Beyond station 16: A pathway-aware framework for gallbladder cancer lymphadenectomy after neoadjuvant therapy

Abstract

Gallbladder cancer is an aggressive biliary tract malignancy and lymph node status is among the strongest determinants of outcome. For decades, the surgical debate has focused on the extent of lymphadenectomy and on whether para-aortic or interaortocaval nodal involvement should be regarded as regional extension or systemic disease. This binary framing is useful for staging but anatomically incomplete. Classical lymphatic studies described three drainage routes: cholecysto-celiac, cholecysto-retropancreatic and cholecysto-mesenteric. These pathways involve stations 12, 8, 9, 13, 17 and 14 before converging toward station 16, especially 16a2 and 16b1. Current Western algorithms often focus on the hepatoduodenal ligament and treat para-aortic/interaortocaval nodal disease as a contraindication to curative-intent surgery. This Opinion Review proposes a pathway-aware framework for interpreting lymphadenectomy after neoadjuvant therapy. The concept is hypothesis-generating, not a validated therapeutic recommendation. For staging, reporting and research purposes, nodal assessment may be described by both nodal yield and station distribution; a six-node harvest limited to station 12 provides different anatomical information from a six-node harvest sampled across celiac, retropancreatic, mesenteric and para-aortic convergence basins. We do not advocate indiscriminate extended lymphadenectomy. Rather, in medically fit patients with adequate physiological reserve, no systemic progression and realistic R0 resection, pathway mapping and selective clearance may be discussed as an expert-center investigational framework. The key question is whether the involved pathway remains surgically controllable after biological selection, not simply whether station 16 is regional or metastatic.

Key Words: Gallbladder neoplasms; Lymph node excision; Neoadjuvant therapy; Hepatobiliary surgery; Lymphatic pathways; Para-aortic lymph nodes; Nodal yield; Surgical oncology

Core Tip: Station 16 is better understood as the convergence basin of three gallbladder lymphatic pathways rather than as an isolated boundary. This Opinion Review proposes that pathway-aware reporting may complement lymph-node count by documenting station distribution. The framework remains hypothesis-generating: Selective clearance of stations 13, 17, 14 and 16a2-16b1 should not be considered a standard surgical requirement, and may be discussed only in medically fit responders after neoadjuvant therapy, when systemic progression is absent, R0 resection is realistic and expert hepatobiliary surgery is available.

INTRODUCTION

The modern debate on gallbladder cancer (GBC) lymphadenectomy has often been framed as a dispute over the para-aortic or interaortocaval basin. Station 16, particularly 16a2 and 16b1, is commonly used to separate potentially curable locoregional disease from biologically systemic disease. In earlier surgical work on incidental GBC and nodal evaluation we emphasized that reoperation should pursue R0 resection and locoregional nodal clearance[1-3]. That principle remains important, but it must now be interpreted in a more explicit evidence hierarchy. The anatomical premise is established: Lymph from the gallbladder drains through cholecysto-celiac, cholecysto-retropancreatic and cholecysto-mesenteric routes before reaching abdomino-aortic or interaortocaval nodes[4-6]. A pathway-oriented review must therefore discuss stations 8, 9, 12, 13, 17 and 14 before discussing 16a2-16b1. The clinical implication is less certain. Surgical series and technical reports support the importance of regional lymphadenectomy and explain why para-aortic nodes are often treated cautiously[7-10]. However, contemporary guidelines and consensus documents continue to prioritize appropriate staging, avoidance of futile radical surgery and individualized treatment rather than routine extended dissection[11-19]. The review question is therefore: How should surgeons interpret gallbladder nodal disease when anatomical pathways, nodal yield and response to neoadjuvant therapy point in different directions? The authors’ answer is a conceptual framework, not a standard-of-care recommendation. Station 16 should be viewed as a convergence basin of upstream lymphatic pathways, while any extension of dissection beyond conventional regional lymphadenectomy should remain investigational and restricted to carefully selected patients. The strict classification of an involved node as regional or distant may be less informative than the broader question of whether the involved lymphatic pathway still represents surgically controllable disease.

METHODS OF THIS OPINION REVIEW

This invited Opinion Review was prepared as a narrative synthesis rather than as a systematic review or meta-analysis. We searched PubMed, Europe PMC, publisher databases, guideline websites and institutional teaching material from database inception to August 26, 2026. A final bibliographic verification was performed immediately before resubmission on September 5, 2026; all 2026 references were retained only when publication status and PMID/DOI or publisher records could be verified. The principal search concepts were: GBC; gallbladder carcinoma; incidental GBC; lymphadenectomy; lymph-node dissection; lymph-node yield; station 13; station 14; station 16; interaortocaval lymph node; para-aortic lymph node; neoadjuvant therapy; biliary tract cancer guidelines; and Japanese gastric cancer para-aortic lymph-node dissection. Eligible sources were prioritized if they directly addressed at least one of five domains: (1) Anatomical lymphatic drainage of the gallbladder; (2) Guideline or consensus recommendations; (3) Station-specific surgical series or technical descriptions; (4) Nodal yield, positive-node count or lymph-node ratio; and (5) Neoadjuvant or systemic-treatment evidence relevant to surgical selection. Narrative reviews, editorials and opinion pieces were used only when they clarified terminology or clinical controversy. Case reports were not used to infer efficacy. Because this article is opinion-based, no pooled estimate was calculated and the selection process is not intended to meet PRISMA criteria. The evidence was interpreted according to hierarchy. Anatomical mapping studies were considered supportive for pathway description, but not for therapeutic benefit. Guidelines were considered standards for current practice. Retrospective surgical series were interpreted as hypothesis-generating and subject to selection bias. The authors’ proposed pathway-aware strategy was treated as an expert-center research framework requiring prospective validation.

CURRENT GUIDELINE FRAMEWORK: STARTING FROM, NOT REPLACING, EXISTING STANDARDS

Current guideline and consensus documents remain the practical baseline for decision-making in GBC. National Comprehensive Cancer Network, European Society for Medical Oncology, Thésaurus National de Cancérologie Digestive/Société Nationale Française de Gastro-Entérologie, Associazione Italiana di Oncologia Medica, Americas Hepato-Pancreato-Biliary Association and recent international Delphi recommendations converge on several principles: Surgery should be stage-adapted, should aim at R0 resection when curative intent is realistic, should include adequate regional lymphadenectomy for appropriate staging, and should avoid non-therapeutic radical operations when disseminated disease is present[12-18]. These standards are not challenged by the present review. What remains less clearly operationalized in most Western algorithms is how to interpret suspicious nodes that lie along recognized upstream lymphatic pathways, especially stations 13, 17 and 14, and how to discuss selected 16a2/16b1 disease after response or durable stability with neoadjuvant therapy. Current guidelines do not establish routine retropancreatic, mesenteric-root or para-aortic/interaortocaval clearance as standard therapy. Our proposal should therefore be read as an anatomical and conceptual refinement for multidisciplinary discussion, station-specific reporting and future research, not as a replacement for guideline-based staging or resectability assessment[17-19].

TERMINOLOGY AND TARGET POPULATION

To avoid ambiguity, several terms are used in a restricted sense. Regional lymphadenectomy refers to guideline-concordant nodal clearance performed for staging and local control within accepted oncologic surgery. Extended lymphadenectomy refers to dissection beyond this conventional field, including retropancreatic, mesenteric-root or para-aortic/interaortocaval basins. Para-aortic nodes are nodes along the aorta, while interaortocaval nodes lie between the aorta and inferior vena cava; in this review, 16a2 and 16b1 are discussed as terminal convergence basins, not as the only relevant stations. Pathway-aware nodal assessment denotes station mapping and, only when justified, selective clearance along the expected cholecysto-celiac, cholecysto-retropancreatic or cholecysto-mesenteric routes. It is a proposed conceptual approach for reporting and research and should not be read as a routine therapeutic mandate. The target population for the proposed framework is also deliberately narrow: Medically fit patients with adequate physiological reserve; locally advanced or nodal-suspicious GBC; absence of peritoneal, hepatic or extra-regional progression after restaging; and realistic feasibility of R0 resection in an expert hepatobiliary center. Locally advanced disease includes major local extension or suspicious regional/extra-regional nodal disease in which upfront radical surgery is considered high-risk or potentially futile. Response or durable stability should be assessed by cross-sectional imaging, absence of new metastatic sites, tumor-marker trend when informative, performance status and multidisciplinary team review.

Box 1 Station nomenclature and cross-system interpretation used in this review

Station 12 refers to hepatoduodenal ligament nodes, including periportal, pericholedochal and hepatic-artery subdivisions depending on the classification system. Station 8 refers to nodes along the common hepatic artery, and station 9 to nodes along the celiac trunk. Station 13 is used here for retropancreatic/posterior pancreatic-head nodes; its regional or distant interpretation varies between Western American Joint Committee on Cancer (AJCC)-oriented practice and Japanese biliary classifications. Station 17 is used for nodes along the anterior/inferior pancreaticoduodenal or inferior pancreatic-head region and does not imply an automatic indication for pancreaticoduodenectomy. Station 14 refers to the superior mesenteric axis; in this review, this includes the superior mesenteric vessels, because mesenteric-root lymphatics are anatomically related to the superior mesenteric artery (SMA) and superior mesenteric vein (SMV). Station 16a2/16b1 refers to the para-aortic/interaortocaval convergence basin and is discussed primarily for staging and futility assessment; therapeutic clearance remains investigational.

ANATOMICAL BASIS: THE THREE LYMPHATIC PATHWAYS

Ito et al[4] classified gallbladder lymphatic drainage into three pathways. The cholecysto-retropancreatic pathway was considered the main pathway, with lymph running from the gallbladder and common bile duct region toward retroportal and retropancreatic nodes. The cholecysto-celiac pathway runs through the hepatoduodenal ligament toward the common hepatic artery and celiac nodes. The cholecysto-mesenteric pathway runs toward the superior mesenteric root. These routes may converge with abdomino-aortic lymph nodes near the left renal vein and interaortocaval space[4]. Vital staining and carbon-particle studies support the concept of recognizable drainage routes with variable terminal spread[5,6]. The surgical implication is descriptive rather than prescriptive. Clearance limited to the cystic duct and hepatoduodenal ligament may be sufficient for selected early tumors, but it does not map the entire lymphatic anatomy of more advanced GBC. Conversely, para-aortic sampling or dissection that does not first account for upstream stations 8, 9, 12, 13, 17 and 14 provides incomplete pathway information. The issue is not how far a surgeon can dissect; it is whether station mapping can clarify staging, prognosis or research stratification without implying a proven therapeutic benefit.

Cholecysto-celiac pathway: Stations 12, 8 and 9

The cholecysto-celiac route passes from cystic/pericholedochal nodes to the hepatoduodenal ligament and then toward the common hepatic artery and celiac trunk. The key stations are 12, 8 and 9. Station 12 remains the gateway basin, but stations 8 and 9 are the continuation of the route when tumor stage, imaging or intraoperative findings suggest more advanced spread[4,7,8]. This distinction matters because the phrase regional lymphadenectomy can be interpreted narrowly or anatomically. A narrow portal dissection can provide staging information, but it may not fully define the celiac pathway. A broader dissection toward stations 8 and 9, extending to the common hepatic artery and celiac axis, is a proposed consideration in selected high-risk disease, not a proven survival-improving maneuver.

Cholecysto-retropancreatic pathway: Stations 13 and 17

The cholecysto-retropancreatic pathway leads to stations that are often under-discussed in Western algorithms. Station 13, posterior to the pancreatic head, and station 17, along the inferior border of the pancreatic head, lie on an anatomical route supported by classical mapping and surgical experience[4,5,7]. Their relevance should be separated from the indication for pancreaticoduodenectomy. Kocherization, retropancreatic exposure and nodal clearance can be considered without implying that pancreatic resection is routinely required. Station 13 remains controversial. Western AJCC-based staging has not always accommodated station 13 as a regional basin, whereas Japanese and high-incidence-region practice patterns have more often considered 13 within regional clearance. A recent dedicated study found that station 13-positive stage IIIB and IVB-M0 patients did not behave like stage IVB-M1 patients and suggested reconsideration of station 13 as a regional basin[20]. This is supportive but retrospective evidence; it cannot prove that station 13 dissection itself improves survival. Station 17 is less frequently discussed but is conceptually paired with station 13 along the retropancreatic route. Clearance of station 17 requires deliberate exposure of the inferior pancreatic head/uncinate region and nodal tissue around the superior mesenteric vessels when anatomically indicated. Pancreaticoduodenectomy should remain reserved for selected cases with direct invasion or unavoidable disease clearance requirements, not performed simply because retropancreatic nodes are considered relevant.

Cholecysto-mesenteric pathway: Station 14 and the superior mesenteric axis

The cholecysto-mesenteric pathway explains why station 14 is included in the conceptual map. This route links hepatoduodenal ligament drainage with the superior mesenteric root. In operative anatomy, station 14 can be understood around the superior mesenteric vessels, including both the SMA and SMV, because pancreatic head, uncinate and mesenteric-root lymphatics run through this region. Failure to record this route has two potential consequences. First, nodal disease along the superior mesenteric axis may be interpreted as unpredictable skip disease rather than as spread along a recognized pathway. Second, a numerically adequate harvest may miss an entire drainage route. This is why lymph-node count should be reported together with station distribution for research and prognostic documentation. The three pathway routes and their station-specific implications are summarized schematically in Figure 1 and Table 1.

Figure 1 Semi-anatomical map of the three lymphatic pathways of gallbladder cancer. The cholecysto-celiac pathway (green) involves stations 12, 8 and 9; the cholecysto-retropancreatic pathway (blue) involves stations 12, 13 and 17; the cholecysto-mesenteric pathway (orange) involves station 14 along the superior mesenteric vessels. All pathways converge toward station 16, particularly 16a2 and 16b1. This is an original schematic prepared by the authors based on classical lymphatic studies and Japanese Society of Biliary Surgery station nomenclature[4-6]. The route sequences are simplified and should not be interpreted as universally fixed anatomy. IVC: Inferior vena cava; SMA: Superior mesenteric artery; SMV: Superior mesenteric vein.

Table 1 Pathway-oriented interpretation of gallbladder cancer lymphadenectomy.

Pathway	Main stations	Meaning	Proposed surgical consideration	Key caution
Cholecysto-celiac	12 → 8 → 9 → 16	Spread through the hepatoduodenal ligament toward the common hepatic artery and celiac axis	Consider stations 8 and 9 when stage, imaging or intraoperative findings suggest celiac-route risk	Schematic pathway based on anatomical literature; not a universal sequence
Cholecysto-retropancreatic	12 → 13 → 17 → 16	Main route described in anatomical studies; involves posterior pancreatic head and inferior pancreatic border	Consider retropancreatic exposure and station 13/17 assessment when suspicious or high-risk	Station 13/17 relevance does not automatically imply pancreaticoduodenectomy
Cholecysto-mesenteric	12 → 14 → 16	Drainage toward the superior mesenteric root and vessels	Consider station 14 around both SMA and SMV when mesenteric-route risk is present	Apparent skip disease may reflect a recognized route but remains variably reported
Para-aortic/interaortocaval convergence	16a2/16b1	Terminal convergence near the left renal vein and interaortocaval space	Sampling may avoid futile surgery; clearance is investigational in selected responders	Do not infer therapeutic benefit from anatomy alone

The station sequences are schematic and based on classical anatomical studies and Japanese Society of Biliary Surgery nomenclature[4-6]. They do not exclude anatomical variability or alternative drainage. Surgical implications are proposed considerations, not uniform requirements. SMA: Superior mesenteric artery; SMV: Superior mesenteric vein.

STATION 16: STAGING, FUTILITY ASSESSMENT AND INVESTIGATIONAL CLEARANCE

Station 16 is the point at which anatomical logic and oncological caution collide. Kondo et al[9] reported poor outcomes in para-aortic node-positive patients and did not support routine para-aortic lymphadenectomy in advanced GBC. Agarwal et al[10] showed that routine 16b1 biopsy prevented non-therapeutic radical resection in 18.6% of patients judged resectable by preoperative imaging and staging laparoscopy. More recent staging-laparoscopy data in biliary tract cancer also found para-aortic metastasis in 26.1% and avoided unnecessary laparotomy in 30.4% of selected patients, further supporting para-aortic sampling as a staging and futility-assessment maneuver rather than evidence of therapeutic benefit from para-aortic clearance itself[21]. These findings support the current Western caution: Station 16 positivity often indicates systemic biology and may redirect treatment away from radical surgery. Other series suggest that station 16 positivity is not biologically identical in every patient. Murakami et al[22] reported selected long-term outcomes after radical resection in biliary carcinoma with para-aortic nodal involvement. Aggarwal et al[23] found that selected GBC patients with interaortocaval nodal metastasis who underwent curative resection and adjuvant therapy had survival inferior to regional node-positive patients but better than those treated palliatively. These observations are retrospective and highly selected. This is the space in which biology-driven surgery should be discussed: They justify discussion, not routine adoption. For this reason, station 16 should be interpreted as the final convergence of cholecysto-celiac, cholecysto-retropancreatic and cholecysto-mesenteric spread and should be assigned different roles in different circumstances. Sampling can be used for staging and to avoid futile radical surgery. Dissection may be considered for clearance only in exceptional, biologically selected patients after neoadjuvant therapy. Therapeutic benefit remains unproven, and this distinction between staging value and treatment value is essential.

LYMPH-NODE YIELD: FROM NUMBERS TO ANATOMICAL ADEQUACY

Nodal staging in GBC has moved from location-based categories toward number-based assessment. The AJCC 8^th edition classifies nodal disease by the number of positive regional nodes[11]. Ito et al[24] showed that retrieval and examination of at least six nodes improves risk stratification, especially among node-negative patients. Negi et al[25] emphasized lymph-node ratio, and Sakata et al[26] showed that positive-node count independently determines prognosis. Yoon et al[27] recently proposed retrieval of at least 11 lymph nodes as a reference point to reduce false node-negative staging; importantly, this should be interpreted as a staging-accuracy signal rather than proof that harvesting more nodes directly improves survival. Tang et al[28] reported that fusion lymph-node dissection increased the number of retrieved nodes compared with standard dissection and improved detection of positive nodes without a statistically significant increase in postoperative complications. Cheng et al[29] described standardized laparoscopic en-bloc lymphadenectomy with high rates of adequate nodal harvest in most T1b-T3 cases, supporting technical feasibility. International benchmark work showed that even retrieval of at least four nodes is a realistic high-quality benchmark across centers, illustrating the gap between ideal and routine practice[30]. A contemporary comparative study across biliary tract cancers cautioned that extended lymphadenectomy was not independently associated with improved overall or recurrence-free survival and may increase morbidity in major resections[31]. Systematic review data support the six-node threshold as a practical adequacy standard for staging[32]. Table 2 summarizes these source-specific metrics without visually implying direct comparability. The next step is not to abandon numerical thresholds, but to interpret them anatomically and cautiously. Until prospective data validate station mapping as an independent prognostic or therapeutic measure, it should be regarded as a descriptive quality metric and a research variable. The evidence hierarchy supporting the pathway-aware framework is summarized in Table 3.

Table 2 Source-specific lymph-node metrics and interpretation.

Ref.	Reported metric	Metric type	Interpretation for this review
AJCC 8th edition[11]	Number-based pN classification	Staging framework	Supports quantitative nodal staging; does not define an extended operative field
Ito et al[24] and Widmann et al[32]	At least six examined nodes	Staging/adequacy threshold	Useful quantitative floor for staging, not proof of therapeutic benefit
Yoon et al[27]	11-node cutoff proposed to reduce false N0 staging	Staging-accuracy reference	Supports careful nodal evaluation; survival association should not be read as causation
Tang et al[28]	Fusion LND increased mean yield vs standard dissection	Technical yield comparison	Demonstrates feasibility and detection gain; not definitive survival evidence
Vega et al[30]	At least four nodes as an international benchmark	Pragmatic quality benchmark	Shows real-world heterogeneity and difficulty achieving higher thresholds
Giehl-Brown et al[31]	Extended LND ≥ 6 associated with morbidity in major resections without independent OS/RFS benefit	Retrospective comparative caution	Reinforces separation of staging value from unproven therapeutic value

LND: Lymph-node dissection; OS: Overall survival; RFS: Recurrence-free survival.

Table 3 Evidence hierarchy underlying the pathway-aware framework.

Evidence domain	What is established	What remains uncertain	Implication for this review
Anatomical studies	Three lymphatic routes and variable convergence toward para-aortic/interaortocaval nodes are described[4-6]	Anatomy alone does not prove survival benefit from extended dissection	Provides the map, not the indication
Guidelines and consensus	Regional lymphadenectomy, adequate staging and avoidance of futile radical surgery are emphasized[11-19]	Guidelines do not validate routine pathway-oriented extended clearance after neoadjuvant therapy	Current standards remain the baseline
Retrospective station-specific series	Station 13 and interaortocaval disease may not behave uniformly as distant disease in selected patients[20,23]	Selection bias is substantial and therapeutic benefit is unproven	Supports hypothesis generation only
Nodal-yield studies	Node count, positive-node count and lymph-node ratio have prognostic value[24-26,28-30,32,44]	The independent value of station distribution requires validation	Report both number and map
Neoadjuvant selection	Response or stability can identify more favorable biology[36,37]	Response does not prove benefit from extended nodal clearance	Use as a filter, not proof

INCIDENTAL GBC AND RE-RESECTION

Incidental GBC remains the most frequent presentation of potentially resectable disease in many Western settings. Prior experience suggested that laparoscopic cholecystectomy does not necessarily worsen survival when oncological principles are respected, and that reoperation should pursue R0 resection and nodal clearance[1,2]. The AFC-GBC-2009 study shaped modern practice by supporting re-resection for T2/T3 incidental GBC and by questioning routine common bile duct resection when not otherwise indicated[33]. Contemporary reviews similarly emphasize that surgery must be tailored to T stage, tumor location, margins, nodal suspicion and patient fitness[34]. The pathway-oriented framework is particularly useful in incidental GBC because the index cholecystectomy usually provides no meaningful nodal staging. A second operation limited to liver bed resection and small station-12 sampling may satisfy a historical definition of radicalization, but it may not provide the anatomical and quantitative nodal information needed for modern decision-making. At the same time, recent data comparing direct and incidental GBC remind us that lymphadenectomy may primarily inform staging and treatment planning rather than guarantee a survival benefit in every subgroup[35].

NEOADJUVANT THERAPY AS A BIOLOGICAL FILTER

Neoadjuvant therapy is not yet supported in GBC by the same level of evidence available in rectal, gastric or pancreatic cancer. It is nevertheless increasingly relevant in locally advanced or borderline resectable disease. Sirohi et al[36] reported that neoadjuvant chemotherapy increased resectability in a subset of patients with locally advanced GBC. A recent SEER analysis of stage III/IV GBC without distant metastases reported longer survival in patients treated with neoadjuvant therapy followed by surgery than in patients treated with direct surgery, while emphasizing that the role of lymph-node dissection after neoadjuvant therapy remains unclear[37]. Systemic treatment has also changed. Adjuvant capecitabine after resection is supported by BILCAP[38]. Durvalumab plus gemcitabine/cisplatin and pembrolizumab plus gemcitabine/cisplatin have changed first-line treatment for advanced biliary tract cancer and are reflected in contemporary guideline updates[12,14,39,40]. These advances do not prove that extended lymphadenectomy improves outcomes. They support a narrower point: Response to treatment can help identify patients with more favorable biology. In practice, response or durable stability should be evaluated by imaging, absence of new metastatic disease, tumor-marker trend when informative, preserved performance status and multidisciplinary review. A radiological decrease in nodal size alone is not enough. Nodal response may simply reflect systemic sensitivity and does not prove that surgical removal of residual nodal tissue improves survival. This is why the proposed pathway-oriented operation must be described as biological selection plus surgical hypothesis, not as established therapy.

THE JAPANESE GASTRIC CANCER ANALOGY

The analogy with gastric cancer is useful only if used cautiously. Prophylactic para-aortic node dissection is not a universal standard, and GBC has different anatomy and biology. Nevertheless, Japanese gastric cancer practice provides a conceptual precedent for integrating response to systemic therapy with extended nodal disease. The Japanese gastric cancer treatment guidelines and Japan Clinical Oncology Group experience describe selected settings in which neoadjuvant chemotherapy and para-aortic node dissection have been evaluated for extensive nodal metastases[41,42]. The lesson is not that GBC should copy gastric PAND. It is that para-aortic disease can be discussed through treatment response, resectability, morbidity and biology rather than anatomy alone. In GBC, that discussion must be even more cautious because prospective comparative evidence is lacking.

PROPOSED PATHWAY-ORIENTED SURGICAL STRATEGY

The proposed framework has four components. Representative intraoperative panels illustrating selected surgical components of this framework are shown in Figure 2. First, station 12 is the gateway basin and can provide the minimum regional staging field in operations intended to go beyond simple cholecystectomy. Second, stations 8 and 9 may be documented or sampled when the cholecysto-celiac pathway is radiologically, intraoperatively or biologically suspicious. Third, station 13 and, in selected cases, station 17 may be evaluated when the retropancreatic pathway is involved or suspicious. Fourth, station 14 may be recorded or sampled when the superior mesenteric route is clinically plausible. Station 16a2/16b1 is best considered a convergence basin and may be sampled when suspicious to avoid futile surgery. These components should not be read as a required operative checklist. The purpose of each maneuver must be explicit: Anatomical mapping describes the expected route; sampling clarifies staging and may redirect therapy; dissection can improve pathological staging and may contribute to clearance of macroscopic or suspicious nodal disease; therapeutic clearance is the least-proven purpose and should be discussed only in exceptional patients with adequate physiological reserve, controlled disease after neoadjuvant therapy, no occult spread at exploration and realistic R0 resection. Similar principles of careful portal, aortocaval and retropancreatic dissection have been described in minimally invasive re-resection settings[43]. Pathology should mirror the surgical concept. Practical station-specific decision criteria are summarized in Table 4. Reports should include total lymph-node harvest, positive-node count, lymph-node ratio, stations examined and stations involved. A report stating six negative nodes without a station map is less informative than a report showing distributed clearance across relevant pathways. Recent national database work further supports the prognostic value of interpreting positive nodes in relation to the total evaluated denominator[44].

Figure 2 Original intraoperative images illustrating pathway-aware lymphadenectomy and associated radical surgical steps in selected gallbladder cancer. A: Original anonymized intraoperative image showing hepatoduodenal ligament skeletonization and arterial landmarks during extended hepatobiliary lymphadenectomy after neoadjuvant therapy. The panel supports the discussion of the hepatoduodenal/celiac route; B: Original anonymized intraoperative image illustrating retropancreatic/para-aortic nodal tissue harvesting. The panel supports the conceptual discussion of retropancreatic exposure and convergence-basin assessment, and is not presented as a routine indication; C: Original anonymized intraoperative image of hepatic radicalization involving segments 4b and 5. This panel documents the liver component accompanying selected R0-intent surgery and is not presented as a lymphadenectomy panel; D: Original anonymized image of hepatic radicalization specimen. It is included to show the resection component paired with nodal assessment in selected cases; E: Original anonymized image of en bloc nodal tissue corresponding to stations 12, 8 and 9. This panel supports the concept of station-specific specimen reporting. Original image from the authors’ surgical experience. Reproduced courtesy of the General Surgery Unit, Enna Hospital, with written patient consent and institutional authorization. RHA: Right hepatic artery; LHA: Left hepatic artery; CHA: Common hepatic artery; LGA: Left gastric artery; SA: Splenic artery; CA: Celiac axis.

Table 4 Practical station-specific decision criteria in selected patients.

Station/region	Primary purpose	When to consider	When to avoid
12	Regional staging and gateway assessment	Radical/re-resection intended to stage beyond simple cholecystectomy[11,17-19,24]	Frailty, nonoperative intent or disseminated disease
8/9	Celiac pathway mapping and selected sampling/clearance	Suspicious nodes, T2/T3 or more advanced disease, or celiac-route concern[4,7,8]	Low-risk early disease without suspicion; no evidence supports routine use
13/17	Retropancreatic pathway mapping and selected assessment	Suspicious retropancreatic nodes, high-risk biology or expert HPB exposure available[4,5,7,20]	If clearance would require disproportionate morbidity or if no R0 operation is possible
14	Mesenteric pathway assessment	Superior mesenteric-root suspicion or disease pattern compatible with this route[4-6]	Routine use without pathway risk or when systemic progression is present
16a2/16b1	Futility assessment by sampling; exceptional investigational clearance	Suspicious convergence-basin disease after response/stability and no occult spread[9,10,21-23]	Progression, new metastases, poor reserve or no realistic R0 resection[9,12-18,23]

The table separates anatomical mapping, staging/sampling and therapeutic clearance. The latter remains investigational and should be discussed only in expert-center multidisciplinary settings. Citations in the table indicate the anatomical, staging or retrospective literature informing each station-specific consideration; they do not establish a therapeutic standard.

ETHICAL BALANCE: AVOIDING BOTH THERAPEUTIC NIHILISM AND OVERTREATMENT

The pathway-oriented framework should not be interpreted as an invitation to maximal surgery. Para-aortic or interaortocaval nodal involvement remains a major adverse prognostic factor, and progression during systemic therapy, peritoneal dissemination, multifocal liver metastases, unreconstructable vascular involvement or poor physiological reserve should generally redirect treatment away from radical resection[9,12-18,23]. In such patients, extended lymphadenectomy would risk adding morbidity without a credible oncologic objective. At the same time, a rigidly nihilistic approach may be difficult to justify in medically fit patients who show objective response or durable disease stability after neoadjuvant therapy, without systemic progression and with a realistic possibility of R0 resection. In that restricted setting, the decision should not depend only on whether a nodal station is labelled regional or metastatic; it should also consider whether the involved lymphatic pathway can be safely sampled or cleared as part of a coherent multimodal plan, without compromising recovery or postoperative systemic therapy[23,36,38-40,44,45]. This remains a hypothesis-generating proposal and should be discussed transparently with patients, including the uncertainty of benefit and the possibility of intraoperative abandonment if occult disease is found.

LIMITATIONS AND ALTERNATIVE PERSPECTIVES

The principal limitation of this review is that the proposed pathway-oriented framework is not supported by prospective randomized or comparative evidence showing improved overall survival, disease-free survival, recurrence pattern, quality of life or postoperative treatment delivery. Contemporary cohort data linking adequate lymphadenectomy and adjuvant capecitabine to improved outcomes are important but remain retrospective and do not validate extended pathway-oriented clearance[45]. Most available clinical data are vulnerable to selection bias: Medically fit patients who respond to neoadjuvant therapy are already biologically selected before surgery. Radiologic nodal assessment is also imperfect. Nodal size, metabolic activity and marker trends can suggest response, but they cannot reliably distinguish residual viable disease, sterilized nodal metastasis and inflammatory change. Operative morbidity must be considered seriously. Retropancreatic, mesenteric-root and para-aortic dissection can increase operative complexity, bleeding risk, lymphatic leak, delayed recovery and the possibility of postponing systemic therapy. Recent biliary tract cancer data linking extended lymphadenectomy with increased morbidity in major resections reinforce that these harms could offset any hypothetical oncological benefit[31]. A further limitation is nomenclature. Western and Japanese nodal classifications do not always align, and stations such as 13, 14 and 16 may be interpreted differently across institutions. For now, regional-versus-distant classification remains a clinically useful staging convention. The pathway-oriented model should complement, not replace, guideline-based staging until prospective data support a change in practice.

FUTURE DIRECTIONS

The most useful next step is not broader adoption, but better documentation. A multicenter registry should record baseline nodal mapping, neoadjuvant regimen, objective response or stability, station-by-station harvest, pathological response, lymph-node ratio, R0 rate, severe morbidity, time to postoperative systemic therapy, recurrence pattern, survival and quality of life. The international Delphi consensus provides a framework for standardized terminology, but contentious areas such as borderline resectability and extended nodal clearance still need data[18]. Such a registry should separate station 13 from station 16 positivity, report stations 14 and 17 explicitly, and distinguish upfront surgery from surgery after biological selection. Without this detail, the literature will continue to mix anatomical station, tumor burden and treatment biology. Pathway-aware reporting is expected to help in three different ways that should not be conflated: It may improve treatment documentation, refine prognostication and support research stratification. Whether it changes treatment decisions or improves outcomes must be tested prospectively. Box 2 Minimum evidentiary conditions before clinical testing of pathway-aware extended clearance. Before the proposed framework can be tested clinically, future studies should include: (1) Prospectively defined eligibility and exclusion criteria; (2) Standardized station nomenclature with explicit mapping of stations 13, 14, 17 and 16a2/16b1; (3) Predefined stopping rules for occult metastases, progression, unreconstructable vascular involvement or poor physiological reserve; (4) Station-by-station pathology with positive-node count and lymph-node ratio; and (5) Outcomes that include R0 rate, severe morbidity, time to postoperative systemic therapy, quality of life, recurrence pattern, disease-free survival and overall survival. Until such conditions are met, pathway-aware extended clearance should remain an expert-center research hypothesis rather than an operative standard. The proposed decision pathway after neoadjuvant selection is summarized in Figure 3.

Figure 3 Proposed algorithm for biology-driven, pathway-aware nodal assessment after neoadjuvant selection in locally advanced or nodal-suspicious gallbladder cancer. The left branch identifies situations in which radical lymph-node dissection should not be pursued. The yellow box marks the authors’ investigational framework rather than standard-of-care management. GBC: Gallbladder cancer; HPB: Hepatopancreatobiliary; LND: Lymph-node dissection; LNR: Lymph-node ratio; MDT: Multidisciplinary team; QoL: Quality of life; DFS: Disease-free survival; OS: Overall survival; CT: Computed tomography; MRI: Magnetic resonance imaging; PET: Positron emission tomography.

CONCLUSION

GBC lymphadenectomy should not be reduced to a binary argument over station 16. The gallbladder drains through cholecysto-celiac, cholecysto-retropancreatic and cholecysto-mesenteric pathways involving stations 12, 8, 9, 13, 17 and 14 before convergence toward 16a2/16b1. We propose that nodal reports describe both quantitative yield and anatomical station distribution: How many nodes were harvested, and from which pathway? We do not advocate indiscriminate extended lymphadenectomy. We propose a hypothesis-generating, pathway-aware framework for selected medically fit responders after neoadjuvant therapy, when systemic progression is absent, R0 resection is realistic and expertise is available. The decisive question is not only whether station 16 is regional or metastatic, but whether the involved pathway remains surgically controllable after neoadjuvant selection. This strategy requires prospective validation before it can influence standard practice.