</td></tr><tr><td>C-ESD</td><td>6 (16.7)</td></tr><tr><td>H-ESD</td><td>0</td></tr><tr><td>EFTR</td><td>0</td></tr></tbody></table>

C-EMR, conventional endoscopic mucosal resection; C-ESD, conventional endoscopic submucosal dissection; EFTR: endoscopic full-thickness resection; H-ESD: hybrid endoscopic submucosal dissection; NR, not reported; U-EMR, underwater endoscopic mucosal resection

<table><caption>► Table 4 Characteristics of inflammatory lesions.</caption><thead><tr><th>Characteristic</th><th></th></tr></thead><tbody><tr><td>Lesions, n</td><td>21</td></tr><tr><td>Lesion size: mean (SD), mm</td><td>9.9 (14.2)</td></tr><tr><td>Location, n (%)</td><td></td></tr><tr><td>Appendix</td><td>0</td></tr><tr><td>Cecum</td><td>5 (23.8)</td></tr><tr><td>Right colon</td><td>11 (52.4)</td></tr><tr><td>Hepatic flexure</td><td>1 (4.8)</td></tr><tr><td>Transverse colon</td><td>2 (9.5)</td></tr><tr><td>Splenic flexure</td><td>0</td></tr><tr><td>Left colon</td><td>1 (4.8)</td></tr><tr><td>Sigmoid</td><td>1 (4.8)</td></tr><tr><td>Color, n (%)</td><td></td></tr><tr><td>Buff-yellow</td><td>8 (38.1)</td></tr><tr><td>Same as background</td><td>6 (28.6)</td></tr><tr><td>Lighter than background</td><td>3 (14.3)</td></tr><tr><td>Redish</td><td>1 (4.8)</td></tr><tr><td>NR</td><td>3 (14.3)</td></tr><tr><td>Consistency, n (%)</td><td></td></tr><tr><td>Soft</td><td>1 (4.8)</td></tr><tr><td>Hard</td><td>13 (61.9)</td></tr><tr><td>NR</td><td>7 (33.3)</td></tr><tr><td>Macroscopic type, n (%)</td><td></td></tr><tr><td>Hill</td><td>2 (9.5)</td></tr><tr><td>Sphere</td><td>7 (33.3)</td></tr><tr><td>Pedunculated</td><td>1 (4.8)</td></tr><tr><td>NR</td><td>11 (52.4)</td></tr><tr><td>Endoscopy technique, n (%)</td><td></td></tr><tr><td>Forceps</td><td>0</td></tr><tr><td>Cold snare polypectomy</td><td>1 (4.8)</td></tr><tr><td>Hot snare polypectomy</td><td>0</td></tr><tr><td>C-EMR</td><td>2 (9.5)</td></tr><tr><td>U-EMR</td><td>0</td></tr><tr><td>C-ESD</td><td>11 (52.4)</td></tr><tr><td>H-ESD</td><td>0</td></tr><tr><td>EFTR</td><td>7 (33.3)</td></tr></tbody></table>

C-EMR: conventional endoscopic mucosal resection; C-ESD: conventional endoscopic submucosal dissection; EFTR: endoscopic full-thickness resection; H-ESD, hybrid endoscopic submucosal dissection; NR, not reported; U-EMR, underwater endoscopic mucosal resection.
<figure><img src="image_6.png" /><figcaption>► **Fig. 3** Example of inflammatory submucosal lesion in the colon (granuloma). Endoscopic view in white light (a) and virtual chromoendoscopy (a') and microscopic examination of the resection specimen (HPS staining, low (b) and high (b') magnification).</figcaption></figure>

In addition to the four biopsies, the study included 77.1% (81/105) R0 en bloc resections and 19.0% (20/105) R1 resections. For malignant lesions, en bloc R0 resection was obtained for the four EFTR resections, none (0/1) with conventional ESD resection, and one of the four conventional EMR. For benign lesions requiring en bloc R0 resection, it was obtained for the EFTR resection and the two conventional EMR.

Immediate complications included 5.7% (6/105) perforations and one bleed, all managed endoscopically during the procedure. All perforations occurred after conventional ESD and bleeding occurred after conventional EMR. There were no delayed complications and no need for surgery.

## Appropriateness of endoscopic management

In the study, 11.4% of lesions (12/105) required endoscopic resection and no endoscopic resection was required in 88.7% of cases (93/105). Among the lesions requiring endoscopic resection, 41.7% (5/12) were resected curatively, with en bloc R0 resection of two GISTs in the right colon (conventional EMR and EFTR), a grade 2 neuroendocrine neoplasia in the sigmoid (EFTR), a grade 1 neuroendocrine neoplasia in the left colon (EFTR), a desmoid tumor in the cecum (EFTR), and two hamartomatous lesions in the cecum and appendix (conventional EMR).

In the study, 58.3% (7/12) of lesions requiring endoscopic resection were not resected curatively, with a metastatic grade 2 neuroendocrine neoplasia in the sigmoid (conventional EMR), a neuroectodermal tumor in the left colon (EFTR), a marginal lymphoma in the right colon, with R1 resection (deep margin invasion) by conventional EMR, a leiomyosarcoma in the transverse colon (conventional EMR) and a GIST in the hepatic flexure, with R1 resection (deep margin invasion) by conventional ESD (► **Table 5**).

<table><caption>► **Table 5** Appropriateness of endoscopic management.</caption><thead><tr><th colspan="2">Endoscopic management</th></tr></thead><tbody><tr><td>Lesions, n</td><td>105</td></tr><tr><td>■ Lesions not requiring endoscopic resection, n (%)</td><td>93 (88.7)</td></tr><tr><td>■ Lesions requiring endoscopic resection, n (%)</td><td>12 (11.4)</td></tr><tr><td>■ Curative resection, n (%)</td><td>5 (41.7)</td></tr><tr><td>■ Not curative resection, n (%)</td><td>7 (58.3)</td></tr></tbody></table>

## Discussion

This study demonstrates that submucosal lesions of the colon, although rare, are in a large proportion non-malignant and may not require R0 en bloc endoscopic resection.

In fact, when the lesion resembles a hill with gentle slopes, has a soft consistency and a buff-yellow color, visualization of fat beneath the mucosa after mucosal resection using a cold snare would allow additional biopsy for histological confirmation of a lipoma. This unroofing technique has already been described for large, symptomatic lipomas [5].

For colonic submucosal lesions without a typical lipoma appearance, spherical in shape and hard in consistency, a low-risk, low-cost histological diagnostic technique such as biopsy forceps or cold snare polypectomy may be sufficient to obtain histology and exclude non-malignant lesions. The effectiveness of simple techniques such as bite-on-bite biopsies or cold snare polypectomy in obtaining histological material of sufficient quality for these hard consistency submucosal lesions, therefore, should be evaluated in the future.

In contrast, when a malignant lesion is diagnosed during the initial sampling, a step-up approach toward advanced endoscopic resection seems justified. A meta-analysis describing efficacy and safety of the EFTR resection technique for colorectal lesions showed an R0 rate and technical success of over 80%, with few adverse effects, but with only 11% (61/555) submucosal lesions [6]. Another meta-analysis showed for ESD of rectal NET a complete resection rate of 89%, 4% adverse events and < 1% local recurrence [7]. In our study, and despite the small number of relevant cases, EFTR also appears to be the most effective technique for achieving en bloc resection with margins, with no reported AEs. Most submucosal lesions were smaller than 20 mm and, consequently, EFTR was almost never contraindicated due to lesion size, because previous reports have shown the relatively low rate of R0 resection beyond 20 mm with this technique [8]. Although ESD is probably better suited to large lesions over 20 mm, the technique seems to have an imperfect R0 resection rate, with a high rate of perforations in this indication, where the depth is difficult to predict and the lesion often buried in the muscle.

The main limitation of our study is due to its retrospective design. First, lesions included were those of undetermined diagnosis, with a probable exclusion of lesions with an obvious lipoma appearance, which could explain the discrepancy between the number of lesions supplied by the centers. Conse-
quently, the proportion of lipomas in the study probably does not reflect the true epidemiology of submucosal colonic lesions. Second, ESD has been used as a means of diagnosis, but the discovered proportion of non-malignant lesions has taught us the need for low-morbidity techniques to obtain histology to decide whether advanced resection is indicated.

## Conclusions

In conclusion, most colonic submucosal lesions are not malignant and, therefore, do not warrant advanced endoscopic resection for R0 purposes. Simple diagnostic techniques for obtaining histology should be tested to propose a step-up selective approach with secondary endoscopic resection (EFTR) for the rare malignant lesions discovered during histological sampling in the first stage.

## Conflict of Interest

The authors declare that they have no conflict of interest.

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