Prognostic Impact of Para-Aortic Lymph Node Metastasis in Resected Non-Pancreatic Periampullary Cancers

Background Surgery remains debatable in para-aortic lymph node (PALN, station 16b1) metastasis in non-pancreatic periampullary cancer (NPPAC). This study examined the impact of PALN metastasis on outcomes following pancreaticoduodenectomy (PD) in NPPAC. Methods A retrospective analysis of patients with NPPAC who were explored for PD with PALN dissection was performed. Based on the extent of nodal involvement on final histopathology, they were stratified as node-negative (N0), regional node involved (N+) and metastatic PALN (N16+) and their outcomes were compared. Results Between 2011 and 2022, 153/887 PD patients underwent a PALN dissection, revealing N16+ in 42 patients (27.4%), of whom 32 patients underwent resection. The 3-years overall survival (OS) for patients with N16+ was 28% (95% confidence interval [CI] 13–60%), notably lower than the 67% (95% CI 53–83.5%; p = 0.007) for those without PALN metastasis. Stratified by nodal involvement, the median OS for N+ and N16+ patients was similar (28.4 months and 26.2 months, respectively). The N0 subgroup had a significantly longer 3-years OS of 87.5% (95% CI 79–96.7%; p = 0.0051). Interestingly, 10 patients not offered resection following N16+ identified on frozen section had a median survival of only 9 months. The perioperative morbidity and mortality in patients undergoing PD with PALN dissection were similar to standard resections. Conclusion In a select group of patients with NPPAC, PD in isolated PALN metastasis was associated with improved OS. The survival in this group of patients was comparable with regional node-positive patients and significantly better than palliative treatment alone. Supplementary material The online version of this article (10.1245/s10434-024-15847-z) contains supplementary material, which is available to authorized users.

PD is a complex surgical procedure and is inherently associated with significant morbidity. 16The potential survival benefit of a radical resection in advanced disease therefore needs to justify the morbidity and potential mortality risk associated with surgery.Over the last two decades, highvolume centers across the world have consistently reported improved perioperative outcomes for PD.Although the major morbidity rate remains around 30%, mortality rates of around 2-3% have consistently been reported as compared with historical figures of more than 5%. 16,17e hypothesized that in patients with NPPAC with limited PALN involvement as a solitary site of metastasis, radial resection might be associated with better survival as compared with chemotherapy alone, provided a margin-negative resection is achieved, without a significant increase in morbidity.This study aimed to contribute to the understanding of the role of radical resection in the treatment of NPPAC with isolated PALN involvement, with a focus on survival outcomes and its implications for clinical decision making and treatment strategies.

MATERIALS AND METHODS
The study included patients with suspected or biopsyproven non-pancreatic periampullary adenocarcinoma who underwent PD in the Gastro-Intestinal Disease Management Group at Tata Memorial Centre, Mumbai, India, between 2011 and 2022.
The preoperative evaluation included contrast-enhanced cross-sectional imaging and a serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)-19.9 level estimation.The preferred initial imaging modality was a triphasic contrast-enhanced computed tomography scan of the thorax, abdomen, and pelvis (CECT TAP) with a pancreatic protocol. 18Magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) or 18-fluorodeoxyglucose positron emission tomography (FDG-PET) were used selectively.A side-viewing endoscopy (SVE) and/or endoscopic ultrasound (EUS) were performed in select cases whenever indicated to document the lesion and to obtain tissue diagnosis.In patients who had undergone a biopsy elsewhere, a pathology review was obtained at our institute.
All patients with suspected periampullary cancers (arising from the ampulla of Vater, distal common bile duct [CBD], and duodenum), thought to be resectable on imaging, were discussed in a multidisciplinary joint clinic and then planned for surgical exploration.Cancers that originated from the pancreatic head and those with non-adenocarcinoma histology were excluded from the analysis.
Preoperative biliary drainage was performed in patients with elevated bilirubin >15 mg/dL, features of cholangitis, or in patients needing presurgery rehabilitation or neoadjuvant therapy.Surgical resection was planned after 4-6 weeks of biliary drainage. 19ll patients underwent a PD with a standard lymphadenectomy. 1,16Resection was committed after confirming the absence of gross metastatic disease.A Kocher maneuver was performed and PALN (station 16b1) dissection (sampling or clearance) was carried out in patients with radiologically indeterminate or suspicious PALN, or an intraoperative suspicion of nodal involvement.The PALN 'sampling' involved a limited excision of the fibro-fatty tissue in the inter-aortocaval region (16b1 int) between the lower border of the left renal vein and the origin of the inferior mesenteric artery (IMA), along with the left PALNs bounded laterally by the left gonadal vein (16b1 lat).A systematic 'clearance' of this template was performed if a frozen section (FS) analysis confirmed metastasis.
The International Study Group of Pancreatic Surgery (ISGPS) definitions were used to define complications such as postoperative pancreatic fistula (POPF), post-pancreatectomy hemorrhage (PPH) and delayed gastric emptying (DGE).][22][23] Postoperative complications were recorded following the Clavien-Dindo classification system, with grades IIIa and above being considered significant morbidity. 24Deaths occurring within 90 days of surgery were considered as postoperative mortality.
The demographic, histopathological, and outcome variables were compared between the groups.Pathology review included assessment of tumor epicenter, tumor size, histological differentiation, lymphovascular invasion (LVI) and perineural invasion (PNI).In deeply infiltrating lesions causing architectural distortion, the epicenter characterization into ampullary, distal bile duct or duodenum is sometimes uncertain.These NPPAC were classified as periampullary tumors not otherwise specified (NOS).
Adjuvant chemotherapy was administered in fit patients with T3/T4 and/or node-positive disease.Adjuvant radiation therapy (RT) was considered selectively in margin-positive resections or extensive nodal metastasis after a multidisciplinary discussion.
The data of the present study were collected in the course of common clinical practice and, accordingly, the signed informed consent was obtained from each patient for any surgical and clinical procedure.The study protocol was in accordance with the ethical standards of the Institutional Research Committee and the 1964 Helsinki Declaration and its later amendments.

Statistics
Outcome variables included complication rate, recurrence, and overall survival (OS) for the above-mentioned groups.OS was calculated from the date of diagnosis to the date of death or the last follow-up, while disease-free survival (DFS) was calculated from the date of surgery to the date of clinical or radiological evidence of disease recurrence.Survival estimation was performed using the Kaplan-Meier survival function, and the Cox proportional hazards model was used for multivariate analysis to determine the significance of variables found to be significant in univariate analysis.All analysis was performed using Statistical Product and Service Solutions (SPSS) version 26 (IBM Corporation, Armonk, NY, USA) and a p-value <0.05 was considered statistically significant.

Patient Cohort, and Operative and Histopathological Characteristics
Overall, 887 patients with suspected or biopsy-proven NPPAC underwent PD in the study period, of whom 153 patients (17.2%) underwent PD with PALN sampling.
The median age of the patients was 56 years (range 32-82 years), with a 60% male predominance.On clinicoradiologic evaluation, the tumors were most commonly epicentered at the ampulla (78.3%), followed by the distal CBD (18.2%) and the duodenum (3.5%).Seven of the 153 resected patients received chemotherapy with neoadjuvant intent.Three patients had suspicious nodal disease on imaging, three had an elevated CA-19.9, and one patient received chemotherapy before presentation at our institute (Table 1).
The baseline clinical, demographic, and operative characteristics are elaborated in Table 1.All patients underwent a PD.Pylorus-preserving PD was performed in 70.6% (101/143) of patients, while 37 underwent a classical Whipple's procedure (25.8%).
Among the 153 patients where PALN sampling or dissection was performed, the decision was prompted by either the presence of radiological indeterminate PALN (n = 31, 3.5%), or an intraoperative suspicion of involved PALN or locally advanced disease (n = 82, 9.24%).In 40 patients (4.5%), sampling was performed at the surgeon's discretion.
A FS analysis of PALN was performed in 86 patients (56.2%), of whom 26 patients had metastasis to PALN (PALN FS+).Among these 26 patients, PD with station 16b1 clearance was performed in 16 patients, while resection was abandoned in 10.The decision to abandon curative resection in these 10 cases was made based on careful consideration of advanced age, medical comorbidities in a 'high-risk' pancreas, and/or extensive retroperitoneal nodal disease not amenable for R0 resection.Five patients had multiple station PALN involvement, three patients had multiple comorbidities (two with coronary artery disease and one with hepatic cirrhosis), and two patients were >70 years of age with borderline performance status.These cases were treated with chemotherapy alone.These cases were analyzed separately and survival was compared with the resected N16+ patients (Fig. 1).
There was no significant difference in the clinical and surgical characteristics between N16+, N+, and N0 patients.The three subgroups were similar in terms of sex (p = 0.574), median age (p = 0.174), clinico-radiological site of primary (p = 0.478), and preoperative biliary drainage (p = 0.727) (Table 1).
In the N16+ group, a median of four PALNs were sampled (range 1-19 nodes).A median of two lymph nodes were reported positive (range 1-6 nodes).All 32 N16+ cases who underwent PD were associated with regional lymph node metastasis; over 80% of these had pN2 disease (p < 0.05).The median regional node harvest was 26 nodes (12-55 nodes) with a median of seven positive regional nodes (range 2-30 nodes).
A significant correlation between increasing tumor size (p = 0.045), pT stage, and nodal status (pN) was identified (p < 0.05).As compared with N0, N+ and N16+ patients were more frequently associated with T3/T4 tumors and larger tumors (p < 0.05).A significant correlation between the presence of LVI and PNI was also observed (p < 0.05).The histopathological characteristics are depicted in Table 2. Prognostic Impact of Para-Aortic Lymph …

Morbidity and Mortality Comparison
The major morbidity rate (Clavien-Dindo grades IIIa and above) was 38% (55/143 patients) and the postoperative mortality rate was 4.9% (7/143 patients).Four patients had multiorgan dysfunction and sepsis, secondary to POPF-C (two patients), PPH-C (one patient), and postoperative acute pancreatitis (POAP; one patient).Three patients suffered cardiac events in the postoperative period.Performance of PALN dissection in addition to standard PD did not increase postoperative morbidity (p = 0.457) or mortality (p = 0.243) (Table 3).
The median OS of the 10 patients in whom resection was abandoned after a FS analysis showed N16+ was only 9 months, significantly shorter than the N16+ subgroup (p = 0.001)

DISCUSSION
The current study includes 10 patients for whom surgery was abandoned.Multiple station PALN involvement not amenable for R0 resection, patients' advanced age, comorbidities, and performance status influenced the decision not to offer surgery in these patients.It may not be appropriate to compare the outcomes of these patients with resected patients, as they have more advanced disease or comorbidities and a worse performance status.However, the literature does seem to suggest that patients who  15,29 In a multicentric cohort study from The Netherlands, the median OS for patients with PALN metastasis who underwent a palliative bypass procedure was 7 months versus 11 months for PD (p = 0.049). 29However, postoperative morbidity was significantly increased in the resection group (43.8% vs. 7.4%) and multivariate analysis showed that severe comorbidities were independently associated with decreased survival in patients with PALN metastasis.PD is a complex surgical procedure and is associated with significant morbidity even in specialized high-volume centers. 16,17Possible survival benefits of performing radical resections must outweigh the morbidity and mortality risk associated with it.Careful selection to offer resection to patients who are likely to have better perioperative outcomes and complete systemic therapy postoperatively is important.The presence of extensive disease and severe comorbidities may therefore serve as an important criteria in the case of selection.Avoidance of resection in these 10 patients assessed to be 'high risk' also likely contributed to keeping perioperative outcomes comparable.In our experience, there was no significant difference in overall morbidity, chyle leak rates, re-exploration rates, and mortality between N16+ and the remainder of the patients, justifying its selective use in patients with good performance status, minimal comorbidities, or low to moderate fistula risk scores.
[13][14][15]29,30 PALN sampling provided an opportunity to make an informed decision to either offer resection or abandon it in 26/86 (30.2%) patients in which FS analysis was performed.Patients who underwent resection could undergo complete clearance.Similarly, among the 67 patients for whom FS analysis of the sampled PALN was not performed, and were only sent for final histology, 16 (23.8%)were found to have PALN metastasis.These findings suggest that PALN sampling and FS analysis may have important implications in deciding the optimal treatment strategy during exploration for PD.Prognostic Impact of Para-Aortic Lymph … Furthermore, as a FS analysis was not performed in all cases, some patients only received para-aortic sampling with PD, likely leading to inadequate staging.These factors limit the generalization of the study findings.However, to the best of our knowledge, this is the largest experience of resection in isolated N16+ disease in NPPAC.It comprehensively reports outcomes in patients offered PALN dissection in PD for NPPAC.Being a standalone comprehensive cancer center, most treatment decisions were guided by a multidisciplinary tumor board discussion and patients were encouraged to complete their adjuvant therapies as planned.

CONCLUSION
In a select group of patients with NPPAC, PD in isolated PALN metastasis was associated with improved OS. Survival in these patients was found to be comparable with regional node-positive patients and was significantly better than palliative treatment alone.Routine intraoperative PALN sampling and its analysis by FS may help determine the optimal strategy for isolated PALN metastasis during surgery for NPPAC.

TABLE 1
Patient demographics and operative characteristics Bold value indicates significant p-value PALN para-aortic lymph node, CBD common bile duct, ERCP endoscopic retrograde cholangiopancreatography, PTBD percutaneous transhepatic biliary drainage, CT chemotherapy, CTRT concurrent chemoradiotherapy, NA not available

TABLE 2
Histopathological characteristics Bold values indicate significant p-value PALN para-aortic lymph node, IQR interquartile range, LVI lymphovascular invasion, PNI perineural invasion, HPR histopathology report, LN lymph node, NA not available, NOS not otherwise specified, CBD common bile duct

TABLE 5
Previous studies evaluating the role of PALN dissection in periampullary cancers Bold values indicate the findings and details of the current study