Reassessing the role of lymph node dissection in pancreatic cancer surgery: Balancing oncologic control and immune function preservation

Abstract

Lymph node dissection (lymphadenectomy) remains a critical component of pancreatic cancer surgery, contributing to accurate staging and guiding adjuvant therapy. The debate between standard and extended lymphadenectomy persists, with evidence showing no significant survival advantage of extended dissection over the standard approach. Extended lymphadenectomy, while increasing the number of lymph nodes retrieved, is associated with longer operative times, greater blood loss, and higher morbidity. More importantly, lymph nodes serve as critical immune hubs, and excessive removal may compromise systemic immune surveillance, which is vital in the context of emerging immunotherapies for pancreatic cancer. This minireview synthesizes the oncological and immunological perspectives on lymphadenectomy, advocating for a personalized approach to lymph node management in pancreatic cancer surgery, focusing on balancing oncologic outcomes with immune preservation.

Key Words: Pancreatic cancer; Lymphadenectomy; Extended lymph node dissection; Immune response; Surgical oncology; Tumor microenvironment

Core Tip: The extent of lymph node dissection in pancreatic cancer surgery remains contentious. While extended lymphadenectomy does not improve survival outcomes, it increases morbidity and may impair immune function. This minireview calls for a more individualized approach to lymphadenectomy, considering both oncologic efficacy and immune preservation, in line with the evolving landscape of immunotherapy.

INTRODUCTION

Pancreatic cancer is one of the most lethal malignancies worldwide, with a dismal five-year survival rate and limited curative options. It is characterized by an aggressive clinical course, early metastatic spread, and resistance to conventional therapies. Surgical resection remains the cornerstone of treatment for resectable disease, offering the only chance for long-term survival. As part of the surgical strategy, lymph node dissection (lymphadenectomy) plays a critical role in accurate staging, optimizing local control, and guiding the administration of adjuvant therapies. However, the appropriate extent of lymphadenectomy, whether standard or extended, has been the subject of extensive debate over the past two decades. Beyond traditional oncologic considerations, recent interest has focused on the immunological implications of lymphadenectomy, given that lymph nodes are central sites for antigen presentation and T-cell priming in antitumor immunity (Table 1).

Table 1 Comparison of standard and extended lymphadenectomy.

Outcome	Standard lymphadenectomy	Extended lymphadenectomy	Ref.
Overall survival	No difference in survival	No difference in survival	[1-3,7,8]
Operating time	Shorter operating time	Longer operating time (50.13 minutes)	[2,3,7]
Blood loss	Less blood loss	Increased blood loss (137.43 mL)	[2,3,7]
Complications	Similar complication rates	Trend toward increased morbidity	[1,2,7]
Quality of life	Better quality of life	Worse quality of life	[9]
Lymph node retrieval	Fewer lymph nodes retrieved	More lymph nodes retrieved	[2,3,7]

STANDARD VS EXTENDED LYMPHADENECTOMY

Standard lymphadenectomy typically involves the systematic removal of lymph nodes in the immediate vicinity of the pancreatic tumor, such as the anterior and posterior pancreatoduodenal nodes, the pyloric nodes, and the pericholedochal lymph nodes. This approach is grounded in the concept of removing the most likely sites of regional spread while minimizing surgical trauma and postoperative complications. In contrast, extended lymphadenectomy includes a more radical dissection of lymphatic tissue along major vascular structures such as the celiac trunk, superior mesenteric artery, and para-aortic region. The underlying rationale for extended lymphadenectomy is that it may remove micrometastatic disease that would otherwise escape detection, thus potentially improving overall survival and reducing recurrence.

Multiple randomized controlled trials (RCTs), prospective cohort studies, and meta-analyses have attempted to clarify whether extended lymphadenectomy offers any tangible benefit over the standard approach. A comprehensive meta-analysis of five RCTs comprising 724 patients revealed no statistically significant difference in overall survival between the two groups (hazard ratio = 1.10, P = 0.46)[1]. Similarly, a high-quality Cochrane systematic review including seven RCTs with 843 patients concluded that extended lymphadenectomy failed to demonstrate any survival advantage (log hazard ratio = 0.12, 95% confidence interval: -3.06 to 3.31, P = 0.94), and the overall evidence quality was deemed very low[2]. A large Japanese multicenter RCT by Nimura et al[3], involving 112 patients, corroborated these findings and noted that extended dissection increased intraoperative burden, including longer operative times and greater intraoperative blood loss, without improving long-term outcomes.

However, more recent studies have provided updated perspectives on the role of extended lymphadenectomy in the current context of pancreatic cancer surgery, particularly as advancements in surgical techniques and the increasing use of adjuvant therapies influence treatment strategies. For example, a recent systematic review and meta-analysis examined the role of extended lymphadenectomy and concluded that while survival benefits remain uncertain, extended lymphadenectomy improved staging accuracy and guided better treatment planning for high-risk patients[4]. Furthermore, Lyu et al[5] demonstrated that extended lymphadenectomy, when combined with neoadjuvant chemotherapy, can reduce morbidity in patients with resectable pancreatic cancer, especially those with increased lymph node involvement. Additionally, Lee and yeh[6] highlighted the emerging role of molecular profiling in the selection of candidates for extended lymphadenectomy, noting that biomarkers such as Kirsten rat sarcoma 2 viral oncogene homolog mutations and microsatellite instability can help predict which patients will benefit most from this approach.

SURGICAL MORBIDITY AND QUALITY OF LIFE

The impact of extended lymphadenectomy on surgical morbidity has also been well documented. Extended procedures tend to prolong operative duration and increase technical complexity. Staerkle et al[2] reported a mean increase in operative time of over 50 minutes and an average increase in intraoperative blood loss of 137.43 mL in patients who underwent extended lymphadenectomy. Although overall complication rates such as pancreatic fistula, delayed gastric emptying, and postoperative infections were not significantly different between the two approaches, some studies observed a trend toward increased morbidity, particularly in terms of infectious and gastrointestinal complications[7,8].

Importantly, the quality of life of patients undergoing extended lymphadenectomy has been shown to be adversely affected. In a prospective randomized trial, Farnell et al[9] found that patients who underwent extended dissection reported significantly worse outcomes in several quality-of-life domains, including bowel control, diarrhea, and body image. These symptoms often persisted during long-term follow-up, underscoring the need to consider patient-centered outcomes when evaluating surgical approaches.

SUBGROUP CONSIDERATIONS AND PROGNOSTIC FACTORS

While the overall data do not support routine extended lymphadenectomy, some studies have attempted to identify specific patient subgroups who might benefit from a more aggressive nodal dissection. For instance, Pedrazzoli et al[10] conducted a multicenter trial and observed a trend toward improved survival in lymph node-positive patients undergoing extended lymphadenectomy, although this did not reach statistical significance. Additionally, retrospective studies have suggested that patients with smaller, non-advanced tumors may have a modest improvement in long-term survival with extended lymphadenectomy[11,12]. Nevertheless, these findings require confirmation through larger, well-powered trials.

The identification of patients who may benefit from extended lymphadenectomy can be refined by considering multiple factors. For example, patients with lymph node-positive disease, which can be identified through preoperative imaging such as contrast-enhanced computed tomography or positron emission tomography scans, may be more likely to benefit from a more extensive dissection. Similarly, patients with tumors that are smaller, well-differentiated, or show limited vascular invasion may be more suitable candidates for extended lymphadenectomy due to a lower risk of micrometastatic spread. Moreover, the integration of molecular profiling, including the identification of biomarkers such as Kirsten rat sarcoma 2 viral oncogene homolog mutations and microsatellite instability, is increasingly being recognized as important in the selection of patients who may benefit from a more aggressive surgical approach.

Another key prognostic variable is the number of lymph nodes retrieved and examined during surgery. A higher lymph node yield is consistently associated with improved staging accuracy and better survival outcomes, potentially due to enhanced detection of micrometastases and improved selection for adjuvant therapy. Analyses of large national databases such as the National Cancer Data Base have demonstrated a positive correlation between lymph node yield and survival, though this relationship may be confounded by other variables such as tumor biology, institutional experience, and use of adjuvant therapies[13-17]. Given the evolving landscape of surgical techniques, preoperative imaging, and molecular profiling, the decision to perform extended lymphadenectomy should be made on a case-by-case basis. Future studies are needed to standardize patient selection criteria and to refine the role of extended lymphadenectomy based on these factors.

IMMUNOLOGICAL IMPLICATIONS OF LYMPHADENECTOMY

An emerging area of interest is the immunologic consequence of lymphadenectomy in the setting of pancreatic cancer. Lymph nodes are not only sites of metastatic disease but also critical components of the immune system. They serve as hubs for the priming and activation of cytotoxic T cells, regulatory T cells, and dendritic cells, which play essential roles in recognizing and eliminating malignant cells. Excessive removal of these immune-competent sites may impair systemic immune surveillance and diminish the host’s capacity to mount an effective antitumor response.

This concern is particularly relevant in the era of immunotherapy, where strategies to enhance the host immune system are central to novel treatment paradigms. Although pancreatic ductal adenocarcinoma is generally considered an immunologically “cold” tumor with a highly suppressive microenvironment, ongoing clinical trials are exploring the combination of immunotherapy with chemotherapy and targeted therapy. Thus, understanding the interplay between surgical technique and immune function is crucial for optimizing multimodal treatment strategies. Currently, clinical data directly addressing the immune consequences of lymphadenectomy in pancreatic cancer are limited, but preclinical studies and translational research suggest this is an area warranting further investigation.

LIMITATIONS AND FUTURE DIRECTIONS

We acknowledge that the current manuscript relies heavily on preclinical and translational research when discussing the potential harm of excessive lymph node removal on immune surveillance. While these studies provide valuable insights into the theoretical implications of lymphadenectomy on the immune system, there remains a notable gap in clinical evidence directly linking the extent of lymphadenectomy to immune markers or immunotherapy responses in pancreatic cancer. The clinical data available on this topic are still limited, and further studies are needed to validate these preclinical findings in human patients. As the field of immunotherapy in pancreatic cancer continues to evolve, it is crucial to explore how the extent of lymphadenectomy influences immune function and its potential impact on response to immunotherapy. Future research should aim to address this gap by incorporating larger cohort studies, clinical trials, and immune profiling analyses to better understand the immunological consequences of extended lymphadenectomy.

To guide future work in this area, we propose that multicenter trials specifically designed to investigate the immunological effects of lymph node removal in pancreatic cancer patients be prioritized. Furthermore, integrating immune markers and biomarkers into the clinical decision-making process could help identify patients who may benefit from extended dissection or, conversely, those who could be harmed by excessive lymph node removal. This evolving area of research holds promise for optimizing the surgical approach in pancreatic cancer, balancing oncologic control with immune preservation, and potentially improving patient outcomes when combined with emerging immunotherapies.

RETHINKING THE ROLE OF EXTENDED DISSECTION

The practical significance of extended lymphadenectomy continues to be questioned. For instance, Shiozaki et al[18] investigated the impact of dissecting lymph nodes around the superior mesenteric artery and found that this approach increased perioperative complications without offering any improvement in survival. This reinforces the notion that a more extensive surgical dissection does not necessarily correlate with better oncologic outcomes and may, in fact, compromise patient safety and recovery. As such, the decision to perform extended lymphadenectomy should be made on a case-by-case basis, taking into account tumor characteristics, lymph node involvement, patient fitness, and institutional expertise.

CONCLUSION

In conclusion, while lymphadenectomy remains an essential component of pancreatic cancer surgery, current evidence does not support the routine use of extended lymphadenectomy. Standard lymphadenectomy provides comparable oncologic outcomes with reduced operative risk and better quality of life. Extended dissection may be reserved for highly selected patients, such as those with radiographically suspicious lymphadenopathy or favorable tumor biology, but its broad application cannot be justified based on available data (Figure 1). Furthermore, the immunologic functions of lymph nodes must be considered in the modern therapeutic landscape, especially as immunotherapy becomes increasingly integrated into pancreatic cancer treatment. Future research should aim to delineate the immunological impact of lymph node removal and identify biomarkers to guide the extent of lymphadenectomy. A personalized, multidisciplinary approach that balances oncologic efficacy with immune preservation may ultimately yield the most favorable outcomes for patients with pancreatic cancer.

Figure 1 Comparison of standard vs extended lymphadenectomy in pancreatic cancer surgery. This figure visually contrasts standard and extended lymphadenectomy, highlighting both oncological and immunological outcomes. Standard lymphadenectomy is associated with lower morbidity and preserved immune function, while extended lymphadenectomy offers no survival benefit and increases complications, potentially impairing immune function.