Letter to the Editor: Deep margin positivity in small rectal neuroendocrine tumors - pathological insights for post-endoscopic submucosal dissection management

Abstract

The management of small rectal neuroendocrine tumors (NETs) with positive vertical margins after endoscopic resection remains controversial. In light of the recent study by Qiao et al published in World Journal of Clinical Oncology, which reported excellent oncologic outcomes following both endoscopic submucosal dissection (ESD) and hybrid ESD for stage 1 rectal NETs, we provide a pathology-centered reinterpretation of margin positivity. Despite multiple non-R0 resections, predominantly due to positive vertical margins, no patients developed local recurrence or metastasis. From a histopathological perspective, apparent margin involvement is frequently attributable to technical artifacts such as thermal injury, tissue distortion, tangential sectioning, or specimen fragmentation rather than true residual viable tumor. Moreover, the intrinsic biological indolence of small, well-differentiated (G1) rectal NETs further explains the low risk of recurrence. Together, these observations support a risk-stratified, surveillance-oriented management strategy and underscore the importance of nuanced pathological interpretation to avoid unnecessary salvage surgery while maintaining oncologic safety.

Key Words: Rectal neuroendocrine tumor; Endoscopic submucosal dissection; Positive vertical margin; Non-R0 resection; Pathologic margin assessment

Core Tip: Positive vertical margins after endoscopic resection of small, well-differentiated rectal neuroendocrine tumors do not necessarily indicate residual disease. Technical artifacts and the intrinsic indolence of G1 tumors support a risk-adapted, surveillance-based approach rather than routine salvage surgery after non-R0 resection.

TO THE EDITOR

We read with interest the study published in World Journal of Clinical Oncology by Qiao et al[1] comparing endoscopic submucosal dissection (ESD) and hybrid ESD for stage 1 rectal neuroendocrine tumors (NETs). While the procedural validation of hybrid ESD is valuable, the study highlights a critical clinical dilemma: The management of Non-curative resection (Non-R0) resections. Specifically, the reported discordance between positive vertical margins and the absence of recurrence warrants a deeper pathology-centered analysis. Herein, we discuss the technical and biological factors contributing to “pseudopositive” margins and propose how these insights should refine clinical decision-making to avoid unnecessary salvage interventions.

NON-R0 RESECTION IN RECTAL NETS: A PATHOLOGY-CENTERED INTERPRETATION

Qiao et al[1] reported that 12 cases met the definition of non-curative resection, including 11 tumors with positive vertical margins and one with vascular invasion, yet none developed local recurrence or metastasis during a median follow-up of 25 months (range, 10-76 months). Notably, in several of the margin-positive cases, salvage surgery or scar biopsy was performed and no residual tumor was identified histologically. These observations are consistent with recent retrospective series from East Asia and Europe, in which incomplete or margin-positive endoscopic resection of small rectal NETs was associated with very low rates of local recurrence or metastasis under surveillance[2-4].

From the pathology perspective, the apparent disconnect between “positive margin” and “residual disease” deserves deeper consideration. Small rectal NETs [< 20 mm, grade 1 (G1)] are typically well-differentiated, slowly proliferative, and confined to the mucosa or superficial submucosa, with a low risk of nodal spread when standard criteria are met[2-6]. In such cases, margin interpretation is frequently complicated by several technical and biological factors: (1) Thermal artifact from ESD or snaring: High-frequency energy can carbonize or denature deep margins, creating “pseudopositive” or indeterminate involvement; cells at the cut edge may be devitalized rather than viable[7]; (2) Specimen contraction and tissue distortion: Formalin fixation and tissue handling may produce apparent proximity of tumor cells to the deep edge that does not reflect the in vivo situation; (3) Tangential sectioning or fragmentation: Particularly relevant for hybrid ESD when snaring is used, which may alter deep tissue orientation and make the margin appear artificially close[8]; and (4) Biologic indolence of G1 rectal NETs: Even where minimal tumor foci remain, several long-term outcome studies suggest that the true recurrence potential of small G1 rectal NETs after endoscopic resection is extremely low, especially in the absence of lymphovascular invasion[2-6].

The biological inertia of small, G1 rectal NETs is further supported by their characteristic molecular profile. These tumors typically exhibit low proliferative activity, reflected by a low Ki-67 index and mitotic rate, and retain stable neuroendocrine differentiation without evidence of genomic instability. Molecular alterations associated with aggressive neuroendocrine neoplasms, such as TP53 or RB1 inactivation, are notably absent in G1 rectal NETs. This molecular quiescence provides a biological explanation for the indolent clinical behavior of these tumors and helps explain why microscopic residual disease, when present, rarely translates into clinically meaningful recurrence.

Thus, a vertical margin labeled as “positive” on microscopy does not necessarily equate to viable tumor remaining in vivo. The results presented by Qiao et al[1] provide real-world clinical corroboration of this pathology-based reasoning.

CLINICAL DECISION-MAKING AFTER NON-R0 RESECTION: HOW THIS STUDY INFORMS PRACTICE

The management of positive vertical margins after endoscopic resection of small rectal NETs remains controversial. Although Non-R0 resection has traditionally prompted additional surgery, growing evidence indicates that margin status alone does not reliably predict oncologic outcomes in well-differentiated early rectal NETs.

A recent systematic review and meta-analysis demonstrated that additional salvage treatment after incomplete endoscopic resection did not significantly reduce local recurrence or metastasis in low-risk tumors, particularly those that were small, grade 1, and lacked lymphovascular invasion[9]. Consistently, long-term cohort studies have reported comparable outcomes between patients managed with surveillance and those undergoing additional treatment when adverse pathological features are absent[2-4]. These findings suggest that routine salvage surgery may represent overtreatment in biologically indolent tumors.

Accordingly, remedial intervention should be selectively reserved for patients with established high-risk features, including higher tumor grade [≥ grade 2 (G2)], lymphovascular invasion, deep submucosal or muscularis propria invasion, larger tumor size, or evidence of residual disease on follow-up evaluation[5,6]. In contrast, active surveillance appears to be oncologically safe for small, well-differentiated rectal NETs without these risk factors, despite histologically positive margins[2-4].

Within this context, the findings of Qiao et al[1] are clinically instructive. Despite multiple Non-R0 resections due to positive vertical margins, no local recurrence or metastasis was observed during follow-up, supporting the view that margin positivity in this setting often reflects technical artifacts rather than true residual disease. Careful pathological interpretation of the deep margin is therefore essential to guide risk-adapted clinical decision-making and to avoid unnecessary overtreatment.

PRACTICAL IMPLEMENTATION OF A RISK-STRATIFIED MANAGEMENT STRATEGY

Implementation of a risk-stratified strategy can be achieved through a standardized clinico-pathological workflow. Initial risk assessment should integrate tumor size, grade (Ki-67/mitotic count), depth of invasion, and lymphovascular invasion, with endoscopic ultrasonography and/or pelvic magnetic resonance imaging used selectively; European NET society recommends magnetic resonance imaging (MRI) for tumors ≥ 10 mm, G2-grade 3 (G3) lesions, or when nodal involvement is suspected on endoscopic ultrasonography (EUS)[5]. Management should then be linked to risk groups: Low-risk tumors (e.g., G1, ≤ 10 mm, lymphovascular invasion negative (L0) or vascular invasion negative (V0), superficial submucosal involvement, no suspicious nodes) may be managed by observation, whereas higher-risk features (≥ G2, lymphovascular Invasion positive, deeper invasion, larger size, or suspected residual disease) should prompt consideration of additional local resection or surgery.

Equally important is standardized pathological reporting. Reports should document margin status and clarify whether deep-margin positivity is potentially confounded by cautery injury, tissue distortion, tangential sectioning, or fragmentation, thereby helping distinguish true residual disease from pseudopositivity. Surveillance should follow guideline-based schedules: No routine follow-up is required after R0 resection of G1 L0/V0 tumors ≤ 10 mm, whereas patients with lymphovascular invasion positive or vascular invasion postive or G2–G3 tumors ≤ 10 mm should undergo periodic endoscopic and imaging surveillance for at least 5 years. For R1 resection in otherwise low-risk tumors where repeat endoscopic therapy is not performed, longitudinal endoscopic and EUS/MRI-based surveillance may be considered after shared decision-making[8].

HYBRID ESD AND PATHOLOGICAL ASSESSMENT: PRACTICAL CONSIDERATIONS

Qiao et al[1] demonstrate that hybrid ESD significantly reduces procedure time compared to conventional ESD while maintaining identical R0 resection rates and safety profiles. These findings corroborate prior studies suggesting that hybrid ESD achieves histologic completeness comparable to full ESD with greater procedural efficiency[8,10-12]. From a pathological perspective, a primary concern with hybrid techniques is whether the snaring phase introduces crush artifact or thermal damage that compromises deep margin assessment. However, the identical R0 rates and absence of recurrence in the hybrid group suggest that for small, well-demarcated NETs, snaring does not meaningfully impair histologic interpretability[8,10]. To further validate this, future investigations should incorporate representative photomicrographs comparing deep margins, define explicit criteria for evaluating thermally altered tissue, and report interobserver agreement among pathologists.

CONCLUSION

The frequent absence of recurrence following histologically incomplete resections necessitates a reappraisal of deep margin positivity in small rectal NETs. We argue that this discrepancy often stems from technical artifacts and tumor indolence rather than true residual disease. Consequently, clinical management should evolve from reflexive salvage surgery toward a surveillance-based strategy for low-risk cases. To support this shift, pathological reporting must rigorously distinguish between thermal or mechanical distortion and viable tumor tissue, ensuring that therapeutic decisions are driven by biological risk rather than procedural artifacts.